U.S. patent application number 10/208047 was filed with the patent office on 2003-07-31 for processes for producing optically active 2-amino-1-phenylethanol derivatives.
This patent application is currently assigned to Daicel Chemical Industries, Ltd.. Invention is credited to Ito, Michio, Matsuyama, Akinobu.
Application Number | 20030143701 10/208047 |
Document ID | / |
Family ID | 27522075 |
Filed Date | 2003-07-31 |
United States Patent
Application |
20030143701 |
Kind Code |
A1 |
Matsuyama, Akinobu ; et
al. |
July 31, 2003 |
Processes for producing optically active 2-amino-1-phenylethanol
derivatives
Abstract
An (R)-2-amino-1-phenylethanol derivative shown by the general
formula (IIa) 1 wherein R.sup.1 and R.sup.5 represent a hydrogen
atom, etc.; R.sup.2, R.sup.3 and R.sup.4 independently represent a
halogen atom, etc., or a salt thereof, can readily be produced (1)
by permitting a microorganism belonging to the genus
Rhodosporidium, the genus Comamonas or the like to act on a mixture
of corresponding (R)-form and (S)-form to asymmetrically utilize,
or (2) by permitting a microorganism belonging to the genus
Lodderomyces, the genus Pilimelia or the like to act on a
corresponding aminoketone derivative to asymmetrically reduce. An
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative
having a high optical purity can easily be obtained from the
compound of the formula (IIa) or a salt thereof. Said derivative is
useful as an intermediate for producing an anti-obesity agent and
so on.
Inventors: |
Matsuyama, Akinobu;
(Arai-shi, JP) ; Ito, Michio; (Joetsu-shi,
JP) |
Correspondence
Address: |
PILLSBURY WINTHROP, LLP
P.O. BOX 10500
MCLEAN
VA
22102
US
|
Assignee: |
Daicel Chemical Industries,
Ltd.
|
Family ID: |
27522075 |
Appl. No.: |
10/208047 |
Filed: |
July 31, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10208047 |
Jul 31, 2002 |
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09597830 |
Jun 19, 2000 |
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09597830 |
Jun 19, 2000 |
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09095733 |
Jun 11, 1998 |
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6114582 |
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09095733 |
Jun 11, 1998 |
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08738864 |
Oct 28, 1996 |
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5811293 |
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08738864 |
Oct 28, 1996 |
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08343952 |
Nov 17, 1994 |
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5629200 |
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Current U.S.
Class: |
435/128 |
Current CPC
Class: |
Y10S 435/822 20130101;
C07C 213/10 20130101; Y10S 435/911 20130101; C07C 213/00 20130101;
C07C 213/04 20130101; C12P 13/008 20130101; C12P 13/001 20130101;
C12P 7/22 20130101; C12P 41/001 20130101; C07C 231/18 20130101;
C12P 41/002 20130101; C12P 41/00 20130101; C07C 213/08 20130101;
Y02P 20/55 20151101; C07C 213/00 20130101; C07C 215/08 20130101;
C07C 213/04 20130101; C07C 215/08 20130101; C07C 213/08 20130101;
C07C 215/08 20130101; C07C 213/10 20130101; C07C 215/08
20130101 |
Class at
Publication: |
435/128 |
International
Class: |
C12P 013/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 18, 1993 |
JP |
289419 |
Apr 24, 1994 |
JP |
83014 |
Nov 24, 1993 |
JP |
319046 |
Aug 4, 1994 |
JP |
183217 |
Mar 10, 1994 |
JP |
40172 |
Claims
What is claimed is:
1. A process for producing an (R)-2-amino-1-phenylethanol
derivative which comprises: permitting a microorganism or a
preparation thereof which is capable of acting on a mixture of
enantiomers of a 2-amino-1-phenylethanol compound of the general
formula (I) 19wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 represent, the same or different, a hydrogen atom, a
halogen atom, an optionally substituted lower alkyl group, a
hydroxyl group which may be protected with a protective group, an
optionally substituted alkoxy group, an optionally substituted
cycloalkyloxy group, an optionally substituted aralkyloxy group, an
optionally substituted aryloxy group, an optionally substituted
lower alkylthio group, an optionally substituted acyl group, a
carboxyl group which may be protected with a protective group, an
optionally substituted lower alkoxycarbonyl group, a nitro group or
an optionally substituted amino group, or a salt thereof, to
produce a corresponding (R)-2-amino-1-phenylethanol shown by the
general formula (IIa) 20wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 have the same meanings as defined above, or a salt
thereof, to act on said mixture of enantiomers, and harvesting or
recovering the product (R)-form shown by the general formula (IIa)
or a salt thereof.
2. A process for producing an (R)-2-amino-1-phenylethanol
derivative according to claim 1, wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 respectively represent a group selected from
the group consisting of: (1) a hydrogen atom; (2) a halogen atom;
(3) a C.sub.1-4 alkyl group which may be substituted with a
substituent selected from the group consisting of a hydroxyl group,
a C.sub.1-4 alkoxy group, benzoyl group, an optionally substituted
C.sub.6-12 aryl group, a C.sub.1-4 alkylthio group and a halogen
atom; (4) a hydroxyl group which may be protected with a protective
group; (5) a C.sub.1-4 alkoxy group which may be substituted with a
substituent selected from the group consisting of a halogen atom, a
hydroxyl group and a C.sub.1-4 alkoxy group; (6) a C.sub.3-10
cycloalkyloxy group which may be substituted with a substituent
selected from the group consisting of a C.sub.1-4 alkyl group, a
hydroxyl group and a halogen atom; (7) a C.sub.7-20 aralkyloxy
group which may be substituted with a substituent selected from the
group consisting of a C.sub.1-4 alkyl group, a C.sub.6-12 aryl
group, a hydroxyl group, a C.sub.1-4 alkoxy group, a nitro group
and a halogen atom; (8) a C.sub.6-16 aryloxy group which may be
substituted with a substituent selected from the group consisting
of a C.sub.1-4 alkyl group, a hydroxyl group, a C.sub.1-4 alkoxy
group, a nitro group and a halogen atom; (9) a C.sub.1-4 alkylthio
group which may be substituted with a substituent selected from the
group consisting of a halogen atom, a hydroxyl group and a
C.sub.1-4 alkoxy group; (10) an acyl group selected from the group
consisting of (a) a C.sub.1-6 acyl group which may be substituted
with a substituent selected from the group consisting of a hydroxyl
group, a C.sub.1-4 alkoxy group, a C.sub.1-4 alkylthio group and a
halogen atom, (b) a C.sub.7-20 acyl group having an aromatic ring
which may be substituted with a substituent and (c) an acyl group
having a heterocyclic ring which may be substituted with a
substituent; (11) a carboxyl group which may be protected with a
protective group; (12) an optionally substituted C.sub.2-5
alkoxycarbonyl group; (13) a nitro group; and (14) an amino group
which may be substituted with a substituent selected from the group
consisting of (a) a C.sub.1-4 alkyl group which may be substituted
with a substituent selected from the group consisting of a hydroxyl
group, a C.sub.1-4 alkoxy group, benzoyl group, a C.sub.1-4
alkylthio group and a halogen atom, (b) a C.sub.7-20 aralkyl group
which may be substituted with a substituent selected from the group
consisting of a C.sub.1-4 alkyl group, a hydroxyl group, a
C.sub.1-4 alkoxy group, a nitro group and a halogen atom, (c) a
C.sub.1-6 acyl group which may be substituted with a substituent
selected from the group consisting of a hydroxyl group, a C.sub.1-4
alkoxy group, a C.sub.1-4 alkylthio group and a halogen atom, (d) a
C.sub.7-20 acyl group having an aromatic ring which may be
substituted with a substituent selected from the group consisting
of a C.sub.1-4 alkyl group, a hydroxyl group, a C.sub.1-4 alkoxy
group, a nitro group and a halogen atom, (e) an acyl group having a
heterocyclic ring which may be substituted with a substituent
selected from the group consisting of a C.sub.1-4 alkyl group, a
hydroxyl group, a C.sub.1-4 alkoxy group, a nitro group and a
halogen atom, and (f) a carboxyl group which may be protected with
a protective group.
3. A process for producing an (R)-2-amino-1-phenylethanol
derivative according to claim 1, wherein R.sup.1 and R.sup.5
independently represent a hydrogen atom or a C.sub.1-4 alkyl group;
R.sup.2, R.sup.3 and R.sup.4 respectively represent a hydrogen
atom, a halogen atom, a C.sub.1-4 alkyl group which may be
substituted with a halogen atom or a hydroxyl group, a hydroxyl
group, a C.sub.1-4 alkoxy group, a C.sub.7-20 aralkyloxy group, a
C.sub.7-20 acyl group having an aromatic ring, a nitro group or an
amino group which may be substituted with a C.sub.1-6 acyl
group.
4. A process for producing an (R)-2-amino-1-phenylethanol
derivative according to claim 1, wherein said microorganism is a
strain of microorganism selected from the group consisting of
microorganisms belonging to the genus Hansenula, the genus
Geotrichum, the genus Candida, the genus Cryptococcus, the genus
Rhodosporidium, the genus Rhodotorula, the genus Saccharomyces, the
genus Sporobolomyces, the genus Kluyveromyces, the genus
Issatchenkia, the genus Pichia, the genus Botryoascus, the genus
Debaryomyces, the genus Lipomyces, the genus Metschnikowia, the
genus Saccharomycodes, the genus Schizoblastosporion, the genus
Stepahnoascus, the genus Sterigmatomyces, the genus
Zygosaccharomyces, the genus Sporidiobolus, the genus Malassezia,
the genus Torulaspora, the genus Corynebacterium, the genus
Gluconobacter, the genus Promicromonospora, the genus Pseudomonas,
the genus Bordetella, the genus Acetobacter, the genus Bacillus,
the genus Agrobacterium, the genus Arthrobacter, the genus
Amauroascus, the genus Brevibacterium, the genus Micrococcus, the
genus Aureobacterium, the genus Azotobacter, the genus Xanthomonas,
the genus Klebsiella, the genus Comamonas, the genus Mycobacterium,
the genus Terrabacter, the genus Agrocybe, the genus Trichoderma,
the genus Alternaria, the genus Hamigera, the genus Moniliella, the
genus Pholiota, the genus Podospola, the genus Aegerita, the genus
Streptomyces, the genus Saccharomycopsis and the genus
Leucosporidium.
5. A process for producing (R)-2-amino-1-phenylethanol derivative
according to claim 1, wherein said microorganism is a strain of
microorganism selected from the group consisting of microorganisms
belonging to Hansenula anomala, Geotrichum candidum, Candida
albicans, Candida parapsilosis, Candida gropengiesseri, Candida
aaseri, Candida beechii, Candida atmospherica, Candida natalensis,
Candida paludigena, Candida sake, Candida pintolopesii var.
pintolopesii, Cryptococcus neoformans, Rhodosporidium spaerocarpum,
Rhodosporidium diobovatum, Rhodotorula rubra, Rhodotorula glutinis
var. dairenensis, Saccharomyces montanus, Sporobolomyces roseus,
Kluyveromyces marxianus var. bulgaricus, Kluyveromyces lactis,
Issatchenkia scutulata var. scutulata, Pichia thermotolerans,
Pichia farinosa, Botryoascus synnaedendrus, Debaryomyces hansenii,
Lipomyces starkeyi, Metschnikowia bicuspidata, Saccharomycodes
ludwigii, Schizoblastosporion kobayashii, Stepahnoascus ciferrii,
Sterigmatomyces halophilus, Zygosaccharomyces rouxii,
Zygosaccharomyces fermentati, Sporidiobolus salmonicolor,
Sporidiobolus pararoseus, Malassezia furfur, Torulaspora
delbrueckii, Corynebacterium aquaticum, Corynebacterium mediolanum,
Gluconobacter asaii, Gluconobacter oxydans, Gluconobacter
frateurii, Promicromonospora citrea, Pseudomonas aeruginosa,
Pseudomonas riboflavina, Pseudomonas fluorescens, Pseudomonas
putida, Pseudomonas syncyanea, Pseudomonas diminuta, Pseudomonas
chlororaphis, Pseudomonas fragi, Pseudomonas sp. ATCC 14676,
Bordetella bronchiseptica, Acetobacter sp. IFO 3248, Acetobacter
sp. IFO 3297, Acetobacter pasteurianus, Bacillus subtilis, Bacillus
cereus, Bacillus coagulans, Bacillus brevis, Bacillus sphaericus,
Agrobacterium radiobacter, Arthrobacter ureafaciens, Amauroascus
reticulatus, Brevibacterium linens, Micrococcus roseus,
Aureobacterium testaceum, Azotobacter vinelandii, Xanthomonas
campestris pv oryzae, Klebsiella pneumoniae, Comamonas
testosteroni, Mycobacterium diernhoferi, Terrabacter tumescens,
Agrocybe cylindracea, Trichoderma viride, Alternaria kikuchiana,
Hamigera avellanea, Moniliella acetoabutans, Pholiota nameko,
Podospola cardonaria, Aegerita candida, Streptomyces cinereoruber,
Rhodococcus amidophilis, Rhodococcus equi, Saccharomycopsis
capsularis and Leucosporidium scottii.
6. A process for producing a 2-amino-1-phenylethanol derivative
comprising; allowing (a) a compound shown by the general formula
(III) 21wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5
represent, the same or different, a hydrogen atom, a halogen atom,
an optionally substituted lower alkyl group, a hydroxyl group which
may be protected with a protective group, an optionally substituted
alkoxy group, an optionally substituted cycloalkyloxy group, an
optionally substituted aralkyloxy group, an optionally substituted
aryloxy group, an optionally substituted lower alkylthio group, an
optionally substituted acyl group, a carboxyl group which may be
protected with a protective group, an optionally substituted lower
alkoxycarbonyl group, a nitro group or an optionally substituted
amino group; or (b) a compound shown by the general formula (IV)
22wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
same meanings as defined above; Z represents a hydrogen atom or a
protective group for hydroxyl group; and X represents a halogen
atom; to react with a compound shown by the general formula
(V)Y--NH.sub.2 (V)wherein Y represents a hydrogen atom or a group
which can be left in the reaction, further, when Y is the group
which can be left in the reaction, allowing Y to be left, to obtain
the compound shown by the general formula (VI) 23wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and Z have the same meanings as
defined above; which comprises adding an acid to the reaction
products containing the compound of the general formula (VI) to
precipitate or crystallize said compound as a salt and, thereby,
isolating the compound of the general formula (VI).
7. A process for producing a 2-amino-1-phenylethanol derivative
according to claim 6, wherein the salt is formed in an organic
solvent.
8. A process for producing a 2-amino-1-phenylethanol derivative
according to claim 6, wherein an optically active organic acid is
used as the acid to obtain the optically active compound of the
formula (VI).
9. A process for producing a 2-amino-1-phenylethanol derivative
according to claim 8, wherein an optically active hydroxycarboxylic
acid or an optically active amino acid, which may protected with a
protective group on the amino acid, having a side chain possessing
a polar group is employed as the optically active organic acid.
10. A process for producing a 2-amino-1-phenylethanol derivative
according to claim 6, wherein 1 gram equivalent or less of an
inorganic acid relative to 1 mole of the 2-amino-1-phenylethanol
derivative shown by the formula (VI) is added to the reaction
products.
11. A process for producing a 2-amino-1-phenylethanol derivative
according to claim 6, wherein 0.8 gram equivalent or more of an
organic acid relative to 1 mole of the compound of the formula (VI)
is added to the reaction products.
12. A process for producing a 2-amino-1-phenylethanol derivative
according to claim 6, wherein 1 gram equivalent or more of the acid
relative to 1 mole of the total amount of the
2-amino-1-phenylethanol compound of the general formula (VI) and a
position-isomer thereof, and a base are added to the reaction
products to liberate the position-isomer, and the compound of the
general formula (VI) is precipitated or crystallized as a salt to
isolate said compound.
13. A process for producing a 2-amino-1-phenylethanol derivative
according to claim 12, wherein an organic base is employed as the
base.
14. A process for producing a 2-amino-1-phenylethanol derivative
according to claim 13, wherein an organic base having an
electrolytic dissociation exponent pKa value of 9.3 to 11.5 is
used.
15. A process for producing a 2-amino-1-phenylethanol derivative
according to claim 6, wherein an optically active compound of the
general formula (III) or an optically active compound of the
general formula (IV) is used to obtain an optically active compound
of the general formula (VI).
16. A process for producing an (R)-2-amino-1-phenylethanol
derivative which comprises: permitting a microorganism or a
preparation thereof which is capable of acting on a compound shown
by the general formula (VII) 24wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 represent, the same or different, a hydrogen
atom, a halogen atom, an optionally substituted lower alkyl group,
a hydroxyl group which may be protected with a protective group, an
optionally substituted alkoxy group, an optionally substituted
cycloalkyloxy group, an optionally substituted aralkyloxy group, an
optionally substituted aryloxy group, an optionally substituted
lower alkylthio group, an optionally substituted acyl group, a
carboxyl group which may be protected with a protective group, an
optionally substituted lower alkoxycarbonyl group, a nitro group or
an optionally substituted amino group, or a salt thereof, to
produce a corresponding (R)-2-amino-1-phenylethanol compound shown
by the general formula (IIa) 25wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 have the same meanings as defined above, or a
salt thereof, to act on said compound or a salt thereof and
harvesting or recovering the product optically active compound or a
salt thereof.
17. A process for producing an (R)-2-amino-1-phenylethanol
derivative according to claim 16, wherein said microorganism is a
strain of microorganism selected from the group consisting of
microorganisms belonging to the genus Candida, the genus
Lodderomyces, the genus Catenuloplanes, the genus Pilimelia, the
genus Saccharothrix, the genus Seratia, the genus Enterococcus, the
genus Lactobacillus, the genus Pediococcus and the genus
Lactococcus.
18. A process for producing an (R)-2-amino-1-phenylethanol
derivative according to claim 16, wherein said microorganism is a
strain of microorganism selected from the group consisting of
microorganisms belonging to Candida maltosa, Lodderomyces
elongisporus, Catenuloplanes japonicus, Pilimelia terevasa,
Saccharothrix australiensis, Seratia marcescens, Enterococcus
faecalis, Lactobacillus casei subsp. casei, Pediococcus
acidilactici and Lactococcus lactis subsp. lactis.
19. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
shown by the general formula (XI) 26wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 represent, the same or different, a
hydrogen atom, a halogen atom, an optionally substituted lower
alkyl group, a hydroxyl group which may be protected with a
protective group, an optionally substituted alkoxy group, an
optionally substituted cycloalkyloxy group, an optionally
substituted aralkyloxy group, an optionally substituted aryloxy
group, an optionally substituted lower alkylthio group, an
optionally substituted acyl group, a carboxyl group which may be
protected with a protective group, an optionally substituted lower
alkoxycarbonyl group, a nitro group or an optionally substituted
amino group; and Z represents a hydrogen atom or a protective group
for hydroxyl group; R.sup.7 and R.sup.8 represent, (A)
respectively, a group selected from the group consisting of a
hydrogen atom, an optionally substituted lower alkyl group, an
optionally substituted cycloalkyl group, an optionally substituted
aralkyl group, an optionally substituted aryl group, an optionally
substituted acyl group, a carboxyl group which may be protected
with a protective group, an optionally substituted lower
alkoxycarbonyl group, an optionally substituted amino group, an
optionally substituted alkylsulfonyl group, an optionally
substituted arylsulfonyl group and a hydroxyl group which may be
protected with a protective group, or (B) R.sup.7 represents a
group shown by the formula (IX): --O--R.sup.7a, and R.sup.8
represents a group shown by the formula (X): --O--R.sup.8a, wherein
R.sup.7a and R.sup.8a may form an optionally substituted ring with
the adjacent oxygen atoms; R.sup.6, R.sup.9 and R.sup.10
independently represent a group selected from a group consisting of
a hydrogen atom, a halogen atom, an optionally substituted lower
alkyl group, an optionally substituted cycloalkyl group, an
optionally substituted aralkyl group, an optionally substituted
aryl group, a hydroxyl group which may be substituted with a
protective group, an optionally substituted alkoxy group, an
optionally substituted cycloalkyloxy group, an optionally
substituted aralkyloxy group, an optionally substituted aryloxy
group, an optionally substituted lower alkylthio group, an
optionally substituted aralkylthio group, an optionally substituted
acyl group, a carboxyl group which may be protected with a
protective group, an optionally substituted lower alkoxycarbonyl
group, a nitro group and an optionally substituted amino group; and
R.sup.11 represents a lower alkyl group, which comprises: a
reaction of an (R)-2-amino-1-phenylethanol compound shown by the
general formula (II) 27wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and Z have the same meanings as defined above, or a salt
thereof, with a compound shown by the general formula (VIII)
28wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11
have the same meanings as defined above, and a reducing reaction of
the reaction product of said reaction.
20. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 19, wherein, in the formula (VIII), R.sup.7 and
R.sup.8 represent; (A) the same or different, a group selected from
the group consisting of: (1) a hydrogen atom; (2) a C.sub.1-4 alkyl
group which may be substituted with a substituent selected from the
group consisting of a hydroxyl group, a C.sub.1-4 alkoxy group,
benzoyl group, a C.sub.1-4 alkylthio group, a halogen atom and an
amino group which may be substituted with a substituent; (3) a
C.sub.3-10 cycloalkyl group which may be substituted with a
substituent selected from the group consisting of a C.sub.1-4 alkyl
group, a hydroxyl group and a halogen atom; (4) a C.sub.7-20
aralkyl group which may be substituted with a substituent selected
from the group consisting of a C.sub.1-4 alkyl group, a C.sub.6-12
aryl group, a hydroxyl group, a C.sub.1-4 alkoxy group, a nitro
group and a halogen atom; (5) a C.sub.6-16 aryl group which may be
substituted with a substituent selected from the group consisting
of a C.sub.1-4 alkyl group, a C.sub.6-12 aryl group, a hydroxyl
group, a C.sub.1-4 alkoxy group, a nitro group and a halogen atom;
(6) an acyl group selected from the group consisting of (a) a
C.sub.1-6 acyl group which may be substituted with a substituent
selected from the group consisting of a hydroxyl group, a C.sub.1-4
alkoxy group, a C.sub.1-4 alkylthio group and a halogen atom, (b) a
C.sub.7-20 acyl group having an aromatic ring which may be
substituted with a substituent and (c) an acyl group having a
heterocyclic ring which may be substituted with a substituent; (7)
a carboxyl group which may be protected with a protective group;
(8) an optionally substituted C.sub.2-5 alkoxycarbonyl group; (9)
an amino group which may be substituted with a substituent selected
from the group consisting of (a) a C.sub.1-4 alkyl group which may
be substituted with a substituent selected from the group
consisting of a hydroxyl group, a C.sub.1-4 alkoxy group, benzoyl
group, a C.sub.1-4 alkylthio group and a halogen atom, (b) a
C.sub.7-20 aralkyl group which may be substituted with a
substituent selected from the group consisting of a C.sub.1-4 alkyl
group, a hydroxyl group, a C.sub.1-4 alkoxy group, a nitro group
and a halogen atom, (c) a C.sub.1-6 acyl group which may be
substituted with a substituent selected from the group consisting
of a hydroxyl group, a C.sub.1-4 alkoxy group, a C.sub.1-4
alkylthio group and a halogen atom, (d) a C.sub.7-20 acyl group
having an aromatic ring which may be substituted with a
substituent, (e) an acyl group having a heterocyclic ring which may
be substituted with a substituent and (f) a carboxyl group which
may be protected with a protective group; (10) a C.sub.1-4
alkylsulfonyl group which may be substituted with a substituent
selected from the group consisting of a hydroxyl group, a C.sub.1-4
alkoxy group, benzoyl group, a C.sub.1-4 alkylthio group and a
halogen atom; (11) a C.sub.6-20 arylsulfonyl group which may be
substituted with a substituent selected from the group consisting
of a C.sub.1-4 alkyl group, a hydroxyl group, a C.sub.1-4 alkoxy
group, a nitro group and a halogen atom; and (12) a hydroxyl group
which may be protected with a protective group; or (B) R.sup.7 is a
group of the formula (IX): --O--R.sup.7a, and R.sup.8 is a group of
the formula (X): --O--R.sup.8a, where R.sup.7a and R.sup.8a may
form an optionally substituted C.sub.1-4 alkylene group, a carbonyl
group or a thiocarbonyl group; R.sup.6, R.sup.9 and R.sup.10
independently represent a group selected from the group consisting
of: (1) a hydrogen atom; (2) a halogen atom; (3) a C.sub.1-4 alkyl
group which may be substituted with a substituent selected from the
group consisting of a hydroxyl group, a C.sub.1-4 alkoxy group,
benzoyl group, a C.sub.1-4 alkylthio group, a halogen atom and an
amino group which may be substituted with a substituent; (4) a
C.sub.3-10 cycloalkyl group which may be substituted with a
substituent selected from the group consisting of a C.sub.1-4 alkyl
group, a hydroxyl group and a halogen atom; (5) a C.sub.7-20
aralkyl group which may be substituted with a substituent selected
from the group consisting of a C.sub.1-4 alkyl group, a C.sub.6-12
aryl group, a hydroxyl group, a C.sub.1-4 alkoxy group, a nitro
group and a halogen atom; (6) a C.sub.6-16 aryl group which may be
substituted with a substituent selected from the group consisting
of a C.sub.1-4 alkyl group, a C.sub.6-12 aryl group, a hydroxyl
group, a C.sub.1-4 alkoxy group, a nitro group and a halogen atom;
(7) a hydroxyl group which may be protected with a protective
group; (8) a C.sub.1-4 alkoxy group which may be substituted with a
substituent selected from the group consisting of a hydroxyl group,
a C.sub.1-4 alkoxy group, a halogen atom and an amino group which
may be substituted with a substituent; (9) a C.sub.3-10
cycloalkyloxy group which may be substituted with a substituent
selected from the group consisting of a C.sub.1-4 alkyl group, a
hydroxyl group and a halogen atom; (10) a C.sub.7-20 aralkyloxy
group which may be substituted with a substituent selected from the
group consisting of a C.sub.1-4 alkyl group, a C.sub.6-12 aryl
group, a hydroxyl group, a C.sub.1-4 alkoxy group, a nitro group
and a halogen atom; (11) a C.sub.6-16 aryloxy group which may be
substituted with a substituent selected from the group consisting
of a C.sub.1-4 alkyl group, a hydroxyl group, a C.sub.1-4 alkoxy
group, a nitro group and a halogen atom; (12) a C.sub.1-4 alkylthio
group which may be substituted with a substituent selected from the
group consisting of a hydroxyl group, a C.sub.1-4 alkoxy group and
a halogen atom; (13) a C.sub.7-20 aralkylthio group which may be
substituted with a substituent selected from the group consisting
of a C.sub.1-4 alkyl group, a hydroxyl group, a C.sub.1-4 alkoxy
group, a nitro group and a halogen atom; (14) an acyl group
selected from the group consisting of (a) a C.sub.1-6 acyl group
which may be substituted with a substituent selected from the group
consisting of a hydroxyl group, a C.sub.1-4 alkoxy group, a
C.sub.1-4 alkylthio group and a halogen atom, (b) a C.sub.7-20 acyl
group having an aromatic ring which may be substituted with a
substituent and (c) an acyl group having a heterocyclic ring which
may be substituted with a substituent; (15) a carboxyl group which
may be protected with a protective group; (16) an optionally
substituted C.sub.2-5 alkoxycarbonyl group; (17) a nitro group; and
(18) an amino group which may be substituted with a substituent
selected from the group consisting of (a) a C.sub.1-4 alkyl group
which may be substituted with a substituent selected from the group
consisting of a hydroxyl group, a C.sub.1-4 alkoxy group, benzoyl
group, a C.sub.1-4 alkylthio group and a halogen atom, (b) a
C.sub.7-20 aralkyl group which may be substituted with a
substituent selected from the group consisting of a C.sub.1-4 alkyl
group, a hydroxyl group, a C.sub.1-4 alkoxy group, a nitro group
and a halogen atom, (c) a C.sub.1-6 acyl group which may be
substituted with a substituent selected from the group consisting
of a hydroxyl group, a C.sub.1-4 alkoxy group, a C.sub.1-4
alkylthio group and a halogen atom, (d) a C.sub.7-20 acyl group
having an aromatic ring which may be substituted with a
substituent, (e) an acyl group having a heterocyclic ring which may
be substituted with a substituent, (f) a carboxyl group which may
be protected with a protective group; R.sup.11 represents a
C.sub.1-4 alkyl group; and in the formula (II), Z represents (A) a
hydrogen atom or (B) a protective group for hydroxyl group selected
from the group consisting of (a) a C.sub.1-4 alkyl group which may
be substituted with a substituent, (b) an allyl group which may be
substituted with a substituent, (c) a C.sub.3-10 cycloalkyl group
which may be substituted with a substituent, (d) a 5- or 6-membered
heterocyclic group, which may be substituted with a substituent,
having an oxygen atom or a sulfur atom as a hetero atom other than
carbon atoms, (e) a C.sub.7-20 aralkyl group which may be
substituted with a substituent, (f) a silyl group which may be
substituted with a substituent, (g) a C.sub.1-6 acyl group which
may be substituted with a substituent, (h) a C.sub.7-20 acyl group
having an aromatic ring which may be substituted with a
substituent, (i) an acyl group having a heterocyclic ring which may
be substituted with a substituent, (j) a C.sub.2-5 alkoxycarbonyl
group which may be substituted with a substituent, (k) a C.sub.8-20
aralkyloxycarbonyl group which may be substituted with a
substituent, (l) a C.sub.7-20 aryloxycarbonyl group which may be
substituted with a substituent, (m) a C.sub.1-4 alkylsulfonyl group
which may be substituted with a substituent and (n) a C.sub.6-20
arylsulfonyl group which may be substituted with a substituent.
21. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 20, wherein said optionally substituted
C.sub.1-4 alkylene group formed by R.sup.7a and R.sup.8a is an
optionally substituted methylene group shown by the following
formula (XII) 29wherein R.sup.a and R.sup.b (A) independently
represent: (1) a hydrogen atom; (2) a C.sub.1-4 alkyl group; (3) a
C.sub.1-4 haloalkyl group; (4) a C.sub.6-20 aryl group which may be
substituted with a substituent selected from the group consisting
of a halogen atom, a C.sub.1-4 alkyl group, a C.sub.6-12 aryl
group, a hydroxyl group, a C.sub.1-4 alkoxy group and a nitro
group; (5) a C.sub.1-4 alkoxy group; (6) an amino group which may
be substituted with a substituent; (7) a carboxyl group or a salt
thereof; (8) a C.sub.2-5 alkoxycarbonyl group which may be
substituted with a substituent selected from the group consisting
of a C.sub.1-4 alkoxy group, a C.sub.1-4 alkoxy-C.sub.1-4 alkoxy
group, a C.sub.7-20 aralkyloxy group, a benzoyl group, a C.sub.1-4
alkylthio group and a halogen atom; (9) a hydroxymethyl group; and
(10) a C.sub.1-4 alkoxy-methyl group which may be substituted on
the alkoxy group with a substituent selected from the group
consisting of a carboxyl group, a C.sub.2-5 alkoxycarbonyl group, a
hydroxyl group and a C.sub.1-4 alkoxy group; or (B) R.sup.a and
R.sup.b may form a C.sub.5-7 cycloalkyl group with the adjacent
carbon atom.
22. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 20, where, in the general formula (VIII),
R.sup.7 and R.sup.8 (A) respectively represent a hydrogen atom or a
hydroxyl group which may be protected with a protective group
selected from the group consisting of a C.sub.1-4 alkyl group, a
C.sub.7-20 aralkyl group and C.sub.1-6 acyl group, or (B) R.sup.7
is the group of the formula (IX): --O--R.sup.7a, and R.sup.8 is the
group of the formula (X): --O--R.sup.8a, where, in the methylene
group shown by the general formula (XII) formed together by
R.sup.7a and R.sup.8a, R.sup.a and R.sup.b (i) independently
represent a group selected from the group consisting of (a) a
hydrogen atom; (b) a C.sub.1-4 alkyl group; (c) a carboxyl group or
a salt thereof; (d) a C.sub.2-5 alkoxycarbonyl group which may be
substituted with a substituent; (e) a hydroxymethyl group; and (f)
a C.sub.1-4 alkoxy-methyl group which may be substituted on the
alkoxy group with a substituent; or (ii) R.sup.a and R.sup.b may
form a C.sub.5-7 cycloalkyl group together with the adjacent carbon
atom; R.sup.6, R.sup.9 and R.sup.10 respectively represent a
hydrogen atom or a C.sub.1-4 alkyl group; R.sup.11 represents a
methyl group or an ethyl group; and in the formula (II), Z
represents a hydrogen atom.
23. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 19, wherein the optically active compound of the
general formula (II) is allowed to react with the compound of the
general formula (VIII) and hydrogen in the presence of a catalyst
for catalytic reduction.
24. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 19, wherein the optically active compound shown
by the general formula (II) is allowed to react with the compound
shown by the general formula (VIII), and the resultant product is
hydrogenated.
25. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 23, wherein the reaction is conducted in the
presence of an acid catalyst.
26. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 19, which further comprises: adding an acid to
the reaction products and fractionally crystallizing from the
resultant mixture to isolate the (R,R)-isomer of the general
formula (XI).
27. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 26, wherein a base in an amount of 0.05 to 0.9
gram equivalent relative to 1 mole of the total amount of the salt
of the (R,R)-isomer of the general formula (XI) and the salt of an
(R,S)-isomer of the general formula (XIII) 30wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11 and Z have the same meanings as defined
above, is added to liberate the (R,S)-isomer and the (R,R)-isomer
is precipitated or crystallized as the salt.
28. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 19, which further comprises: (1) a step of
permitting a microorganism or a preparation thereof which is
capable of acting on a mixture of enantiomers of a
2-amino-1-phenylethanol compound shown by the general formula (I)
31wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
same meanings as defined above, or a salt thereof to produce an
(R)-2-amino-1-phenylethanol compound shown by the general formula
(IIa) 32wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the same meanings as defined above, or a salt thereof, to act on
said mixture of enantiomers, to produce the optically active
compound shown by the general formula (II) where Z represents a
hydrogen atom or a salt thereof, or (2) further to said step (1), a
step of introducing a protective group to the hydroxyl group of the
optically active compound of the general formula (II) wherein Z
represents a hydrogen atom or a salt thereof produced in said step
(1), to produce the optically active compound of the general
formula (II) where Z represents a protective group for hydroxyl
group, or a salt thereof.
29. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 19, which further comprises: (1) a step of
permitting a microorganism or a preparation thereof which is
capable of acting on a compound shown by the general formula (VII)
33wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
same meanings as defined above, or a salt thereof to produce a
corresponding (R)-2-amino-1-phenylethanol compound shown by the
general formula (IIa) 34wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 have the same meanings as defined above, or a salt
thereof, to act on said compound or a salt thereof, to produce the
product optically active compound of the general formula (II) where
Z represent a hydrogen atom, or a salt thereof or (2) further to
said step (1), a step of introducing a protective group to the
hydroxyl group of the optically active compound of the general
formula (II) wherein Z represents a hydrogen atom or a salt thereof
produced in said step (1), to produce the optically active compound
of the general formula (II) where Z represents a protective group
for hydroxyl group, or a salt thereof.
30. A process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)am- ino]ethanol derivative
according to claim 28, which further comprises: step(s) of allowing
(a) a compound shown by the general formula (III) 35wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the same
meanings as defined above, or (b) a compound shown by the general
formula (IV) 36wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 have the same meanings as defined above; Z represents a
hydrogen atom or a protective group for hydroxyl group; and X
represents a halogen atom, to react with a compound shown by the
general formula (V)Y--NH.sub.2 (V)wherein Y represents a hydrogen
atom or a group which can be left in the reaction, further allowing
Y to be left when Y is the group which can be left in the reaction,
and adding an acid to the reaction products containing the compound
shown by the general formula (VI) 37wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and Z have the same meanings as defined
above, to isolate the compound of the general formula (VI) by
precipitating or crystallizing said compound as a salt, and
further, when Z is the protective group for hydroxyl group,
cleaving the protective group, to produce a mixture of enantiomers
of 2-amino-1-phenylethanol compound shown by the general formula
(I) or a salt thereof.
31. A process for producing an (S)-2-amino-1-phenylethanol
derivative, which comprises: permitting a microorganism or a
preparation thereof which is capable of acting on a mixture of
enantiomers of a 2-amino-1-phenylethanol compound of the general
formula (I) 38wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 represent, the same or different, a hydrogen atom, a
halogen atom, an optionally substituted lower alkyl group, a
hydroxyl group which may be protected with a protective group, an
optionally substituted alkoxy group, an optionally substituted
cycloalkyloxy group, an optionally substituted aralkyloxy group, an
optionally substituted aryloxy group, an optionally substituted
lower alkylthio group, an optionally substituted acyl group, a
carboxyl group which may be protected with a protective group, an
optionally substituted lower alkoxycarbonyl group, a nitro group or
an optionally substituted amino group, or a salt thereof to produce
a corresponding (S)-form shown by the general formula (XV)
39wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
same meanings as defined above, or a salt thereof to act on said
mixture of enantiomers, and harvesting or recovering the product
optically active compound shown by the general formula (XV) or a
salt thereof.
32. A process for producing an (S)-2-amino-1-phenylethanol
derivative according to claim 31, wherein said microorganism is a
strain of microorganism selected from the group consisting of the
microorganisms belonging to the genus Saccharomyces, the genus
Pichia, the genus Schizosaccharomyces, the genus Candida, the genus
Hansenula, the genus Yarrowia, the genus Geotrichum, the genus
Brevibacterium, the genus Corynebacterium, the genus Xanthomonas,
the genus Actinomaqura, the genus Enterobacter, the genus
Pseudomonas, the genus Hafnia, the genus Actinoplanes, the genus
Escherichia, the genus Bacillus, the genus Listonella, the genus
Nosardioides, the genus Amycolata, the genus Aspergillus, the genus
Penicillium, the genus Corynespora, the genus Fusarium, the genus
Gelasinospora, the genus Helminthosporium, the genus Mortierelia,
the genus Neosartorya, the genus Phytophthora, the genus
Talaromyces, the genus Scolecobasidium and the genus
Rhodococcus.
33. A process for producing an (S)-2-amino-1-phenylethanol
derivative according to claim 31, wherein said microorganism is a
strain of microorganism selected from the group consisting of the
microorganisms belonging to Saccharomyces cerevisiae, Pichia
fabianii, Schizosaccharomyces pombe, Candida guilliermondii,
Candida melibiosica, Hansenula polymorpha, Yarrowia lipolytica,
Geotrichum capitatum, Micrococcus luteus, Brevibacterium iodinum,
Corynebacterium sepedonicum, Xanthomonas sp. IFO 12997,
Actinomaqura cremea subsp. cremea, Enterobacter aerogenes,
Pseudomonas aeruginosa, Hafnia alvei, Actinoplanes lobatus,
Escherichia coli, Bacillus licheniformis, Listonella anguillarum,
Nosardioides flavus, Amycolata autotrophica, Aspergillus niger,
Aspergillus ficuum, Aspergillus cavdidus, Aspergillus oryzae,
Aspergillus oryzae var. brunneus, Aspergillus tamarii, Penicillium
chrysogenum, Corynespora cassiicola, Fusarium solani, Gelasinospora
cerealis, Helminthosporium sigmoideum var. irreavl, Mortierelia
isabellina, Mortierelia ramanniana var. ramanniana, Neosartorya
fischeri var. spinosa, Phytophthora capsici, Talaromyces flavus
var. flavus, Scolecobasidium terreum, Rhodococcus luteus,
Rhodococcus erythropolis and Rhodococcus globerrulus.
34. A process for producing an (S)-2-amino-1-phenylethanol
derivative which comprises: permitting a microorganism or a
preparation thereof which is capable of acting on a compound shown
by the general formula (VII) 40wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 represent, the same or different, a hydrogen
atom, a halogen atom, an optionally substituted lower alkyl group,
a hydroxyl group which may be protected with a protective group, an
optionally substituted alkoxy group, an optionally substituted
cycloalkyloxy group, an optionally substituted aralkyloxy group, an
optionally substituted aryloxy group, an optionally substituted
lower alkylthio group, an optionally substituted acyl group, a
carboxyl group which may be protected with a protective group, an
optionally substituted lower alkoxycarbonyl group, a nitro group or
an optionally substituted amino group, or a salt thereof, to
produce a corresponding optically active compound shown by the
general formula (XV) 41wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 have the same meanings as defined above, or a salt
thereof, to act on said compound or a salt thereof, and harvesting
or recovering the product optically active compound shown by the
general formula (XV) or a salt thereof.
35. A process for producing an (S)-2-amino-1-phenylethanol
derivative according to claim 34, wherein said microorganism is a
strain of microorganism selected from the group consisting of the
microorganisms belonging to the genus Botryoascus, the genus
Brettanomyces, the genus Candida, the genus Citeromyces, the genus
Clavispora, the genus Debaryomyces, the genus Dipodascus, the genus
Eremascus, the genus Galactomyces, the genus Geotrichum, the genus
Issatchenkia, the genus Kluyveromyces, the genus Kondoa, the genus
Lipomyces, the genus Malassezia, the genus Oosporidium, the genus
Pachysolen, the genus Pichia, the genus Rhodosporidium, the genus
Rhodotorula, the genus Saccharomyces, the genus Saccharomycodes,
the genus Saccharomycopsis, the genus Schizoblastosporion, the
genus Schizosaccharomyces, the genus Sporidiobolus, the genus
Sporobolomyces, the genus Wickerhamiella, the genus Wingea, the
genus Zygosaccharomyces, the genus Bacillus, the genus Comamonas,
the genus Rhodobacter, the genus Enterococcus, the genus
Lactobacillus, the genus Pediococcus, the genus Leuconostoc and the
genus Streptococcus.
36. A process for producing an (S)-2-amino-1-phenylethanol
derivative according to claim 34, wherein said microorganism is a
strain of microorganism selected from the group consisting of the
microorganisms belonging to Botryoascus synnaedendrus,
Brettanomyces anomalus, Candida albicans, Candida beechii, Candida
ergatensis, Candida fusiformata, Candida guilliermondii, Candida
halonitratophila, Candida oregonensis, Candida peltata, Candida
parapsilosis, Candida sorboxylosa, Citeromyces matritensis,
Clavispora lusitaniae, Debaryomyces hansenii var. hansenii,
Dipodascus ovetensis, Eremascus fertilis, Galactomyces reessii,
Geotrichum fermentans, Geotrichum candidum, Geotrichum capitatum,
Geotrichum klebahnii, Issatchenkia scutulata var. scutulata,
Kluyveromyces lactis, Kluyveromyces marxianus var. bulgaricus,
Kondoa malvinella, Lipomyces starkeyi, Malassezia furfur,
Oosporidium margaritiferum, Pachysolen tannophilus, Pichia
farinosa, Pichia holstii, Pichia subpelliculosa, Pichia toletana,
Rhodosporidium diobovatum, Rhodotorula glutinis, Rhodotorula
glutinis var. dairenensis, Saccharomyces kluyveri, Saccharomyces
paradoxus, Saccharomycodes ludwigii, Saccharomycopsis capsularis,
Schizoblastosporion kobayasii, Schizosaccharomyces pombe,
Sporidiobolus pararoseus, Sporobolomyces pararoseus, Sporobolomyces
salmonicolor, Wickerhamiella domercquii, Wingea robertsii,
Zygosaccharomyces bailii, Zygosaccharomyces fermentati, Bacilus
subtilis, Comamonas terrigena, Rhodobacter sphaeroides,
Enterococcus faecalis, Lactobacillus lactis, Pediococcus
acidilactici, Leuconostoc mesenteroides subsp. dextranicum,
Leuconostoc mesenteroides, Leuconostoc oenos and Streptpcoccus
uberis.
37. A process for separating an optically active
2-amino-1-phenylethanol derivative from a mixture of enantiomers of
said derivative which comprises: (1) subjecting a mixture of
enantiomers of 2-amino-1-phenylethanol compound shown by the
general formula (I) 42wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 represent, the same or different, a group selected from
the group consisting of a hydrogen atom, a halogen atom, an
optionally substituted lower alkyl group, a hydroxyl group which
may be protected with a protective group, an optionally substituted
alkoxy group, an optionally substituted cycloalkyloxy group, an
optionally substituted aralkyloxy group, an optionally substituted
aryloxy group, an optionally substituted lower alkylthio group, an
optionally substituted acyl group, a carboxyl group which may be
protected with a protective group, an optionally substituted lower
alkoxycarbonyl group, a nitro group and an optionally substituted
amino group, or a salt thereof to a treatment with a microorganism
or a preparation derived therefrom which is capable of selectively
utilizing a corresponding (S)-form of said compound or a salt
thereof, allowing the microorganism or a preparation derived
therefrom to selectively utilize the (S)-form of said compound or a
salt thereof, and recovering the (R)-form of said compound or a
salt thereof; or (2) subjecting said mixture of enantiomers to a
treatment with a microorganism or a preparation derived therefrom
which is capable of selectively utilizing the corresponding
(R)-form of said compound or a salt thereof, allowing the
microorganism or a preparation derived therefrom to selectively
utilize the (R)-form or a salt thereof, and recovering the (S)-form
of said compound or a salt thereof.
38. A process for asymmetrically reducing an aminoketone derivative
to a corresponding optically active 2-amino-1-phenylethanol
derivative which comprises: (1) subjecting a compound shown by the
general formula (VII) 43wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 represent, the same or different, a group selected from
the group consisting of a hydrogen atom, a halogen atom, an
optionally substituted lower alkyl group, a hydroxyl group which
may be protected with a protective group, an optionally substituted
alkoxy group, an optionally substituted cycloalkyloxy group, an
optionally substituted aralkyloxy group, an optionally substituted
aryloxy group, an optionally substituted lower alkylthio group, an
optionally substituted acyl group, a carboxyl group which may be
protected with a protective group, an optionally substituted lower
alkoxycarbonyl group, a nitro group and an optionally substituted
amino group, or a salt thereof to a treatment with a microorganism
or a preparation derived therefrom which is capable of
asymmetrically reducing said compound or a salt thereof to a
corresponding (R)-2-amino-1-phenylethanol derivative shown by the
general formula (IIa) 44wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 have the same meanings as defined above, or a salt
thereof, and recovering the product optically active compound or a
salt thereof; or (2) subjecting said compound or a salt thereof to
a treatment with a microorganism or a preparation derived therefrom
which is capable of asymmetrically reducing said compound or a salt
thereof to a corresponding (S)-2-phenylethanol derivative shown by
the general formula (XV) 45wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 have the same meanings as defined above, or a
salt thereof, and recovering the product optically active compound
or a salt thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to processes for producing
2-amino-1-phenylethanol derivatives and optically active
enantiomers thereof which are important intermediates for synthesis
of (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivatives. The present invention further relates to processes for
producing the
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivatives
which are useful as medical compounds or intermediate products
thereof.
BACKGROUND OF THE INVENTION
[0002] As anti-obesity agents or anti-diabetic agents belonging to
a new category of agents without using insulin,
1-phenyl-2-[(2-phenyl-1-alkylet- hyl)amino]ethanol derivatives are
noted since the derivatives act selectively on a
.beta..sub.3-receptor in vivo, thus having extremely low side
effects. Pharmacological studies on the
1-phenyl-2-[(2-phenyl-1-alky- lethyl)amino]ethanol derivatives have
revealed that the .beta..sub.3-action substantially depends on
(R,R)-form thereof (see J. Med. Chem., 35, 3081 (1992), and U.S.
Pat. No. 5,061,727). For example, the above-mentioned U.S. patent
discloses that an (R,R)-5-[2-[[2-(3-chlor-
ophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylic
acid disodium salt has a higher activity than the corresponding
(S,S)-form by a factor of 47.
[0003] For the production of an optically active
1-phenyl-2-[(2-phenyl-1-a- lkylethyl)amino]ethanol derivative,
there is known an optical resolution of a racemic form or a
racemate, or an asymmetric synthesis.
[0004] For example, Japanese Patent Application Laid-open No.
320153/1993 (JP-A-5-320153) corresponding to the above mentioned
U.S. Pat. Nos. 5,061,727, 5,106,867 and Japanese Patent Application
Laid-open No. 18340/1983 (JP-A-58-18340) disclose a method of
producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivative which comprises (1) allowing a racemic phenylethanol
derivative to react with a phenylacetone derivative and a reducing
agent such as sodium cyanoborohydride to produce a mixture of four
species of optical isomers of a
1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative, (2)
isolating and removing an (R,S)-isomer and an (S,R)-isomer from the
mixture, and (3) optically resoluting an (R,R)-isomer and an
(S,S)-isomer by a diastereomer method. According to the method,
however, it is necessary to isolate and purify the only
(R,R)-isomer from a mixture of the four species of optical isomers,
therefore, the processes are complicated and the yield is
decreased. Further, since large quantities of raw materials are
required, the method is also disadvantageous in economical
factors.
[0005] The U.S. patents and the Journal of Medicinal Chemistry as
mentioned above disclose a method allowing an (R)-3-chlorostyrene
oxide derivative to react with an (R)-1-methyl-2-phenylethylamine
derivative. The (R)-1-methyl-2-phenylethylamine derivative used as
a raw material or reactant in the method, however, has a strong
antihypnotic or arousal action and it requires a particular
attention when handled, therefore is not suited for a use in
commercial production. Further, a lot of steps or processes are
required to obtain the above-mentioned
(R)-1-methyl-2-phenylethylamine derivative. For example, the
(R)-methyl-2-phenylethylamine derivative is prepared from L-DOPA
through six steps, namely, introduction of a protective group into
an amino group, esterification, reduction of the resulting ester,
converting a hydroxyl group to a mesyloxy group, deprotection of
the protective group and reduction.
[0006] On the other hand, as a method of producing an optically
active 2-amino-1-phenylethanol derivative used as a raw material or
a reactant for the 1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivative in the present invention, there is known a method of
optical resolution of a corresponding racemic form with the use of
an optically resoluting agent. Japanese Patent Application
Laid-open No. 9979/1989 (JP-A-64-9979) [Japanese Patent Publication
No. 48791/1992 (JP-B-4-48791)], for instance, discloses a method of
optically resoluting a racemic 2-amino-1-(3-chlorophenyl)ethanol
with N-(t-butoxycarbonyl)-D-alanine to obtain an optically active
(R)-form.
[0007] Further, Japanese Patent Application Laid-open No.
85247/1990 (JP-A-2-85247) discloses a method of optically
resoluting a racemic 2-amino-1-(4-chlorophenyl) ethanol with using
D-tartaric acid. Moreover, Journal of Japan Chemical Society, 1985,
(5), pp. 910 to 913 discloses a method of optically resoluting a
racemic 2-amino-1-phenylethanol with employing 3-aminobenzoic acid
as a optically resoluting agent.
[0008] According to these methods, however, the object optically
active 2-amino-1-phenylethanol derivative can not be produced
expediently and efficiently since the racemic
2-amino-1-phenylethanol derivative to be subjected to the optical
resolution can not be obtained in a simple and easy manner with
good yield.
[0009] For instance, as a method of producing the
2-amino-1-phenylethanol derivative, a method of reducing a
nitrogen-containing compound, and a method utilizing an addition
reaction of ammonia are known.
[0010] As examples of the method of reducing a nitrogen-containing
compound, there are known (a) a method of reducing mandelonitrile
[see J. Org. Chem., 45 (14), 2785 (1980), Japanese Patent
Application Laid-open No. 27/1971 (JP-A-46-27) and the like], (b) a
method of reducing mandelic acid amide [refer to J. Appl. Chem., 1
(1951), 469] and (c) a method of reducing a nitro compound [see
Coll. Czech. Chem. Comm., 43 (7), 1917 (1978)].
[0011] In the method (a), however, since mandelonitrile is
instable, the hydroxyl group is required to be protected to obtain
the object compound with high yield. Further, the reaction is
conducted in the presence of a great amount of a reducing agent
such as LiAlH.sub.4 and NaBH.sub.4 and an activating catalyst, thus
the method is disadvantageous in economical factors and requires
attention to be handled. Moreover, the purity of the obtained
2-amino-1-phenylethanol derivative is low of about 95%. In the
methods (b) and (c), since a large quantity of LiAlH.sub.4 and the
like is used as the reducing agent, there are problems similar
thereto. According to the method (c) where nitromethane is employed
as a solvent it is highly dangerous and needs a sufficient care
when handled.
[0012] As the method utilizing an addition reaction of ammonia,
there is known (d) a method of allowing an epoxy compound to react
with ammonia [see Syn. Com., 3 (3), 177, (1973), and (e) a method
of allowing a halohydrin compound to react with ammonia [refer
Indian. J. Chem., SECT. B, 31B, 821 (1992)]. Although the reaction
procedures are expedient, in these methods, however, a
1-amino-2-phenylethanol derivative as a position isomer of the
2-amino-1-phenylethanol derivative is liable to be by-produced. The
position-isomer can hardly be removed by an isolating and purifying
process generally used such as distillation, recrystallization and
extraction, therefore, complicated procedures such as column
purification are required.
[0013] On the other hand, a method of obtaining an optically active
2-amino-1-phenylethanol with the use of a microorganism is known.
That is, Chemistry Express, 4, 9, 621 to 624 (1989) discloses
microorganisms belonging to the genus Staphylococcus, the genus
Micrococcus, the genus Rhodococcus and the genus Neisseria produce,
respectively, an optically active 2-amino-1-phenylethanol from
2-amino-1-phenylethanol and .alpha.-aminoacetophenone.
SUMMARY OF THE INVENTION
[0014] Accordingly, it is an object of the present invention to
provide a process for efficiently producing an optically active
(R)-2-amino-1-phenylethanol derivative, which is useful for the
efficient production of an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative
with a good yield, with high yield and optical purity.
[0015] It is another object of the present invention to provide a
process of producing efficiently the optically active compound,
which is useful for the production of the (R,R)-isomer and is
available and easy to handle or treat, with high optical
purity.
[0016] A yet another object of the present invention is to provide
a process whereby a 2-amino-1-phenylethanol derivative which is
useful for obtaining the optically active compound efficiently can
be obtained in an expedient manner with good yield and high
purity.
[0017] Still another object of the present invention is to provide
a process for producing an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]e- thanol derivative
having a higher optical purity efficiently with high yield.
[0018] A further object of the invention is to provide a process
for producing an (S)-form, which is useful for production of the
optically active compound, efficiently with good yield.
[0019] The present invention further relates to a process for
separating the optically active compound, to a process for
asymmetrically reducing an aminoketone compound to the optically
active compound, and to a use of a microorganism in production of
the optically active compounds.
[0020] After much studies and efforts to accomplish the above
mentioned objects, the present inventors found (i) that a
2-amino-1-phenylethanol derivative having high purity can be
obtained by a specific isolation or purification method, (ii) that
an optically active (R)- or (S)-2-amino-1-phenylethanol derivative
having high optical purity can be obtained efficiently by a method
with the aid of a specific microorganism, and (iii) that an
optically active (R,R)-1-phenyl-2-[(2-ph-
enyl-1-alkylethyl)amino]ethanol derivative can easily or readily be
produced by a reaction of the (R)-form with a phenylacetone
derivative, and a reducing reaction of the reaction product of the
above reaction with high yield, high optical purity and
selectivity. The present invention has been accomplished based on
the above findings.
[0021] Thus, the present invention provides a process for producing
an (R)-2-amino-1-phenylethanol derivative which comprises:
[0022] permitting a microorganism or a preparation thereof which is
capable of acting on a mixture of enantiomers of a
2-amino-1-phenylethanol compound shown by the general formula (I)
2
[0023] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5
represent, the same or different, a hydrogen atom, a halogen atom,
an optionally substituted lower alkyl group, a hydroxyl group which
may be protected with a protective group, an optionally substituted
alkoxy group, an optionally substituted cycloalkyloxy group, an
optionally substituted aralkyloxy group, an optionally substituted
aryloxy group, an optionally substituted lower alkylthio group, an
optionally substituted acyl group, a carboxyl group which may be
protected with a protective group, an optionally substituted lower
alkoxycarbonyl group, a nitro group, an optionally substituted
amino group, or a salt thereof, to produce an
(R)-2-amino-1-phenylethanol compound shown by the general formula
(IIa) 3
[0024] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the same meanings as defined above, or a salt thereof,
[0025] to act on the mixture of enantiomers, and
[0026] harvesting or recovering the product (R)-form or a salt
thereof.
[0027] The hydroxyl group of the 2-amino-1-phenylethanol derivative
shown by the general formula (I) may be protected with a protective
group. Such derivative, that is, a compound shown by the general
formula (VI) 4
[0028] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the same meanings as defined above; and Z represents a hydrogen
atom or a protective group for hydroxyl group, may be prepared by
various methods, for example, by a method comprising:
[0029] allowing a compound shown by the general formula (III) 5
[0030] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the same meanings as defined above, or a compound shown by the
general formula (IV) 6
[0031] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and Z
have the same meanings as defined above; and X represents a halogen
atom, to react with a compound shown by the general formula (V)
Y--NH.sub.2 (V)
[0032] wherein Y represents a hydrogen atom or a group which can be
left in the reaction, further, when Y is the group which can be
left in the reaction, allowing Y to be left, and
[0033] adding an acid to the reaction product(s) to precipitate or
crystallize the compound of the general formula (VI) as a salt to
isolate or purify.
[0034] The (R)-2-amino-1-phenylethanol derivative of the general
formula (IIa) or a salt thereof can also be obtained by, for
example, a method comprising:
[0035] permitting a microorganism which is capable of acting on a
compound shown by the general formula (VII) 7
[0036] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the same meanings as defined above, or a salt thereof to produce a
corresponding optically active compound shown by the general
formula (IIa) or a salt thereof, to act on the compound or a salt
thereof and
[0037] harvesting or recovering the product optically active
compound of the general formula (IIa) or a salt thereof.
[0038] The optically active compound of the general formula (IIa)
or a salt thereof is useful for an intermediate for production of
an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivative.
[0039] The present invention further provides a process for
producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivative shown by the general formula (XI) 8
[0040] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the same meanings as defined above;
[0041] R.sup.7 and R.sup.8 represent;
[0042] (A) respectively, a group selected from the group consisting
of a hydrogen atom, an optionally substituted lower alkyl group, an
optionally substituted cycloalkyl group, an optionally substituted
aralkyl group, an optionally substituted aryl group, an optionally
substituted acyl group, a carboxyl group which may be protected
with a protective group, an optionally substituted lower
alkoxycarbonyl group, an optionally substituted amino group, an
optionally substituted alkylsulfonyl group, an optionally
substituted arylsulfonyl group and a hydroxyl group which may be
protected with a protective group, or
[0043] (B) R.sup.7 represents a group shown by the formula (IX):
--O--R.sup.7a and R.sup.8 represents a group shown by the formula
(X): --O--R.sup.8a wherein R.sup.7a and R.sup.8a may form an
optionally substituted ring with the adjacent oxygen atoms;
[0044] R.sup.6, R.sup.9 and R.sup.10 independently represent a
group selected from a group consisting of a hydrogen atom, a
halogen atom, an optionally substituted lower alkyl group, an
optionally substituted cycloalkyl group, an optionally substituted
aralkyl group, an optionally substituted aryl group, a hydroxyl
group which may be substituted with a protective group, an
optionally substituted alkoxy group, an optionally substituted
cycloalkyloxy group, an optionally substituted aralkyloxy group, an
optionally substituted aryloxy group, an optionally substituted
lower alkylthio group, an optionally substituted aralkylthio group,
an optionally substituted acyl group, a carboxyl group which may be
protected with a protective group, an optionally substituted lower
alkoxycarbonyl group, a nitro group and an optionally substituted
amino group; R.sup.11 represents a lower alkyl group, which
comprises:
[0045] a reaction of an (R)-2-amino-1-phenylethanol compound shown
by the general formula (II) 9
[0046] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and Z
have the same meanings as defined above, or a salt thereof, with a
compound shown by the general formula (VIII) 10
[0047] wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and
R.sup.11 have the same meanings as defined above, or a salt
thereof, and
[0048] a reducing reaction of the reaction product of the
reaction.
[0049] Further, an (S)-form or a salt thereof corresponding to the
(R)-form of the general formula (IIa) can be obtained by, for
example, a process which comprises:
[0050] permitting a microorganism or a preparation thereof which is
capable of acting on a mixture of enantiomers of the
2-amino-1-phenylethanol derivative of the general formula (I) or a
salt thereof to produce an (S)-form shown by the general formula
(XV) 11
[0051] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the same meanings as defined above, or a salt thereof to act on a
mixture of the enantiomers, and harvesting or recovering the
product (S)-form or a salt thereof.
[0052] The optically active compound of the general formula (XV) or
a salt thereof can also be obtained by permitting a microorganism
or a preparation thereof which is capable of acting on the compound
shown by the general formula (VII) or a salt thereof to produce the
corresponding optically active compound of the formula (XV) or a
salt thereof, to act on said compound or a salt thereof, and
harvesting or recovering the product optically active compound of
the general formula (XV) or a salt thereof.
[0053] The present invention still further discloses a process for
separating an (R)- or (S)-2-amino-1-phenylethanol derivative from a
mixture of these enantiomers, a process for asymmetrically reducing
the aminoketone compound of the general formula (VII) to the
corresponding (R)- or (S)-2-amino-1-phenylethanol derivative, a use
of a microorganism or a preparation thereof for the production of
the (R)- or (S)-form or a salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0054] As the halogen atom in R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 in the general formula (II), (IIa) or the like, there
may be mentioned fluorine atom, chorine atom, bromine atom and
iodine atom.
[0055] The optionally substituted lower alkyl group includes, for
example, (a) an optionally substituted alkyl group having 1 to 4
carbon atoms (for instance, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, s-butyl and t-butyl groups). Examples of the
substituent(s) for the C.sub.1-4 alkyl group includes a hydroxyl
group, a C.sub.1-4 alkoxy group, a benzoyl group, a C.sub.6-12 aryl
group (e.g. phenyl group) which may be substituted with a
substituent (for example, a C.sub.1-4 alkoxy group, etc.), a
C.sub.1-4 alkylthio group and a halogen atom. As examples of such
substituted C.sub.1-4 alkyl group, there may be mentioned (b) a
C.sub.1-4 alkyl group substituted with hydroxyl group(s) (for
example, hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,
2,2-dihydroxyethyl, 3,3-dihydroxypropyl group, etc.), (c) a
C.sub.1-4 alkoxy-C.sub.1-4 alkyl group (for instance,
methoxymethyl, ethoxymethyl, t-butoxymethyl, 1-ethoxyethyl,
2-methoxyethyl group, etc.), (d) phenacyl group, (e) a C.sub.1-4
alkylthio-C.sub.1-4 alkyl group (e.g. a C.sub.1-4 alkylthiomethyl
such as methylthiomethyl, ethylthiomethyl group, etc.), (f) a
C.sub.1-4 haloalkyl group having 1 or more of halogen atoms such as
chloromethyl, 2-chloroethyl, 3-chloropropyl, 4-chlorobutyl,
dichloromethyl, trichloromethyl, trifluoromethyl,
2,2,2-trichloroethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, and other groups.
[0056] As the protective group for hydroxyl group, there may be
mentioned protective groups for a hydroxyl group generally employed
in the field of organic synthesis. Such protective groups include,
for example, (A) a group which forms an ether bond with an oxygen
atom, (B) a group which forms an ester bond with an oxygen atom,
(C) a group which forms a carbonate with an oxygen atom and (D) a
group which forms a sulfonic acid ester with an oxygen atom.
[0057] Examples of the group (A) which forms an ether bond with an
oxygen atom include (1) an optionally substituted lower alkyl
group, (2) an optionally substituted allyl group, (3) an optionally
substituted cycloalkyl group, (4) an optionally substituted
heterocyclic group, (5) an optionally substituted aralkyl group and
(6) an optionally substituted silyl group.
[0058] The optionally substituted lower alkyl group (1) includes,
for example, (a) an optionally substituted alkyl group having 1 to
4 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl,
i-butyl, s-butyl and t-butyl groups. The substituents for the
C.sub.1-4 alkyl group include, for example, a C.sub.1-4 alkoxy
group, a C.sub.1-4 alkoxy-C.sub.1-4 alkoxy group, a C.sub.7-20
aralkyloxy group, a benzoyl group, a C.sub.1-4 alkylthio group, a
halogen atom and so on. Examples of such substituted C.sub.1-4
alkyl group include (b) a C.sub.1-4 alkoxy-C.sub.1-4 alkyl group
such as methoxymethyl, ethoxymethyl, t-butoxymethyl,
1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl (especially a
C.sub.1-4 alkoxy-C.sub.1-2 alkyl group); (c) a C.sub.1-4
alkoxy-C.sub.1-4 alkoxy-C.sub.1-4 alkyl group such as
2-methoxyethoxymethyl, 2-ethoxymethoxymethyl and the like
(specifically a C.sub.1-4 alkoxy-C.sub.1-4 alkoxy-C.sub.1-2 alkyl
group); (d) a C.sub.7-20 aralkyloxy-C.sub.1-4 alkyl group such as
benzyloxymethyl (especially, a C.sub.7-20 aralkyloxymethyl group);
(e) a phenacyl group; (f) a C.sub.1-4 alkylthio-C.sub.1-4 alkyl
group such as methylthiomethyl, ethylthiomethyl (specifically a
C.sub.1-4 alkylthiomethyl group); and (g) a C.sub.1-4 haloalkyl
group having one or more of halogen atoms such as trichloromethyl,
trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl and the
like.
[0059] As the substituent for the allyl group (2) include, for
instance, substituents for the C.sub.1-4 alkyl group mentioned in
the above (1). Examples of the optionally substituted cycloalkyl
group (3) include a cycloalkyl group having 3 to 10 carbon atoms
such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl and cyclodecyl groups. The substituent(s)
for the cycloalkyl group include, for example, a halogen atom, a
C.sub.1-4 alkyl group, and a hydroxyl group.
[0060] As the optionally substituted heterocyclic group (4), there
may be mentioned, for example, an optionally substituted 5- or
6-membered heterocyclic group having, other than carbon atoms, an
oxygen atom or a sulfur atom as a hetero atom. The optionally
substituted heterocyclic group may frequently be a non-aromatic
perhydroheterocyclic group. The 5- or 6-membered heterocyclic group
includes, for instance, tetrahydrofuranyl, tetrahydrothiofuranyl,
tetrahydropyranyl and tetrahydrothiopyranyl groups. Examples of the
substituents for the heterocyclic group include a halogen atom, a
C.sub.1-4 alkyl group, a C.sub.1-4 alkoxy group such as methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy and
t-butoxy, and substituents as mentioned above in lower alkyl group
(1).
[0061] Practical examples of the optionally substituted
heterocyclic group include an optionally substituted
tetrahydropyranyl group (e.g. tetrahydropyranyl,
3-bromotetrahydropyranyl, 4-methoxytetrahydropyranyl, etc.), an
optionally substituted tetrahydrothiopyranyl group (for example,
tetrahydrothiopyranyl, 3-bromotetrahydrothiopyranyl,
4-methoxytetrahydrothiopyranyl, etc.), an optionally substituted
tetrahydrofuranyl group (for instance, tetrahydrofuranyl, etc.),
and an optionally substituted tetrahydrothiofuranyl group (e.g.
tetrahydrothiofuranyl).
[0062] Examples of the optionally substituted aralkyl group (5)
include an optionally substituted aralkyl group having 7 to 20
carbon atoms (e.g. benzyl, etc.). The substituent for the aralkyl
group includes, for instance, a C.sub.1-4 alkyl group; a C.sub.6-12
aryl group such as phenyl group; a hydroxyl group, a C.sub.1-4
alkoxy group; a nitro group; and a halogen atom. Examples of such
substituent may be referred to those in the above group (4).
Typical examples of the optionally substituted aralkyl group
include benzyl, o-chlorobenzyl, o-nitrobenzyl, p-chlorobenzyl,
p-methoxybenzyl, p-methylbenzyl, p-nitrobenzyl, 2,6-dichlorobenzyl,
diphenylmethyl, trityl and the like.
[0063] The substituent for the silyl group (6) includes a
C.sub.7-20 aralkyl group such as benzyl group and substituents as
mentioned in the aralkyl group (5). Examples of the optionally
substituted silyl group (6) include trimethylsilyl, triethylsilyl,
t-butyldimethylsilyl, tribenzylsilyl, triphenylsilyl and so on.
[0064] As the group (B) which forms an ester bond with an oxygen
atom, there may be mentioned, for example, an optionally
substituted acyl group including (1) an acyl group having 1 to 6
carbon atoms which may be substituted with a hydroxyl group, a
C.sub.1-4 alkoxy group, C.sub.1-4 alkylthio group, a halogen atom
and the like (for instance, formyl, acetyl, chloroacetyl,
trifluoroacetyl, propionyl, isopropionyl, butyryl, isobutyryl,
valeryl, isovaleryl, pivaloyl and the like); (2) a C.sub.7-16 acyl
group having an aromatic ring which may be substituted with, for
example, a C.sub.1-4 alkyl group, a hydroxyl group, a C.sub.1-4
alkoxy group, a nitro group or a halogen atom (e.g. benzoyl,
p-phenylbenzoyl, toluoyl, naphthoyl and others); (3) an acyl group
having a heterocyclic ring (e.g. furoyl, thenoyl, nicotinoyl and
isonicotinoyl groups) which may be substituted with, for instance,
a C.sub.1-4 alkyl group, a hydroxyl group, a C.sub.1-4 alkoxy
group, a nitro group or a halogen atom.
[0065] The group (C) which forms a carbonate with an oxygen atom
includes, for instance, (1) a C.sub.2-5 alkoxycarbonyl group such
as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
s-butoxycarbonyl and t-butoxycarbonyl which may be substituted
with, for example, a C.sub.1-4 alkoxy group which may be
substituted with a C.sub.1-4 alkoxy group; a C.sub.7-20 aralkyloxy
group; benzoyl group; a C.sub.1-4 alkylthio group; or a halogen
atom; (2) a C.sub.8-20 aralkyloxycarbonyl group such as
benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,
p-methylbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
o-nitrobenzyloxycarbonyl, etc. which may be substituted with a
C.sub.1-4 alkyl group, a hydroxyl group, a C.sub.1-4 alkoxy group,
a nitro group, a halogen atom, etc., (3) a C.sub.7-20
aryloxycarbonyl group which may be substituted with a C.sub.1-4
alkyl group, a hydroxyl group, a C.sub.1-4 alkoxy group, a nitro
group, a halogen atom, etc., such as phenoxycarbonyl,
4-methylphenyloxycarbonyl, 4-nitrophenyloxycarbonyl,
4-chlorophenyloxycarbonyl, naphthyloxycarbonyl and so on.
[0066] Examples of the group (D) which forms a sulfonic acid ester
with an oxygen atom include, for instance, (1) an alkylsulfonyl
group such as a C.sub.1-4 alkylsulfonyl group which may be
substituted with, for instance, a C.sub.1-4 alkoxy group, a
C.sub.1-4 alkoxy-C.sub.1-4 alkoxy group, a C.sub.7-20 aralkyloxy
group, a benzoyl group, a C.sub.1-4 alkylthio group and a halogen
atom (e.g. methanesulfonyl, ethanesulfonyl, propanesulfonyl,
butanesulfonyl, trichloromethanesulfonyl, trifluoromethanesulfonyl,
etc.); (2) an optionally substituted arylsulfonyl group including a
C.sub.6-20 arylsulfonyl group which may be substituted with, for
example, a C.sub.1-4 alkyl group, a hydroxyl group, a C.sub.1-4
alkoxy group, a nitro group or a halogen atom such as
benzenesulfonyl, m-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl,
p-chlorobenzenesulfonyl, p-bromobenzenesulfonyl, p-toluenesulfonyl,
naphthalenesulfonyl and others.
[0067] The optionally substituted alkoxy group includes, for
instance, an optionally substituted alkoxy group having 1-4 carbon
atoms (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, s-butoxy, or t-butoxy group) and others. Examples of the
substituent for the alkoxy group include a hydroxyl group, a
C.sub.1-4 alkoxy group, a halogen atom and the like. As the
substituted alkoxy group, there may be mentioned, for example, a
hydroxy-C.sub.1-4 alkoxy group such as hydroxymethoxy,
2-hydroxyethoxy, 1,2-dihydroxyethoxy, 2,2-dihydroxyethoxy, and
3,3-dipropoxyethoxy groups; a C.sub.1-4 alkoxy-C.sub.1-4 alkoxy
group such as methoxymethoxy, ethoxymethoxy, 1-ethoxyethoxy, and
other groups.
[0068] The substituent for the cycloalkyloxy group include, for
instance, a halogen atom, a C.sub.1-4 alkyl group, a hydroxyl group
and the like. Examples of the cycloalkyloxy group include a
C.sub.3-10 cycloalkyloxy group such as cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy,
cyclooctyloxy, cyclononyloxy and cyclodecyloxy groups.
[0069] The optionally substituted aralkyloxy group include a
C.sub.7-20 aralkyloxy group which may be substituted with, for
examples, a C.sub.1-4 alkyl group, a C.sub.6-12 aryl group, a
hydroxyl group, a C.sub.1-4 alkoxy group, a nitro group, or a
halogen atom as exemplified above, such as benzyloxy,
m-bromobenzyloxy, m-chlorobenzyloxy and other groups.
[0070] Examples of the optionally substituted aryloxy group include
a C.sub.6-16 aryloxy group such as phenoxy group. The substituents
for the aryloxy group include, for instance, a C.sub.1-4 alkyl
group, a hydroxyl group, a C.sub.1-4 alkoxy group, a nitro group, a
halogen atom as exemplified above.
[0071] As the lower alkylthio group, there may be mentioned, for
example, a C.sub.1-4 alkylthio group such as methylthio, ethylthio,
propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio,
t-butylthio, and other groups. The substituent for the lower
alkylthio group include, for instance, a hydroxyl group, a
C.sub.1-4 alkoxy group, a halogen atom and so on.
[0072] Examples of the optionally substituted acyl group include
(1) an acyl group having 1 to 6 carbon atoms which may be
substituted with a halogen atom, a hydroxyl group, a C.sub.1-4
alkoxy group, C.sub.1-4 alkylthio group (for instance, formyl,
acetyl, chloroacetyl, trifluoroacetyl, propionyl, isopropionyl,
butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like);
(2) a C.sub.7-16 acyl group having an aromatic ring which may be
substituted with, for example, a C.sub.1-4 alkyl group, a hydroxyl
group, a C.sub.1-4 alkoxy group, a nitro group or a halogen atom
(e.g. benzoyl, p-phenylbenzoyl, toluoyl, naphthoyl and others); (3)
an acyl group having a heterocyclic ring which may be substituted
with, for instance, a C.sub.1-4 alkyl group, a hydroxyl group, a
C.sub.1-4 alkoxy group, a nitro group or a halogen atom (e.g.
furoyl, thenoyl, nicotinoyl and isonicotinoyl groups).
[0073] The protective group for carboxyl group includes, for
instance, an optionally substituted C.sub.1-4 alkyl group, an
optionally substituted C.sub.6-16 aryl group, an optionally
substituted C.sub.7-20 aralkyl group, an optionally substituted
amino group. As the optionally substituted C.sub.1-4 alkyl group,
etc., there may be mentioned the optionally substituted alkyl
group, etc., as exemplified above. The optionally substituted amino
group include an optionally substituted amino group as mentioned
just hereinbelow as well as an amino group substituted with a
C.sub.7-20 aralkyl group.
[0074] Practical examples of the protected carboxyl group include
(a) a C.sub.1-4 alkoxy-carbonyl group which may be substituted
with, for example, a hydroxyl group, a C.sub.1-4 alkoxy group, etc.
(for instance, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, t-butoxycarbonyl, methoxymethoxycarbonyl,
methoxyethoxy carbonyl group, etc.), (b) a C.sub.6-16
aryloxy-carbonyl group which may be substituted with a C.sub.1-4
alkyl group, a hydroxyl group, a C.sub.1-4 alkoxy group, a nitro
group or a halogen atom (e.g. phenoxycarbonyl,
4-methylphenyloxycarbonyl, 4-methoxyphenyloxycarbonyl,
4-nitrophenyloxycarbonyl, 4-chlorophenyloxycarbonyl,
naphtyloxycarbonyl, etc.), (c) a C.sub.7-20 aralkyloxy-carbonyl
group which may be substituted with a C.sub.1-4 alkyl group, a
C.sub.6-12 aryl group such as phenyl group, a hydroxyl group, a
C.sub.1-4 alkoxy group, a nitro group or a halogen atom (for
instance, benzyloxycarbonyl, m-chlorobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, and others), and (d) a carbamoyl group
which may be substituted with a C.sub.1-4 alkyl group, a C.sub.7-20
aralkyl group, a C.sub.1-6 acyl group, a C.sub.7-16 acyl group
having an aromatic group and others (e.g. carbamoyl,
benzylaminocarbonyl, etc.).
[0075] The carboxyl group may also form a salt. For such a salt,
there is no restriction, and examples of the salt include a salt
with an inorganic base including an alkali metal salt (e.g. a
sodium salt, a potassium salt, etc.), an alkaline earth metal salt
such as a magnesium salt, a calcium salt and a barium salt, the
other metal salt such as a zinc salt and an aluminum salt, and an
ammonium salt; a salt with an organic base including pyridine, a
tri-C.sub.1-4 alkylamine (e.g. tri-methylamine, triethylamine, and
so on).
[0076] Examples of the lower alkoxycarbonyl group include a
C.sub.2-5 alkoxycarbonyl group such as methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl,
t-butoxycarbonyl, and so on. The substituent for the lower
alkoxycarbonyl group include, for instance, those exemplified in
the substituent for the alkoxy group as mentioned above.
[0077] As the substituents for the optionally substituted amino
group, there may be mentioned, for instance, an optionally
substituted C.sub.1-4 alkyl group, an optionally substituted
C.sub.7-20 aralkyl group, an optionally substituted C.sub.1-6 acyl
group, an optionally substituted C.sub.7-16 acyl group having an
aromatic ring, an optionally substituted acyl group having a
heterocyclic group, as exemplified above and a substituted carbonyl
group. As such substituted carbonyl group, there may be mentioned,
for instance, an optionally substituted acyl group and a carboxyl
group protected with a protective group as mentioned above.
[0078] Typical examples of the optionally substituted amino group
include (a) an amino group, (b) an amino group which is substituted
with an optionally substituted C.sub.1-4 alkyl group (for example,
methylamino, ethylamino, propylamino, t-butylamino, dimethylamino,
diethylthio, dipropylamino, dibutylamino, etc.), (c) an amino group
substituted with an optionally substituted C.sub.7-20 aralkyl group
(for instance, benzylamino group and the like), (d) an amino group
which is substituted with an optionally substituted C.sub.1-6 acyl
group (for instance, formylamino, acetylamino, valerylamino,
isovalerylamino, pivaloylamino, etc.,), (e) an amino group which is
substituted with an optionally substituted C.sub.7-16 acyl group
having an aromatic ring (e.g. benzoylamino group, etc.,), (f) an
amino group substituted with an optionally substituted acyl group
having a heterocyclic ring (for instance, nicotinoylamino group and
the like), (g) an amino group which is substituted with a
substituted carboxyl group (for instance,
acetylaminomethylcarbonylamino, acetylaminoethylcarbonylamino,
hydroxymethylcarbonylamino, hydroxyethylcarbonylamino,
methoxycarbonylamino, ethoxycarbonylamino group and the like).
[0079] Preferred examples of R.sup.1 and R.sup.5 include a hydrogen
atom, a C.sub.1-4 alkyl group, and others, especially a hydrogen
atom.
[0080] As the typical examples of R.sup.2, R.sup.3, R.sup.4, there
may be mentioned a hydrogen atom, a halogen atom, a C.sub.1-4 alkyl
group which may be substituted with a halogen atom or a hydroxyl
group including, for example, a C.sub.1-4 alkyl group, a C.sub.1-4
haloalkyl group, a hydroxy-C.sub.1-4 alkoxy group etc., a hydroxy
group, a C.sub.1-4 alkoxy group, a C.sub.7-20 aralkyloxy group, a
C.sub.7-20 acyl group having an aromatic ring, an optionally
substituted amino group (specifically an amino group which is
substituted with a C.sub.1-6 acyl group) and a nitro group.
Specifically preferred of R.sup.2, R.sup.3 and R.sup.4 include, for
example, a halogen atom.
[0081] Examples of the protective group for hydroxyl group in Z
include protective groups for hydroxyl group generally used in the
field of organic synthesis, such as the protective groups for
hydroxyl group (A) to (D) as mentioned above in the explanation of
R.sup.1 to R.sup.5.
[0082] Practically, a hydrogen atom, a silyl group which may be
substituted with for example a C.sub.1-4 alkyl group, a C.sub.1-6
acyl group, especially a hydrogen atom is frequently used as Z.
[0083] Typical examples of the compound shown by the general
formula (II) include, other than (a) (R)-2-amino-1-phenylethanol,
(b) (R)-2-amino-1-phenylethanol derivatives which are protected on
the hydroxyl group, (c) (R)-2-amino-1-phenylethanol derivatives
which are substituted with a hydroxyl group on the phenyl group,
(d) (R)-2-amino-1-phenylethanol derivatives substituted with two
hydroxyl groups on the phenyl group, (e)
(R)-2-amino-1-phenylethanol derivatives substituted with a halogen
atom on the phenyl group, (f) (R)-2-amino-1-phenylethanol
derivatives substituted with two halogen atoms on the phenyl group,
(g) (R)-2-amino-1-phenylethanol derivatives substituted with three
halogen atoms on the phenyl group, (h) (R)-2-amino-1-phenylethanol
derivatives substituted with four halogen atoms on the phenyl
group, (i) (R)-2-amino-1-phenylethanol derivatives substituted with
five halogen atoms on the phenyl group, (j)
(R)-2-amino-1-phenylethanol derivatives substituted with an
optionally substituted lower alkyl group on the phenyl group, (k)
(R)-2-amino-1-phenylethanol derivatives substituted with an
optionally substituted lower alkoxy group on the phenyl group, (1)
(R)-2-amino-1-phenylethanol derivative substituted with a nitro
group on the phenyl group, (m) (R)-2-amino-1-phenylethanol
derivatives substituted with an optionally substituted amino group
on the phenyl group, (n) (R)-2-amino-1-phenylethanol derivatives
substituted with a hydroxyl group which may be protected with a
protective group, an optionally substituted cycloalkyloxy group, an
optionally substituted aralkyloxy group, an optionally substituted
aryloxy group, an optionally substituted amino group, a carboxyl
group which may be protected with a protective group, and the
like.
[0084] Examples of the (R) 2-amino-1-phenylethanol derivatives
which are protected on the hydroxyl group (b) include
(R)-2-amino-1-phenyl-O-trimet- hylsilylethanol,
(R)-2-amino-1-phenyl-O-t-butyldimethylsilylethanol,
(R)-2-amino-1-phenyl-O-tetrahydropyranylethanol,
(R)-2-amino-1-phenyl-O-a- cetylethanol and others.
[0085] As the derivatives (c) substituted with a hydroxyl group on
the phenyl group, there may be mentioned, for instance,
(R)-2-amino-1-(2-hydroxyphenyl)ethanol,
(R)-2-amino-1-(3-hydroxyphenyl)et- hanol,
(R)-2-amino-1-(4-hydroxyphenyl)ethanol,
(R)-2-amino-1-(3-methylthio- -4-hydroxyphenyl)ethanol,
(R)-2-amino-1-(3-hydroxymethyl-4-hydroxyphenyl)e- thanol,
(R)-2-amino-1-(3-methoxycarbonyl-4-hydroxyphenyl)ethanol,
(R)-2-amino-1-(3-hydroxyethoxy-4-hydroxyphenyl)ethanol,
(R)-2-amino-1-(3-ethoxymethyl-4-hydroxyphenyl)ethanol,
(R)-2-amino-1-[3-hydroxy-5-(1,2-dihydroxypropyl)phenyl]ethanol and
so on.
[0086] The derivatives (d) substituted with two hydroxyl groups on
the phenyl group include, for example,
(R)-2-amino-1-(2,3-dihydroxyphenyl)eth- anol,
(R)-2-amino-1-(2,4-dihydroxyphenyl)ethanol,
(R)-2-amino-1-(2,5-dihyd- roxyphenyl)ethanol,
(R)-2-amino-1-(2,6-dihydroxyphenyl)ethanol,
(R)-2-amino-1-(3,4-dihydroxyphenyl)ethanol,
(R)-2-amino-1-(3,5-dihydroxyp- henyl)ethanol,
(R)-2-amino-1-(4,5-dihydroxy-3-methylphenyl)ethanol,
(R)-2-amino-1-(3,4-dihydroxy-2-methylphenyl)ethanol and others.
[0087] Examples of the derivatives (e) substituted with a halogen
atom on the phenyl group include an
(R)-2-amino-1-(2-halophenyl)ethanol derivative such as
(R)-2-amino-1-(2-fluorophenyl)ethanol,
(R)-2-amino-1-(2-chlorophenyl)ethanol,
(R)-2-amino-1-(2-bromophenyl)ethan- ol,
(R)-2-amino-1-(2-iodophenyl)ethanol,
(R)-2-amino-1-(2-chloro-3-hydroxy- phenyl)ethanol,
(R)-2-amino-1-(2-chloro-4-hydroxyphenyl)ethanol,
(R)-2-amino-1-(2-chloro-4-benzyloxyphenyl)ethanol, etc.; an
(R)-2-amino-1-(3-halophenyl)ethanol derivative such as
(R)-2-amino-1-(3-chlorophenyl)-O-trimethylsilylethanol,
(R)-2-amino-1-(3-chlorophenyl)-O-t-butyldimethylsilylethanol,
(R)-2-amino-1-(3-chlorophenyl)-O-acetylethanol,
(R)-2-amino-1-(3-fluoroph- enyl)ethanol,
(R)-2-amino-1-(3-chlorophenyl)ethanol,
(R)-2-amino-1-(3-bromophenyl)ethanol,
(R)-2-amino-1-(3-iodophenyl)ethanol- ,
(R)-2-amino-1-(3-fluoro-4-methoxyphenyl)ethanol,
(R)-2-amino-1-(3-chloro- -4-methoxyphenyl)ethanol,
(R)-2-amino-1-(4-benzyloxy-3-chloro-5-methoxyphe- nyl)ethanol,
(R)-2-amino-1-(5-ethoxy-4-benzyloxy-3-chlorophenyl)ethanol, and
(R)-2-amino-1-(3-chloro-4-methylthiophenyl)ethanol; an
(R)-2-amino-1-(4-halophenyl)ethanol derivative such as
(R)-2-amino-1-(4-fluorophenyl)ethanol,
(R)-2-amino-1-(4-chlorophenyl)etha- nol,
(R)-2-amino-1-(4-bromophenyl)ethanol,
(R)-2-amino-1-(4-iodophenyl)eth- anol, and the like.
[0088] As the derivatives (f) substituted with two halogen atoms on
the phenyl group, there may be mentioned, for example,
(R)-2-amino-1-(2,3-dihalophenyl)ethanol derivatives such as
(R)-2-amino-1-(2,3-difluorophenyl)ethanol,
(R)-2-amino-1-(2,3-dichlorophe- nyl)ethanol,
(R)-2-amino-1-(2,3-dibromophenyl)ethanol,
(R)-2-amino-1-(2,3-diiodophenyl)ethanol,
(R)-2-amino-1-(2-fluoro-3-chloro- phenyl)ethanol and so on;
(R)-2-amino-1-(2,4-dihalophenyl)ethanol derivatives such as
(R)-2-amino-1-(2,4-difluorophenyl)ethanol,
(R)-2-amino-1-(2,4-dichlorophenyl)ethanol,
(R)-2-amino-1-(2,4-dibromophen- yl)ethanol,
(R)-2-amino-1-(2,4-diiodophenyl)ethanol and the like;
(R)-2-amino-1-(2,5-dihalophenyl)ethanol derivatives such as
(R)-2-amino-1-(2,5-difluorophenyl)ethanol,
(R)-2-amino-1-(2,5-dichlorophe- nyl)ethanol,
(R)-2-amino-1-(2,5-dibromophenyl)ethanol and
(R)-2-amino-1-(2,5-diiodophenyl)ethanol; an
(R)-2-amino-1-(2,6-dihalophen- yl)ethanol derivative such as
(R)-2-amino-1-(2,6-difluorophenyl)ethanol,
(R)-2-amino-1-(2,6-dichlorophenyl)ethanol,
(R)-2-amino-1-(2,6-dibromophen- yl)ethanol,
(R)-2-amino-1-(2,6-diiodophenyl)ethanol and the like;
(R)-2-amino-1-(3,4-dihalophenyl)ethanol derivatives such as
(R)-2-amino-1-(3,4-difluorophenyl)ethanol,
(R)-2-amino-1-(3,4-dichlorophe- nyl)ethanol,
(R)-2-amino-1-(3,4-dibromophenyl)ethanol,
(R)-2-amino-1-(3,4-diiodophenyl)ethanol,
(R)-2-amino-1-(3-chloro-4-bromop- henyl)ethanol,
(R)-2-amino-1-(3,4-dichlorophenyl)-O-trimethylsilylethanol,
(R)-2-amino-1-(3,4-dichlorophenyl)-O-acetylethanol and so on;
(R)-2-amino-1-(3,5-dihalophenyl)ethanol derivatives such as
(R)-2-amino-1-(3,5-difluorophenyl)ethanol,
(R)-2-amino-1-(3,5-dichlorophe- nyl)ethanol,
(R)-2-amino-1-(3,5-dibromophenyl)ethanol,
(R)-2-amino-1-(3,5-diiodophenyl)ethanol,
(R)-2-amino-1-(3,5-difluoro-4-me- thylaminophenyl)ethanol,
(R)-2-amino-1-(3,5-dichloro-4-methylaminophenyl)e- thanol,
(R)-2-amino-1-(3,5-dibromo-4-methylaminophenyl)ethanol,
(R)-2-amino-1-(3,5-dichloro-4-aminophenyl)ethanol,
(R)-2-amino-1-(3,5-dichloro-4-methylphenyl)ethanol,
(R)-2-amino-1-(3,5-dichloro-4-ethoxycarbonylaminophenyl)ethanol,
(R)-2-amino-1-(4-amino-3-bromo-5-fluorophenyl)ethanol and
(R)-2-amino-1-(4-amino-3-bromo-5-chlorophenyl)ethanol; and the
like.
[0089] The derivatives (g) substituted with three halogen atoms on
the phenyl group include, for instance,
(R)-2-amino-1-(2,3,4-trihalophenyl)et- hanol derivatives such as
(R)-2-amino-1-(2,3,4-trifluolophenyl)ethanol,
(R)-2-amino-1-(2,3,4-trichlorophenyl)ethanol,
(R)-2-amino-1-(2,3,4-tribro- mophenyl)ethanol,
(R)-2-amino-1-(2,3,4-triiodophenyl)ethanol and so on;
(R)-2-amino-1-(2,3,5-trihalophenyl)ethanol derivatives such as
(R)-2-amino-1-(2,3,5-trifluorophenyl)ethanol,
(R)-2-amino-1-(2,3,5-trichl- orophenyl)ethanol,
(R)-2-amino-1-(2,3,5-tribromophenyl)ethanol and
(R)-2-amino-1-(2,3,5-triiodophenyl)ethanol;
(R)-2-amino-1-(2,3,6-trihalop- henyl)ethanol derivatives such as
(R)-2-amino-1-(2,3,6-trifluolophenyl)eth- anol,
(R)-2-amino-1-(2,3,6-trichlorophenyl)ethanol,
(R)-2-amino-1-(2,3,6-tribromophenyl)ethanol,
(R)-2-amino-1-(2,3,6-triiodo- phenyl)ethanol and the like;
(R)-2-amino-1-(2,4,5-trihalophenyl)ethanol derivatives such as
(R)-2-amino-1-(2,4,5-trifluolophenyl)ethanol,
(R)-2-amino-1-(2,4,5-trichlorophenyl)ethanol,
(R)-2-amino-1-(2,4,5-tribro- mophenyl)ethanol and
(R)-2-amino-1-(2,4,5-triiodophenyl)ethanol;
(R)-2-amino-1-(2,4,6-trihalophenyl)ethanol derivatives such as
(R)-2-amino-1-(2,4,6-trifluolophenyl)ethanol,
(R)-2-amino-1-(2,4,6-trichl- orophenyl)ethanol,
(R)-2-amino-1-(2,4,6-tribromophenyl)ethanol,
(R)-2-amino-1-(2,4,6-triiodophenyl)ethanol and so on; an
(R)-2-amino-1-(3,4,5-trihalophenyl)ethanol derivative such as
(R)-2-amino-1-(3,4,5-trifluorophenyl)ethanol,
(R)-2-amino-1-(3,4,5-trichl- orophenyl)ethanol,
(R)-2-amino-1-(3,4,5-tribromophenyl)ethanol,
(R)-2-amino-1-(3,4,5-triiodophenyl)ethanol,
(R)-2-amino-1-(3-chloro-4,5-d- ifluorophenyl)ethanol,
(R)-2-amino-1-(3-fluoro-4,5-dichlorophenyl)ethanol and the
like.
[0090] Examples of the derivatives (h) substituted with four
halogen atoms on the phenyl group include an
(R)-2-amino-1-(2,3,4,5-tetrahalophenyl)eth- anol derivative such as
(R)-2-amino-1-(2,3,4,5-tetrafluorophenyl)ethanol,
(R)-2-amino-1-(2,3,4,5-tetrachlorophenyl)ethanol,
(R)-2-amino-1-(2,3,4,5-- tetrabromophenyl)ethanol,
(R)-2-amino-1-(2,3,4,5-tetraiodophenyl)ethanol and others; an
(R)-2-amino-1-(2,3,4,6-tetrahalophenyl)ethanol derivative such as
(R)-2-amino-1-(2,3,4,6-tetrafluorophenyl)ethanol,
(R)-2-amino-1-(2,3,4,6-tetrachlorophenyl)ethanol,
(R)-2-amino-1-(2,3,4,6-- tetrabromophenyl)ethanol,
(R)-2-amino-1-(2,3,4,6-tetraiodophenyl)ethanol, etc.; an
(R)-2-amino-1-(2,3,5,6-tetrahalophenyl)ethanol derivative such as
(R)-2-amino-1-(2,3,5,6-tetrafluorophenyl)ethanol,
(R)-2-amino-1-(2,3,5,6-tetrachlorophenyl)ethanol,
(R)-2-amino-1-(2,3,5,6-- tetrabromophenyl)ethanol,
(R)-2-amino-1-(2,3,5,6-tetraiodophenyl)ethanol and the like.
[0091] The derivatives (i) substituted with five halogen atoms on
the phenyl group include, for instance,
(R)-2-amino-1-(2,3,4,5,6-pentafluorop- henyl)ethanol,
(R)-2-amino-1-(2,3,4,5,6-pentachlorophenyl)ethanol,
(R)-2-amino-1-(2,3,4,5,6-pentabromophenyl)ethanol,
(R)-2-amino-1-(2,3,4,5,6-pentaiodophenyl)ethanol and so on.
[0092] Examples of the derivatives (j) substituted with an
optionally substituted lower alkyl group on the phenyl group
include an (R)-2-amino-1-(2-C.sub.1-4 alkyl-phenyl)ethanol
derivative such as (R)-2-amino-1-(2-methylphenyl)ethanol,
(R)-2-amino-1-(2-ethylphenyl)ethan- ol,
(R)-2-amino-1-(2-propylphenyl)ethanol,
(R)-2-amino-1-(2-t-butylphenyl)- ethanol and
(R)-2-amino-1-(2-methylphenyl)-O-trimethylsilylethanol; an
(R)-2-amino-1-(3-C.sub.1-4 alkyl-phenyl)ethanol derivative such as
(R)-2-amino-1-(3-methylphenyl)ethanol,
(R)-2-amino-1-(3-ethylphenyl)ethan- ol,
(R)-2-amino-1-(3-propylphenyl)ethanol,
(R)-2-amino-1-(3-t-butylphenyl)- ethanol and
(R)-2-amino-1-(3-methylphenyl)-O-trimethylsilylethanol; an
(R)-2-amino-1-(4-C.sub.1-4 alkyl-phenyl)ethanol derivative such as
(R)-2-amino-1-(4-methylphenyl)ethanol,
(R)-2-amino-1-(4-ethylphenyl)ethan- ol,
(R)-2-amino-1-(4-propylphenyl)ethanol,
(R)-2-amino-1-(4-t-butylphenyl)- ethanol and
(R)-2-amino-1-(4-methylphenyl)-O-trimethylsilylethanol; an
(R)-2-amino-1-(2-C.sub.1-4 haloalkyl-phenyl)ethanol derivative such
as (R)-2-amino-1-(2-chloromethylphenyl)ethanol,
(R)-2-amino-1-[2-(2-chloroet- hyl)phenyl]ethanol,
(R)-2-amino-1-[2-(3-chloropropyl)phenyl]ethanol,
(R)-2-amino-1-[2-(4-chlorobutyl)phenyl]ethanol,
(R)-2-amino-1-(2-trichlor- omethylphenyl)ethanol,
(R)-2-amino-1-(2-trifluoromethylphenyl)ethanol and
(R)-2-amino-1-(2-chloromethylphenyl)-O-trimethylsilylethanol; an
(R)-2-amino-1-(3-C.sub.1-4 haloalkyl-phenyl)ethanol derivative such
as (R)-2-amino-1-(3-chloromethylphenyl)ethanol,
(R)-2-amino-1-[3-(2-chloroet- hyl)phenyl]ethanol,
(R)-2-amino-1-[3-(3-chloropropyl)phenyl]ethanol,
(R)-2-amino-1-[3-(4-chlorobutyl)phenyl]ethanol,
(R)-2-amino-1-(3-trichlor- omethylphenyl)ethanol,
(R)-2-amino-1-(3-trifluoromethylphenyl)ethanol,
(R)-2-amino-1-(3-trifluoromethylphenyl)-O-trimethylsilylethanol,
(R)-2-amino-1-(3-trifluoromethylphenyl)-O-acetylethanol,
(R)-2-amino-1-[3-(1,1,2,2,2-pentafluoroethyl)
phenyl]-O-acetylethanol and
(R)-2-amino-1-(3-chloromethylphenyl)-O-trimethylsilylethanol; an
(R)-2-amino-1-(4-C.sub.1-4 haloalkyl-phenyl)ethanol derivative such
as (R)-2-amino-1-(4-chloromethylphenyl)ethanol,
(R)-2-amino-1-[4-(2-chloroet- hyl)phenyl]ethanol,
(R)-2-amino-1-[4-(3-chloropropyl)phenyl]ethanol,
(R)-2-amino-1-[4-(4-chlorobutyl)phenyl]ethanol,
(R)-2-amino-1-(4-trichlor- omethylphenyl)ethanol,
(R)-2-amino-1-(4-trifluoromethylphenyl)ethanol and
(R)-2-amino-1-(4-chloromethylphenyl)-O-trimethylsilylethanol; an
(R)-2-amino-1-[3-(hydroxy-C.sub.1-4 alkyl)phenyl]ethanol derivative
such as (R)-2-amino-1-[3-(hydroxymethyl)phenyl]ethanol and so
on.
[0093] As the derivatives (k) substituted with a lower alkoxy group
on the phenyl group, there may be mentioned, for example, a
derivative substituted with one lower alkoxy group on the phenyl
group such as (R)-2-amino-1-(2-methoxyphenyl)ethanol,
(R)-2-amino-1-(3-methoxyphenyl)et- hanol,
(R)-2-amino-1-(4-methoxyphenyl)ethanol,
(R)-2-amino-1-(2-ethoxyphen- yl)ethanol,
(R)-2-amino-1-(3-ethoxyphenyl)ethanol, (R)-2-amino-1-(4-ethoxy-
phenyl)ethanol and so on; a derivative substituted with two lower
alkoxy groups on the phenyl group such as
(R)-2-amino-1-(2,3-dimethoxyphenyl)eth- anol,
(R)-2-amino-1-(2,3-diethoxyphenyl)ethanol,
(R)-2-amino-1-(2,4-dimeth- oxyphenyl)ethanol,
(R)-2-amino-1-(2,4-diethoxyphenyl)ethanol,
(R)-2-amino-1-(2,5-dimethoxyphenyl)ethanol,
(R)-2-amino-1-(2,5-diethoxyph- enyl)ethanol,
(R)-2-amino-1-(2,6-dimethoxyphenyl)ethanol,
(R)-2-amino-1-(2,6-diethoxyphenyl)ethanol,
(R)-2-amino-1-(3,4-dimethoxyph- enyl)ethanol,
(R)-2-amino-1-(3,4-diethoxyphenyl)ethanol,
(R)-2-amino-1-(3,5-dimethoxyphenyl)ethanol,
(R)-2-amino-1-(3,5-diethoxyph- enyl)ethanol and
(R)-2-amino-1-(3-hydroxyethoxy-4-t-butoxyphenyl)ethanol; a
derivative which is substituted with an alkoxy group and a hydroxyl
group on the phenyl group such as
(R)-2-amino-1-(2-hydroxy-3-methoxypheny- l)ethanol,
(R)-2-amino-1-(2-hydroxy-4-methoxyphenyl)ethanol,
(R)-2-amino-1-(2-hydroxy-5-methoxyphenyl)ethanol,
(R)-2-amino-1-(2-hydrox- y-6-methoxyphenyl)ethanol,
(R)-2-amino-1-(3-hydroxy-2-methoxyphenyl)ethano- l,
(R)-2-amino-1-(3-hydroxy-4-methoxyphenyl)ethanol,
(R)-2-amino-1-(3-hydroxy-5-methoxyphenyl)ethanol,
(R)-2-amino-1-(3-hydrox- y-6-methoxyphenyl)ethanol,
(R)-2-amino-1-(4-hydroxy-2-methoxyphenyl)ethano- l,
(R)-2-amino-1-(4-hydroxy-3-methoxyphenyl)ethanol,
(R)-2-amino-1-(5-hydroxy-2-methoxyphenyl)ethanol,
(R)-2-amino-1-(5-hydrox- y-3-methoxyphenyl)ethanol,
(R)-2-amino-1-(6-hydroxy-2-methoxyphenyl)ethano- l,
(R)-2-amino-1-(6-hydroxy-3-methoxyphenyl)ethanol,
(R)-2-amino-1-(2-hydroxy-3-ethoxyphenyl)ethanol,
(R)-2-amino-1-(2-hydroxy- -4-ethoxyphenyl)ethanol,
(R)-2-amino-1-(2-hydroxy-5-ethoxyphenyl)ethanol,
(R)-2-amino-1-(2-hydroxy-6-ethoxyphenyl)ethanol,
(R)-2-amino-1-(3-hydroxy- -2-ethoxyphenyl)ethanol,
(R)-2-amino-1-(3-hydroxy-4-ethoxyphenyl)ethanol,
(R)-2-amino-1-(3-hydroxy-5-ethoxyphenyl)ethanol,
(R)-2-amino-1-(3-hydroxy- -6-ethoxyphenyl)ethanol,
(R)-2-amino-1-(4-hydroxy-2-ethoxyphenyl)ethanol,
(R)-2-amino-1-(4-hydroxy-3-ethoxyphenyl)ethanol,
(R)-2-amino-1-(5-hydroxy- -2-ethoxyphenyl)ethanol,
(R)-2-amino-1-(5-hydroxy-3-ethoxyphenyl)ethanol,
(R)-2-amino-1-(6-hydroxy-2-ethoxyphenyl)ethanol,
(R)-2-amino-1-(6-hydroxy- -3-ethoxyphenyl)ethanol and others.
[0094] The derivatives (1) substituted with a nitro group on the
phenyl group include, for example,
(R)-2-amino-1-(2-nitrophenyl)ethanol,
(R)-2-amino-1-(3-nitrophenyl)ethanol,
(R)-2-amino-1-(2-methyl-3-nitrophen- yl)ethanol,
(R)-2-amino-1-(4-nitrophenyl)ethanol and the like.
[0095] Examples of the derivative (m) substituted with an
optionally substituted amino group on the phenyl group include
(R)-2-amino-1-(3-aminophenyl)ethanol,
(R)-2-amino-1-(3-amino-4-methoxyphe- nyl)ethanol,
(R)-2-amino-1-(3-acetylaminophenyl)ethanol,
(R)-2-amino-1-(4-acetylaminophenyl)ethanol,
(R)-2-amino-1-(3-acetylamino-- 4-hydroxyphenyl)ethanol,
(R)-2-amino-1-(3-acetylamino-4-methoxyphenyl)etha- nol,
(R)-2-amino-1-(3-acetylamino-4-benzyloxyphenyl)ethanol,
(R)-2-amino-1-(3-acetylaminomethylcarbonylamino-4-hydroxyphenyl)ethanol,
(R)-2-amino-1-(3-formylamino-4-hydroxyphenyl)ethanol,
(R)-2-amino-1-(3-hydroxymethylcarbonylamino-4-hydroxyphenyl)ethanol,
(R)-2-amino-1-[3-hydroxymethylcarbonylamino-4-(p-methoxyphenyl)methylphen-
yl]ethanol, (R)-2-amino-1-l(5-formylamino-3-hydroxyphenyl)ethanol,
(R)-2-amino-1-(3-carbamoyl-4-hydroxyphenyl)ethanol, and so on.
[0096] As the derivatives (n) substituted with a hydroxyl group
which may be protected with a protective group, an optionally
substituted cycloalkyloxy group, an optionally substituted
aralkyloxy group, an optionally substituted aryloxy group, an
optionally substituted acyl group, or a carboxyl group which may be
protected with a protective group, there may be mentioned, for
example, (R)-2-amino-1-(2-benzyloxyphe- nyl)ethanol,
(R)-2-amino-1-(2-benzylcarbonylphenyl)ethanol,
(R)-2-amino-1-(2-benzylcarbonyloxyphenyl)ethanol,
(R)-2-amino-1-(3-methox- ycarbonyl-4-cyclohexyloxyphenyl)ethanol,
(R)-2-amino-1-(3,4-dibenzyloxyphe- nyl)ethanol,
(R)-2-amino-1-(3-hydroxymethyl-4-benzyloxyphenyl)ethanol,
(R)-2-amino-1-(3,5-dibenzyloxyphenyl)ethanol,
(R)-2-amino-1-(3,5-di-t-but- oxycarbonylphenyl)ethanol and the
like.
[0097] Preferred examples of the compound shown by the general
formula (II) as exemplified above include
(R)-2-amino-1-phenylethanol; an (R)-2-amino-1-phenylethanol
derivative substituted with a halogen atom(s) on the phenyl group
[for example, a derivative substituted with one or two of halogen
atoms, specifically a derivative substituted with one or two of
halogen atoms on the 2-, 3- or 4-position of the phenyl group such
as an (R)-2-amino-1-(3-halophenyl)ethanol derivative,
(R)-2-amino-1-(4-halophenyl)ethanol derivative, an
(R)-2-amino-1-(3,4-dihalophenyl)ethanol derivative and the like];
an (R)-2-amino-1-phenylethanol derivative substituted, on the
phenyl group, with an optionally substituted C.sub.1-4 alkyl group,
an optionally substituted C.sub.1-4 alkoxy group or an optionally
substituted amino group such as an (R)-2-amino-1-(3-C.sub.1-4
alkyl-phenyl)ethanol derivative, an (R)-2-amino-1-(3-C.sub.1-4
haloalkyl-phenyl)ethanol derivative, an (R)-2-amino-1-(3-C.sub.1-4
alkoxy-phenyl)ethanol derivative, an (R)-2-amino-1-(3-C.sub.1-6
acylaminophenyl)ethanol derivative, an (R)-2-amino-1-(4-C.sub.1-4
alkyl-phenyl)ethanol derivative, an (R)-2-amino-1-(4-C.sub.1-4
haloalkyl-phenyl)ethanol derivative, an (R)-2-amino-1-(4-C.sub.1-4
alkoxy-phenyl)ethanol derivative, an (R)-2-amino-1-(4-C.sub.1-6
acylaminophenyl)ethanol derivative and others.
[0098] The (R)-2-amino-1-phenylethanol derivative shown by the
general formula (II) wherein Z is a hydrogen atom, namely, the
compound shown by the general formula (IIa) can be prepared by
various methods, for example, a chemical synthetic method, and the
compound of the general formula (IIa) can advantageously be
produced by a method utilizing a microorganism or a preparation
thereof.
[0099] The optically active (R)-form shown by the general formula
(IIa) can be readily or easily prepared, for example, by (A)
permitting a specific microorganism or a preparation thereof to act
on a mixture of the enantiomers of the 2-amino-1-phenylethanol
derivative of the general formula (I) or a salt thereof, or (B)
permitting a specific microorganism or a preparation thereof to act
on the compound of the general formula (VII) or a salt thereof, and
harvesting or recovering the product (R)-2-amino-1-phenylethanol
derivative.
[0100] The optically active compound can also be prepared by, for
instance, (C) a method for obtaining the compound by allowing an
aminating agent to act on an optically active compound of the
formula (III) or an optically active compound of the formula (IV),
adding an acid to the reaction product(s) to isolate or purify by
precipitating or crystallizing the optically active compound of the
formula (VI) as a salt, and further, when Z in the formula (VI) is
a protective group for hydroxyl group, cleaving the protective
group; or (D) a method comprising permitting an aminating agent to
act on a compound shown by the formula (III) or a compound shown by
the formula (IV), adding an optically active acid to the reaction
product(s) to precipitate or crystallize the optically active
compound of the formula (VI) as a salt for isolation or
purification, and further, where Z in the formula (VI) is the
protective group for hydroxyl group, cleaving the protective group
to obtain the optically active compound.
[0101] The method (A) just mentioned above is explained
hereinbelow.
[0102] In this method, a mixture of the enantiomers of the
2-amino-1-phenylethanol derivative used as a raw material can be
prepared by, for instance, (a) a method which comprises allowing a
trialkylsilylcyanide such as trimethylsilylcyanide to react with a
corresponding benzaldehyde derivative in the presence of a Lewis
acid such as anhydrous aluminium chloride to produce an
O-trialkylsilylmandelonitrile derivative such as
O-trimethylsilylmandelon- itrile derivative, subjecting the
resultant compound to a treatment with a reducing agent such as
sodium borohydride, and to hydrolysis with an acid [see Japanese
Patent Application Laid-open No. 5445/1981 (JP-A-56-5445) and U.S.
Pat. No. 5,061,727 as mentioned above] (hereinafter referred to as
reducing method), (b) a method which comprises allowing an
aminating agent such as NH.sub.3 to act on a corresponding compound
(styrene oxide derivative) to obtain the product compound wherein
the epoxide ring is opened (hereinafter referred to as styrene
oxide-aminating method), (c) a method allowing an aminating agent
such as NH.sub.3 to act on the corresponding styrene halohydrin
derivative (hereinafter briefly referred to as halohydrin-aminating
method), or the like.
[0103] In these methods, the hydroxyl group of the compound of the
general formula (I) may be protected with a proper protective
group. Such compound where the hydroxyl group may be protected with
a protective group is shown by the general formula (VI), and after
completion of the reaction, the compound of the general formula (I)
can be easily be obtained by cleaving the protecting group.
Examples of the protective group for the hydroxyl group include
those exemplified in the explanation of Z in the formula (II).
[0104] According to the styrene oxide-aminating method (b) and
halohydrin-aminating method (c), differing from the reducing method
(a), it is not necessary to use a large amount of a reducing agent
having a high cost, and the object compound can easily or readily
be obtained by using an aminating agent.
[0105] In the styrene oxide-aminating method (b), the styrene oxide
derivative used as a raw material can be obtained by a conventional
manner, for example, by oxidizing a corresponding styrene
derivative.
[0106] As the aminating agent, for example, a compound shown by the
general formula (V)
Y--NH.sub.2 (V)
[0107] wherein Y represents a hydrogen atom or a group which can be
left in the reaction, can be employed. Examples of the group
represented by Y which can be left in the reaction include an
optionally substituted C.sub.1-4 alkyl group (for example, allyl
group; phenacyl group; a C.sub.1-6 acyloxy-C.sub.1-4 alkyl group
such as 3-acetoxypropyl group; an optionally substituted C.sub.1-4
alkoxy-C.sub.1-4 alkyl group such as methoxymethyl,
2-chloroethoxymethyl group and so on; a C.sub.7-16
aralkyloxy-C.sub.1-4 alkyl group such as benzyloxymethyl group; an
optionally substituted a C.sub.7-16 aralkyl group (for instance,
benzyl, triphenylmethyl, a C.sub.1-4 alkoxy-C.sub.7-16 aralkyl
group such as 3,4-dimethoxybenzyl, di(p-methoxyphenyl)methyl and
(p-methoxyphenyl)diphenylmethyl group) and others. As the C.sub.1-4
alkyl group and the like, there may be employed the C.sub.1-4 alkyl
group and the like as mentioned in the explanation of R.sup.1 to
R.sup.5. Practical examples of Y include a hydrogen atom.
[0108] The reaction may be carried out in an inert solvent. The
solvent includes, for instance, alcohols including lower alcohols
(e.g. a C.sub.1-4 alcohol such as methanol, ethanol, propanol,
t-butanol); aromatic hydrocarbons such as benzene, toluene, xylene,
ethylbenzene and the like; aliphatic hydrocarbons such as pentane,
hexane, heptane, octane and so on; alicyclic hydrocarbons such as
cyclohexane, methylcyclohexane, etc.; halogenated hydrocarbons such
as carbon tetrachloride, chloroform, dichloromethane and
1,2-dichloroethane; ethers such as diethyl ether, dibutyl ether,
dioxane, tetrahydrofuran and others; ketones such as acetone,
methyl ethyl ketone and the like; esters such as methyl acetate and
ethyl acetate. As such solvent, alcohols can frequently be
used.
[0109] The conditions of the reaction can be selected from a
suitable range depending on the species of the aminating agent and
other factors, as far as the yield and the like will not be
affected adversely, and the reaction temperature is, for example,
about 0 to 80.degree. C. and preferably about 20 to 60.degree. C.,
and the reaction time is, usually, about from 5 minutes to 24
hours.
[0110] In the above-mentioned reaction, where Y is the group which
can be left in the reaction, the compound of the general formula
(I) can readily or easily be obtained by allowing Y to be left in a
conventional manner.
[0111] In the halohydrin-aminating method (c), the reaction may be
conducted in the same manner as in the styrene oxide-aminating
method (b), except that the corresponding styrene halohydrin
derivative is employed as a raw material. The styrene halohydrin
derivative used as a raw material can be obtained by a conventional
manner, for example, by halogenating a corresponding acetophenone
derivative and reducing the resulting compound.
[0112] In the aminating methods (b) and (c), while depending on the
reaction conditions, a by-product such as a position isomer of the
object compound shown by the general formula (XVI) 12
[0113] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and Z
have the same meanings as defined above, or a dimer shown by the
general formula (XVII) and (XVII') 13
[0114] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and Z
have the same meanings as defined above, or the like. The amount of
the by-product(s) may depend on the species of the compound, the
reaction conditions and other factors, and is, usually, in the
styrene oxide-aminating method, such that the ratio of the
2-amino-1-phenylethanol derivative of the general formula (I): the
position isomer of the general formula (XVI): other by-product such
as the dimer equals about 7:1:2 by weight. The proportions of the
2-amino-1-phenylethanol derivative of the general formula (I), the
position isomer and dimer thereof can for example be analyzed by
high performance liquid chromatography or the like.
[0115] The 2-amino-1-phenylethanol derivative can be isolated or
purified by utilizing difference in the basicity and/or solubility
between the derivative and the by-product(s), that is, the
derivative can readily or easily be isolated and purified from a
mixture containing such by-product(s) by adding an acid to the
reaction products containing the by-product(s) and forming a salt
of the object compound.
[0116] The isolation and purification can be carried out in an
inert solvent. The solvent may not be critical as far as the
2-amino-1-phenylethanol derivative and the by-product can be
dissolved therein and the salt of the 2-amino-1-phenylethanol
derivative is insoluble therein, and includes organic solvent such
as alcohols, ketones, aliphatic hydrocarbons, alicyclic
hydrocarbons, aromatic hydrocarbons, ethers, esters and halogenated
hydrocarbons as exemplified above. These solvents may be used
singly or in combination.
[0117] The amount of the solvent is, usually, about 0.5 to 100
times by weight, preferably about 1 to 20 times by weight and more
preferably about 5 to 15 times by weight relative to the total
amount of the reaction products.
[0118] The formation of the salt of the 2-amino-1-phenylethanol
derivative can be conducted by using any of an inorganic acid or an
organic acid. As such method, there may be mentioned, for instance,
(ia) a method adding an acid the reaction products to obtain a salt
of the 2-amino-1-phenylethanol derivative selectively by
precipitating or crystallization the salt, or (ib) a method
allowing not only the 2-amino-1-phenylethanol derivative but also
other reaction product(s) having an amino group to form a salt,
adding a base to the resultant mixture, making the impurity to be
free or liberated by salt-exchange to obtain the salt of the
2-amino-1-phenylethanol derivative selectively.
[0119] Examples of the inorganic acid include hydrochloric acid,
sulfuric acid, nitric acid, phosphoric acid, boric acid, carbonic
acid and the like. Typical example of the inorganic acid include
hydrochloric acid.
[0120] As the organic acid, there may be mentioned, for example,
saturated aliphatic monocarboxylic acids such as formic acid,
acetic acid, propionic acid, butyric acid, isobutyric acid, valeric
acid, pivalic acid and O-benzoyl glycolic acid; saturated aliphatic
dicarboxylic acids such as oxalic acid, malonic acid, succinic
acid, glutaric acid, adipic acid, pimeric acid, suberic acid and
others; unsaturated aliphatic carboxylic acids such as acrylic
acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic
acid, maleic acid, fumaric acid, citraconic acid, mesaconic acid,
and so on; aliphatic hydroxycarboxylic acids such as glycolic acid,
lactic acid, malic acid, tartaric acid, hydroxybutyric acid,
hydroxyacrylic acid, glyceric acid, tartoronic acid, citric acid
and others; carbocyclic carboxylic acids such as camphoric acid,
benzoic acid, phthalic acid, isophthalic acid, terephthalic acid,
naphthoic acid, o-chlorobenzoic acid, m-chlorobenzoic acid,
p-chlorobenzoic acid, o-toluic acid, m-toluic acid, p-toluic acid,
2,5-dimethylbenzoic acid, 3,4-dimethylbenzoic acid,
3,5-dimethylbenzoic acid, 2,4,6-trimethylbenzoic acid,
o-methoxybenzoic acid, m-methoxybenzoic acid, p-methoxybenzoic
acid, o-aminobenzoic acid, m-aminobenzoic acid, p-aminobenzoic
acid, vanilic acid, veratoric acid, cinnamic acid,
3,4-dihydroxycinnamic acid, 3,4-dimethoxycinnamic acid, benzilic
acid, 3-phenylpropionic acid and the like; aromatic
hydroxycarboxylic acids such as salicylic acid, m-hydroxybenzoic
acid, p-hydroxybenzoic acid, gallic acid, tropic acid and so on;
heterocyclic carboxylic acids such as nicotinic acid and
isonicotinic acid; amino acids which may be protected on the amino
group with a protective group (for example, glycine,
N-(t-butoxycarbonyl)alanine and the like); sulfonic acids such as
benzenesulfonic acid, p-toluenesulfonic acid,
2,5-dimethylbenzenesulfonic acid, 2,4,6-trimethylbenzenesulfonic
acid, methanesulfonic acid and others.
[0121] Preferred examples of the organic acids include a C.sub.1-3
saturated aliphatic monocarboxylic acid such as formic acid and
acetic acid; a C.sub.1-6 saturated aliphatic dicarboxylic acid such
as oxalic acid and succinic acid; and a C.sub.6-15 carbocyclic
carboxylic acid such as benzoic acid and the like.
[0122] The amount of the acid may be selected from a wide range
depending on the species of the acid, and is, for example, relative
to 1 mole of the compound of the general formula (VI), about 1 gram
equivalent or less, and preferably about 0.8 to 1 gram equivalent
in case of the inorganic acid. When the amount of the acid is too
small, the salt would not be formed sufficiently thus the yield is
liable to decrease. On the other hand, when an excess amount of the
acid is added, a by-product such as the position-isomer forms a
salt and the purity tends to decrease. When utilizing an organic
acid, probably because the solubility of a salt of the
by-product(s) such as the position isomer formed with an organic
acid is extremely high, while the solubility of a salt of the
compound of the general formula (VI) formed with an organic acid is
low, even when an excess amount of the organic acid is added, the
organic acid salt of the compound of the general formula (VI) can
selectively be precipitated or crystallized. The proportion of the
acid in case of the organic acid is, usually about 0.8 gram
equivalent or more (for example about 0.8 to 8 gram equivalents),
preferably about 1 to 3 gram equivalents and more preferably about
1 to 2 gram equivalents relative to 1 mole of the compound of the
formula (VI). The reaction temperature of the formation of the salt
may, usually, be about 0.degree. C. to 100.degree. C., preferably
about 10 to 80.degree. C. and more preferably about 20 to
70.degree. C. The reaction time is not critical and is, for
example, about 10 minutes to 10 hours.
[0123] After formation of the salt, the salt of the
2-amino-1-phenylethanol derivative can be recovered from the
reaction mixture by a conventional manner such as filtration. The
temperature of filtration is, usually, about 0 to 50.degree. C. and
preferably about 10 to 30.degree. C.
[0124] According to the method (ia), the salt of the
2-amino-1-phenylethanol derivative can selectively be precipitated
since the basicity of the compound of the general formula (VI) is
higher than the basicity of the by-products such as the
position-isomer and dimer, and the solubility of the salt of the
compound of the general formula (VI) is smaller relative to the
solubility of the salts of the by-products. Thus, the
2-amino-1-phenylethanol derivative can efficiently be isolated and
purified. In the salt of the 2-amino-1-phenylethanol derivative as
obtained by such method, the content of impurities is generally
about 2 weight % or less, and the salt of the
2-amino-1-phenylethanol derivative, can frequently be obtained in
the yield of, for instance, about 90% or more.
[0125] As the method for isolation of the 2-amino-1-phenylethanol
derivative, the method (ib) can also be employed which comprises
forming corresponding salts to products having an amino group
including the position-isomer, liberating impurities selectively by
adding a base, and recovering the salt of the
2-amino-1-phenylethanol derivative of the general formula (VI).
[0126] In the method (ib), the salts of reaction products may be
formed in the same manner as in the method (ia) except for the
using amount of the acid. In the method (ib), the amount of the
acid is, relative to 1 mole of the total amount of the
2-amino-1-phenylethanol derivative and the position-isomer thereof,
about 1 gram equivalent or more and preferably about 1 to 3 gram
equivalents. Addition of too little amount of the acid tends to
make the yield decreased, and addition of a too much amount of the
acid would be liable to make the cost high and reduce economic
properties.
[0127] When recovering the produced salts in a conventional method
such as filtration after forming the salts, impurities other than
the position-isomer would be removed and the obtained salts are
frequently a mixture of the salt of the object compound and the
salt of the position-isomer thereof. The ratio of the
position-isomer and the compound of the general formula (VI) may be
the same as the ratio before formation of the salts.
[0128] In this method (ib), the isolation or purification may be
conducted by using the higher basicity of the compound of the
general formula (VI) relative to the basicity of the corresponding
position-isomer. That is, the salt of the 2-amino-1-phenylethanol
derivative of the general formula (VI) is selectively recovered by
allowing a base to act on the salts obtained by the procedure
mentioned above to liberate or set free the position-isomer
selectively. More practically, the position isomer can selectively
be liberated by, for example, dispersing the salts to a solvent,
and adding a base to the dispersion. As the solvent used for
dispersing the salts, any solvents having poor solubility for the
salts and having good solubility for the free form of the
position-isomer can be used, and for example, the solvents as
exemplified above can be employed.
[0129] The base includes inorganic bases and organic bases.
Examples of the inorganic bases include alkali metal hydroxides
such as sodium hydroxide, potassium hydroxide and lithium
hydroxide; alkaline earth metal hydroxides such as magnesium
hydroxide, calcium hydroxide and barium hydroxide; alkali metal
carbonates such as sodium carbonate, potassium carbonate and
lithium carbonate; alkaline earth metal carbonate such as magnesium
carbonate, calcium carbonate and barium carbonate; alkali metal
hydrogencarbonates such as sodium hydrogencarbonate and potassium
hydrogencarbonate. The organic bases include, for example, metal
alkoxides such as alkali metal alkoxides (for example, a sodium or
potassium C.sub.1-4 alkoxide such as sodium methoxide, sodium
ethoxide, sodium propoxide, sodium butoxide, potassium methoxide,
potassium ethoxide, potassium propoxide and potassium butoxide,
etc.); primary amines such as an aliphatic primary amine including
a monoalkylamine (e.g. a C.sub.1-8 alkylamine such as methylamine,
ethylamine, propylamine, butylamine, etc.) and an aromatic primary
amine (e.g. aniline, toluidine, benzylamine, naphthylamine etc.);
secondary amines such as an dialkylamine (e.g. a di-C.sub.1-8
alkylamine such as dimethylamine, diethylamine, dipropylamine,
diisopropylamine, dibutylamine, diisobutylamine, di-s-butylamine,
di-t-butylamine, etc.), an aromatic secondary amine (for example,
N-methylaniline, N-ethylaniline, dibenzylaniline, diphenylamine and
the like), and cyclic amines such as pipecoline, piperidine,
morpholine, pyrrolidine, etc.; tertiary amines such as a
trialkylamine (e.g. a tri-C.sub.1-8 alkylamine such as
trimethylamine, triethylamine, tripropylamine, tributylamine,
etc.), N,N-di-substituted alkanolamines such as N,N-di-C.sub.1-4
alkyl alkanolamine (e.g. N,N-dimethylethanolamine and the like),
N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine,
triphenylamine, tribenzylamine, N-methylmorpholine,
N-methylpiperidine and others; basic nitrogen-containing
heterocyclic compounds such as pyridine, picoline, quinoline, and
others. These bases can be employed singly or in combination.
[0130] Preferred examples of the base include organic bases,
specifically amines. Typically, bases having an electrolytic
dissociation exponent pKa value (hereinafter briefly referred to as
pKa value) between the pKa value of the 2-amino-1-phenylethanol
derivative and the pKa value of the impurities such as the
position-isomer thereof can advantageously be used as the base. By
using such a base, the impurities can selectively be liberated.
Preferred examples of the base include a base having a pKa value of
about 9.3 to 11.5, for example, a C.sub.1-8 alkylamine such as
ethylamine (pKa=10.8); a di-C.sub.1-8 alkylamine such as
diethylamine (pKa=10.4); a tri-C.sub.1-8 alkylamine such as
triethylamine (pKa=11.0); and a cyclic amine such as piperidine
(pKa=11.1). Practically preferred base includes, for instance, a
base having a pKa value of about 10 to 11.3 and more preferably
about 10.5 to 11.2.
[0131] The amount of the base is not critical as far as being 1
gram equivalent or more relative to 1 mole of the position-isomer,
and is generally about 0.1 to 1.0 gram equivalent and preferably
about 0.3 to 0.6 gram equivalent relative to 1 mole of the total
amount of the salt of 2-amino-1-phenylethanol derivative and the
salt of the position-isomer. When the amount of the base is
exceedingly small, removal of the position-isomer is liable to be
insufficient, and when the amount is too much, the economic
availabilities tends to decrease. The reaction time and temperature
may be selected from the same range as mentioned in the formation
of the salt.
[0132] By adding such base, the salt of the position-isomer would
be salt-exchanged with the base to be liberated, thus the
2-amino-1-phenylethanol derivative remains in the form of salt. The
salt of the 2-amino-1-phenylethanol derivative can be readily
isolated by conducting, for example, filtration as mentioned above.
The salt of the derivative thus obtained has high purity and the
content of impurities such as a by-product is usually about 2% or
less. The product may occasionally contain a salt formed with the
base which is salt-exchanged and the acid used for the salt
formation, and in such a case, the salt can easily be removed in
the liberation. Further, after adding the acid, the base may be
added without isolating the salt.
[0133] The isolation (purification) of the object
2-amino-1-phenylethanol derivative can also be carried out by
changing the order of the addition of the salt and the addition of
the base, that is the salt of the 2-amino-1-phenylethanol
derivative may be formed by, after adding the base, adding the acid
to the reaction products. In such a method, the adding amount of
the acid is generally about 0.8 to 2.0 gram equivalents and
preferably about 1.0 to 1.5 gram equivalents relative to 1 mole of
the compound of the general formula (VI). Addition of the acid in a
proportion of less than 0.8 gram equivalent tends to make the yield
decreased and addition of the acid in an amount of exceeding 2.0
gram equivalents would make the removal of impurities insufficient
and the purity is liable to lessen. The acid may frequently be
added in an amount of 1 gram equivalent or more relative to 1 mole
of the total amount of the compound of the general formula (VI) and
the position-isomer thereof.
[0134] According to the above-mentioned methods, the salt of the
2-amino-1-phenylethanol derivative of the general formula (VI) can
selectively be isolated and purified by removing the
position-isomer of the object compound or other by-products from
the reaction products.
[0135] The 2-amino-1-phenylethanol derivative having high purity
can be obtained by liberating the salt of the
2-amino-1-phenylethanol derivative thus obtained in a conventional
manner. The liberation can be carried out by allowing the salt of
the 2-amino-1-phenylethanol derivative to react with a base, for
example by dissolving or dispersing the salt in water or an organic
solvent, adding a base as, for example, an aqueous solution to
resultant mixture, and after liberating the compound, extracting
the resulting free compound with an organic solvent, and when
necessary washing the extract with water, and removing off the
solvent.
[0136] As the organic solvent, hydrophobic organic solvents such as
aliphatic hydrocarbons, aromatic hydrocarbons, halogenated
hydrocarbons, ethers, esters can be employed as mentioned above.
These solvents can be used singly or in combination. Among such
solvents, halogenated hydrocarbons and esters can advantageously be
employed. The proportion of the solvent in the extraction of
liberated 2-amino-1-phenylethanol derivative is, relative to the
total amount of the salt, about 0.5 to 40 times by weight and
preferably about 1 to 20 times by weight.
[0137] Examples of the base include inorganic bases including
alkali metal hydroxides such as sodium hydroxide, potassium
hydroxide and lithium hydroxide; alkali metal carbonates such as
sodium carbonate, potassium carbonate and lithium carbonate; alkali
metal hydrogencarbonates such as sodium hydrogencarbonate,
potassium hydrogencarbonate and lithium hydrogencarbonate; alkaline
earth metal hydroxides such as magnesium hydroxide. The amount of
the base is, usually, about 0.8 to 10 gram equivalents and
preferably about 1 to 8 gram equivalents relative to 1 mole of
total amount of the salt. The using amount of the water in the
extraction of liberated 2-amino-1-phenylethanol derivative is,
relative to the total amount of the salt, for example, about 1 to
50 times by weight and preferably about 5 to 20 times by
weight.
[0138] The compound of the general formula (VI) can easily be
converted to the 2-amino-1-phenylethanol derivative of the general
formula (I) by cleaving the protective group for hydroxyl group in
a conventional manner, and be supplied to, for example, the
following production of the optically active compound with the aid
of a microorganism.
[0139] The microorganism to be employed in accordance with the
method (A) may be any strain of microorganism that is capable of
acting on a mixture of the enantiomers of the
2-amino-1-phenylethanol derivative of the general formula (I) or a
salt thereof to produce the (R)-2-amino-1-phenylethanol compound of
the general formula (IIa) or a salt thereof. Such microorganisms
include, for example, microorganisms which selectively utilize the
(S)-form among the both enantiomers of the 2-amino-1-phenylethanol
derivative, and microorganisms which selectively convert the
(S)-form to another compound including the (R)-form.
[0140] Examples of the microorganisms having such capability
include a strain of microorganisms belonging to the genus
Hansenula, the genus Geotrichum, the genus Candida, the genus
Cryptococcus, the genus Rhodosporidium, the genus Rhodotorula, the
genus Saccharomyces, the genus Sporobolomyces, the genus
Kluyveromyces, the genus Issatchenkia, the genus Pichia, the genus
Botryoascus, the genus Debaryomyces, the genus Lipomyces, the genus
Metschnikowia, the genus Saccharomycodes, the genus
Schizoblastosporion, the genus Stepahnoascus, the genus
Sterigmatomyces, the genus Zygosaccharomyces, the genus
Sporidiobolus, the genus Malassezia, the genus Torulaspora, the
genus Corynebacterium, the genus Gluconobacter, the genus
Promicromonospora, the genus Pseudomonas, the genus Bordetella, the
genus Acetobacter, the genus Bacillus, the genus Agrobacterium, the
genus Arthrobacter, the genus Amauroascus, the genus
Brevibacterium, the genus Micrococcus, the genus Aureobacterium,
the genus Azotobacter, the genus Xanthomonas, the genus Klebsiella,
the genus Comamonas, the genus Mycobacterium, the genus
Terrabacter, the genus Agrocybe, the genus Trichoderma, the genus
Alternaria, the genus Hamigera, the genus Moniliella, the genus
Pholiota, the genus Podospola, the genus Aegerita, the genus
Streptomyces, the genus Saccharomycopsis, the genus Leucosporidium,
Rhodococcus amidophilis, Rhodococcus equi and others.
[0141] Practical examples of the microorganisms capable of acting
on a mixture of the enantiomers of the 2-amino-1-phenylethanol
derivative of the general formula (I) to produce the corresponding
(R)-2-amino-1-phenylethanol derivative include strains of
microorganisms as mentioned below:
[0142] (1) the genus Hansenula: Hansenula anomala IFO 0707,
etc.,
[0143] (2) the genus Geotrichum: Geotrichum candidum IFO 4601,
Geotrichum candidum IFO 4598, etc.,
[0144] (3) the genus Candida: Candida albicans IFO 1594, Candida
albicans IFO 1856, Candida parapsilosis IFO 1022, Candida
gropengiesseri IFO 0659, Candida aaseri IFO 10404, Candida beechii
IFO 10229, Candida atmospherica IFO 1969, Candida natalensis IFO
1981, Candida paludigena IFO 10330, Candida sake IFO 1149, Candida
pintolopesii var. pintolopesii IFO 0729, etc.,
[0145] (4) the genus Cryptococcus: Cryptococcus neoformans IAM
4788, etc.,
[0146] (5) the genus Rhodosporidium: Rhodosporidium spaerocarpum
IFO 1438, Rhodosporidium diobovatum IFO 0688, etc.,
[0147] (6) the genus Rhodotorula: Rhodotorula rubra IFO 0406,
Rhodotorula rubra AHU 3948, Rhodotorula glutinis var. dairenensis
IFO 0415, etc.,
[0148] (7) the genus Saccharomyces: Saccharomyces montanus IFO
0021, etc.,
[0149] (8) the genus Sporobolomyces: Sporobolomyces roseus IFO
1040, etc.,
[0150] (9) the genus Kluyveromyces: Kluyveromryces marxianus var.
bulgaricus IAM 4829, Kluyveromyces lactis IFO 1267, etc.,
[0151] (10) the genus Issatchenkia: Issatchenkia scutulata var.
scutulata IFO 10069, Issatchenkia scutulata var. scutulata IFO
10070, etc.,
[0152] (11) the genus Pichia: Pichia thermotolerans IFO 10024,
Pichia farinosa IFO 1163, etc.,
[0153] (12) the genus Botryoascus: Botryoascus synnaedendrus IFO
1604, etc.,
[0154] (13) the genus Debaryomyces: Debaryomyces hansenii IFO 0083,
etc.,
[0155] (14) the genus Lipomyces: Lipomyces starkeyi IFO 1289,
etc.,
[0156] (15) the genus Metschnikowia: Metschnikowia bicuspidata IFO
1408, etc.,
[0157] (16) the genus Saccharomycodes: Saccharomycodes ludwigii IFO
0798, etc.,
[0158] (17) the genus Schizoblastosporion: Schizoblastosporion
kobayashii IFO 1644, etc.,
[0159] (18) the genus Stepahnoascus: Stepahnoascus ciferrii IFO
1854, etc.,
[0160] (19) the genus Sterigmatomyces: Sterigmatomyces halophilus
IFO 1488, etc.,
[0161] (20) the genus Zygosaccharomyces: Zygosaccharomyces rouxii
IFO 0510, Zygosaccharomyces rouxii IAM 4114, Zygosaccharomyces
fermentati IFO 0021, etc.,
[0162] (21) the genus Sporidiobolus: Sporidiobolus salmonicolor IFO
1845, Sporidiabolus pararoseus IFO 1107, etc.,
[0163] (22) the genus Malassezia: Malassezia furfur IFO 0656,
etc.,
[0164] (23) the genus Torulaspora: Torulaspora delbrueckii IFO
0955, etc.,
[0165] (24) the genus Corynebacterium: Corynebacterium aquaticum
IFO 12154, Corynebacterium mediolanum JCM 3346, etc.,
[0166] (25) the genus Gluconobacter: Gluconobacter asaii IFO 3265,
Gluconobacter oxydans IFO 3255, Gluconobacter oxydans IFO 3130,
Gluconobacter oxydans IFO 3289, Gluconobacter frateuril IFO 3271,
etc.,
[0167] (26) the genus Promicromonospora: Promicromonospora citrea
IFO 12397, etc.,
[0168] (27) the genus Pseudomonas: Pseudomonas aeruginosa IFO 3899,
Pseudomonas riboflavina IFO 13584, Pseudomonas fluorescens IFO
3925, Pseudomonas putida IFO 12996, Pseudomonas syncyanea IFO 3757,
Pseudomonas diminuta IFO 12697, Pseudomonas chlororaphis IFO 3522,
Pseudomonas fragi IFO 3458, Pseudomonas sp. ATCC 14676, etc.,
[0169] (28) the genus Bordetella: Bordetella bronchiseptica IFO
13691, etc.,
[0170] (29) the genus Acetobacter: Acetobacter sp. IFO 3248,
Acetobacter sp. IFO 3297, Acetobacter pasteurianus ATCC 10245,
Acetobacter pasteurianus IFO 3259, Acetobacter pasteurianus IFO
3277, etc.,
[0171] (30) the genus Bacillus: Bacillus subtilis IFO 3013,
Bacillus subtilis IFO 3009, Bacillus cereus AHU 1355, Bacillus
cereus AHU 1707, Bacillus cereus IFO 3001, Bacillus coagulans IAM
1115, Bacillus brevis IFO 3331, Bacillus sphaericus IFO 3525,
etc.,
[0172] (31) the genus Agrobacterium: Agrobacterium radiobacter IFO
12664, etc.,
[0173] (32) the genus Arthrobacter: Arthrobacter ureafaciens IFO
12140, etc.,
[0174] (33) the genus Amauroascus: Amauroascus reticulatus IFO
9196, etc.,
[0175] (34) the genus Brevibacterium: Brevibacterium linens IFO
12141, etc.,
[0176] (35) the genus Micrococcus: Micrococcus roseus IFO 3764,
etc.,
[0177] (36) the genus Aureobacterium: Aureobacterium testaceum IFO
12675, etc.,
[0178] (37) the genus Azotobacter: Azotobacter vinelandii IFO
13581, etc.,
[0179] (38) the genus Xanthomonas: Xanthomonas campestris pv oryzae
IAM 1657, etc.,
[0180] (39) the genus Klebsiella: Klebsiella pneumoniae IFO 3317,
etc.,
[0181] (40) the genus Comamonas: Comamonas testosteroni IFO 12048,
Comamonas testosteroni IAM 1048, etc.,
[0182] (41) the genus Mycobacterium: Mycobacterium diernhoferi IFO
3707, etc.,
[0183] (42) the genus Terrabacter: Terrabacter tumescens IFO 12960,
etc.,
[0184] (43) the genus Agrocybe: Agrocybe cylindracea IFO 30299,
etc.,
[0185] (44) the genus Trichoderma: Trichoderma viride IFO 5720,
etc.,
[0186] (45) the genus Alternaria: Alternaria kikuchiana IFO 5778,
etc.,
[0187] (46) the genus Hamigera: Hamigera avellanea IFO 7721,
etc.,
[0188] (47) the genus Moniliella: Moniliella acetoabutans IFO 9481,
etc.,
[0189] (48) the genus Pholiota: Pholiota nameko IFO 6141, etc.,
[0190] (49) the genus Podospola: Podospola cardonaria IFO 30294,
etc.,
[0191] (50) the genus Aegerita: Aegerita candida IFO 6988,
etc.,
[0192] (51) the genus Streptomyces: Streptomyces cinereoruber HUT
6142, etc.,
[0193] (52) the genus Saccharomycopsis: Saccharomycopsis capsularis
IFO 0672, etc.,
[0194] (53) the genus Leucosporidium: Leucosporidium scottii IFO
1923, Leucosporidium scottii IFO 1924, etc.,
[0195] (54) Rhodococcus amidophilis: Rhodococcus amidophilis IFO
0144, etc.,
[0196] (55) Rhodococcus equi: Rhodococcus equi JCM 1313, etc.
[0197] At least one of these microorganisms may be used. By
permitting the microorganism or a preparation thereof acting on a
mixture of the enantiomers of the 2-amino-1-phenylethanol
derivative of the general formula (I), the ratio of the (R)-form
among the both enantiomers would be increased.
[0198] The microorganisms identified hereinabove by IFO numbers are
described in the "List of Cultures, Ed. 9 (1992)" published by
Institute for Fermentation, Osaka (IFO), Japan and are available
from the same Institute. The microorganisms designated by JCM
numbers are listed in "Catalogs of Microbial Strains, Ed. 5 (1992)"
published by the Culture Collection of The Institute of Physical
and Chemical Research, Japan and available from the same Culture
Collection. The microorganisms identified by ATCC numbers are
listed in "Catalogue of Bacteria and Bacteria Phages, Ed. 18
(1992)", "Catalogue of Yeasts, Ed. 18 (1990)" and "Catalogue of
Filamentous Fungi, Ed. 18 (1990)" each published by the American
Type Culture Collection (ATCC) and are respectively available from
the same organization. The microorganism designated by DSM numbers
are listed in "Catalogue of strains (1989)" published by the German
Collection of Microorganisms and Cell Cultures (DSM) and are
available from the same organization. The microorganisms titled by
IAM numbers are listed in "Catalogue of Strains" published by the
Cell & Functional Polymer General Center, Institute of
Molecular Cell Biology of Tokyo University, Japan, and are
available by the same institute. The microorganisms designated by
BGSC numbers are listed in "Strains and Data" published by the
Bacillus Genetic Stock Center (BGSC), and are available from the
same stock center. The microorganisms identified by AHU numbers are
listed in "Catalogue of Cultures, Ed. 5 (1992)" published by the
Japan Federation of Cell Collection, and are available from Faculty
of Agriculture, Hokkaido University, Japan. The microorganisms
titled by IFM numbers and HUT numbers are respectively available
from Chiba University, Japan and Hiroshima University, Japan.
[0199] For the purposes of the invention, any of wild strains,
mutants and recombinant strains which can be obtained by a genetic
engineering technique such as cell fusion or gene manipulation can
suitably be used, as far as having the ability or capability of
acting on a mixture of the enantiomers of the
2-amino-1-phenylethanol derivative of the general formula (I) to
produce the corresponding (R)-form.
[0200] A microorganism such as above is, usually, grown in a
culture medium and submitted to the reaction with a mixture of
enantiomers of the compound of the general formula (I).
[0201] The medium used for growing the strain for use in the
invention is not critical in composition only if the selected
strain may grow and multiply therein. The medium may frequently be
a fluid medium containing sources of carbon and nitrogen and other
nutrients. Any carbon source which the strain can utilize may be
employed. As the sources of carbon, there may be employed, for
example, various carbohydrates or saccharides such as glucose,
fructose, sucrose, dextrin, starch, etc.; alcohols such as
sorbitol, methanol, ethanol, glycerol, etc.; organic acids such as
fumaric acid, citric acid, acetic acid, propionic acid, etc. and
the corresponding salts; hydrocarbons such as paraffin; and various
mixtures thereof. The sources of nitrogen include, for instance,
inorganic acid ammonium salts such as ammonium chloride, ammonium
sulfate, ammonium phosphate, etc.; organic acid ammonium salts such
as ammonium fumarate, ammonium citrate, etc.; inorganic or organic
nitrogen-containing materials such as meat extract, yeast extract,
malt extract, peptone (polypeptone), corn steep liquor, casein
hydrolysate, urea, etc.; and various mixtures thereof.
[0202] In the medium, there may be incorporated appropriate amounts
of those nutrients which are commonly employed in the cultivation
of microorganisms, such as inorganic salts, trace metal salts and
vitamins. Where necessary, there may also be incorporated factors
which may promote growth of the strain used and/or factors which
may augment its ability to produce the object compound of the
invention, for example, the 2-amino-1-phenylethanol derivative of
the general formula (I), as well as a buffer substance which may
assist in the maintenance of the medium at a given pH.
[0203] The cultivation of the microorganism is carried out under
conditions optimal for the growth of the particular strain, for
example at a medium pH in the range of about 2.0 to 9.5, preferably
about 3 to 8, and an incubation temperature in the range of about
20 to 45.degree. C., preferably about 25 to 37.degree. C. The
cultivation may be aerobic or anaerobic. The cultivation time is,
for example, about 5 to 120 hours, preferably about 12 to 72
hours.
[0204] The proportions of the (R)-form and the (S)-form in the
substrate mixture of enantiomers of the 2-amino-1-phenylethanol
derivative shown by the general formula (I) are not critical by it
is advantageous for commercial purposes to employ a racemic form of
the 2-amino-1-phenylethanol derivative.
[0205] The method of asymmetric utilization is not critical so far
as the function of a microorganism or a preparation thereof is
acted on the 2-amino-1-phenylethanol derivative of the general
formula (I) to produce the (R)-2-amino-1-phenylethanol derivative
of the general formula (IIa), and may, for example, be whichever of
the following alternatives: (1) a technique adding a mixture of
enantiomers of the 2-amino-1-phenylethanol derivative to the
culture medium where the microorganism is cultivated, (2) a
technique which comprises separating the microbial cells from the
culture broth, e.g. by centrifugation, resuspending the cells,
either as they are or after washing, in a buffer solution, water or
the like, and adding a mixture of enantiomers of the
2-amino-1-phenylethanol derivative to the resulting cell suspension
to treat the mixture therewith, (3) a technique which comprises
permitting a treated preparation of cells such as disrupted cells,
acetone-treated cells, lyophilized cells, instead of viable cells
as such, to react with a mixture of enantiomers of the
2-amino-1-phenylethanol derivative, (4) a technique which comprises
immobilizing the cells or preparation thereof can be employed as
immobilized by known techniques such as the polyacrylamide gel
method, sulfurcontaining polysaccharide gel method (e.g.
carrageenin gel method), alginic acid gel method, agar gel method
and so on, and permitting the cells or a preparation thereof to act
on a mixture of enantiomers of the 2-amino-1-phenylethanol
derivative. The enzyme purified from such a cell preparation can
also be used. The enzyme can be obtained with the use of known
purification processes in a suitable combination.
[0206] There are cases in which this reaction proceeds with
advantage of a higher yield of the objective optically active
compound in the presence of a carbon source such as glucose,
sucrose, ethanol, methanol or paraffin; phosphoric acid; or a
nitrogen source such as yeast extract or corn steep liquor which
serve as an energy source.
[0207] A mixture of enantiomers of the 2-amino-1-phenylethanol
derivative can be used as it is or in the form of a solution,
suspension or dispersion containing a suitable solvent. As the
solvent, water or an organic solvent which will not interfere with
the reaction can be employed. A suspension or a dispersion prepared
with a surfactant can also be used when necessary. The mixture of
enantiomers of the 2-amino-1-phenylethanol derivative may be added
in bolus at the beginning of the reaction or in several
installments.
[0208] The optimal cell concentration of the reaction system can be
selected from the range where the yield and the optical purity of
the desired optically active compound will not be adversely
affected. A typical cell concentration may for example be, on a dry
cell basis, about 0.1 to 500 g/liter and preferably about 1 to 300
g/liter. The concentration of the substance mixture of enantiomers
of the 2-amino-1-phenylethanol derivative is not particularly
restricted and is, for example, about 0.01 to 20% by weight and
preferably about 0.1 to 10% by weight.
[0209] The reaction conditions of the asymmetric utilization can be
selected from the ranges that will not detract from the yield of
the object compound. For example, the pH of the reaction system can
be selected from the range of pH about 2 to 10 and preferably pH
about 3 to 8. The reaction temperature is selected from the range
of, for example, about 10 to 60.degree. C. and preferably from
about 20 to 40.degree. C. and more preferably from about 20 to
35.degree. C. The reaction can be conducted with stirring or under
stationary conditions for about 1 to 120 hours. As a tendency, the
longer the reaction time, the higher is the optical purity of the
(R)-2-amino-1-phenylethanol derivative.
[0210] Thus, when permitting the specific microorganism or a
preparation thereof to act on a mixture of enantiomers of the
2-amino-1-phenylethanol derivative, the asymmetric utilization can
proceed smoothly or advantageously to produce the corresponding
2-amino-1-phenylethanol derivative having an (R)-configuration with
a high selectivity.
[0211] The (R)-2-amino-1-phenylethanol derivative of the general
formula (IIa) produced by the reaction can be recovered or
harvested by the separation and purification procedures generally
known. For example, the (R)-2-amino-1-phenylethanol derivative
having a high optical purity can be easily obtained by subjecting
the reaction mixture, directly or after separation of the cells, to
the conventional purification procedure such as membrane
separation, extraction with an organic solvent (for example,
hexane, chloroform, ethyl acetate and the like), column
chromatography, vacuum concentration, distillation, crystallization
and recrystallization. The optical purity of the
(R)-2-amino-1-phenylethanol derivative can be measured by, for
instance, high performance liquid chromatography (HPLC) using an
optical resolution column.
[0212] The method (B) where the compound of the general formula
(IIa) is obtained from the compound of the general formula (VII)
(aminoketone compound) with the aid of a microorganism is explained
hereinbelow.
[0213] In the method (B), the compound of the general formula (IIa)
or a salt thereof can easily or readily be obtained by permitting a
microorganism or a preparation thereof to act on the compound of
the general formula (VII) or a salt thereof (aminoketone
derivative) to asymmetrically reduce and harvesting or recovering
the produced (R)-2-amino-1-phenylethanol derivative.
[0214] As examples of the aminoketone derivative of the general
formula (VII) used as a raw material, there may be mentioned
aminoketone derivatives corresponding to the compounds as mentioned
as practical examples of the (R)-2-amino-1-phenylethanol derivative
of the general formula (II).
[0215] The aminoketone derivative can be used as a free amine-form
but a salt with an inorganic acid or an organic acid may also be
employed. The inorganic acid include, for example, hydrochloric
acid, sulfuric acid, phosphoric acid and so on. As the organic
acid, for instance, the aliphatic monocarboxylic acids and
aliphatic polycarboxylic acids and the like exemplified in the
explanation of the isolation and purification of the
2-amino-1-phenylethanol derivative may be employed.
[0216] The compound of the general formula (VII) can be prepared by
a known method, for example, by allowing the compound shown by the
general formula (XVIII) 14
[0217] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 have the
same meanings as defined above, and X represents a halogen atom to
react with an aminating agent. As the aminating agent, there may be
employed hexamethylenetetramine and others, as well as the
aminating agents as exemplified above. Examples of the halogen atom
shown by X include fluorine atom, chorine atom, bromine atom and
iodine atom.
[0218] Any strain of microorganism can be used for the process, as
far as being capable of acting on the aminoketone derivative of the
general formula (VII) to produce the corresponding
(R)-2-amino-1-phenylethanol derivative of the general formula
(IIa).
[0219] Such microorganisms having the capability include, for
instance, a strain of microorganism belonging to the genus Candida,
the genus Lodderomyces, the genus Catenuloplanes, the genus
Pilimelia, the genus Saccharothrix, the genus Seratia, the genus
Enterococcus, the genus Lactobacillus, the genus Pediococcus and
the genus Lactococcus.
[0220] Typical examples of the microorganism that is capable of
acting on the aminoketone compound to produce the corresponding
(R)-2-amino-1-phenylethanol derivative include following strains of
microorganisms:
[0221] (56) the genus Candida: Candida maltosa IFO 1977, Candida
maltosa IFO 1978, etc.,
[0222] (57) the genus Lodderomyces: Lodderomyces elongisporus IFO
1676, etc.,
[0223] (58) the genus Catenuloplanes: Catenuloplanes japonicus IFO
14176, etc.,
[0224] (59) the genus Pilimelia: Pilimelia terevasa IFO 14556,
etc.,
[0225] (60) the genus Saccharothrix: Saccharothrix australiensis
IFO 14444, etc.,
[0226] (61) the genus Seratia: Seratia marcescens IFO 3735,
etc.,
[0227] (62) the genus Enterococcus: Enterococcus faecalis IFO
12964, etc.,
[0228] (63) the genus Lactobacillus: Lactobacillus casei subsp.
casel NRIC 1042, etc.,
[0229] (64) the genus Pediococcus: Pediococcus acidilactici NRIC
1089, etc.,
[0230] (65) the genus Lactococcus: Lactococcus lactis subsp. lactis
AHU 1089, etc.
[0231] At least one of these microorganisms can be employed. For
the purposes of the invention, any of wild strains, mutants and
recombinant strains which can be obtained by a genetic engineering
technique such as cell fusion or gene manipulation can suitably be
used, as far as having the above mentioned ability or
capability.
[0232] The microorganisms identified hereinabove by IFO numbers and
AHU number can be available from the organizations. The strain of
microorganism designated by NRIC number is listed in "Catalogue of
Microbial Strains 2nd Ed. (1992)" published by the Laboratory of
Microbial Strain Collection, Tokyo Agriculture University, Japan
and is available from the institution.
[0233] The cultivation, reaction, and recovery of the product can
be carried out in the similar manner as in the method (A) using a
mixture of enantiomers of the 2-amino-1-phenylethanol derivative of
the general formula (I).
[0234] The methods (C) and (D) are illustrated and explained
hereinbelow.
[0235] The method (C) can readily or easily be carried out by
utilizing the optically active enantiomer of (R)-form respectively
as the compound of the formula (III) or compound of the formula
(IV) used as a reactant when isolating and purifying the
2-amino-1-phenylethanol derivative as a precipitated salt from the
reaction products obtained in the aminating methods (b), (c) in the
method (A).
[0236] The (R)-2-amino-1-phenylethanol derivative having high
optical purity can be obtained in an expedient procedure with high
yield according to this method.
[0237] The method (D) can readily be conducted, when isolating and
purifying the 2-amino-1-phenylethanol derivative as a precipitated
salt from the reaction products obtained in the aminating methods
(b), (c) in the method (A), by utilizing an acid capable of
optically resoluting, for instance, an optically active organic
acid, as the acid used for the formation of the salt. When using
the optically active organic acid, not only the object compound can
be isolated from the by-products such as the position-isomer and
dimer but also the (S)-form and the (R)-form of the
2-amino-1-phenylethanol derivative can easily be isolated since the
acid acts as an optically resoluting agent and a diastereomer salt
is formed by the acid.
[0238] Examples of the optically active organic acid include
aliphatic hydroxycarboxylic acids such as D-lactic acid, L-lactic
acid, D-malic acid, L-malic acid, D-tartaric acid, L-tartaric acid,
D-di-p-toluoyltartaric acid, L-di-p-toluoyltartaric acid, and the
like; carbocyclic carboxylic acids such as (R)-2-phenylpropionic
acid, (S)-ibuprofen, (R)-2-(2,5-dimethylphenyl)propionic acid,
(S)-2-(2,5-dimethylphenyl)propionic acid,
(R)-(-)-2-(2,4,6-trimethylpheny- l)propionic acid,
(S)-(+)-2-(2,4,6-trimethylphenyl)propionic acid and so on; aromatic
hydroxycarboxylic acids such as D-mandelic acid, L-mandelic acid,
etc.; sulfonic acids such D-camphorsulfonic acid, L-camphorsulfonic
acid, and the like; and optically active D- or L-amino acids which
may be protected with a protective group on the amino group.
[0239] The amino acid includes, for example, amino acids having a
non-polar group in the side chain such as non-polar amino acids
including aliphatic non-polar amino acids such as alanine, valine,
leucine, isoleucine, methionine and proline, aromatic non-polar
amino acids such as tryptophan, phenylalanine and anthranic acid;
amino acids having a polar group in the side chain including polar
amino acids having no charge such as serine, threonine, cysteine
tyrosine, asparagine and glutamine, polar amino acids having
plus-charge such as lysine, histidine and arginine, polar amino
acids having minus-charge such as aspartic acid and glutamic
acid.
[0240] Examples of the protective group for amino group include an
optionally substituted C.sub.1-6 acyl group (e.g. formyl, acetyl
group, etc.), an optionally substituted C.sub.7-16 acyl group
having an aromatic ring such as benzoyl and phthaloyl groups, an
optionally substituted C.sub.1-4 alkoxy-carbonyl group (for
instance t-butoxycarbonyl group), an optionally substituted
C.sub.6-16 aryloxy-carbonyl group, an optionally substituted
C.sub.7-20 aralkyloxy-carbonyl group (for example
benzyloxycarbonyl, p-nitrobenzyloxycarbonyl group, etc.), an
optionally substituted C.sub.7-20 aralkyl group such as benzyl and
triphenylmethyl, and others. Practical examples of the protective
group for the amino group include an optionally substituted
C.sub.1-4 alkoxy-carbonyl group such as t-butoxycarbonyl, and an
optionally substituted C.sub.7-20 aralkyloxy-carbonyl group such as
benzyloxycarbonyl group.
[0241] The functional group in the side chain of the amino acid,
for instance, a hydroxyl group, a mercapto group, a carboxyl group,
or an amino group may be protected with a conventional protective
group such as those exemplified above.
[0242] The (R)-2-amino-1-phenylethanol derivative can efficiently
be obtained by selecting and using a suitable optical resoluting
agent among these agents depending on the species of the object
(R)-2-amino-1-phenylethanol derivative.
[0243] As preferred examples of the optically active organic acid,
there may be mentioned optically active aliphatic or aromatic
hydroxycarboxylic acids which may be protected with a protective
group on the hydroxyl group, optically active amino acids which may
be protected with a protective group on the amino group. Among
these optically active hydroxy carboxylic acids, an optically
active tartaric acid which may be protected with a protective group
on the hydroxyl group such as D-(or L-) tartaric acid and D-(or
L-)di-p-toluoyl tartaric acid can be preferably employed. As the
optically active amino acid, preferred is an optically active
aliphatic non-polar amino acid which may be protected with a
protective group on the amino group such as
N-(t-butoxycarbonyl)-L-(or D-)alanine, as well as an optically
active amino acid having a polar group in the side chain such as
polar non-charge amino acid which may be protected with a
protective group on the amino group and/or on the functional group
of the side chain such as N-(t-butoxycarbonyl)-O-benzyl-- L-(or
D-)threonine, N-(t-butoxycarbonyl)-S-benzyl-L (or D)-cysteine,
N-(t-butoxycarbonyl)-L (or D)-tyrosine and others.
[0244] Formation and isolation of the salt can be conducted in the
similar manner to those in the formation of the acid by using an
organic acid in the method (A).
[0245] According to the method (D), the (R)-2-amino-1-phenylethanol
derivative having an extremely high purity, for example, the
content of the impurity is about 2% or less, and the optical purity
of about 99% e e or more, can efficiently be obtained.
[0246] The compound of the general formula (IIa) can readily or
easily be converted to the compound of the general formula (II) by,
if necessary, introducing a suitable protective group to the
hydroxyl group. Such compound of the general formula (II) is useful
for the production of the
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivative.
[0247] The process of producing the
(R,R)-1-phenyl-2-[(2-phenyl-1-alkyleth- yl)amino]ethanol derivative
of the general formula (XI) is illustrated hereinbelow.
[0248] In R.sup.7 and R.sup.8 of the general formula (XI), as the
optionally substituted lower alkyl group, the carboxyl group which
may be protected with a protective group, the optionally
substituted lower alkoxycarbonyl group, the optionally substituted
amino group, the optionally substituted alkylsulfonyl group and the
optionally substituted arylsulfonyl group, there may be employed
the optionally substituted lower alkyl group and the like as
mentioned in the explanation of R.sup.1 to R.sup.5.
[0249] The optionally substituted aryl group, the optionally
substituted aralkyl group and the optionally substituted acyl group
in R.sup.7 and R.sup.8 include, for instance, an optionally
substituted C.sub.6-16 aryl group and an optionally substituted
C.sub.7-20 aralkyl group and an optionally substituted acyl group
as exemplified in the explanation of the protective group for
hydroxyl group.
[0250] As examples of the optionally substituted cycloalkyl group,
there may be mentioned a C.sub.3-10 cycloalkyl group (e.g.
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl or cyclodecyl group) which may be
substituted with a substituents such as a C.sub.1-4 alkyl group, a
hydroxyl group, a halogen atom and so on.
[0251] The protective group for hydroxyl group in R.sup.7 and
R.sup.8 include, for example, protective groups for hydroxyl group
generally used in the field of organic synthesis such as the
protective groups for hydroxyl group (A) to (D) exemplified in
R.sup.1 to R.sup.5.
[0252] When R.sup.7 and R.sup.8 are respectively the group (IX):
--O--R.sup.7a and the group (X): --O--R.sup.8a, and R.sup.7a and
R.sup.8a form a ring together with the adjacent oxygen atoms, the
ring may for example be a 5- to 10-membered ring, preferably a 5-
to 8-membered ring and more preferably a 5- or 6-membered ring.
Such R.sup.7a and R.sup.8a includes, for instance, an optionally
substituted alkylene group, a carbonyl group, a thiocarbonyl group
and others.
[0253] As the alkylene group, there may be mentioned, for instance,
an alkylene group having 1 to 4 carbon atoms such as methylene,
ethylene, trimethylene and the like. Preferred alkylene group
includes a methylene group.
[0254] The optionally substituted methylene group includes, for
example, a group shown by the following formula (XII) 15
[0255] wherein R.sup.a and R.sup.b represent, (i) the same or
different, a hydrogen atom, a C.sub.1-4 alkyl group, a C.sub.1-4
haloalkyl group, an optionally substituted C.sub.6-20 aryl group, a
C.sub.1-4 alkoxy group, an optionally substituted amino group, a
carboxyl group or a salt thereof, an optionally substituted
alkoxycarbonyl group, a hydroxymethyl group or an optionally
substituted alkoxymethyl group, or (ii) R.sup.a and R.sup.b may
form a C.sub.5-7 cycloalkyl group together with the adjacent carbon
atom.
[0256] The C.sub.1-4 alkyl group, the C.sub.1-4 haloalkyl group and
the C.sub.1-4 alkoxy group in R.sup.a and R.sup.b include those
exemplified in R.sup.1 to R.sup.5. The optionally substituted
C.sub.6-20 aryl group in R.sup.a and R.sup.b includes, for
instance, phenyl, 4-methoxyphenyl, 2-nitrophenyl and others. As the
substituted amino group, there may be mentioned, for example, a
mono- or di-C.sub.1-4 alkylamino group such as methylamino,
dimethylamino, ethylamino, diethylamino and others.
[0257] As the substituents for the C.sub.6-20 aryl group, amino
group and the like, there may be referred to those mentioned in the
explanation of R.sup.1 to R.sup.5.
[0258] As the salt of the carboxyl group represented by R.sup.a and
R.sup.b, any salt can be employed. A salt which is
pharmacologically acceptable may frequently be used. Examples of
such salt include a salt with an inorganic base such as an alkali
metal salt (e.g. a sodium salt or a potassium salt), an alkaline
earth metal salt (for instance, a magnesium salt, a calcium salt or
a barium salt), a metal salt (e.g. a zinc salt or an aluminum salt)
and an ammonium salt; a salt with an organic base such as a salt
with pyridine, a tri-C.sub.1-3 alkylamine (e.g. trimethylamine,
triethylamine, etc.) and so on.
[0259] The optionally substituted alkoxycarbonyl group in R.sup.a
and R.sup.b includes, for instance, an optionally substituted
C.sub.2-5 alkoxycarbonyl group as mentioned in R.sup.1 to
R.sup.5.
[0260] As examples of the optionally substituted alkoxymethyl group
in R.sup.a and R.sup.b, there may be mentioned an optionally
substituted a C.sub.1-4 alkoxy-methyl group which may be
substituted on the alkyl with a substituent. Such substituent for
the alkoxymethyl group include, for example, a carboxyl group, a
C.sub.2-5 alkoxycarbonyl group, a hydroxyl group and a C.sub.1-4
alkoxy group. The C.sub.2-5 alkoxycarbonyl group and the C.sub.1-4
alkoxy group in the C.sub.1-4 alkoxy-methyl group can be referred
to the groups as mentioned in R.sup.1 to R.sup.5. Typical examples
of the optionally substituted alkoxymethyl group include (a) a
C.sub.1-4 alkoxy-methyl group such as methoxymethyl, ethoxymethyl,
propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl,
s-butoxymethyl and t-butoxymethyl; (b) a carboxy-C.sub.1-4
alkoxy-methyl group such as carboxymethoxymethyl,
carboxyethoxymethyl, carboxypropoxymethyl, carboxybutoxymethyl,
etc.; (c) a C.sub.2-5 alkoxycarbonyl-C.sub.1-4 alkoxy-methyl group
such as methoxycarbonylmethoxymethyl, ethoxycarbonylmethxoymethyl,
isopropoxycarbonylmethoxymethyl, 2-butoxycarbonylethoxymethyl and
others; (d) a hydroxy-C.sub.1-4 alkoxy-methyl group such as
2-hydroxyethoxymethyl, 3-hydroxypropoxymethyl and the like; (e) a
C.sub.1-4 alkoxy-C.sub.1-4 alkoxymethyl group such as
2-methoxyethoxymethyl, 2-ethoxyethoxymethyl, 3-methoxypropoxymethyl
and so on.
[0261] The C.sub.5-7 cycloalkyl group includes cyclopentyl,
cyclohexyl and cycloheptyl groups.
[0262] As preferred examples of the optionally substituted
methylene group shown by the formula (XII), there may be mentioned,
for instance, (a) the group of the formula (XII) wherein R.sup.a
and R.sup.b are, the same or different, a hydrogen atom, a
C.sub.1-4 alkyl group or a C.sub.5-7 cycloalkyl group formed with
R.sup.a, R.sup.b and the adjacent carbon atom (e.g. a methylene
group, a C.sub.2-4 alkylidene group such as an ethylidene group and
an isopropylidene group; a C.sub.5-7 cycloalkylidene group such as
a cyclopentylidene and a cyclohexylidene, and so on); (b) the group
of the formula (XII) where R.sup.a and R.sup.b are respectively a
carboxyl group or a salt thereof, an optionally substituted
alkoxycarbonyl group, a hydroxymethyl group or an optionally
substituted alkoxymethyl group. Specifically preferred is the group
of the formula (XII) where R.sup.a and R.sup.b are, the same or
different, a carboxyl group or a salt thereof, or a C.sub.2-5
alkoxycarbonyl group.
[0263] As preferred examples of R.sup.7 and R.sup.8, there may be
mentioned (1) a hydrogen atom, a hydroxyl group which may be
protected with a protective group, or (2) R.sup.7 is the group
shown by the formula (IX): --O--R.sup.7, and R.sup.8 is the group
of the formula (X): --O--R.sup.8a.
[0264] Practically preferred examples of R.sup.7 and R.sup.8
include, a hydrogen atom, a hydroxyl group which may be protected
with a protective group selected from C.sub.1-4 alkyl group, a
C.sub.7-20 aralkyl group or a C.sub.1-6 acyl group; or R.sup.7 and
R.sup.8 are respectively the group of the formula (IX)
--O---R.sup.7a and the group (X) --O--R.sup.8a, and in the
optionally substituted methylene group if the general formula (XII)
formed by incorporation of R.sup.1 and R.sup.2 where R.sup.a and
R.sup.b are respectively a carboxyl group or a salt thereof, or a
C.sub.2-5 alkoxycarbonyl group.
[0265] The halogen atom, the optionally substituted lower alkyl
group, the optionally substituted cycloalkyl group, the protective
group for hydroxyl group, the optionally substituted alkoxy group,
the optionally substituted cycloalkyloxy group, the optionally
substituted aralkyloxy group, the optionally substituted aryloxy
group, the optionally substituted lower alkylthio group, the
optionally substituted acyl group, the protective group for
carboxyl group, the optionally substituted lower alkoxy carbonyl
group, the optionally substituted amino group in R.sup.6, R.sup.9
and R.sup.10 include, for example, those mentioned in R.sup.1 to
R.sup.5 and R.sup.7, R.sup.8.
[0266] As examples of the optionally substituted aralkylthio group,
there may be mentioned a C.sub.7-20 alkylthio group (for example,
benzylthio, or naphthylthio group) which may be substituted with a
substituent such as a C.sub.1-4 alkyl group, a hydroxyl group, a
C.sub.1-4 alkoxy group, a nitro group, a halogen atom and
others.
[0267] The optionally substituted aryl group and the optionally
substituted aralkyl group include, for instance, the optionally
substituted C.sub.6-16 aryl group and the optionally substituted
C.sub.7-20 aralkyl group as mentioned in the explanation of the
protective group for hydroxyl group.
[0268] As the substituent for the lower alkyl group and the lower
alkoxy group, an optionally substituted amino group as mentioned
above can also be employed.
[0269] Typical examples of R.sup.6, R.sup.9 and R.sup.10 include a
hydrogen atom, a C.sub.1-4 alkyl group, specifically a hydrogen
atom.
[0270] Examples of the lower alkyl group in R.sup.11 include a
C.sub.1-4 alkyl group as mentioned in R.sup.1 to R.sup.5. Methyl
group and ethyl group, specifically methyl group, can
advantageously be used as R.sup.11.
[0271] As examples of the compound of the general formula (VIII)
there may be mentioned, methyl=phenylmethyl=ketone (phenyl
acetone); a phenylacetone derivative such as ethyl=benzyl=ketone,
propyl=phenylmethyl=ketone, isopropyl=phenylmethyl=ketone,
butyl=phenylmethyl=ketone, isobutyl=phenylmethyl=ketone,
s-butyl=phenylmethyl=ketone, t-butyl=phenylmethyl=ketone, and so
on; a derivative having a substituent on the 2-position of the
phenyl group such as methyl=2-methylphenylmethyl=ketone,
ethyl=2-chlorophenylmethyl=ke- tone,
methyl=2-ethylphenylmethyl=ketone,
ethyl=2-methylphenylmethyl=ketone- ,
methyl=2-methoxyphenylmethyl=ketone,
methyl=2-benzyloxyphenylmethyl=keto- ne,
ethyl=2-benzyloxyphenylmethyl=ketone and so on; a derivative having
a substituent on the 3-position of the phenyl group such as
methyl=3-methylphenylmethyl=ketone,
ethyl=3-chlorophenylmethyl=ketone,
methyl=3-methoxycarbonyl-2-methoxyphenylmethyl=ketone,
ethyl=3-methoxycarbonyl-2-methoxyphenylmethyl=ketone,
methyl=2-methyl-3-aminoethoxyphenylacetone and others; a derivative
substituted on the 4-position of the phenyl group such as
methyl=4-methylphenylmethyl=ketone,
ethyl=4-methylphenylmethyl=ketone, 4-ethylphenylmethyl=ketone,
ethyl=4-ethylphenylmethyl=ketone, 4-hydroxyphenylmethyl=ketone,
ethyl=4-hydroxyphenylmethyl=ketone,
methyl=4-methoxyphenylmethyl=ketone,
ethyl=4-methoxyphenylmethyl=ketone,
methyl=4-benzyloxyphenylmethyl=ketone,
ethyl-4-benzyloxyphehylmethyl=keto- ne,
methyl=4-hydroxyethoxyphenylmethyl=ketone,
methyl=4-(2-ethoxyethoxy)ph- enylmethyl=ketone,
methyl=4-(2-dimethylaminoethoxy)phenylmethyl=ketone,
methyl=4-methylthiophenylmethyl=ketone,
methyl=4-benzylthiophenylmethyl=k- etone,
methyl=4-hydroxycarbonylphenylmethyl=ketone,
methyl=4-methoxycarbonylphenylmethyl=ketone,
methyl=4-carbamoylphenylmeth- yl=ketone,
methyl=4-dimethylaminocarbonylphenylmethyl=ketone,
methyl=4-benzylaminocarbonylphenylmethyl=ketone,
methyl=4-aminophenyl-met- hyl=ketone,
methyl=4-acetylaminophenylmethyl=ketone,
methyl=4-acetylaminomethylphenylmethyl=ketone,
methyl=4-ethoxycarbonylami- nophenylmethyl=ketone,
methyl=4-methoxycarbonylmethylaminophenylmethyl=ket- one,
methyl=4-acetylphenylmethyl=ketone,
methyl=4-(o-methoxyphenyl)phenylm- ethyl=ketone,
methyl=4-(m-methoxycarbonylphenyl)phenylmethyl=ketone,
methyl=4-(p-chlorophenyl)phenylmethyl=ketone,
methyl=4-(p-hydroxyphenyl)p- henylmethyl=ketone,
methyl=4-(p-chlorophenylmethyl)phenylmethyl=ketone,
methyl=4-(p-methoxyphenylmethyl)phenylmethyl=ketone, and the like;
a derivative substituted with substituents on the 2,4-positions,
2,5-positions or 3,4-positions of the phenyl group such as
methyl=2-methoxy-4-methoxycarbonylphenyl-methyl=ketone,
methyl=3,4-dimethoxyphenylmethyl=ketone,
methyl=3,4-dihydroxyphenylmethyl- =ketone,
ethyl=3,4-dihydroxyphenylmethyl=ketone, methyl=3,4-dimethoxycarbo-
nylphenylmethyl=ketone,
ethyl=3,4-dimethoxycarbonylphenylmethyl=ketone,
methyl=3-methoxy-4-methoxycarbonylphenylmethyl=ketone,
methyl=3-methyl-4-methoxyphenylmethyl=ketone,
methyl=3-methylamino-4-benz- yloxyphenylmethyl=ketone,
methyl=3-methoxycarbonyl-4-hydroxyphenylmethyl=k- etone,
methyl=3-chloro-4-hydroxyphenylmethyl=ketone,
methyl=3-fluoro-4-methoxycarbonylphenylmethyl=ketone,
methyl=3-fluoro-4-methylaminoethoxyphenylmethyl=ketone,
2-iodo-5-methoxyphenylmethyl=ketone, etc.; a derivative substituted
with substituents on the 2,3,4-positions or the 2,4,5-positions of
the phenyl group such as 2,3,4-trimethoxyphenylmethyl=ketone,
methyl=3,5-difluoro-4-methoxyphenylmethyl=ketone, and others; a
C.sub.1-4 alkyl=(1,3-benzodioxol-5-yl)methyl=ketone such as
methyl=(1,3-benzodioxol- -5-yl)methyl ketone; a C.sub.1-4
alkyl=(2,2-di-C.sub.1-4 alkyl-1,3-benzodioxol-5-yl)methyl=ketone
derivative such as
methyl=(2,2-dimethyl-1,3-benzodioxol-5-yl)methyl=ketone; a
C.sub.1-4 alkyl=[2,2-bis(C.sub.2-5
alkoxycarbonyl)-1,3-benzodioxol-5-yl]methyl=keto- ne such as
[dimethyl 5-(2-oxopropyl)-1,3-benzodioxole-2,2-dicarboxylate],
methyl=[diethyl
5-(2-oxopropyl)-1,3-benzodioxole-2,2-dicarboxylate],
methyl=(2,2-dimethoxycarbonyl-1,3-benzodioxol-5-yl)methyl=ketone,
ethyl=(2,2-dimethoxycarbonyl-1,3-benzodioxol-5-yl)methyl=ketone,
methyl=(2,2-bisethoxycarbonyl-1,3-benzodioxol-5-yl)methyl=ketone
and so on; a C.sub.1-4 alkyl=[2,2-di(hydroxy-C.sub.1-4
alkoxy-C.sub.1-4 alkyl)-1,3-benzodioxol-5-yl]methyl=ketone such as
methyl=(2,2-dihydroxyet-
hoxymethyl-1,3-benzodioxol-5-yl)methyl=ketone; a C.sub.1-4
alkyl=[2,2-di-(C.sub.2-5 alkoxycarbonyl-C.sub.1-4 alkoxy-C.sub.1-4
alkyl)-1,3-benzodioxol-5-yl]methyl=ketone derivative such as
methyl=[2,2-di-(methoxycarbonylmethoxymethyl)-1,3-benzodioxol-5-yl]methyl-
=ketone,
ethyl=[2,2-di-(methoxycarbonylmethoxymethyl)-1,3-benzodioxol-5-yl-
]methyl=ketone and so on; a C.sub.1-4
alkyl=(1,4-benzodioxin-6-yl)methyl=k- etone derivative such as
methyl=(1,4-benzodioxin-6-yl)methyl=ketone and the like.
[0272] As preferred examples of the above compounds, there may be
mentioned a C.sub.1-4 alkyl=phenylmethyl=ketone derivative; a
C.sub.1-4 alkyl=3,4-di-C.sub.1-4 alkoxyphenylmethyl=ketone
derivative; a C.sub.1-4 alkyl=3,4-dihydroxyphenylmethyl=ketone
derivative; a C.sub.1-4 alkyl=3,4-dihydroxyphenylmethyl=ketone
derivative; a C.sub.1-4 alkyl=[2,2-bis(C.sub.2-5
alkoxycarbonyl)-1,3-benzodioxol-5-yl]methyl=keto- ne derivative; a
C.sub.1-4 alkyl=[2,2-di-(C.sub.2-5 alkoxycarbonyl-C.sub.1-4
alkoxy-C.sub.1-4 alkyl)-1,3-benzodioxol-5-yl]met- hyl=ketone
derivative.
[0273] The compound shown by the general formula (XI) is a compound
obtainable by a combination of the (R)-2-amino-1-phenylethanol
derivative of the general formula (II) and the phenylacetone
derivative of the general formula (VIII), and practically includes,
for example, (a) an (R,R)-1-phenyl-2-[(2-phenyl-1-C.sub.1-4
alkylethyl)amino]ethanol derivative, (b) an
(R,R)-1-phenyl-2-([2-(2-substituted phenyl)-1-C.sub.1-4
alkyl-ethyl]amino]ethanol derivative, (c) an
(R,R)-1phenyl-2-[[2-(3-substituted phenyl)-1-C.sub.1-4
alkyl-ethyl]amino]ethanol derivative, (d) an
(R,R)-1-phenyl-2-[[2-(4-subs- tituted phenyl)-1-C.sub.1-4
alkyl-ethyl]amino]ethanol derivative, (e) an
(R,R)-1-phenyl-2-[[2-(3,4-di-substituted phenyl)-1-C.sub.1-4
alkyl-ethyl]amino]ethanol derivative, (f) an
(R,R)-1-(2-halophenyl)-2-[(2- -phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative, (g) an (R,R)-1-(2-substituted
phenyl)-2-[(2-phenyl-1-C.sub.1-4 alkyl-ethyl)amino]ethanol
derivative, (h) an (R,R)-1-(3-halophenyl)-2-[(2-
-phenyl-1-C.sub.1-4 alkyl-ethyl)amino]ethanol derivative, (i) an
(R,R)-1-(3-substituted phenyl)-2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative, (j) an
(R,R)-1-(4-halophenyl)-2-[(2- -phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative, (k) an (R,R)-1-(4-substituted
phenyl)-2-[(2-phenyl-1-C.sub.1-4 alkyl-ethyl)amino]ethanol
derivative, (1) an (R,R)-1-(2,3-di-halophenyl)--
2-[(2-phenyl-1-C.sub.1-4 alkyl-ethyl)amino]ethanol derivative, (m)
an (R,R)-1-(2,4-di-substituted phenyl)-2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative, (n) an
(R,R)-1-(3,4-di-halophenyl)-- 2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative, (o) an
(R,R)-1-(3,4-di-substituted phenyl)-2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative, (p) an
(R,R)-1-(3,5-di-substituted phenyl)-2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative, (q) an
(R,R)-1-(3,4,5-tri-substituted phenyl)-2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative and so on.
[0274] (a) The (R,R)-1-phenyl-2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative include, for example,
(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol,
(R,R)-1-phenyl-2-[(2-phenyl-1-ethylethyl)amino]ethanol,
(R,R)-1-phenyl-2-[(2-phenyl-1-propylethyl)amino]ethanol,
(R,R)-1-phenyl-2-[(2-phenyl-1-isopropylethyl)amino]ethanol,
(R,R)-1-phenyl-2-[(2-phenyl-1-butylethyl)amino]ethanol,
(R,R)-1-phenyl-2-[(2-phenyl-1-isobutylethyl)amino]ethanol,
(R,R)-1-phenyl-2-[(2-phenyl-1-s-butylethyl)amino]ethanol,
(R,R)-1-phenyl-2-[(2-phenyl-1-t-butylethyl) amino]ethanol and the
like.
[0275] (b) Examples of the (R,R)-1-phenyl-2-[[2-(2-substituted
phenyl)-1-C.sub.1-4 alkyl-ethyl]amino]ethanol derivative include
(R,R)-1-phenyl-2-[[2-(2-chlorophenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(2-methylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(2-methoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(2-benzyloxyphenyl)-1-methylethyl]amino]ethanol,
and others.
[0276] (c) As the (R,R)-1-phenyl-2-[[2-(3-substituted
phenyl)-1-C.sub.1-4 alkyl-ethyl]amino]ethanol derivative, there may
be mentioned, for example,
(R,R)-1-phenyl-2-[[2-(3-methylphenyl)-1-methylethyl]amino]ethano-
l,
(R,R)-1-phenyl-2-[[2-(3-methoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(3-methylaminoethoxyphenyl)-1-methylethyl]amino]etha-
nol and so on.
[0277] (d) The (R,R)-1-phenyl-2-[[2-(4-substituted
phenyl)-1-C.sub.1-4 alkyl-ethyl]amino]ethanol derivative includes,
for instance,
(R,R)-1-phenyl-2-[[2-(4-phenylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(4-methylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(4-ethylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(4-hydroxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(4-benzyloxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(4-hydroxyethoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(4-dimethylaminomethoxyphenyl)-1-methylethyl]amino]e-
thanol,
(R,R)-1-phenyl-2-[[2-(4-methylthiophenyl)-1-methylethyl]amino]etha-
nol,
(R,R)-1-phenyl-2-[[2-(4-benzylthiophenyl)-1-methylethyl]amino]ethanol-
,
(R,R)-1-phenyl-2-[[2-(4-hydroxycarbonylphenyl)-1-methylethyl]amino]ethan-
ol, (R,R)-1-phenyl-2-[[2-(4-methoxycarbonylphenyl)
-1-methylethyl]amino]et- hanol,
(R,R)-1-phenyl-2-[[2-(4-carbamoylphenyl)-1-methylethyl]amino]ethano-
l,
(R,R)-1-phenyl-2-[[2-(4-dimethylaminocarbonylphenyl)-1-methylethyl]amin-
o]ethanol,
(R,R)-1-phenyl-2-[[2-(4-benzylaminocarbonylphenyl)-1-methylethy-
l]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(4-acetylaminocarbonylphenyl)-1-meth-
ylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(4-acetylaminomethylphenyl)-1--
methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(4-acetylphenyl)-1-methyle- thyl]amino]ethanol
and others.
[0278] (e) Examples of the (R,R)-1-phenyl-2-[[2-(3,4-di-substituted
phenyl)-1-C.sub.1-4 alkyl-ethyl]amino]ethanol derivative include
(R,R)-1-phenyl-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(3,4-dimethoxyphenyl)-1-ethylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-(3,4-dimethoxyphenyl)-1-propylethyl]amino]ethanol,
(R,R)-1-phenyl-2-[[2-[3,4-(bismethoxycarbonylmethoxy)methylenedioxyphenyl-
]-1-methylethyl]amino]ethanol and the like.
[0279] (f) As the (R,R)-1-(2-halophenyl)-2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative, there may be mentioned, for
instance,
(R,R)-1-o-chlorophenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol- ,
(R,R)-1-(2-chlorophenyl)-2-[[2-(2-chlorophenyl)-1-methylethyl]amino]etha-
nol,
(R,R)-1-(2-chlorophenyl)-2-[[2-(2-methylphenyl)-1-methylethyl]amino]e-
thanol,
(R,R)-1-(2-chlorophenyl)-2-[[2-(2-methoxyphenyl)-1-methylethyl]ami-
no]ethanol,
(R,R)-1-(2-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methyle-
thyl]amino]ethanol,
(R,R)-1-(2-fluorophenyl)-2-[(2-phenyl-1-methylethyl)am-
ino]ethanol,
(R,R)-1-(2-fluorophenyl)-2-[[2-(2-chlorophenyl)-1-methylethyl-
]amino]ethanol,
(R,R)-1-(2-fluorophenyl)-2-[[2-(2-methylphenyl)-1-methylet-
hyl]amino]ethanol,
(R,R)-1-(2-fluorophenyl)-2-[[2-(2-methoxyphenyl)-1-meth-
ylethyl]amino]ethanol,
(R,R)-1-(2-fluorophenyl)-2-[[2-(3,4-dimethoxyphenyl-
)-1-methylethyl]amino]ethanol, etc.
[0280] (g) Examples of the (R,R)-1-(2-substituted
phenyl)-2-[(2-phenyl-1-C- .sub.1-4 alkyl-ethyl)amino]ethanol
derivative include
(R,R)-1-(2-methylphenyl)-2-phenyl-1-methylethyl)amino]ethanol,
(R,R)-1-(2-methylphenyl)-2-[[2-(2-chlorophenyl)-1-methylethyl]amino]ethan-
ol,
(R,R)-1-(2-methylphenyl)-2-[[2-(2-methylphenyl)-1-methylethyl]amino]et-
hanol,
(R,R)-1-(2-methylphenyl)-2-[[2-(2-methoxyphenyl)-1-methylethyl]amin-
o]ethanol,
(R,R)-1-(2-methylphenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylet-
hyl]amino]ethanol,
(R,R)-1-(2-hydroxyphenyl)-2-[(2-phenyl-1-methylethyl)am-
ino]ethanol,
(R,R)-1-(2-hydroxyphenyl)-2-[[2-(2-chlorophenyl)-1-methylethy-
l]amino]ethanol,
(R,R)-1-(2-hydroxyphenyl)-2-[[2-(2-methylphenyl)-1-methyl-
ethyl]amino]ethanol,
(R,R)-1-(2-hydroxyphenyl)-2-[[2-(2-methoxyphenyl)-1-m-
ethylethyl]amino]ethanol,
(R,R)-1-(2-hydroxyphenyl)-2-[[2-(3,4-dimethoxyph-
enyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(2-methoxyphenyl)-2-[(2-phenyl--
1-methylethyl)amino]ethanol,
(R,R)-1-(2-methoxyphenyl)-2-[[2-(2-chlorophen-
yl)-1-methylethyl]amino]ethanol,
(R,R)-1-(2-methoxyphenyl)-2-[[2-(2-methyl-
phenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(2-methoxyphenyl)-2-[[2-(2-me-
thoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(2-methoxyphenyl)-2-[[2--
(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(2-benzyloxyphe-
nyl)-2-[(2-phenyl-1-methylethyl)amino]ethanol,
(R,R)-1-(2-benzyloxyphenyl)-
-2-[[2-(2-chlorophenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(2-benzyloxyphenyl)-2-[[2-(2-methylphenyl)-1-methylethyl]amino]et-
hanol,
(R,R)-1-(2-benzyloxyphenyl)-2-[[2-(2-methoxyphenyl)-1-methylethyl]a-
mino]ethanol,
(R,R)-1-(2-benzyloxyphenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-me-
thylethyl]amino]ethanol,
(R,R)-1-(2-benzylcarbonylphenyl)-2-[(2-phenyl-1-m-
ethylethyl)amino]ethanol and so on.
[0281] (h) As the (R,R)-1-(3-halophenyl)-2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative, there may be mentioned, for
example,
(R,R)-1-(3-chlorophenyl)-2-[(2-phenyl-1-methylethyl)amino]ethano-
l,
(R,R)-1-(3-chlorophenyl)-2-[[2-(2-chlorophenyl)-1-methylethyl]amino]eth-
anol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(2-methylphenyl)-1-methylethyl]amino]-
ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(2-methoxyphenyl)-1-methylethyl]am-
ino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(2-benzyloxyphenyl)-1-methylet-
hyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(3-methylphenyl)-1-methy-
lethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(3-methoxyphenyl)-1-m-
ethylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(3-methylaminoeth-
oxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4--
methylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2--
(4-ethylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[-
2-(4-phenylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-
-[[2-(4-hydroxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-hydroxyphenyl)-1-ethylethyl]amino]ethan-
ol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]e-
thanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-benzyloxyphenyl)-1-methylethyl]a-
mino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-hydroxyethoxyphenyl)-1-met-
hylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-dimethylaminomet-
hoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-
-methylthiophenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-
-[[2-(4-benzylthiophenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-hydroxycarbonylphenyl)-1-methylethyl]am-
ino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-methoxycarbonylphenyl)-1-me-
thylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-carbamoylphenyl-
)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-dimethyla-
minocarbonylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)--
2-[[2-(4-benzylaminocarbonylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-acetylaminocarbonylphenyl)-1-methylethy-
l]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-acetylaminomethylphenyl-
)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(4-acetylphe-
nyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dime-
thoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-(-
3,4-dimethoxyphenyl)-1-ethylethyl]amino]ethanol,
(R,R)-1-(3-chlorophenyl)--
2-[[2-[3,4-(bismethoxycarbonylmethoxy)methylenedioxyphenyl]-1-methylethyl]-
amino]ethanol,
(R,R)-1-(3-chlorophenyl)-2-[[2-[3,4-(bismethoxycarbonylmeth-
oxy)methylenedioxyphenyl]-1-ethylethyl]amino]ethanol,
(R,R)-1-(3-fluorophenyl)-2-[(2-phenyl-1-methylethyl)amino]ethanol
and so on.
[0282] (i) As examples of the (R,R)-1-(3-substituted
phenyl)-2-[(2-phenyl-1-C.sub.1-4 alkyl-ethyl)amino]ethanol
derivative, there may be mentioned
(R,R)-1-(3-methylphenyl)-2-[(2-phenyl-1-methylethy-
l)amino]ethanol,
(R,R)-1-(3-methylphenyl)-2-[[2-(2-chlorophenyl)-1-methyle-
thyl]amino]ethanol,
(R,R)-1-(3-methylphenyl)-2-[[2-(2-methoxyphenyl)-1-met-
hylethyl]amino]ethanol,
(R,R)-1-(3-methylphenyl)-2-[[2-(3,4-dimethoxypheny-
l)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-hydroxyphenyl)-2-[(2-phenyl)-1--
methylethylamino]ethanol,
(R,R)-1-(3-trifluoromethylphenyl)-2-[(2-phenyl)--
1-methylethylamino]ethanol,
(R,R)-1-(3-trifluoromethylphenyl)-2-[[2-(2-chl-
orophenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-trifluoromethylphenyl)--
2-[[2-(2-methylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-trifluoromethylphenyl)-2-[[2-(2-methoxyphenyl)-1-methylethyl]a-
mino]ethanol,
(R,R)-1-(3-trifluoromethylphenyl)-2-[[2-(4-benzylphenyl)-1-m-
ethylethyl]amino]ethanol,
(R,R)-1-(3-trifluoromethylphenyl)-2-[[2-(3,4-dim-
ethoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-trifluoromethylpheny-
l)-2-[[2-(3,4-dimethoxyphenyl)-1-ethylethyl]amino]ethanol, etc.
[0283] (j) The (R,R)-1-(4-halophenyl)-2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative includes, for instance,
(R,R)-1-(4-chlorophenyl)-2-[(2-phenyl-1-methylethyl]amino]ethanol,
(R,R)-1-(4-chlorophenyl)-2-[[2-(2-chlorophenyl)-1-methylethyl]amino]ethan-
ol,
(R,R)-1-(4-chlorophenyl)-2-[[2-(2-methylphenyl)-1-methylethyl]amino]et-
hanol,
(R,R)-1-(4-chlorophenyl)-2-[[2-(2-methoxyphenyl)-1-methylethyl]amin-
o]ethanol,
(R,R)-1-(4-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylet-
hyl]amino]ethanol and the like.
[0284] (k) Examples of the (R,R)-1-(4-substituted
phenyl)-2-[(2-phenyl-1-C- .sub.1-4 alkyl-ethyl)amino]ethanol
derivative include,
(R,R)-1-(4-methylphenyl)-2-[(2-phenyl-1-methylethyl]amino]ethanol,
(R,R)-1-(4-methyl-phenyl)-2-[[2-(2-chlorophenyl)-1-methylethyl]amino]etha-
nol,
(R,R)-1-(4-methylphenyl)-2-[[2-(2-methoxyphenyl)-1-methylethyl]amino]-
ethanol,
(R,R)-1-(4-methylphenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethy-
l]amino]ethanol,
(R,R)-1-(4-hydroxyphenyl)-2-[(2-phenyl-1-methylethyl)amin-
o]ethanol,
(R,R)-1-(4-hydroxyphenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methyle-
thyl]amino]ethanol,
(R,R)-1-(4-trifluoromethylphenyl)-2-[(2-phenyl-1-methy-
lethyl]amino]ethanol,
(R,R)-1-(4-trifluoromethylphenyl)-2-[[2-(2-chlorophe-
nyl)-1-methylethyl]amino]ethanol, (R,R)-1-(4-trifluoromethylphenyl)
-2-[[2-(2-methylphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(4-trifluoromethylphenyl)-2-[[2-(2-methoxyphenyl)-1-methylethyl]a-
mino]ethanol,
(R,R)-1-(4-trifluoromethylphenyl)-2-[[2-(3,4-dimethoxyphenyl-
)-1-methylethyl]amino]ethanol,
(R,R)-1-(4-methoxyphenyl)-2-[[2-(4-methoxyp-
henyl)-1-methylethyl]amino]ethanol and so on.
[0285] (l) As the (R,R)-1-(2,3-di-substituted
phenyl)-2-[(2-phenyl-1-C.sub- .1-4 alkyl-ethyl)amino]ethanol
derivative, there may be mentioned, for instance,
(R,R)-1-(2-fluoro-3-chlorophenyl)-2-[(2-phenyl-1-methylethyl]am-
ino]ethanol,
(R,R)-1-(2-fluoro-3-chlorophenyl)-2-[[2-(2-chlorophenyl)-1-me-
thylethyl]amino]ethanol,
(R,R)-1-(2-fluoro-3-chlorophenyl)-2-[[2-(2-methyl-
phenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(2-fluoro-3-chlorophenyl)-2-[-
[2-(2-methoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(2-fluoro-3-chlo-
rophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(2-fluoro-3-chlorophenyl)-2-[[2-[3,4-(bismethoxycarbonylmethoxy)m-
ethylenedioxyphenyl]-1-methylethyl]amino]ethanol,
(R,R)-1-(2-chloro-3-hydr-
oxyphenyl)-2-[(2-phenyl-1-ethylethyl]amino]ethanol and others.
[0286] (m) The (R,R)-1-(2,4-di-substituted
phenyl)-2-[(2-phenyl-1-C.sub.1-- 4 alkyl-ethyl)amino]ethanol
derivative includes, for example,
(R,R)-1-(2-chloro-4-hydroxyphenyl)-2-[(2-phenyl-1-methylethyl]amino]ethan-
ol,
(R,R)-1-(2-chloro-4-benzyloxyphenyl)-2-[(2-phenyl-1-methylethyl]amino]-
ethanol, and the like.
[0287] (n) Examples of the
(R,R)-1-(3,4-di-halophenyl)-2-[(2-phenyl-1-C.su- b.1-4
alkyl-ethyl)amino]ethanol derivative include
(R,R)-1-(3,4-dichloroph-
enyl)-2-[(2-phenyl-1-methylethyl]amino]ethanol,
(R,R)-1-(3,4-dichloropheny- l)
-2-[[2-(2-chlorophenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3,4-dichlorophenyl)-2-[[2-(2-methylphenyl)-1-methylethyl]amino]e-
thanol, (R,R)-1-(3,4-dichlorophenyl)
-2-[[2-(2-methoxyphenyl)-1-methylethy- l]amino]ethanol,
(R,R)-1-(3,4-dichlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)--
1-methylethyl]amino]ethanol,
(R,R)-1-(3,4-dichlorophenyl)-2-[[2-(3,4-dimet-
hoxyphenyl)-1-ethylethyl]amino]ethanol,
(R,R)-1-(3,4-dichlorophenyl)-2-[[2-
-[3,4-(bismethoxycarbonylmethoxy)methylenedioxyphenyl]-1-methylethyl]amino-
]ethanol and so on.
[0288] (o) As the (R,R)-1-(3,4-di-substituted
phenyl)-2-[(2-phenyl-1-C.sub- .1-4 alkyl-ethyl)amino]ethanol
derivative, there may be mentioned, for instance,
(R,R)-1-(3,4-dihydroxyphenyl)-2-[(2-phenyl-1-methylethyl)
amino]ethanol,
(R,R)-1-(3,4-dihydroxyphenyl)-2-[[2-(3,4-dihydroxyphenyl)--
1-methylethyl]amino]ethanol,
(R,R)-1-(3,4-dihydroxyphenyl)-2-[(2-phenyl-1--
ethylethyl)amino]ethanol,
(R,R)-1-(3,4-dimethoxyphenyl)-2-[(2-phenyl-1-met-
hylethyl)amino]ethanol,
(R,R)-1-(3-fluoro-4-methoxyphenyl)-2-[(2-phenyl-1--
methylethyl)amino]ethanol,
(R,R)-1-[3-(2-hydroxyethoxy)-4-(t-butoxy)phenyl-
]-2-[(2-phenyl-1-methylethyl)amino]ethanol,
(R,R)-1-(3-acetylamino-4-hydro-
xyphenyl)-2-[(2-phenyl-1-methylethyl)amino]ethanol,
(R,R)-1-(3-acetylamino-4-methoxyphenyl)-2-[(2-phenyl-1-methylethyl)amino]-
ethanol,
(R,R)-1-(3-methylthio-4-hydroxyphenyl)-2-[(2-phenyl-1-methylethyl-
)amino]ethanol,
(R,R)-1-(3-hydroxymethyl-4-hydroxyphenyl)-2-[(2-phenyl-1-m-
ethylethyl)amino]ethanol,
(R,R)-1-(3-methoxycarbonyl-4-hydroxyphenyl)-2-[(-
2-phenyl-1-methylethyl)amino]ethanol,
(R,R)-1-(3-methoxycarbonyl-4-cyclohe-
xyloxyphenyl)-2-[(2-phenyl-1-methylethyl) amino]ethanol,
(R,R)-1-(3-carbamoyl-4-hydroxyphenyl)-2-[(2-phenyl-1-methylethyl)amino]et-
hanol,
(R,R)-1-[3-hydroxymethylcarbonylamino-4-(4-methoxyphenylmethyl)phen-
yl]-2-[(2-phenyl-1-methylethyl) amino]ethanol, etc.
[0289] (p) As examples of the an (R,R)-1-(3,5-di-substituted
phenyl)-2-[(2-phenyl-1-C.sub.1-4 alkyl-ethyl)amino]ethanol
derivative,
(R,R)-1-(3,5-dihydroxyphenyl)-2-[(2-phenyl-1-methylethyl)amino]ethanol,
(R,R)-1-(3,5-dibenzyloxyphenyl)-2-[(2-phenyl-1-methylethyl)amino]ethanol,
(R,R)-1-(3,5-di-t-butoxycarbonylphenyl)-2-[(2-phenyl-1-methylethyl)amino]-
ethanol, and the like.
[0290] (q) The (R,R)-1-(3,4,5-tri-substituted
phenyl)-2-[(2-phenyl-1-C.sub- .1-4 alkyl-ethyl)amino]ethanol
derivative includes, for example,
(R,R)-1-(3,5-dichloro-4-methylaminophenyl)-2-[(2-phenyl-1-methylethyl)ami-
no]ethanol,
(R,R)-1-(4-amino-3-bromo-5-fluorophenyl)-2-[(2-phenyl-1-methyl-
ethyl)amino]ethanol,
(R,R)-1-(4-benzyloxy-3-chloro-5-methoxyphenyl)-2-[(2--
phenyl-1-methylethyl)amino]ethanol,
(R,R)-1-(4,5-dihydroxy-3-methylphenyl)-
-2-[(2-phenyl-1-methylethyl)amino]ethanol and others.
[0291] Typical examples of the compounds mentioned above include an
(R,R)-1-phenyl-2-[(2-phenyl-1-C.sub.1-4 alkyl-ethyl)amino]ethanol
derivative such as
(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethano- l,
(R,R)-1-phenyl-2-[(2-phenyl-1-ethylethyl)amino]ethanol and the
like; (R,R)-1-phenyl-2-[[2-[3,4-di-substituted (e.g.
di-C.sub.1-4alkoxy)-phenyl- ]-1-C.sub.1-4 alkyl-ethyl]amino]ethanol
derivative such as
(R,R)-1-phenyl-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol;
an (R,R)-1-(3-halophenyl)-2-[(2-phenyl-1-C.sub.1-4
alkyl-ethyl)amino]ethanol derivative such as
(R,R)-1-(3-chloro)phenyl-2-[-
(2-phenyl-1-methylethyl)amino]ethanol; an
(R,R)-1-(3-halophenyl)-2-[[2-[3,- 4-di-substituted (e.g.
3,4-di-C.sub.1-4 alkoxy)-phenyl]-1-C.sub.1-4
alkyl-ethyl]amino]ethanol derivative such as
(R,R)-1-(3-chlorophenyl)-2-[-
[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol; an
(R,R)-1-(3-substituted
phenyl)-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative such as
(R,R)-1-(3-methylphenyl)-2-[(2-phenyl-1-methylethyl)am-
ino]ethanol,
(R,R)-1-(3-trifluoromethylphenyl)-2-[(2-phenyl-1-methylethyl)-
amino]ethanol; an (R,R)-1-(3-substituted
phenyl)-2-[[2-[3,4-di-substituted (e.g. 3,4-di-C.sub.1-4
alkoxy)-phenyl]-1-C.sub.1-4 alkyl-ethyl]amino]ethanol derivative
such as (R,R)-1-(3-methylphenyl)-2-[-
[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol,
(R,R)-1-(3-trifluoromethylphenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methyleth-
yl]amino]ethanol and the like; an (R,R)-1-(4-substituted
phenyl)-2-[(2-phenyl-1-C.sub.1-4 alkyl-ethyl)amino]ethanol
derivative such as
(R,R)-1-(4-chlorophenyl)-2-[(2-phenyl-1-methylethyl)amino]ethanol-
; an (R,R)-1-(-4-halophenyl)-2-[[2-[3,4-di-substituted (e.g.
3,4-di-C.sub.1-4 alkoxy)phenyl]-1-C.sub.1-4
alkyl-ethyl]amino]ethanol derivative such as
(R,R)-1-(4-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-
-methylethyl]amino]ethanol; an
(R,R)-1-(3,4-di-halophenyl)-2-[(2-phenyl-1-- C.sub.1-4
alkyl-ethyl)amino]ethanol derivative such as
(R,R)-1-(3,4-dichlorophenyl)-2-[(2-phenyl-1-methylethyl)amino]ethanol;
an (R,R)-1-(3,4-dihalophenyl)-2-[[2-[3,4-di-substituted (e.g.
3,4-di-C.sub.1-4 alkoxy)phenyl]-1-C.sub.1-4
alkyl-ethyl]amino]ethanol derivative such as
(R,R)-1-(3,4-dichlorophenyl)-2-[[2-(3,4-dimethoxypheny-
l)-1-methylethyl]amino]ethanol and so on.
[0292] In this method, the phenylacetone derivative of the general
formula (VIII) used as a raw material can easily be obtained by a
conventional method, for example, dry distillation of a mixture of
an acetic acid salt such as an acetic acid with an alkaline earth
metal (e.g. calcium acetate and barium acetate) and a phenylacetic
acid salt corresponding to the compound of the general formula
(VIII) such as a phenyl acetic acid salt with an alkaline earth
metal salt (for instance, calcium phenylacetate, barium
phenylacetate, etc.) or others (see Org. Synth., Coll. Vol. II, 389
(1943), etc.)
[0293] The method of the present invention is characterized by
comprising a reaction of the (R)-2-amino-1-phenylethanol compound
of the general formula (II) or a salt thereof with the compound of
the general formula (VIII) (phenylacetone derivative) and a
reducing reaction of the reaction product of the above reaction.
The (R,R)-1-phenyl-2-[[2-(phenyl)-1-methyl- ethyl]amino]ethanol
derivative of the general formula (XI) obtained in the method
includes a corresponding salt.
[0294] The reducing reaction may for example be conducted with
using a reducing agent. The reaction may also be carried out in the
presence of a catalyst for catalytic reduction. The reaction may be
carried out, for instance, by (1) a method which comprises
dehydrating-condensing the (R)-2-amino-1-phenylethanol derivative
of the general formula (II) or a salt thereof and the compound of
the general formula (VIII), and then hydrogenating the resultant
compound (hereinafter refereed to as stepwise method), (2) a method
of allowing the (R)-2-amino-1-phenylethanol compound of the general
formula (II) or a salt thereof to react with the compound of the
general formula (VIII) and hydrogen in the presence of a catalyst
for catalytic reduction (hereinafter referred to as one-pot
method), and others.
[0295] According to the reductive aminating method as above using
an optically active 2-amino-1-phenylethanol compound or a salt
thereof and a phenylacetone derivative, the products are only two
species of optical isomers. Further, when hydrogenation is
conducted using hydrogen in the presence of a catalyst for
catalytic reduction, the diastereomer-ratio can be increased
significantly and the object optical isomer can be advantageously
obtained. Moreover, such a method using a catalyst for catalytic
reduction is suitable for commercial production, since the object
compound can be isolated only by filtrating off the catalyst for
catalytic reduction and distilling off a solvent, and thus
after-treatment is easy.
[0296] The stepwise method (1) is illustrated hereinbelow.
[0297] The stepwise method (1) is characterized in that an
imine-form or an enamine-form can certainly or reliably be obtained
by conducting dehydrating-condensation before hydrogenation, and
the conversion ratio of the raw materials to the object compound
can be increased, thus the purification can be carried out
easily.
[0298] The dehydrating-condensation of the 2-amino-1-phenylethanol
compound of the general formula (II) or a salt thereof and the
phenylacetone derivative of the general formula (VIII) can be
carried out by a conventional manner, for instance, using an inert
solvent which can be boiled azeotropically with water, removing the
water out of the reaction system by means of, for example, a trap
means such as Dene-Stark trap. The solvent is not restricted as far
as being inert and boiling with water azeotropically, and includes,
for instance, organic solvents such as hydrocarbons including
aromatic hydrocarbons (e.g. benzene, toluene, xylene, ligroin,
petroleum ether, etc.) and aliphatic hydrocarbons (for example,
pentane, hexane, heptane, octane, and others) as exemplified in the
explanation of the production of the compound of the general
formula (IIa).
[0299] The dehydrating-condensation may also be conducted by using
a solvent, for example, an inert solvent which is capable of
boiling with water azeotropically and removing water out of the
reaction system with distilling off the solvent. Such solvent
includes, for example, organic solvents such as lower alcohols
(e.g. a C.sub.1-4 alcohol such as methanol, ethanol, propyl
alcohol, isopropyl alcohol, butanol, t-butanol, etc.) as well as
aromatic hydrocarbons and aliphatic hydrocarbons mentioned
above.
[0300] The reaction may be carried out in the presence of an acid
catalyst. As such an acid, acids used in the following one-pot
method (2) can be employed.
[0301] The ratio of the (R)-2-amino-1-phenylethanol compound of the
general formula (II) or a salt thereof relative to the
phenylacetone derivative of the general formula (VIII) is usually
such that the former/the latter equals about 0.5 to 2.0 (molar
ratio) and preferably about 0.8 to 1.2 (molar ratio).
[0302] As the reducing agent, there may be mentioned, for example,
a metal hydride such as sodium cyanoborohydride and sodium
borohydride, hydrogen and others. Hydrogen may usually be employed
in combination with a catalyst for catalytic reduction. Use of
hydrogen as the reducing agent can render the object
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]etha- nol derivative
to be produced preferently among the two species of diastereomers
by asymmetric induction. The catalyst for catalytic reduction
include, for instance, a nickel catalyst such as Raney-nickel
catalyst; a platinum group catalyst including a platinum catalyst
such as platinum carbon, platinum black, platinum oxide (e.g. Adams
catalyst), etc., a palladium catalyst, a rhodium catalyst, a
ruthenium catalyst such as ruthenium carbon, ruthenium oxide and
ruthenium black, and a rhenium catalyst. These catalysts can be
employed singly or in combination. Preferred catalyst includes, for
example, a platinum catalyst and a ruthenium catalyst. Among them a
platinum catalyst, specifically platinum oxide, can advantageously
be used.
[0303] The amount of the catalyst for catalytic reduction can be
selected from a range with regard to the reaction rate and economic
factors, and is, generally, about 0.01 to 20 parts by weight,
preferably about 0.01 to 10 parts by weight, more preferably about
0.01 to 5 parts by weight (e.g 0.5 to 5 parts by weight), and
specifically 0.5 to 3 parts by weight relative to 100 parts by
weight of the compound of the general formula (II).
[0304] The reaction temperature is depending on the species or
amount of the raw materials, the species of the catalyst, the
pressure condition and other factors, and is usually about 0 to
100.degree. C., preferably about 10 to 80.degree. C. and more
preferably about 10 to 60.degree. C. The reaction may be carried
out under atmospheric condition or under pressure. The reaction
pressure may range, usually, about from 1 to 100 atm, preferably
about from 1 to 20 atm. The reaction time may be selected from a
shorter time (for example about 10 minutes to 10 hours) under
pressure, and about 1 to 48 hours at atmospheric condition.
[0305] The hydrogenation can be conducted in an inert solvent. The
solvent includes, for instance, organic solvents including alcohols
such as C.sub.1-4 alcohols (e.g. methanol, ethanol, propyl alcohol,
isopropyl alcohol, butanol, t-butanol, etc.); aromatic hydrocarbons
such as benzene, toluene, xylene, ethylbenzene, petroleum ether,
and others; aliphatic hydrocarbons such as pentane, hexane,
heptane, octane, and the like; alicyclic hydrocarbons such as
cyclohexane, methylcyclohexane, cycloheptane, etc.; halogenated
hydrocarbons such as chloroform, dichloromethane,
1,2-dichloroethane and so on; ethers such as diethyl ether,
diisopropyl ether, dibutyl ether, dioxane, tetrahydrofuran and the
like; esters such as methyl acetate, ethyl acetate, isopropyl
acetate and others. Such solvents can be employed independently or
in corporation.
[0306] The explanation of the one-pot method (2) is illustrated
hereinbelow. According to the one-pot method (2), the
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative
of the general formula (XI) can be obtained by allowing the
(R)-2-amino-1-phenylethanol compound of the general formula (II) or
a salt thereof to react with the phenylacetone derivative of the
general formula (VIII) and hydrogen in the presence of a catalyst
for catalytic reduction.
[0307] The reaction may be conducted in the absence of an acid, but
the reaction can be proceeded advantageously in the presence of an
acid. Hydrogenation in the presence of an acid where the acid acts
as a catalyst can increase the conversion ratio of the raw
materials to the object compound, thus the object compound can be
purified easily or readily. The acid may be whichever of an
inorganic acid or an organic acid. The inorganic acid and the
organic acid can be refereed to the inorganic acids and organic
acids including optically active organic acids as exemplified in
the explanation of the production of the compound of the general
formula (IIa).
[0308] As the acid, an acid whereby in the reaction, an adduct
having high solubility to the solvent can be selected from the
above exemplified acids according to the species of the solvent.
Among the inorganic acids, preferred is hydrochloric acid, sulfuric
acid, nitric acid, phosphoric acid and boric acid, and typically
hydrochloric acid, sulfuric acid and nitric acid. Especially,
hydrochloric acid can advantageously be employed. As the organic
acid, favorable includes, for instance, a saturated aliphatic
monocarboxylic acid, a saturated aliphatic dicarboxylic acid, an
unsaturated aliphatic carboxylic acid, a sulfuric acid and the
like. More preferred is a saturated aliphatic monocarboxylic acid,
a saturated aliphatic dicarboxylic acid, an unsaturated aliphatic
carboxylic acid. A C.sub.1-4 carboxylic acid such as formic acid,
acetic acid and propionic acid can advantageously be employed.
[0309] The using amount of the acid may be selected from a wide
range depending on the reaction rate and other factors, and is, for
instance, relative to 100 parts by weight of the compound of the
general formula (II), about 0.1 to 80 parts by weight, preferably
about 0.1 to 50 parts by weight (e.g. about 0.1 t 10 parts by
weight) and more preferably about 0.5 to 10 parts by weight (for
instance, about 0.5 to 5 parts by weight).
[0310] The hydrogenation in the one-pot method (2) can be carried
out with the use of a similar reducing agent, catalyst for
catalytic reduction, reaction solvent and others under a similar
reaction conditions as in the hydrogenation of the stepwise method
(1).
[0311] According to the method which comprises a reaction of the
compound of the general formula (II) or a salt thereof with the
compound of the general formula (VIII) and a reducing reaction of
the resultant product, the object compound, that is, the
(R,R)-1-phenyl-2-[[2-(phenyl)-1-alkylet- hyl]amino]ethanol
derivative can efficiently be obtained with high selectivity.
Further, the (R)-2-amino-1-phenylethanol compound of the general
formula (II) and the compound of the general formula (VIII) used as
raw materials are both easy to handle or treat and obtainable
conveniently. Furthermore, among two of the raw materials, the
phenylacetone derivative is not necessary optically active, thus
the production process is expedient.
[0312] The (R,R)-1-phenyl-2-[[2-(phenyl)-1-alkylethyl]amino]ethanol
derivative having high optical purity can easily or readily
obtained by subjecting the product
(R,R)-1-phenyl-2-[[2-(phenyl)-1-alkylethyl]amino]e- thanol
derivative of the general formula (XI) to purification, if
necessary after adjusting the pH of the reaction mixture, such as
extraction with an organic solvent, vacuum concentration, column
chromatography, distillation, crystallization and
recrystallization.
[0313] When the corresponding (R,S)-isomer, that is a compound of
the general formula (XIII) 16
[0314] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11 and Z have
the same meanings as defined above, is by-produced, the object
(R,R)-isomer can efficiently and selectively be recovered by adding
an acid to the reaction products and subjecting the resultant salt
to fractional crystallization.
[0315] The acid includes an inorganic acid and organic acid.
Examples of the inorganic acid and the organic acid include the
inorganic acids and the organic acids (including optically active
organic acids) as mentioned in the explanation of the production of
the compound of the general formula (IIa). The acids can be
employed independently or in combination.
[0316] Preferred examples of the inorganic acid include
hydrochloric acid, and preferred of the organic acid includes, for
instance, a carbocyclic carboxylic acid, an amino acid which may be
protected on the amino group with a protective group, a sulfonic
acid and the like. Utilization of such acid can reduce the content
of an impurity, thus the (R,R)-isomer having higher optical purity
can be obtained.
[0317] In case of a mixture of the compound of the general formula
(XI) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.9,
R.sup.10 are respectively a hydrogen atom, R.sup.11 is a methyl
group, R.sup.4 is chlorine atom, R.sup.7 and R.sup.8 are
respectively a methoxy group, and the corresponding (R,S)-isomer of
the general formula (XIII), an organic acid, especially an
optionally substituted 2-alkylphenylpropionic acid such as (R)- or
(S)-2-(2,5-dimethylphenyl)propionic acid, or a mixture of these
enantiomers, and (R)-(-)- or
(S)-(+)-2-(2,4,6-trimethylphenyl)propi- onic acid or a mixture of
these enantiomers can advantageously be used. By using these acids,
the (R,R)-isomer can selectively be recovered efficiently.
[0318] The proportion of the acid may be selected from a broad
range depending on the species of the acid, and is, usually, about
0.5 to 2 gram equivalents, preferably about 0.5 to 1.5 gram
equivalents and more preferably about 0.5 to 1.3 gram equivalents
relative to 1 mole of the total of the (R,R)-isomer of the general
formula (XI) and (R,S)-isomer of the general formula (XIII). The
acid is frequently used in a proportion of about 0.8 to 1.2 gram
equivalents and more preferably about 0.9 to 1.1 gram equivalents
relative to 1 mole of the total of the mixture of the (R,R)-isomer
and the (R,S)-isomer.
[0319] After formation of the salt, if required, an base may be
added. As such base, those exemplified in the explanation of the
isolation and purification of the 2-amino-1-phenylethanol
derivative of the general formula (I) can be employed. Typically
preferred examples of the base include a tertiary amine,
specifically an aliphatic tertiary amine. A tri-C.sub.1-8
alkylamine can preferably or advantageously be used among them.
[0320] The adding amount of the base may be selected with regard to
the amount of the (R,R)-isomer of the general formula (XI) or other
factors, and is, for example, relative to 1 mole of the total
amount of the (R,R)-isomer and the (R,S)-isomer, about 0.05 to 0.8
gram equivalent, preferably about 0.05 to 0.6 gram equivalent (for
instance, about 0.05 to 0.5 gram equivalent) and more preferably
about 0.1 to 0.5 gram equivalent.
[0321] Probably because the (R,R)-isomer has a higher basicity than
the (R,S)-isomer, the addition of a base may render the
(R,S)-isomer to be liberated selectively, thus the (R,R)-isomer
having high optical purity can be obtained efficiently.
[0322] The reaction temperature is depending on the species of the
(R,R)-isomer and (R,S)-isomer, and the species of the solvent, and
crystals of the object compound can be obtained, for example, by
heating the mixture to the neighborhood of the boiling point of the
solvent to be dissolved, and (a) cooling to room temperature by
leaving to cool, or (b) cooling to room temperature to about
-10.degree. C. with preventing from formation of an oil. When the
melting point of the compound is lower than the boiling point of
solvent, formation of the salt may preferably be carried out at a
temperature lower than the melting point of the compound.
[0323] The formation of the salt and fractional crystallization may
be conducted in an inert solvent. As the solvent, there may be
mentioned the lower alcohols, aromatic hydrocarbons, aliphatic
hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons,
ethers, esters and others as exemplified in the hydrogenation. Such
solvents can be employed separately or in association. Typical
examples of the solvent include esters (e.g. ethyl acetate, etc.),
lower alcohols (for instance, methanol, ethanol, isopropyl alcohol,
and the like), a mixture of an ester and a lower alcohol (for
instance, ethyl acetate-methanol mixed solvent, ethyl
acetate-ethanol mixed solvent, etc.), a mixture of a lower alcohol
and an ether (foe example, isopropyl alcohol-diisopropyl ether
mixed solvent and the like). Ethyl acetate, isopropyl alcohol,
isopropyl alcohol-diisopropyl ether mixed solvent, and others can
advantageously be employed.
[0324] The (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivative and a salt thereof thus obtained can selectively react
with the .beta..sub.3-receptor in vivo to decrease or reduce blood
sugar significantly and to remarkably restrain or suppress obesity.
The pharmacological activity in the (R,R)-isomer is extremely
higher than those in the other optical isomers. (R,R)-[disodium
5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2-
,2-dicarboxylate] shows, for example, a higher activity than the
corresponding (S,S)-form by a factor of 47 (see the above-mentioned
U.S. patent).
[0325] When the corresponding (S)-form is used instead of the
(R)-2-amino-1-phenylethanol derivative in the reaction, the object
compound (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivative can hardly be produced. Further, use of the racemic
2-amino-1-phenylethanol derivative produces the objective compound
only with a low yield, and 4 species of optical isomers are
produced, thus an isolating process for isolation and removal of a
by-produced optical isomers will be complicated.
[0326] As described above, the (R)-2-amino-1-phenylethanol
derivative used in the present invention is remarkably usable and
effective intermediate to selectively obtain the
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]- ethanol derivative
efficiently with a high yield, thus the (R)-form is remarkably more
usable than the corresponding (S)-form and the racemic form.
[0327] Further, the (R)-2-amino-1-phenylethanol derivative,
differing from the (R)-1-methyl-2-phenylethylamine derivative
conventionally used as the intermediate, does not have an
antihypnotic or arousal action, therefore is easy to handle or
treat and suited for a use in commercial production.
[0328] R.sup.7, R.sup.8 or the both of the compound of the general
formula (XI) can be converted from one substituent to another by a
conventional manner. As such a manner, for example,
(R,R)-1-phenyl-2-[(2-phenyl-1-alky- lethyl)amino]ethanol derivative
where R.sup.7 and R.sup.8 are both methoxy groups can easily be
converted to the compound where R.sup.7a and R.sup.8a together form
the group shown by the formula (XII) in accordance with a method
shown by the following scheme.
[0329] In the following scheme, only the moiety of the phenyl group
where R.sup.7 and R.sup.8 are substituted on is illustrated for
convenience. 17
[0330] In the scheme, R.sup.12, R.sup.13 and R.sup.14 respectively
represent an optionally substituted alkyl group; X.sup.a and
X.sup.b separately represent a halogen atom; and R.sup.6, R.sup.9,
R.sup.10 and R.sup.11 have the same meanings as defined above.
[0331] In the reaction, a compound having a group of the formula
(XII) where R.sup.a and R.sup.b are both optionally substituted
alkoxycarbonyl groups, can easily be prepared by allowing a
demethylating agent such as BBr.sub.3 to react with the compound of
the general formula (XI'a) where R.sup.1 and R.sup.2 are both
methyl groups for demethylation, and allowing a dihalomalonic acid
ester shown by the formula (XIX) such as diethyl dibromomalonate to
react with the demethylated compound in the presence of a base such
as potassium carbonate. The resultant compound can be introduced to
a compound having the group of the formula (XI'd) where R.sup.a and
R.sup.b are both hydroxyl groups by using a reducing agent such as
lithium borohydride. When allowing an alkyl halide of the formula
(XX) to react with the resulting compound in the presence of a base
such as sodium hydride, a compound having the group of the formula
(XII) where R.sup.a and R.sup.b are respectively an optionally
substituted alkoxymethyl group can be prepared.
[0332] Further, hydrolysis of the compound (XI'c) having the group
of the formula (XII) where R.sup.a and R.sup.b are respectively an
optionally substituted alkoxycarbonyl group, in accordance with a
conventional hydrolyzing method such as alkali hydrolysis using an
alkali such as an alkali metal hydroxide (e.g. sodium hydroxide) or
the like can easily or readily afford a compound having the group
of the formula (XII) wherein R.sup.a and R.sup.b are, the same or
different, a carboxyl group or a salt thereof.
[0333] With regard to the method, the disclosures and descriptions
in the above mentioned U.S. Pat. No. 5,061,727 and J. Med. Chem.,
35, 3081 (1992) can be referred and incorporated with the present
specification.
[0334] The (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivative or a salt thereof can advantageously be used, as intact
or, where necessary, subjected to a suitable chemical modification,
as a medicament such as an anti-obesity agent and an anti-diabetic
agent. The processes for such chemical modification may be referred
to the descriptions and disclosures in, for example, the
above-mentioned U.S. Pat. No. 5,061,727, J. Med. Chem., 35, 3081
(1992) and "Protective groups in Organic Synthesis" (T. W. Greene,
A Wiley-Interscience Publication, John Wiley & Sons
(1981)).
[0335] The production of the (S)-2-amino-1-phenylethanol derivative
of the general formula (XV) is illustrated as follows.
[0336] As examples and preferred R.sup.1 to R.sup.5 of the general
formula (XV), there may be mentioned the substituents as mentioned
above for the general formula (IIa).
[0337] Practical examples and preferred examples of the
(S)-2-amino-1-phenylethanol derivative of the general formula (XV)
include (S)-forms corresponding to the compounds exemplified as the
(R)-forms of the general formula (IIa).
[0338] The (S)-2-amino-1-phenylethanol derivative of the general
formula (XV) can be prepared by a variety of methods, for example,
those analogous to the methods mentioned in the
(R)-2-amino-1-phenylethanol derivative of the general formula
(IIa). The object compound of the formula (XV) can by produced by a
chemical synthesis, and can advantageously be produced with the use
of an action of a microorganism or a preparation thereof.
[0339] For instance, the (S)-form of the formula (XV) can readily
and expediently be obtained by, for example, (E) permitting a
specific microorganism or a preparation thereof to act on a mixture
of enantiomers of the 2-amino-1-phenylethanol compound of the
general formula (I) or a salt thereof and harvesting or recovering
the product (S)-2-amino-1-phenylethanol compound or a salt thereof
(hereinafter referred to as asymmetrically utilization method), or
(F) permitting a specific microorganism or a preparation thereof to
the compound of the general formula (VII) or a salt thereof to
asymmetrically reduce and harvesting or recovering the product
optionally active (S)-form or a salt thereof (hereinafter refereed
to as asymmetric reduction method).
[0340] Hereinbelow, explained is the asymmetrically utilization
method (E).
[0341] Any strain of microorganism that is capable of acting on a
mixture of enantiomers of the 2-amino-1-phenylethanol compound of
the general formula (I) or a salt thereof to produce the
corresponding (S)-form. Such microorganism includes, for instance,
a microorganisms which can selectively utilize the (R)-form among
the both enantiomers, and a microorganisms which can selectively
convert the (R)-form to another compound including the (S)-form,
and others.
[0342] Examples of such microorganism include a strain of
microorganism belonging to the genus Saccharomyces, the genus
Pichia, the genus Schizosaccharomyces, the genus Candida, the genus
Hansenula, the genus Yarrowia, the genus Geotrichum, Micrococcus
luteus, the genus Brevibacterium, the genus Corynebacterium, the
genus Xanthomonas, the genus Actinomaqura, the genus Enterobacter,
the genus Pseudomonas, the genus Hafnia, the genus Actinoplanes,
the genus Escherichia, the genus Bacillus, the genus Listonella,
the genus Nosardioides, the genus Amycolata, the genus Aspergillus,
the genus Penicillium, the genus Corynespora, the genus Fusarium,
the genus Gelasinospora, the genus Helminthosporium, the genus
Mortierelia, the genus Neosartorya, the genus Phytophthora, the
genus Talaromyces, the genus Scolecobasidium, the genus Rhodococcus
and so on.
[0343] Practical examples of a strain of microorganism that is
capable of acting on a mixture of enantiomers of the compound of
the general formula (I) or a salt thereof to produce the
corresponding (S)-form include following strains of
microorganisms:
[0344] (66) the genus Saccharomyces: Saccharomyces cerevisiae IFO
0718, Saccharomyces cerevisiae IFO 0735, Saccharomyces cerevisiae
IFO 0206, etc.,
[0345] (67) the genus Pichia: Pichia fabianii IFO 1254, etc.
[0346] (68) the genus Schizosaccharomyces: Schizosaccharomyces
pombe IAM 4890, etc.,
[0347] (69) the genus Candida: Candida guilliermondii IFO 0566,
Candida melibiosica IFO 10238, etc.,
[0348] (70) the genus Hansenula: Hansenula polymorpha DSM 70277,
etc.,
[0349] (71) the genus Yarrowia: Yarrowia lipolytica IFO 0746,
etc.,
[0350] (72) the genus Geotrichum: Geotrichum capitatum IFO 0743,
Geotrichum capitatum IFO 1197, etc.,
[0351] (73) Micrococcus luteus: Micrococcus luteus IAM 12009,
Micrococcus luteus IAM 12144, Micrococcus luteus IAM 1157,
Micrococcus luteus IFO 3333, etc.,
[0352] (74) the genus Brevibacterium: Brevibacterium iodinum IFO
3558, etc.,
[0353] (75) the genus Corynebacterium: Corynebacterium sepedonicum
IFO 3306, etc.,
[0354] (76) the genus Xanthomonas: Xanthomonas sp. IFO 12997,
etc.,
[0355] (77) the genus Actinomaqura: Actinomaqura cremea subsp.
cremea IFO 14182, etc.,
[0356] (78) the genus Enterobacter: Enterobacter aerogenes IFO
12010, etc.,
[0357] (79) the genus Pseudomonas: Pseudomonas aeruginosa IFO 3445,
etc.,
[0358] (80) the genus Hafnia: Hafnia alvei IFO 3731, etc.,
[0359] (81) the genus Actinoplanes: Actinoplanes lobatus IFO 12513,
etc.,
[0360] (82) the genus Escherichia: Escherichia coli IAM 1239,
etc.,
[0361] (83) the genus Bacillus: Bacillus licheniformis BGSC 5A18,
etc.,
[0362] (84) the genus Listonella: Listonella anguillarum IFO 12710,
etc.,
[0363] (85) the genus Nosardioides: Nosardioides flavus IFO 14396,
etc.,
[0364] (86) the genus Amycolata: Amycolata autotrophica IFO 12743,
etc.,
[0365] (87) the genus Aspergillus: Aspergillus niger IFO 4415,
Aspergillus niger AHU 7115, Aspergillus ficuum IFO 4318,
Aspergillus cavdidus IFO 4389, Aspergillus oryzae IFO 4390,
Aspergillus oryzae var. brunneus JCM 2240, Aspergillus tamarii IAM
2138, etc.,
[0366] (88) the genus Penicillium: Penicillium chrysogenum IAM
7142, etc.,
[0367] (89) the genus Corynespora: Corynespora cassiicola IFO 6724,
etc.,
[0368] (90) the genus Fusarium: Fusarium solani IFO 5232, etc.,
[0369] (91) the genus Gelasinospora: Gelasinospora cerealis IFO
6759, etc.,
[0370] (92) the genus Helminthosporium: Helminthosporium sigmoideum
var. irreavl IFO 5273, etc.,
[0371] (93) the genus Mortierelia: Mortierelia isabellina IFO 6336,
Mortierelia ramanniana var. ramanniana IFO 7825, etc.,
[0372] (94) the genus Neosartorya: Neosartorya fischeri var.
spinosa IFO 5955, etc.,
[0373] (95) the genus Phytophthora: Phytophthora capsici IFO 8386,
etc.,
[0374] (96) the genus Talaromyces: Talaromyces flavus var. flavus
IFO 7231, etc.,
[0375] (97) the genus Scolecobasidium: Scolecobasidium terreum IFO
8854, etc.,
[0376] (98) the genus Rhodococcus: Rhodococcus luteus JCM 6162,
Rhodococcus erythropolis JCM 6821, Rhodococcus erythropolis JCM
6827, Rhodococcus globerrulus IFO 14531, and so on.
[0377] These microorganisms can be used singly or in combination.
Permission of the microorganism or a preparation thereof to act on
a mixture of enantiomers of the amino-1-phenylethanol derivative of
the general formula (I) make the ratio of the (S)-form increased
among the both enantiomers.
[0378] The microorganisms respectively designated by IFO, JCM,
ATCC, DSM, IAM, BGSC and AHU numbers are available the
organizations mentioned above.
[0379] For producing the optically active
(S)-2-amino-1-phenylethanol derivative of the formula (XV), any of
wild strains, mutants and recombinant strains which can be obtained
by a genetic engineering technique such as cell fusion or gene
manipulation can preferably be employed as far as having the above
mentioned ability or capability.
[0380] The cultivation of the microorganisms, reaction and recovery
of the reaction product can be carried out in a similar manner as
in the production of the (R)-2-amino-1-phenylethanol derivative of
the general formula (IIa).
[0381] The asymmetric reduction method (F) is illustrated
hereinbelow.
[0382] As the microorganism used in the method, any strain of
microorganism which is capable of asymmetrically reducing the
compound of the general (VII) to produce the corresponding
optically active (S)-2-amino-1-phenylethanol derivative of the
general formula (XV) can be employed.
[0383] Such a microorganism includes, for instance, a strain of
microorganism belonging to the genus Botryoascus, the genus
Brettanomyces, the genus Candida, the genus Citeromyces, the genus
Clavispora, the genus Debaryomyces, the genus Dipodascus, the genus
Eremascus, the genus Galactomyces, the genus Geotrichum, the genus
Issatchenkia, the genus Kluyveromyces, the genus Kondoa, the genus
Lipomyces, the genus Malassezia, the genus Oosporidium, the genus
Pachysolen, the genus Pichia, the genus Rhodosporidium, the genus
Rhodotorula, the genus Saccharomyces, the genus Saccharomycodes,
the genus Saccharomycopsis, the genus Schizoblastosporion, the
genus Schizosaccharomyces, the genus Sporidiobolus, the genus
Sporobolomyces, the genus Wickerhamiella, the genus Wingea, the
genus Zygosaccharomyces, the genus Bacillus, the genus Comamonas,
the genus Rhodobacter, the genus Enterococcus, the genus
Lactobacillus, the genus Pediococcus, the genus Leuconostoc, the
genus Streptococcus and so on.
[0384] As practical examples of the microorganism capable of acting
on the aminoketone derivative of the general formula (VII) to
produce the (S)-2-amino-1-phenylethanol derivative of the general
formula (XV), there may be mentioned following strains of
microorganisms:
[0385] (99) the genus Botryoascus: Botryoascus synnaedendrus IFO
1604, etc.,
[0386] (100) the genus Brettanomyces: Brettanomyces anomalus IFO
0642, etc.,
[0387] (101) the genus Candida: Candida albicans IFO 1856, Candida
beechii IFO 10229, Candida ergatensis IFO 10233, Candida
fusiformata IFO 10225, Candida guilliermondii IFO 0566, Candida
halonitratophila IFO 1595, Candida oregonensis IFO 1980, Candida
peltata IFO 1853, Candida parapsilosis IFO 10305, Candida
sorboxylosa IFO 1578, etc.,
[0388] (102) the genus Citeromyces: Citeromyces matritensis IFO
0954, etc.,
[0389] (103) the genus Clavispora: Clavispora lusitaniae IFO 1019,
etc.,
[0390] (104) the genus Debaryomyces: Debaryomyces hansenii var.
hansenii IFO 0083, etc.,
[0391] (105) the genus Dipodascus: Dipodascus ovetensis IFO 1201,
etc.,
[0392] (106) the genus Eremascus: Eremascus fertilis IFO 0691,
etc.,
[0393] (107) the genus Galactomyces: Galactomyces reessii IFO 1112,
etc.,
[0394] (108) the genus Geotrichum: Geotrichum fermentans CBS
452.83, Geotrichum candidum IFO 4601, Geotrichum capitatum IFO
1197, Geotrichum klebahnii JCM 2171, etc.,
[0395] (109) the genus Issatchenkia: Issatchenkia scutulata var.
scutulata IFO 10069, etc.,
[0396] (110) the genus Kluyveromyces: Kluyveromyces lactis IFO
1267, Kluyveromyces marxianus var. bulgaricus IAM 4829, etc.,
[0397] (111) the genus Kondoa: Kondoa malvinella IFO 1935,
etc.,
[0398] (112) the genus Lipomyces: Lipomyces starkeyi IFO 1289,
etc.,
[0399] (113) the genus Malassezia: Malassezia furfur IFO 0656,
etc.,
[0400] (114) the genus Oosporidium: Oosporidium margaritiferum IFO
1208, etc.,
[0401] (115) the genus Pachysolen: Pachysolen tannophilus IFO 1007,
etc.,
[0402] (116) the genus Pichia: Pichia farinosa IFO 1163, Pichia
holstii IFO 0986, Pichia subpelliculosa IFO 0808, Pichia toletana
IFO 0950, etc.,
[0403] (117) the genus Rhodosporidium: Rhodosporidium diobovatum
IFO 0688, etc.,
[0404] (118) the genus Rhodotorula: Rhodotorula glutinis IFO 0389,
Rhodotorula glutinis var. dairenensis IFO 0415, etc.,
[0405] (119) the genus Saccharomyces: Saccharomyces kluyveri IFO
1894, Saccharomyces paradoxus IFO 0259, etc.,
[0406] (120) the genus Saccharomycodes: Saccharomycodes ludwigii
IFO 0798, etc.,
[0407] (121) the genus Saccharomycopsis: Saccharomycopsis
capsularis IFO 0672, etc.,
[0408] (122) the genus Schizoblastosporion: Schizoblastosporion
kobayasii IFO 1644, etc.,
[0409] (123) the genus Schizosaccharomyces: Schizosaccharomyces
pombe IFO 0358, etc.,
[0410] (124) the genus Sporidiobolus: Sporidiobolus pararoseus JCM
5350, etc.,
[0411] (125) the genus Sporobolomyces: Sporobolomyces pararoseus
IFO 0471, Sporobolomyces salmonicolor AHU 3982, etc.,
[0412] (126) the genus Wickerhamiella: Wickerhamiella domercquii
IFO 1857, etc.,
[0413] (127) the genus Wingea: Wingea robertsii IFO 1277, etc.,
[0414] (128) the genus Zygosaccharomyces: Zygosaccharomyces bailii
DSM 70492, Zygosaccharomyces fermentati IFO 0021, etc.,
[0415] (129) the genus Bacillus: Bacilus subtilis IFO 3037,
etc.,
[0416] (130) the genus Comamonas: Comamonas terrigena IFO 13299,
etc.,
[0417] (131) the genus Rhodobacter: Rhodobacter sphaeroides IFO
12203, etc.,
[0418] (132) the genus Enterococcus: Enterococcus faecalis NRIC
1142, etc.,
[0419] (133) the genus Lactobacillus: Lactobacillus lactis AHU
1059, etc.,
[0420] (134) the genus Pediococcus: Pediococcus acidilactici IFO
3076, etc.,
[0421] (135) the genus Leuconostoc: Leuconostoc mesenteroides
subsp. dextranicum NRIC 1085, Leuconostoc mesenteroides AHU 1071,
Leuconostoc oenos DSM 20252, etc.,
[0422] (136) the genus Streptococcus: Streptpcoccus uberis NRIC
1153, and so on.
[0423] According to this method, any of wild strains, mutants and
recombinant strains which can be obtained by a genetic engineering
technique such as cell fusion or gene manipulation can suitable be
employed so far as having the ability or capability mentioned
above.
[0424] The microorganisms identified hereinabove by IFO, AHU, DSM,
JCM numbers are available from the above organizations. The
microorganisms designated by IAM, numbers are listed "IAM Catalogue
of strains, 1st Ed. (1993) published by the Institute For Research
Promotion of Applied Microbiology, and are available from General
Center of Microbial Algae, Institute of Applied Microbiology, Tokyo
University, Japan.
[0425] The microorganism titled by CBS number is listed in "List of
cultures FUNGI and YEAST, Ed. 32 (1990)" published by the
CENTRAALBUREAU VOOR SCHIMMELCULTURES (CBS) and is available from
the same organization. The microorganisms identified by NRIC
numbers are described in "Catalogue of Microbial Strains, Ed. 2
(1992)" published by Laboratory of Cell Collection, Tokyo
Agricultural University, Japan and are available from the same
Laboratory.
[0426] For the processes for the cultivation of the microorganism,
asymmetric reduction and recovery of the product compound, those in
the production of the (R)-2-amino-1-phenylethanol derivative of the
general formula (IIa) may be referred to.
[0427] Further, the (S)-2-amino-1-phenylethanol derivative of the
general formula (XV) can also be prepared by methods similar to the
methods (C) and (D) of the production of the
(R)-2-amino-1-phenylethanol derivative of the general formula
(IIa). Namely, the (S)-form of the general formula (XV) can easily
or readily be prepared by utilizing corresponding (S)-form
respectively as the compound of the formula (III) or the compound
of the formula (IV) as the reactant in the method (C). The (S)-form
can readily be isolated from the corresponding (R)-form in the
method (D) by, for instance, fractional crystallization.
[0428] The (S)-2-amino-1-phenylethanol derivative of the general
formula (XV) may be converted to the (R)-2-amino-1-phenylethanol
derivative of the formula (IIa) by, for example, subjecting the
(S)-form to nucleophilic substitution reaction accompanied with a
steric inversion. Such reaction can be conducted with the use of a
nucleophilic reagent.
[0429] The (S)-2-amino-1-phenylethanol derivative of the general
formula (XV) can easily be converted to the
(R)-2-amino-1-phenylethanol derivative shown by the general formula
(IIa) by selecting an reagent, a catalyst and reaction conditions
from a suitable range wherein the reaction is proceeded with steric
inversion. For example, the reaction can be carried out in
accordance with the following scheme: 18
[0430] In the general formula (XV), R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 have the same meanings as defined above.
[0431] The conversion of the compound of the general formula (XV)
to the compound of the general formula (IIa) can be carried out by,
for example, the following method according to Mitsunobu
reaction.
[0432] The (R)-2-amino-1-phenylethanol derivative can be obtained
by allowing an organic acid to react with the compound of the
general formula (XV) in the presence of triarylphosphine (e.g.
triphenylphosphine, etc.) and an azodicarboxylic acid ester such as
ethyl azodicarbonate to form the sterically inverted corresponding
organic acid ester, and hydrolyzing the resulting ester. The
organic acid includes, for example, formic acid, acetic acid,
trichloroacetic acid, trifluoroacetic acid, benzoic acid and the
like. The formation of the organic acid ester may be conducted, for
example, at a temperature of about -60.degree. C. to 60.degree. C.
The reaction may be carried out in an inert solvent such as an
aromatic hydrocarbon (for example, benzene, toluene and so on) and
an ether (e.g. tetrahydrofuran, etc.). The proportions of
trialkylphosphine, organic acid and azodicarboxylic acid ester
based on 1 mole of the compound of the general formula (XV) are
respectively about 0.7 to 2.0 moles. The hydrolysis of the organic
acid ester can be conducted by a conventional manner such as
acid-hydrolysis or alkali-hydrolysis.
[0433] Such method utilizing Mitsunobu reaction wherein an
optically active alcohol is sterically inverted to the
corresponding optically active alcohol may refer to methods or
those analogous thereto described, for example, in Synthesis, 1
(1981); Tetrahedron Lett., 1619 (1973); and Bull. Chem. Soc. Jpn.,
44, 3427 (1971), and these descriptions can be incorporated to the
present specification.
[0434] For the conversion of the optically active alcohol to the
corresponding enantiomer, following methods can also be
applied:
[0435] (a) the method comprising esterifying an optically active
alcohol to a carboxylic acid ester such as trichloroacetic acid
ester, and hydrolyzing the resultant carboxylic acid ester, in a
water-ether solvent such as 75% H.sub.2O-dioxane, can also be
applied (see Chem. Lett., 1976, 893), and
[0436] (b) the method which comprises (a) converting an optically
active alcohol to a sulfonic acid ester such as p-toluenesulfonic
acid ester, (b) allowing an organic acid salt such as
tetraethylammonium acetate and sodium acetate (and acetic acid) to
react with the resulting sulfonic acid ester to sterically invert
to the corresponding organic acid ester, and (c) hydrolyzing the
resultant organic acid ester (J. Am. Chem. Soc., 87, 3682, (1965);
and J. Chem. Soc., 1954, 965).
[0437] The obtained (R)-2-amino-1-phenylethanol derivative of the
general formula (IIa) is, as described above, an specifically
important intermediate for production of the
(R,R)-1-phenyl-2-[[2-(phenyl)-1-alkyle- thyl]amino]ethanol
derivative. Accordingly, the (S)-2-amino-1-phenylethano- l
derivative of the general formula (XV) used in the present
invention is remarkably usable as an intermediate for the
(R)-2-amino-1-phenylethanol derivative.
[0438] The methods for conversion of the
(S)-2-amino-1-phenylethanol derivative of the general formula (XV)
to the (R)-2-amino-1-phenylethanol derivative of the general
formula (IIa) can also be applied to the conversion of the
corresponding (R)-form to the (S)-form.
[0439] In the each method as described above, where a compound used
as a raw material has a hydroxyl group or an amino group, the
compound may be subjected to the reaction, if necessary, with being
protected on the hydroxyl group or the amino group with a suitable
protective group (e.g. the protective group for hydroxyl group, the
protective group for amino group as referred to above, and the
like).
[0440] The following examples are intended to illustrate the
invention in further detail and should by no means be construed as
delimiting the scope of the invention.
EXAMPLES
[0441] The quantitative determination and optical purity
determination of product 2-amino-1-phenylethanol derivative in the
reaction mixture were carried out, unless specifically mentioned,
by subjecting the reaction mixture to high performance liquid
chromatography using an optical resolution column (column:
Crownpack CR (trade name), Daicel Chemical Industries, Ltd.; mobile
phase: perchloric acid buffer (pH 2.0); wavelength: 220 nm; flow
rate: 1 ml/min.; column temperature: 40.degree. C.). Under the
determination condition, for example, the retention time for
(R)-2-amino-1-(3-chlorophenyl)ethanol is 16.8 minutes and
(S)-2-amino-1-(3-chlorophenyl)ethanol is 18.5 minutes.
Examples 1 to 100
Production of (R)-2-amino-1-(3-chlorophenyl)ethanol
[0442] Following media (1) and (2) were prepared for growing
microbial strains.
[0443] [Medium for Preparation of Cells (1): for Yeast and
Fungi]
1 Glucose 2.0% by weight Yeast extract 0.3% by weight Malt extract
0.3% by weight Polypeptone 0.5% by weight Deionized water 96.9% by
weight (pH 6.0)
[0444] [Medium for Preparation of Cells (2): for Bacterium and
Actinomyces]
2 Glucose 2.0% by weight Yeast extract 0.5% by weight Meat extract
0.3% by weight Polypeptone 0.3% by weight Ammonium sulfate 0.2% by
weight Potassium primary 0.1% by weight phosphate Deionized water
96.6% by weight (pH 7.0)
[0445] A test tube of 21 mm in inner diameter was charged with 5 ml
of the above mentioned medium respectively. After sterilization,
the tube was inoculated with one of the following microbial
strains. A yeast or fungus was inoculated to the Medium (1) and a
bacterium or actinomyces was inoculated to the Medium (2)
respectively, and the inoculated tube was incubated under shaking
at 30.degree. C. for 48 hours. After the incubation, the wet viable
cells were isolated by centrifuging.
[0446] [Yeasts]
[0447] Example 1: Hansenula anomala IFO 0707
[0448] Example 2: Geotrichum candidum IFO 4601
[0449] Example 3: Geotrichum candidum IFO 4598
[0450] Example 4: Candida albicans IFO 1594
[0451] Example 5: Candida albicans IFO 1856
[0452] Example 6: Candida parapsilosis IFO 1022
[0453] Example 7: Candida gropengiesseri IFO 0659
[0454] Example 8: Candida aaseri IFO 10404
[0455] Example 9: Candida beechii IFO 10229
[0456] Example 10: Candida atmospherica IFO 1969
[0457] Example 11: Candida natalensis IFO 1981
[0458] Example 12: Candida paludigena IFO 10330
[0459] Example 13: Candida sake IFO 1149
[0460] Example 14: Candida pintolopesii var. pintolopesii IFO
0729
[0461] Example 15: Cryptococcus neoformans IAM 4788
[0462] Example 16: Rhodosporidium spaerocarpum IFO 1438
[0463] Example 17: Rhodosporidium diobovatum IFO 0688
[0464] Example 18: Rhodotorula rubra IFO 0406
[0465] Example 19: Rhodotorula rubra AHU 3948
[0466] Example 20: Rhodotorula glutinis var. dairenensis IFO
0415
[0467] Example 21: Sporobolomyces roseus IFO 1040
[0468] Example 22: Kluyveromyces marxianus var. bulgaricus IAM
4829
[0469] Example 23: Kluyveromyces lactis IFO 1267
[0470] Example 24: Issatchenkia scutulata var. scutulata IFO
10069
[0471] Example 25: Issatchenkia scutulata var. scutulata IFO
10070
[0472] Example 26: Pichia thermotolerans IFO 10024
[0473] Example 27: Pichia farinosa IFO 1163
[0474] Example 28: Botryoascus synnaedendrus IFO 1604
[0475] Example 29: Debaryomyces hansenii IFO 0083
[0476] Example 30: Lipomyces starkeyi IFO 1289
[0477] Example 31: Metschnikowia bicuspidata IFO 1408
[0478] Example 32: Saccharomycodes ludwigii IFO 0798
[0479] Example 33: Schizoblastosporion kobayashii IFO 1644
[0480] Example 34: Stepahnoascus ciferrii IFO 1854
[0481] Example 35: Sterigmatomyces halophilus IFO 1488
[0482] Example 36: Zygosaccharomyces rouxii IFO 0510
[0483] Example 37: Zygosaccharomyces rouxii IAM 4114
[0484] Example 38: Zygosaccharomyces fermentati IFO 0021
[0485] Example 39: Sporidiobolus salmonicolor IFO 1845
[0486] Example 40: Sporidiobolus pararoseus IFO 1107
[0487] Example 41: Malassezia furfur IFO 0656
[0488] Example 42: Torulaspora delbrueckii IFO 0955
[0489] Example 43: Saccharomycopsis capsularis IFO 0672
[0490] Example 44: Leucosporidium scottii IFO 1923
[0491] Example 45: Leucosporidium scottii IFO 1924
[0492] [Fungi]
[0493] Example 46: Agrocybe cylindracea IFO 30299
[0494] Example 47: Trichoderma viride IFO 5720
[0495] Example 48: Alternaria kikuchiana IFO 5778
[0496] Example 49: Hamigera avellanea IFO 7721
[0497] Example 50: Moniliella acetoabutans IFO 9481
[0498] Example 51: Pholiota nameko IFO 6141
[0499] Example 52: Podospola cardonaria IFO 30294
[0500] Example 53: Aegerita candida IFO 6988
[0501] [Bacteria and Actinomyces]
[0502] Example 54: Corynebacterium aquaticum IFO 12154
[0503] Example 55: Corynebacterium mediolanum JCM 3346
[0504] Example 56: Gluconobacter asaii IFO 3265
[0505] Example 57: Gluconobacter oxydans IFO 3255
[0506] Example 58: Gluconobacter oxydans IFO 3130
[0507] Example 59: Gluconobacter oxydans IFO 3289
[0508] Example 60: Gluconobacter frateurii IFO 3271
[0509] Example 61: Promicromonospora citrea IFO 12397
[0510] Example 62: Pseudomonas aeruginosa IFO 3899
[0511] Example 63: Pseudomonas riboflavina IFO 13584
[0512] Example 64: Pseudomonas fluorescens IFO 3925
[0513] Example 65: Pseudomonas putida IFO 12996
[0514] Example 66: Pseudomonas syncyanea IFO 3757
[0515] Example 67: Pseudomonas diminuta IFO 12697
[0516] Example 68: Pseudomonas chlororaphis IFO 3522
[0517] Example 69: Pseudomonas fragi IFO 3458
[0518] Example 70: Pseudomonas sp. ATCC 14676
[0519] Example 71: Bordetella bronchiseptica IFO 13691
[0520] Example 72: Acetobacter sp. IFO 3248
[0521] Example 73: Acetobacter sp. IFO 3297
[0522] Example 74: Acetobacter pasteurianus ATCC 10245
[0523] Example 75: Acetobacter pasteurianus IFO 3259
[0524] Example 76: Acetobacter pasteurianus IFO 3277
[0525] Example 77: Bacillus subtilis IFO 3013
[0526] Example 78: Bacillus subtilis IFO 3009
[0527] Example 79: Bacillus cereus AHU 1355
[0528] Example 80: Bacillus cereus AHU 1707
[0529] Example 81: Bacillus cereus IFO 3001
[0530] Example 82: Bacillus coagulans IAM 1115
[0531] Example 83: Bacillus brevis IFO 3331
[0532] Example 84: Bacillus sphaericus IFO 3525
[0533] Example 85: Agrobacterium radiobacter IFO 12664
[0534] Example 86: Arthrobacter ureafaciens IFO 12140
[0535] Example 87: Amauroascus reticulatus IFO 9196
[0536] Example 88: Brevibacterium linens IFO 12141
[0537] Example 89: Micrococcus roseus IFO 3764
[0538] Example 90: Aureobacterium testaceum IFO 12675
[0539] Example 91: Azotobacter vinelandii IFO 13581
[0540] Example 92: Xanthomonas campestris pv oryzae IAM 1657
[0541] Example 93: Klebsiella pneumoniae IFO 3317
[0542] Example 94: Comamonas testosteroni IFO 12048
[0543] Example 95: Comamonas testosteroni IAM 1048
[0544] Example 96: Mycobacterium diernhoferi IFO 3707
[0545] Example 97: Terrabacter tumescens IFO 12960
[0546] Example 98: Streptomyces cinereoruber HUT 6142
[0547] Example 99: Rhodococcus amidophilis IFO 0144
[0548] Example 100: Rhodococcus equi JCM 1313
[0549] A test tube of 21 mm .phi. in inner diameter was charged
with 1 ml of 0.1M potassium phosphate buffer (pH 7.0), and the wet
viable cells obtained above was suspended therein. A racemic
2-amino-1-(3-chlorophenyl- )ethanol (5 .mu.l) was added to the
suspension and reaction was conducted on a reciprocating shaker at
30.degree. C. for 48 hours.
[0550] After completion of the reaction, cells were removed from
the reaction mixture by centrifugation, and the supernatant was
subjected to high performance liquid chromatography to determine
the amount, absolute configuration and optical purity of the
obtained optically active 2-amino-1-(3-chlorophenyl)ethanol. The
results are set forth in Tables 1 to 5. In the following Tables,
the term "amount" means the amount (mg/ml) of the optical active
2-amino-1-(3-chlorophenyl)ethanol contained in the reaction
mixture.
3 TABLE 1 Optical Example Absolute purity Amount No. configuration
(% e e) (mg/ml) 1 R 100 0.01 2 R 61 0.2 3 R 68 0.08 4 R 66 1.1 5 R
100 0.02 6 R 57 0.6 7 R 100 0.9 8 R 82 0.4 9 R 69 0.8 10 R 75 1.3
11 R 57 0.1 12 R 77 0.7 13 R 68 1.5 14 R 63 0.1 15 R 100 0.03 16 R
100 1.0 17 R 55 1.0 18 R 100 0.01 19 R 61 0.1 20 R 82 0.5
[0551]
4 TABLE 2 Optical Example Absolute purity Amount No. configuration
(% e e) (mg/ml) 21 R 77 1.3 22 R 100 0.01 23 R 56 1.1 24 R 78 1.1
25 R 70 1.4 26 R 52 1.2 27 R 99 0.9 28 R 100 1.4 29 R 93 0.7 30 R
100 0.02 31 R 57 1.1 32 R 100 0.02 33 R 77 0.1 34 R 100 0.01 35 R
100 1.0 36 R 95 0.4 37 R 78 0.3 38 R 67 0.04 39 R 100 0.9 40 R 100
1.2
[0552]
5 TABLE 3 Optical Example Absolute purity Amount No. configuration
(% e e) (mg/ml) 41 R 100 0.2 42 R 100 0.03 43 R 100 0.6 44 R 63 1.0
45 R 81 0.1 46 R 48 0.8 47 R 14 0.2 48 R 39 0.2 49 R 11 0.8 50 R 31
0.6 51 R 14 0.4 52 R 14 0.8 53 R 29 2.2 54 R 100 0.1 55 R 14 1.5 56
R 100 2.2 57 R 90 1.3 58 R 79 1.6 59 R 30 3.8 60 R 62 2.5
[0553]
6 TABLE 4 Optical Example Absolute purity Amount No. configuration
(% e e) (mg/ml) 61 R 100 0.4 62 R 72 1.8 63 R 40 1.9 64 R 35 2.6 65
R 26 1.6 66 R 20 2.6 67 R 19 2.3 68 R 12 2.2 69 R 12 3.5 70 R 14
2.1 71 R 100 0.3 72 R 100 1.8 73 R 100 1.6 74 R 24 3.2 75 R 75 2.2
76 R 15 4.2 77 R 100 0.9 78 R 45 1.3 79 R 94 1.6 80 R 30 2.3
[0554]
7 TABLE 5 Optical Example Absolute purity Amount No. configuration
(% e e) (mg/ml) 81 R 21 2.2 82 R 76 1.3 83 R 33 1.7 84 R 13 1.9 85
R 90 1.5 86 R 20 1.4 87 R 75 0.8 88 R 74 3.5 89 R 63 2.2 90 R 43
0.7 91 R 37 1.6 92 R 20 3.3 93 R 13 5.1 94 R 100 1.8 95 R 21 2.2 96
R 100 0.4 97 R 16 1.3 98 R 13 1.4 99 R 12 2.7 100 R 14 3.9
Examples 101 to 111
Production of (R)-2-amino-1-phenylethanol
[0555] A medium for preparation of cells (3) having the following
composition was prepared. For yeasts and fungi, the media for
preparation of cells (1) used in Examples 1 to 100 was
employed.
[0556] [Medium for Preparation of Cells (3): for Bacteria]
8 Glucose 2.0% by weight Yeast extract 0.5% by weight Meat extract
0.3% by weight Polypeptone 0.3% by weight Ammonium sulfate 0.2% by
weight Potassium primary 0.1% by weight phosphate Magnesium sulfate
0.05% by weight Deionized water 96.55% by weight (pH 7.0)
[0557] A test tube of inner diameter of 21 mm was charged with 5 ml
of the media respectively. After sterilization, the tube was
inoculated with one of following microorganism. The medium (1) was
used for a yeast and fungus and the medium (3) was employed for a
bacterium respectively. The inoculated tube was incubated under
shaking at 30.degree. C. for 48 hours.
[0558] Example 101: Candida maltosa IFO 1977
[0559] Example 102: Candida maltosa IFO 1978
[0560] Example 103: Lodderomyces elongisporus IFO 1676
[0561] Example 104: Catenuloplanes japonicus IFO 14176
[0562] Example 105: Pilimelia terevasa IFO 14556
[0563] Example 106: Saccharothrix australiensis IFO 14444
[0564] Example 107: Seratia marcescens IFO 3735
[0565] Example 108: Enterococcus faecalis IFO 12964
[0566] Example 109: Lactobacillus casei subsp. casei NRIC 1042
[0567] Example 110: Pediococcus acidilactici NRIC 1089
[0568] Example 111: Lactococcus lactis subsp. lactis AHU 1089
[0569] Cells were collected by centrifuging and a test tube of
inner diameter of 21 mm was charged with 1 ml of 0.1M phosphate
buffer (pH 7.0) containing 0.5% by weight of
aminomethyl=phenyl=ketone hydrochloride and 5% by weight of
glucose. To the charged tube, were suspended the cells and the
reaction was carried out on a reciproshaker at 30.degree. C. for 48
hours.
[0570] After completion of the reaction, the cells were removed off
by centrifuging, and the supernatant was submitted to high
performance liquid chromatography to determine the amount, the
absolute configuration and the optical purity of the product
(R)-2-amino-1-phenylethanol. The results are shown in Table 6. In
the Table, the term "amount" refers to the amount of the product
(R)-2-amino-1-phenylethanol in the reaction mixture.
9 TABLE 6 Optical Example Absolute purity Amount No. configuration
(% e e) (mg/ml) 101 R 68 2.4 102 R 89 3.1 103 R 100 3.7 104 R 100
1.6 105 R 100 1.6 106 R 100 1.7 107 R 100 1.6 108 R 76 1.8 109 R
100 1.5 110 R 65 2.2 111 R 84 2.1
Examples 112 to 115
Production of (R)-2-amino-1-(3-chlorophenyl)ethanol
[0571] The procedures of cultivation, reaction and determination in
Example 101 were repeated except for employing the following
strains of microorganisms and using
aminomethyl=3-chlorophenyl=ketone hydrochloride instead of
aminomethyl=phenyl=ketone hydrochloride. The proportion, the
absolute configuration and the optical purity of the product
(R)-2-amino-1-(3-chlorophenyl)ethanol were determined. The results
were set forth in Table 7. In the Table, the term "amount" means
the amount of (R)-2-amino-1-(3-chlorophenyl)ethanol in the reaction
mixture (mg/ml).
[0572] Example 112: Lodderomyces elongisporus IFO 1676
[0573] Example 113: Candida maltosa IFO 1978
[0574] Example 114: Candida maltosa IFO 1977
[0575] Example 115: Pilimelia terevasa IFO 14556
10 TABLE 7 Optical Example Absolute purity Amount No. configuration
(% e e) (mg/ml) 112 R 100 2.3 113 R 100 2.3 114 R 100 1.9 115 R 95
1.3
Examples 116 to 118
Production of (R)-2-amino-1-(3,4-dihydroxyphenyl)ethanol
[0576] The cultivation, reaction and analysis were conducted in the
same manner as in Example 101, except that the following strains of
microorganisms were respectively used and
aminomethyl=3,4-dihydroxyphenyl- =ketone hydrochloride was employed
instead of aminomethyl=phenyl=ketone hydrochloride to determine the
proportion, the absolute configuration and the optical purity of
the product (R)-2-amino-1-(3,4-dihydroxyphenyl)etha- nol. The
results are shown in Table 8. In the Table 8, the term "amount"
means the amount of the (R)-2-amino-1-(3,4-dihydroxyphenyl)ethanol
in the reaction mixture (mg/ml).
[0577] Example 116: Lodderomyces elongisporus IFO 1676
[0578] Example 117: Candida maltosa IFO 1977
[0579] Example 118: Candida maltosa IFO 1978
11 TABLE 8 Optical Example Absolute purity Amount No. configuration
(% e e) (mg/ml) 116 R 100 1.9 117 R 100 1.7 118 R 100 2.1
Example 119
Production of (R)-2-amino-1-(3-chlorophenyl)ethanol
[0580] A 2.6-liter jar fermenter was charged with 1.5 liter of GY
medium containing 2.4% by weight of glucose, 1.8% by weight of
yeast extract, 0.2% by weight of ammonium sulfate, 0.1% by weight
of potassium primary phosphate, 15 ppm of ferrous sulfate
heptahydrate, 15 ppm of zinc sulfate heptahydrate. After sterilized
by an autoclave, the jar fermenter was inoculated with Candida
maltosa IFO 1978. The inoculated jar fermenter was incubated at pH
6.0, at 30.degree. C., under aeration at 1 vvm, with stirring at a
rate of 400 rpm for 24 hours.
[0581] After completion of incubation, the cells were collected and
suspended to 1 liter of 0.1M phosphate buffer (pH 6.5) charged in a
2.6-liter jar fermenter. To the mixture, was added 20 g of
aminomethyl=3-chlorophenyl=ketone and 50 g of glucose, and the
reaction was carried out at 30.degree. C., without aeration, and
stirring at a rate of 200 rpm for 48 hours. In the course of the
reaction, the pH of the reaction mixture was adjusted at 6.5 with
the use of an 20% aqueous solution of sodium hydroxide. On the way
of the reaction, according to the analysis of the reaction mixture,
(R)-2-amino-1-(3-chlorophenyl)ethan- ol was produced in a
concentration of 13.2 g per liter.
[0582] After completion of the reaction, the reaction mixture was
acidified to pH 2 or less by using a concentrated hydrochloric
acid, and the cells were removed off by centrifugation. The
obtained supernatant was subjected to dehydration-concentration
with using a vacuum rotary evaporator at a bath-temperature of
50.degree. C. The resultant concentrated was adjusted to pH 9.0 by
adding a 20% aqueous solution of sodium hydroxide and was added
with 50 g of sodium chloride and extracted three times with 300 ml
of methylene chloride. The methylene chloride extract was dried
over anhydrous sodium sulfate and the solvent was removed off under
reduced pressure to obtain 9.8 g of an oily substance. The optical
purity of the obtained (R)-2-amino-1-(3-chlorophenyl)ethanol was
100% e e by the analysis with high performance liquid
chromatography using an optical resolution column [column: product
of Daicel Chemical Industries, Ltd., Crownpack CR (+) (trade
name)]
[0583] In the following Examples 120 to 172, the determination of
optical purity of the obtained
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]eth- anol derivative
or a salt thereof was carried out with high performance liquid
chromatography using an optical resoluting column [column:
manufactured by Daicel Chemical Industries, Ltd., Chiralpack AD
(trade name); solvent: n-hexane/2-propanol/diethylamine=90/10/0.1;
flow rate: 0.5 ml/minute; temperature: 25.degree. C.; wavelength:
230 nm].
Example 120
Production of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methy-
lethyl]amino]ethanol
[0584] To 5.83 g of methyl=3,4-dimethoxyphenylmethyl=ketone, 5.15 g
of (R)-2-amino-1-(3-chlorophenyl)ethanol and 50 mg of platinum
oxide, were added 15 ml of isopropyl alcohol, 30 ml of diisopropyl
ether and 2 drops of acetic acid. The mixture was subjected to
reduction at room temperature and at 1 atm under hydrogen
atmosphere for 24 hours. After completion of the reaction, platinum
oxide was removed off by filtration and the solvent was distilled
off under reduced pressure to obtain 8.43 g of white oil of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-me-
thylethyl]amino]ethanol (yield: 80.3%). The optical purity of the
obtained (R,R)-isomer was 80%.
Examples 121 to 128
Production of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methy-
lethyl]amino]ethanol
[0585]
(R,R)-1-(3-Chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]-
amino]ethanol was obtained in the same manner as in Example 120
except for using 0.344 g of
methyl=3,4-dimethoxyphenylmethyl=ketone, 0.304 g of
(R)-2-amino-1-(3-chlorophenyl)ethanol, 50 mg of platinum oxide and
10 ml of a solvent. The solvent, the yield and the optical purity
of the (R,R)-isomer are set forth in Table 9. In the following
Tables 9 to 13, the term "OMe" means a methoxy group, the term "Me"
refers to a methyl group, the term "NHAc" means an amino group
substituted with an acetyl group, and the term "PTsOH" refers to
p-toluenesulfonic acid. The term "optical purity" refers to the
optical purity of the (R,R)-isomer.
12TABLE 9 Optical Example Solvent Yield purity No. used (%) (%) 121
Methanol 73 75 122 Ethanol 74 75 123 Isopropyl alcohol 70 74 124
Toluene-methanol 78 72 125 Toluene 58 73 126 Tetrahydrofuran 63 74
127 Acetonitrile 50 68 128 Ethyl acetate 55 70
Examples 129 to 141
Production of
(R,R)-1-phenyl-2-[[2-(phenyl)-1-alkylethyl]amino]ethanol
Derivatives
[0586] The procedures of Example 120 were repeated to obtain an
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative
except for using platinum oxide as the catalyst for catalytic
reduction, isopropyl alcohol-diisopropyl ether (1:2) as the
solvent, acetic acid as the acid, and the compounds shown in the
Table 10 as the raw materials. The raw materials, the yields, the
optical purity of the (R,R)-isomer were set forth in Table 10.
13TABLE 10 Optical Example Yield purity No. R.sup.1 R.sup.2 R.sup.3
R.sup.4 R.sup.5 Z R.sup.6 R.sup.7 R.sup.8 R.sup.9 R.sup.10 R.sup.11
(%) (%) 129 H H H H H H H H H H H Me 80 75 130 H H H H H H H OMe
OMe H H Me 82 75 131 H H H H H H H OH OH H H Me 78 75 132 H
CF.sub.3 H H H H H H H H H Me 84 80 133 H H Cl H H H H H H H H Me
83 78 134 H H Cl H H H H OMe OMe H H Me 85 78 135 H Cl Cl H H H H H
H H H Me 80 79 136 H Cl Cl H H H H OMe OMe H H Me 82 79 137 H OMe H
H H H H OMe OMe H H Me 80 78 138 H OMe H H H H H H H H H Me 78 78
139 H NHAc OMe H H H H OMe OMe H H Me 81 82 140 H H CF.sub.3 H H H
H H H H H Me 77 83 141 H H CF.sub.3 H H H H OMe OMe H H Me 82
80
Example 142
Production of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methy-
lethy]amino]ethanol
[0587] To 40 ml of benzene solution of
(R)-2-amino-1-(3-chlorophenyl)ethan- ol (0.304 g), was added 0.344
g of methyl=3,4-dimethoxyphenylmethyl=ketone- . The mixture was
refluxed in an apparatus equipped with a water-trap for one hour
and the water produced was removed from the reaction system. After
cooling the reaction mixture, the solvent was distilled off under
reduced pressure, and the residue was dissolved into 10 ml of
methanol. To the mixture was added platinum oxide, and the reducing
reaction was conducted at room temperature at 1 atm pressure under
hydrogen atmosphere for 24 hours. After removing off platinum oxide
by filtration, the solvent was distilled off under reduced pressure
to give 0.501 g of white oil of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl-
]amino]ethanol (yield 81.0%). The optical purity of the
(R,R)-isomer was 80%.
Examples 143 to 150
Production of
(R,R)-1-phenyl-2-[[2-(phenyl)-1-alkylethyl]amino]ethanol
Derivatives
[0588] (R,R)-1-Phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivatives were obtained in the same manner as in Example 142 by
using isopropyl alcohol-diisopropyl ether (1:2) as the solvent, and
the raw materials and the catalysts for catalytic reduction are set
forth in Table 11. The raw materials, the catalysts for catalytic
reduction, yields and the optical purity of the (R,R)-isomers are
shown in Table 11.
14TABLE 11 Optical Example Yield purity No. R.sup.1 R.sup.2 R.sup.3
R.sup.4 R.sup.5 Z R.sup.6 R.sup.7 R.sup.8 R.sup.9 R.sup.10 R.sup.11
Catalyst (%) (%) 143 H Cl H H H H H OMe OMe H H Me Pt--C 75 80 144
H H H H H H H OMe OMe H H Me Platinum oxide 85 78 145 H H H H H H H
OMe OMe H H Me Pt--C 76 77 146 H H H H H H H H H H H Me Platinum
oxide 82 75 147 H H H H H H H H H H H Me Pt--C 74 72 148 H H H H H
H H H H H H Me Pd--C 60 70 149 H H H H H H H H H H H Me Ru 65 73
150 H H H H H H H H H H H Me Rh 77 77
Example 151
Production of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methy-
lethyl]amino]ethanol
[0589] To 12.36 g of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)--
1-methylethyl]amino]ethanol having an optical purity of 89%, was
added toluene solution of hydrogen chloride to obtain a
hydrochloride of the titled compound, and the solvent was distilled
off under reduced pressure to give an oil. The oil was subjected to
recrystallization by using a mixture of isopropyl alcohol and
diisopropyl ether to give 7.57 g of white powder. A mixture of a
10% sodium hydroxide/ethyl acetate was added to the powder and the
solvent was distilled off to give
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]-
ethanol (7.58 g, optical purity 98%).
Example 152
Production of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methy-
lethyl]amino]ethanol
[0590] To 1 ml of isopropyl alcohol was added 0.103 g of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]-
ethanol having an optical purity of 64% to be dissolved, and 0.057
g of (R)-(-)-2-(2,4,6-trimethylphenyl)propionic acid and 2 ml of
diisopropyl ether were added to the solution successively to give
0.102 g of white powder. To the powder was added 10% sodium
hydroxide/ethyl acetate, and the solvent was distilled off to
afford 0.065 g of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]-
ethanol having an optical purity of 92%.
Example 153
Production of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methy-
lethyl]amino]ethanol
[0591] To 1 ml of isopropyl alcohol was added 0.103 g of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]-
ethanol having an optical purity of 64% to be dissolved and 0.056 g
of (S)-2-(2,5-dimethylphenyl)propionic acid and 4 ml of diisopropyl
ether were added to the solution successively to give 0.046 g of
white powder. A mixture of 10% sodium hydroxide/ethyl acetate was
added to the white powder and the solvent was distilled off to
yield 0.030 g of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]-
ethanol having an optical purity of 99.4%.
Examples 154 to 168
Production of
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
Derivatives
[0592] The procedures of Example 153 were repeated except that
isopropyl alcohol-diisopropyl ether (1:2) was used as the solvent
and the raw materials and the acids shown in Table 12 were employed
to give (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivatives. The optical purity of the raw materials was 65%. The
optical purity of the (R,R)-isomer thus obtained was set forth in
Table 12.
15TABLE 12 Optical Example purity No. R.sup.1 R.sup.2 R.sup.3
R.sup.4 R.sup.5 Z R.sup.6 R.sup.7 R.sup.8 R.sup.9 R.sup.10 R.sup.11
Acid (%) 154 H Cl H H H H H OMe OMe H H Me Hydrochloric acid 85 155
H Cl H H H H H OMe OMe H H Me Acetic acid 85 156 H Cl H H H H H OMe
OMe H H Me Benzoic acid 80 157 H Cl H H H H H OMe OMe H H Me Oxalic
acid 82 158 H Cl H H H H H OMe OMe H H Me 3,5-Dimethylbenzoic acid
85 159 H Cl H H H H H OMe OMe H H Me o-Toluic acid 88 160 H Cl H H
H H H OMe OMe H H Me m-Toluic acid 88 161 H Cl H H H H H OMe OMe H
H Me pTsOH 95 162 H H H H H H H OMe OMe H H Me Hydrochloric acid 80
163 H H H H H H H H H H H Me Hydrochloric acid 83 164 H CF.sub.3 H
H H H H H H H H Me Hydrochloric acid 82 165 H OMe H H H H H H H H H
Me Hydrochloric acid 83 166 H H CF.sub.3 H H H H OMe OMe H H Me
Hydrochloric acid 80 167 H Cl H H H H H H H H H Me Hydrochloric
acid 83 168 H Cl H H H H H H H H H Me Hydrochloric acid 80
Example 169
Production of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methy-
lethyl]amino]ethanol
[0593] To
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methyleth-
yl]amino]ethanol (1.05 g) having an optical purity of 65% was added
a toluene solution of hydrogen chloride to give a hydrochloride,
and the solvent was distilled off under reduced pressure to afford
an oily substance. Triethylamine (0.15 g) was added to the obtained
oily substance, and the mixture was subjected to recrystallization
with the use of a mixture of isopropyl alcohol and diisopropyl
ether to give 0.80 g of white powder. To the white powder was added
10% sodium hydroxide/ethyl acetate, and the solvent was distilled
off to afford 0.70 g of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]a-
mino]ethanol (optical purity 90%).
Examples 170 and 171
Production of
(R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
Derivatives
[0594] (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol
derivatives were obtained in the same manner as in Example 169 by
using isopropyl alcohol-diisopropyl ether (1:2) as the solvent, and
the acids and bases shown in Table 13 as the acids and bases. The
raw materials, the acids, the bases and the optical purity of the
product (R,R)-isomer are set forth in Table 13. The optical purity
of the raw material was 65%. In the Table, the term "HCl" means
hydrochloric acid.
16TABLE 13 Optical Example purity No. R.sup.1 R.sup.2 R.sup.3
R.sup.4 R.sup.5 Z R.sup.6 R.sup.7 R.sup.8 R.sup.9 R.sup.10 R.sup.11
Acid Base (%) 170 H H H H H H H OMe OMe H H Me HCl Triethylamine 88
171 H Cl H H H H H OMe OMe H H Me Acetic acid Triethylamine 85
Example 172
Production of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methy-
lethyl]amino]ethanol
[0595] To a mixture of 5.83 g of
methyl=3,4-dimethoxyphenylmethyl=ketone, 5.15 g of
(R)-2-amino-1-(3-chlorophenyl)ethanol and 50 mg of platinum oxide
were added 15 ml of isopropyl alcohol and 30 ml of diisopropyl
ether, and the reducing reaction was carried out at room
temperature, at 1 atm under hydrogen atmosphere for 24 hours. After
removing off platinum oxide by filtration, the solvent was
distilled off under reduced pressure to give 6.51 g of white oil of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimeth-
oxyphenyl)-1-methylethyl]amino]ethanol (yield 62%). The optical
purity of the (R,R)-isomer was 65%.
Examples 173 to 222
Production of (S)-2-amino-1-(3-chlorophenyl)ethanol
[0596] (S)-2-Amino-1-(3-chlorophenyl)ethanol was produced in the
similar manner as in Examples 1 to 100, except that the following
strains of microorganisms were used respectively.
[0597] The results of determination of the amount, the absolute
configuration and the optical purity of the obtained
(S)-2-amino-1-phenylethanol are shown in Tables 14 to 16. In the
Tables 14 to 16, the term "amount" means the amount (mg/ml) of
(S)-2-amino-1-(3-chlorophenyl)ethanol in the reaction mixture.
[0598] [Yeasts]
[0599] Example 173: Saccharomyces cerevisiae IFO 0718
[0600] Example 174: Saccharomyces cerevisiae IFO 0735
[0601] Example 175: Saccharomyces cerevisiae IFO 0206
[0602] Example 176: Pichia fabianii IFO 1254
[0603] Example 177: Schizosaccharomyces pombe IAM 4890
[0604] Example 178: Candida guilliermondii IFO 0566
[0605] Example 179: Candida melibiosica IFO 10238
[0606] Example 180: Hansenula polymorpha DSM 70277
[0607] Example 181: Yarrowia lipolytica IFO 0746
[0608] Example 182: Geotrichum capitatum IFO 0743
[0609] Example 183: Geotrichum capitatum IFO 1197
[0610] [Fungi]
[0611] Example 184: Aspergillus niger IFO 4415
[0612] Example 185: Aspergillus niger AHU 7115
[0613] Example 186: Aspergillus ficuum IFO 4318
[0614] Example 187: Aspergillus cavdidus IFO 4389
[0615] Example 188: Aspergillus oryzae IFO 4390
[0616] Example 189: Aspergillus oryzae var. brunneus JCM 2240
[0617] Example 190: Aspergillus tamarii IAM 2138
[0618] Example 191: Penicillium chrysogenum IAM 7142
[0619] Example 192: Corynespora cassiicola IFO 6724
[0620] Example 193: Fusarium solani IFO 5232
[0621] Example 194: Gelasinospora cerealis IFO 6759
[0622] Example 195: Helminthosporium sigmoideum var. irreavl IFO
5273
[0623] Example 196: Mortierelia isabellina IFO 6336
[0624] Example 197: Mortierelia ramanniana var. ramanniana IFO
7825
[0625] Example 198: Neosartorya fischeri var. spinosa IFO 5955
[0626] Example 199: Phytophthora capsici IFO 8386
[0627] Example 200: Talaromyces flavus var. flavus IFO 7231
[0628] Example 201: Scolecobasidium terreum IFO 8854
[0629] [Bacteria & Actinomyces]
[0630] Example 202: Micrococcus luteus IAM 12009
[0631] Example 203: Micrococcus luteus IAM 12144
[0632] Example 204: Micrococcus luteus IAM 1157
[0633] Example 205: Micrococcus luteus IFO 3333
[0634] Example 206: Brevibacterium iodinum IFO 3558
[0635] Example 207: Corynebacterium sepedonicum IFO 3306
[0636] Example 208: Xanthomonas Sp. IFO 12997
[0637] Example 209: Actinomaqura cremea subsp. cremea IFO 14182
[0638] Example 210: Enterobacter aerogenes IFO 12010
[0639] Example 211: Pseudomonas aeruginosa IFO 3445
[0640] Example 212: Hafnia alvei IFO 3731
[0641] Example 213: Actinoplanes lobatus IFO 12513
[0642] Example 214: Escherichia coli IAM 1239
[0643] Example 215: Bacillus licheniformis BGSC 5A18
[0644] Example 216: Listonella anguillarum IFO 12710
[0645] Example 217: Nosardioides flavus IFO 14396
[0646] Example 218: Amycolata autotrophica IFO 12743
[0647] Example 219: Rhodococcus luteus JCM 6162
[0648] Example 220: Rhodococcus erythropolis JCM 6821
[0649] Example 221: Rhodococcus erythropolis JCM 6827
[0650] Example 222: Rhodococcus globerrulus IFO 14531
17 TABLE 14 Optical Example Absolute purity Amount No.
configuration (% e e) (mg/ml) 173 S 59 0.3 174 S 100 0.1 175 S 54
0.5 176 S 69 0.9 177 S 70 0.3 178 S 67 0.05 179 S 78 0.1 180 S 66
0.4 181 S 100 0.04 182 S 100 0.2 183 S 73 0.5 184 S 21 0.8 185 S 64
0.3 186 S 57 0.6 187 S 19 0.8 188 S 22 0.7 189 S 24 1.0 190 S 57
0.5 191 S 17 0.6 192 S 14 0.5
[0651]
18 TABLE 15 Optical Example Absolute purity Amount No.
configuration (% e e) (mg/ml) 193 S 52 0.7 194 S 38 0.4 195 S 72
0.4 196 S 31 0.8 197 S 61 0.9 198 S 10 1.0 199 S 24 0.8 200 S 13
0.2 201 S 20 0.8 202 S 97 1.0 203 S 34 5.5 204 S 31 5.2 205 S 55
1.0 206 S 75 1.4 207 S 64 1.8 208 S 53 1.6 209 S 47 1.1 210 S 41
1.1 211 S 12 6.2 212 S 13 3.2
[0652]
19 TABLE 16 Optical Example Absolute purity Amount No.
configuration (% e e) (mg/ml) 213 S 13 0.9 214 S 13 2.2 215 S 12
2.9 216 S 12 6.2 217 S 11 1.4 218 S 10 1.4 219 S 28 2.5 220 S 47
1.8 221 S 40 2.2 222 S 48 1.8
Examples 223 to 282
Production of (S)-2-amino-1-phenylethanol
[0653] A test tube of 21 mm in inner diameter was charged with 5 ml
of YM medium containing 2.0% by weight of glucose, 0.3% by weight
of yeast extract, 0.3% by weight of malt extract and 0.5% by weight
of polypeptone (pH 6.0) for yeast or fungus, or 5 ml of PM medium
containing 2.0% by weight of glucose, 0.5% by weight of yeast
extract, 0.3% by weight of meat extract, 0.3% by weight of
polypeptone, 0.2% by weight of ammonium sulfate, 0.1% by weight of
potassium phosphate and 0.05% by weight of magnesium sulfate (pH
7.0). After sterilization, the tube was respectively inoculated
with one of the following strains of microorganisms. The inoculated
tube was incubated under shaking at 30.degree. C. for 48 hours.
[0654] [Yeasts and Fungi]
[0655] Example 223: Botryoascus synnaedendrus IFO 1604
[0656] Example 224: Brettanomyces anomalus IFO 0642
[0657] Example 225: Candida albicans IFO 1856
[0658] Example 226: Candida beechii IFO 10229
[0659] Example 227: Candida ergatensis IFO 10233
[0660] Example 228: Candida fusiformata IFO 10225
[0661] Example 229: Candida guilliermondii IFO 0566
[0662] Example 230: Candida halonitratophila IFO 1595
[0663] Example 231: Candida oregonensis IFO 1980
[0664] Example 232: Candida peltata IFO 1853
[0665] Example 233: Candida parapsilosis IFO 10305
[0666] Example 234: Candida sorboxylosa IFO 1578
[0667] Example 235: Citeromyces matritensis IFO 0954
[0668] Example 236: Clavispora lusitaniae IFO 1019
[0669] Example 237: Debaryomyces hansenii var. hansenii IFO
0083
[0670] Example 238: Dipodascus ovetensis IFO 1201
[0671] Example 239: Eremascus fertilis IFO 0691
[0672] Example 240: Galactomyces reessii IFO 1112
[0673] Example 241: Geotrichum fermentans CBS 452.83
[0674] Example 242: Geotrichum candidum IFO 4601
[0675] Example 243: Geotrichum capitatum IFO 1197
[0676] Example 244: Geotrichum klebahnii JCM 2171
[0677] Example 245: Issatchenkia scutulata var. scutulata IFO
10069
[0678] Example 246: Kluyveromyces lactis IFO 1267
[0679] Example 247: Kluyveromyces marxianus var. bulgaricus IAM
4829
[0680] Example 248: Kondoa malvinella IFO 1935
[0681] Example 249: Lipomyces starkeyi IFO 1289
[0682] Example 250: Malassezia furfur IFO 0656
[0683] Example 251: Oosporidium margaritiferum IFO 1208
[0684] Example 252: Pachysolen tannophilus IFO 1007
[0685] Example 253: Pichia farinosa IFO 1163
[0686] Example 254: Pichia holstii IFO 0986
[0687] Example 255: Pichia subpelliculosa IFO 0808
[0688] Example 256: Pichia toletana IFO 0950
[0689] Example 257: Rhodosporidium diobovatum IFO 0688
[0690] Example 258: Rhodotorula glutinis IFO 0389
[0691] Example 259: Rhodotorula glutinis var. dairenensis IFO
0415
[0692] Example 260: Saccharomyces kluyveri IFO 1894
[0693] Example 261: Saccharomyces paradoxus IFO 0259
[0694] Example 262: Saccharomycodes ludwigii IFO 0798
[0695] Example 263: Saccharomycopsis capsularis IFO 0672
[0696] Example 264: Schizoblastosporion kobayasii IFO 1644
[0697] Example 265: Schizosaccharomyces pombe IFO 0358
[0698] Example 266: Sporidiobolus pararoseus JCM 5350
[0699] Example 267: Sporobolomyces pararoseus IFO 0471
[0700] Example 268: Sporobolomyces salmonicolor AHU 3982
[0701] Example 269: Wickerhamiella domercquii IFO 1857
[0702] Example 270: Wingea robertsii IFO 1277
[0703] Example 271: Zygosaccharomyces bailii DSM 70492
[0704] Example 272: Zygosaccharomyces fermentati IFO 0021
[0705] [Bacteria]
[0706] Example 273: Bacilus subtilis IFO 3037
[0707] Example 274: Comamonas terrigena IFO 13299
[0708] Example 275: Rhodobacter sphaeroides IFO 12203
[0709] Example 276: Enterococcus faecalis NRIC 1142
[0710] Example 277: Lactobacillus lactis AHU 1059
[0711] Example 278: Pediococcus acidilactici IFO 3076
[0712] Example 279: Leuconostoc mesenteroides subsp. dextranicum
NRIC 1085
[0713] Example 280: Leuconostoc mesenteroides AHU 1071
[0714] Example 281: Leuconostoc oenos DSM 20252
[0715] Example 282: Streptpcoccus uberis NRIC 1153
[0716] The cells were isolated by centrifuging and suspended in 1
ml of 0.1M phosphate buffer (pH 7.0) containing 0.5% by weight of
aminomethyl=phenyl=ketone hydrochloride and 5% by weight of
glucose. A test tube of 21 mm inner diameter was charged with the
suspension and reaction was conducted on a reciprocating shaker at
30.degree. C. for 48 hours.
[0717] After completion of the reaction, the cells were removed
from the reaction suspension by centrifuging. The supernatant was
subjected to the analysis with high performance liquid
chromatography to determine the amount, the absolute configuration
and the optical purity of the product (S)-2-amino-1-phenylethanol.
The results are set forth in Tables 17 to 19. In the Tables 17 to
19, the term "amount" refers to the amount of the
(S)-2-amino-1-phenylethanol in the reaction mixture (mg/ml) and the
term "optical purity" means the optical purity of the (S)-form.
20 TABLE 17 Optical Example Absolute purity Amount No.
configuration (% e e) (mg/ml) 223 S 100 1.6 224 S 100 1.9 225 S 100
1.9 226 S 100 1.6 227 S 91 2.0 228 S 95 1.8 229 S 92 1.7 230 S 100
1.8 231 S 100 1.6 232 S 100 1.8 233 S 100 1.7 234 S 100 1.8 235 S
100 2.6 236 S 74 1.7 237 S 100 1.7 238 S 65 1.9 239 S 66 1.9 240 S
88 2.8 241 S 84 2.0 242 S 100 1.7
[0718]
21 TABLE 18 Optical Example Absolute purity Amount No.
configuration (% e e) (mg/ml) 243 S 90 2.1 244 S 78 3.2 245 S 100
1.7 246 S 100 2.4 247 S 100 1.7 248 S 100 1.9 249 S 71 2.0 250 S
100 1.7 251 S 100 2.5 252 S 74 1.8 253 S 100 1.7 254 S 100 2.2 255
S 100 1.7 256 S 100 1.6 257 S 100 1.9 258 S 76 1.9 259 S 90 1.9 260
S 100 3.4 261 S 100 1.9 262 S 100 1.5
[0719]
22 TABLE 19 Optical Example Absolute purity Amount No.
configuration (% e e) (mg/ml) 263 S 100 1.7 264 S 69 1.7 265 S 100
1.6 266 S 100 1.8 267 S 72 1.6 268 S 100 2.4 269 S 100 1.7 270 S
100 3.1 271 S 100 2.0 272 S 85 1.9 273 S 96 1.6 274 S 94 2.0 275 S
100 1.7 276 S 63 2.9 277 S 100 2.9 278 S 100 1.5 279 S 74 2.4 280 S
100 1.6 281 S 100 2.3 282 S 81 2.7
[0720] In the following Examples 283 to 303, the chemical purity
and the optical purity of the product compound were determined with
high performance liquid chromatography using the following columns,
and unless specifically defined, the term "%" refers to % by
weight.
[0721] chemical purity: column; manufactured by G. L. Science,
Ltd., Innertosyl ODS-2 (trade name)
[0722] optical purity: column; manufactured by Daicel Chemical
Industries, Ltd., Crownpack CR (trade name)
Example 283
Production of 2-amino-1-phenylethanol
[0723] A mixture of 3 kg of a 25% aqueous solution of NH.sub.3 (44
moles) and 1 kg of methanol was heated at 40.degree. C., and 120 g
of styrene oxide (1.0 mole) was added dropwise to the mixture with
taking 30 minutes. After completion of adding, the reaction mixture
was left at 40.degree. C. for 3.5 hours for aging or digesting, and
NH.sub.3 was removed under reduced pressure at 20.degree. C.
Consecutively, the mixture was heated at 40 to 60.degree. C. to
remove a substance having a lower boiling point, to give 135 g of a
concentrate. The concentrate contained 67% by weight of
2-amino-1-phenylethanol (0.66 mole), 19% by weight of the
corresponding position-isomer and 14% by weight of other
by-products.
[0724] The obtained concentrate (13.5 g) was dissolved in 135 g of
dichloroethane, and 3.8 g (0.038 mole) of triethylamine was added
to the solution. The mixture was heated at 50.degree. C. and 1.67
NL (0.075 mole) of gaseous hydrochloric acid was bubbled into the
mixture with taking one hour. After accomplishment of bubbling, the
resultant mixture was left for 30 minutes for aging, and was cooled
at 20.degree. C., and was subjected to vacuum filtration to give
crystals. The obtained wet crystals were dried in vacuo to give
11.4 g of hydrochloride. The composition of the crystals were such
that 93.4% by weight of 2-amino-1-phenylethanol hydrochloride, 0.7%
by weight of the corresponding position-isomer and 6% by weight of
triethylamine hydrochloride, and the other by-products were not
detected. The yield of the object compound from the reaction
concentrate was 93.5%.
[0725] The obtained crystals were dispersed in 10 g of water, and
to the dispersion, was added 11 g of a 25% aqueous solution of
sodium hydroxide (0.068 mole) at 25.degree. C. with taking 20
minutes to liberate the impurity. The resultant mixture was
extracted with 120 g of dichloroethane and the dichloroethane
extract was washed twice with 20 g of saturated aqueous solution of
sodium chloride, and the distillation of the solvent at 40.degree.
C. under reduced pressure gave 7.87 g of crystals of
2-amino-1-phenylethanol having the purity of 99.1%. The yield from
the reaction concentration was 86%.
Example 284
Production of 2-amino-1-phenylethanol
[0726] In 100 g of ethyl acetate was dissolved 13.5 g of the
concentrate obtained in Example 283 by the reaction of styrene
oxide, containing 67% by weight of 2-amino-1-phenylethanol (0.066
mole), 19% by weight of the corresponding position-isomer and 14%
by weight of other by-product. Hydrochloric acid gas (1.46 NL,
0.065 mole) was bubbled into the solution at 60.degree. C. for 20
minutes, and the resultant mixture was cooled at 20.degree. C. The
resultant crystals were isolated by filtration and were dried in
vacuo to give 10.5 g of crystals of salts formed with hydrochloric
acid. The crystals contained 98% by weight of
2-amino-1-phenylethanol hydrochloride and 1.9% by weight of the
corresponding position-isomer, and the other by-products were not
detected. The yield of the object compound from the reaction
concentrate was 90%.
[0727] The liberation in the same manner as in Example 283 gave
7.65 g of 2-amino-1-phenylethanol having a purity of 98.1%. The
yield of the compound from the reaction concentrate was 83%.
Example 285
Production of 2-amino-1-phenylethanol
[0728] The concentrate (13.5 g) obtained from the reaction of
styrene oxide in Example 283 was dissolved in 135 g of
dichloromethane, and into the solution, was bubbled 2.24 NL (0.1
mole) of gaseous hydrochloric acid at 30.degree. C. with taking 30
minutes. The reaction mixture was filtrated to give crystals and
the resultant crystals were dried in vacuo to give 14.0 g of
crystals of salts formed with hydrochloric acid. The composition of
the crystals was such that 78% by weight of 2-amino-1-phenylethanol
hydrochloride and 21.5% by weight of the corresponding
position-isomer, and the other by-products were not detected.
[0729] The crystals were dispersed in 80 g of dichloromethane, and
to the dispersion was added 4.1 g (0.04 mole) of triethylamine at
40.degree. C. The resultant mixture was left for 30 minutes for
aging and was cooled at 20.degree. C. The resultant crystalline
were isolated by filtration and dried in vacuo to afford 10.6 g of
crystals of the acid formed with hydrochloric acid containing 99.2%
by weight of 2-amino-1-phenylethanol hydrochloride and 0.6% by
weight of the corresponding position-isomer. The other by-products
were not detected. The yield of the object compound from the
reaction concentrate was 92.6%.
[0730] The liberation of the salts of hydrochloric acid was
conducted in the same manner as in Example 283 to give 7.78 g of
crystals of 2-amino-1-phenylethanol having a chemical purity of
99.3%, where the yield of the desired from the reaction
concentration was 85.4%.
Examples 286 to 293
Production of 2-amino-1-phenylethanol Derivatives
[0731] The procedures of Example 283 were repeated except for using
the following compounds instead of styrene oxide to obtain the
corresponding 2-amino-1-phenylethanol derivatives.
[0732] Example 286: 3-chlorostyrene oxide
[0733] Example 287: 3,4-dichlorostyrene oxide
[0734] Example 288: 2-methoxystyrene oxide
[0735] Example 289: 3,4-dimethoxystyrene oxide
[0736] Example 290: 4-hydroxystyrene oxide
[0737] Example 291: 3-chloro-4,5-dihydroxystyrene oxide
[0738] Example 292: 2-benzylcarbonylstyrene oxide
[0739] Example 293: 3-hydroxymethyl-4-benzyloxystyrene oxide
[0740] The composition at each step, and the yield are shown in
Table 20. In the Table 20, the symbol "A" represents the
2-amino-1-phenylethanol derivatives, the symbol "B" means the
corresponding position-isomer, and the symbol "C" refers to other
by-product. The numerals in the Table means the composition ratio
(% by weight), and the term "yield" refers to the yield from the
reaction concentrate.
23TABLE 20 Ring-cleavage Example of epoxide Hydrochloride
Liberation Yield No. A B C A B C A B C (%) 286 76 11 13 99 1 0 99 1
0 88 287 79 9 12 99 1 0 99 1 0 89 288 71 13 16 99 1 0 99 1 0 84 289
72 12 16 99 1 0 99 1 0 84 290 65 11 24 98 1 1 98 1 1 75 291 60 12
28 97 1 2 97 1 2 75 292 70 15 15 99 1 0 99 1 0 81 293 68 14 18 98 1
1 98 1 1 77
Example 294
Production of 2-amino-1-phenylethanol
[0741] A mixture of 265 g of a 25% aqueous solution of NH.sub.3
(3.9 moles) and 90 g of methanol was heated at 40.degree. C., and
13.4 g (0.086 mole) of styrene chlorohydrin was added dropwise to
the mixture for 30 minutes. After completion of addition, the
resultant mixture was left for 4 hours for aging. The mixture was
cooled at 20.degree. C. and NH.sub.3 was removed off under reduced
pressure, followed by heating to distill off the solvent until the
amount of the concentrate was reached at 50 g. The concentrate was
extracted twice with 100 g of ethyl acetate to transfer
2-amino-1-phenylethanol and a by-product to the organic extract.
The total amount of the ethyl acetate extract was 210 g containing
3.53% by weight (0.054 mole) of 2-amino-1-phenylethanol, 0.3% by
weight of the corresponding position-isomer and 0.7% by weight of
other by-products.
[0742] The ethyl acetate extract was dehydrated with the use of 10
g of sodium sulfate. The resultant extract was heated at 50.degree.
C., and 1.12 NL (0.05 mole) of hydrochloric acid gas was bubbled
thereto with taking one hour. After cooling at 20.degree. C., the
resultant was filtrated and was dried to give 8.4 g of salts formed
with hydrochloric acid, containing 98.5% by weight of
2-amino-1-phenylethanol salt and 1.3% by weight of the
corresponding position-isomer salt without detecting the other
by-products. The yield from the organic extract was 89%.
[0743] The salts were liberated in the same manner as in Example
283 to afford 6.2 g of 2-amino-1-phenylethanol having a chemical
purity of 98.6%, where the yield from the organic extract was
83%.
Example 295
Production of 2-amino-1-(3-chlorophenyl)ethanol
[0744] To 712 g of a 25% aqueous solution of NH.sub.3 (10.47 moles)
was added 242 g of methanol, and the mixture was heated at
40.degree. C. m-Chlorostyrene oxide (36 g, 0.23 mole) was added
dropwise to the heated mixture for one hour, and after addition,
the resultant mixture was aged for 3.5 hours. With cooling at
20.degree. C., NH.sub.3 was removed off from the mixture under
reduced pressure, and in succession, the solvent was distilled off
by heating to afford 40 g of a concentrate. The composition of the
concentrate was such that 76% by weight (0.175 mole) of
2-amino-1-(3-chlorophenyl)ethanol, 11% by weight of the
corresponding position-isomer and 13% by weight of the other
by-products.
[0745] The concentrate was dissolved in 65 g of ethyl acetate, and
the resultant solution was heated to 70.degree. C. and was added
dropwise with 320 g of ethyl acetate solution containing 67 g (0.35
mole) of N-t-butoxycarbonyl-D-alanine (hereinafter referred to as
Boc-D-alanine) with taking 30 minutes. After addition, the mixture
was aged for 30 minutes, cooled to 5.degree. C. gradually and
filtrated to isolate crystals. The obtained wet crystals comprised
99.9% by weight of the salt of
(R)-2-amino-1-(3-chlorophenyl)ethanol and 0.1% by weight or less of
the position isomer, while the other by-product was not
detected.
[0746] The wet crystals were dispersed in 620 g of dichloroethane,
and to the dispersion, was added dropwise 272 g of a 8% aqueous
solution of sodium hydroxide (0.54 mole) for 30 minutes to
liberate. The water layer was removed from the mixture by
separation, and the organic layer was washed twice with 247 g of
saturated aqueous solution of sodium chloride. Further the layer
was dehydrated over 10 g of sodium sulfate followed by distilling
off the solvent to give 11 g of (R)-2-amino-1-(3-chlorophenyl)-
ethanol. The chemical purity and the optical purity of the compound
were 99.5% and 100% e e respectively, and the corresponding
position-isomer and the other by-products were not detected.
Example 296
Production of (R)-2-amino-1-phenylethanol
[0747] The procedures of Example 295 were followed, except that
27.7 g (0.23 mole) of styrene oxide was employed instead of
3-chlorostyrene oxide, to give 7.3 g of (R)-2-amino-1-phenylethanol
having a chemical purity of 99.2% and an optical purity of 100% e
e. The position-isomer and the other by-products were not
detected.
Example 297
Production of 2-amino-1-phenylethanol
[0748] The title compound (26.8 g) having a chemical purity of 99%
in the same manner as in Example 295, except for using 30.4 g (0.2
mole) of D,L-mandelic acid instead of 67 g (0.35 mole) of
Boc-D-alanine. The corresponding position-isomer was by-produced in
a proportion of 0.9% by weight and the other by-products were not
detected.
Example 298
Production of (R)-2-amino-1-(3-chlorophenyl)ethanol
[0749] The concentrate (3.38 g) containing 15.0 mmol of
2-amino-1-(3-chlorophenyl)ethanol obtained in the same manner as in
Example 295 was added to 20 ml of n-butanol and dissolved at
50.degree. C. The mixture was added with 20 ml of n-butanol
containing 2.10 g (7.5 mmol) of N-t-butoxycarbonyl-L-tyrosine
(hereinafter briefly referred to as Boc-L-Tyr) with stirring slowly
to separate crystals. After cooling to room temperature, the
crystals were isolated by filtration to afford 1.95 g (4.31 mmol)
of (R)-2-amino-1-(3-chlorophenyl)ethanol.Boc-L-Tyr salt. The yield
based on the concentrate was 58.2%.
[0750] The physiological properties of the salt were as
follows:
[0751] m.p.: 188.8.degree. C.
[0752] specific rotation [.alpha.].sub.D.sup.25+12.95 (c=0.926,
methanol)
[0753] To the salt was added 5 ml of 1N aqueous solution of sodium
hydroxide and the mixture was extracted with 10 ml of
1,2-dichloroethane. The organic extract was subjected to distilling
off the solvent under reduced pressure to give 0.73 g (4.25 mmol)
of (R)-2-amino-1-(3-chlorophe- nyl)ethanol. As a result of analysis
of the compound with using optical resoluting column (manufactured
by Daicel Chemical Industries, Ltd., Crownpack CR (+) (trade
name)), the optical purity of the compound was 87.2% e e.
Example 299
Production of (R)-2-amino-1-(3-chlorophenyl)ethanol
[0754] To 15 ml of 1N aqueous solution of hydrochloric acid was
added 3.38 g of the concentrate of the reaction products containing
15.0 mmol of 2-amino-1-phenylethanol obtained in the same manner as
in Example 295. The resultant solution was added with 7.5 ml of 1N
sodium hydroxide solution containing 2.10 g of Boc-L-Tyr (7.5 mmol)
with stirring slowly to precipitate or crystallize crystals. The
crystals were isolated by filtration to give 2.49 g (5.5 mmol) of
(R)-2-amino-1-(3-chlorophenyl)eth- anol.Boc-L-Tyr salt. The yield
relative to (R)-2-amino-1-(3-chlorophenyl)e- thanol in the
concentrate was 73.4%.
[0755] The physiological properties of the salt are set forth
below.
[0756] m.p.: 187.2.degree. C.
[0757] specific rotation [.alpha.].sub.D.sup.25+14.28 (c=0.805,
methanol)
[0758] The salt was added with 5 ml of 1N aqueous solution of
sodium hydroxide, and the mixture was extracted with 10 ml of
1,2-dichloroethane. From the organic extract, was distilled off the
solvent under reduced pressure to afford 0.92 g (5.37 mmol) of
(R)-2-amino-1-(3-chlorophenyl)ethanol. The compound was analyzed in
the same manner as in Example 298, and the optical purity of the
compound was 81.9% e e.
Example 300
Production of (R)-2-amino-1-(3-chlorophenyl)ethanol
[0759] To 40 ml of 4-methyl-2-pentanone were added the concentrate
(3.38 g), containing 2.57 g (15.0 mmol) of 2-amino-1-phenylethanol,
obtained in the similar manner as in Example 295 and 4.67 g (15.0
mmol) of N-t-butoxycarbonyl-O-benzyl-L-threonine (hereinafter
abbreviated as Boc-L-Thr(Bzl)), and dissolved by heating. The
mixture was cooled to room temperature and left over night. The
precipitated crystals were isolated by filtration to give 3.06 g
(6.34 mmol) of (R)-2-amino-1-(3-chlorophenyl-
)ethanol.Boc-L-Thr(Bzl) salt. The yield relative to
(R)-2-amino-1-(3-chlorophenyl)ethanol in the concentrate was
83.9%.
[0760] The physiological properties of the salt are set forth
below.
[0761] m.p.: 144.6.degree. C.
[0762] specific rotation [.alpha.].sub.D.sup.25+9.04 (c=0.862,
methanol)
[0763] To the salt was added 7 ml of 1N aqueous solution of sodium
chloride and the mixture was extracted with 10 ml of
1,2-dichloroethane. The organic extract was subjected to distilling
off the solvent to afford 1.05 g (6.15 mmol) of
(R)-2-amino-1-(3-chlorophenyl)ethanol. As a result of analysis in
the same manner as in Example 298, the optical purity of the
compound was 81.6% e e.
Example 301
Production of (S)-2-amino-1-(3-chlorophenyl)ethanol
[0764] A mixture of 15 ml of ethyl acetate and 10 ml of ethanol was
added with 1.69 g of the concentrate containing 1.29 g (7.5 mmol)
of 2-amino-1-phenylethanol obtained in the same manner as in
Example 295 and 1.16 g (3.75 mmol) of
N-t-butoxycarbonyl-O-benzyl-L-cysteine (hereinafter briefly
referred to as Boc-L-Cys (Bzl)). The resultant mixture was heated
for dissolution and cooled to room temperature, followed by being
left for over night. The crystals separated were isolated by
filtration to afford
(S)-2-amino-1-(3-chlorophenyl)ethanol.Boc-L-Cys (Bzl) salt (1.30 g;
2.69 mmol). The yield of the salt relative to
(S)-2-amino-1-(3-chlorop- henyl)ethanol in the concentrate was
71.6%.
[0765] A 1N aqueous solution of sodium hydroxide (5 ml) was added
to the salt and the mixture was extracted with 5 ml of
1,2-dichloroethane. The 1,2-dichloroethane extract was subjected to
removal of the solvent by distillation under reduced pressure to
give 0.69 g (2.69 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol.
By analyzing the compound in the same manner as in Example 298, the
optical purity of the compound was 95.1% e e.
Example 302
Production of (R)-2-amino-1-(3-chlorophenyl)ethanol
[0766] To 20 ml of methanol were added 1.70 g of the concentrate
obtained in the same manner as in Example 295, containing 1.29 g
(7.50 mmol) of 2-amino-1-(3-chlorophenyl)ethanol, and 2.88 g (7.50
mmol) of L-di-p-toluoyltartaric acid (hereinafter abbreviated as
L-PTTA), and the resultant mixture was heated for dissolution and
added with 20 ml of 4-methyl-2-pentanone. The mixture was cooled to
room temperature and left over night to give crystals. The crystals
precipitated was isolated by filtration to afford 1.69 g (2.63
mmol) of (R)-2-amino-1-(3-chlorophenyl)- ethanol.L-PTTA salt. The
yield of the compound relative to
(R)-2-amino-1-(3-chlorophenyl)ethanol in the concentrate was
70.1%.
[0767] To the salt thus obtained was added 3 ml of 1N aqueous
solution of sodium hydroxide and the mixture was subjected to
extraction with 5 ml of 1,2-dichloroethane. From the organic
extract, was distilled off the solvent to give 0.64 g (2.50 mmol)
of (R)-2-amino-1-(3-chlorophenyl)ethan- ol. The analysis procedure
of Example 298 was followed, and the optical purity of the compound
was 75.7% e e.
Example 303
Production of (R)-2-amino-1-phenylethanol
[0768] n-Butanol (20 ml) was added with the concentrate of the
reaction products obtained in the same manner as in Example 296
which contained 1.67 g (7.50 mmol) of 2-amino-1-phenylethanol, and
2.11 g (7.50 mmol) of Boc-L-Tyr. The resultant mixture was heated
for dissolution, cooled to room temperature and left over night to
precipitate crystals. The crystals were isolated by filtration to
afford 1.06 g (2.10 mmol) of (R)-2-amino-1-phenylethanol.Boc-L-Tyr
salt. The yield of the compound based on
(R)-2-amino-1-phenylethanol in the concentrate was 56.0%.
[0769] To the salt was added 3 ml of a 1N aqueous solution of
sodium hydroxide, and the mixture was extracted with
1,2-dichloroethane. The solvent was distilled from the organic
extract to give 0.46 g (2.08 mmol) of (R)-2-amino-1-phenylethanol.
The analysis of the compound in the similar manner as in Example
298 gave the optical purity of 81.7% e e.
Example 304
Production of
(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methy-
lethyl]amino]ethanol
[0770] To a benzene solution (10 ml) of
(R)-2-amino-1-(3-chlorophenyl)etha- nol (0.52 g) was added 0.58 g
of methyl=3,4-dimethoxyphenylmethyl=ketone. The mixture was
subjected to reflux in an apparatus equipped with a water-trap for
one hour and the produced water was removed off from the reaction
system. After cooling the reaction mixture, the solvent was
distilled off under reduced pressure. The residue was dissolved
into 10 ml of methanol, and with cooling the resultant solution at
a temperature lower than 10.degree. C. and with stirring, the
resultant solution was treated with, little by little, sodium
borohydride (0.14 g) with taking 30 minutes. The reaction mixture
was stirred for further one hour at room temperature and the
solvent was distilled off under reduced pressure. The resultant
residue was dissolved into ethyl acetate and the solution was
washed with water, was dried over anhydrous magnesium sulfate, and
was subjected to filtration. The residue was dried by distilling
off the solvent to give 1.09 g of yellow oil. A part of the oil was
subjected to silica gel chromatography and the obtained compound
was analyzed with high performance liquid chromatography using an
optical resoluting column [column: manufactured by Daicel Chemical
Industries, Ltd., Chiralpack AD (trade name)]. Accordingly, the
ratio of the (R,R)-isomer relative to the (R,S)-isomer obtained by
the fractional crystallization of the diastereomers was such that
the former: the latter was 48:52.
* * * * *