U.S. patent application number 14/097720 was filed with the patent office on 2014-04-03 for process for producing 3-alkoxy-2-amino-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative and intermediate thereof.
This patent application is currently assigned to TAISHO PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is TAISHO PHARMACEUTICAL CO., LTD.. Invention is credited to Yoshihiro KIMURA, Toshihito KUMAGAI, Noriaki MURASE, Koumei OHTA, Hisahide TANIMOTO, Hisaya WADA.
Application Number | 20140094613 14/097720 |
Document ID | / |
Family ID | 44059422 |
Filed Date | 2014-04-03 |
United States Patent
Application |
20140094613 |
Kind Code |
A1 |
MURASE; Noriaki ; et
al. |
April 3, 2014 |
PROCESS FOR PRODUCING 3-ALKOXY-2-AMINO-6-FLUOROBICYCLO [3.1.0]
HEXANE-2,6-DICARBOXYLIC ACID DERIVATIVE AND INTERMEDIATE
THEREOF
Abstract
A process for producing a 3-alkoxy-2-amino-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative represented
by the formula (I) or a salt thereof, which includes converting a
compound represented by the formula (VI) or a salt thereof to the
compound represented by the formula (I) or a salt thereof.
##STR00001##
Inventors: |
MURASE; Noriaki; (Tokyo,
JP) ; KUMAGAI; Toshihito; (Tokyo, JP) ; WADA;
Hisaya; (Tokyo, JP) ; TANIMOTO; Hisahide;
(Tokyo, JP) ; OHTA; Koumei; (Tokyo, JP) ;
KIMURA; Yoshihiro; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TAISHO PHARMACEUTICAL CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
TAISHO PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
44059422 |
Appl. No.: |
14/097720 |
Filed: |
December 5, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13510428 |
May 17, 2012 |
8642777 |
|
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PCT/JP2010/006757 |
Nov 18, 2010 |
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14097720 |
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Current U.S.
Class: |
548/301.1 ;
558/426; 560/53; 562/500; 564/157; 564/169 |
Current CPC
Class: |
C07C 69/757 20130101;
C07C 67/313 20130101; C07C 227/02 20130101; C07C 229/50 20130101;
C07D 235/02 20130101; C07C 237/24 20130101; C07C 255/47 20130101;
C07C 67/313 20130101; C07C 51/08 20130101; C07C 2602/18 20170501;
C07F 7/1804 20130101; C07C 227/02 20130101; C07C 67/31 20130101;
C07C 235/82 20130101; C07C 69/757 20130101; C07C 69/757 20130101;
C07C 229/50 20130101; C07C 67/31 20130101 |
Class at
Publication: |
548/301.1 ;
562/500; 564/169; 560/53; 558/426; 564/157 |
International
Class: |
C07D 235/02 20060101
C07D235/02; C07C 237/24 20060101 C07C237/24; C07C 69/757 20060101
C07C069/757; C07C 255/47 20060101 C07C255/47; C07C 51/08 20060101
C07C051/08; C07C 235/82 20060101 C07C235/82 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 19, 2009 |
JP |
2009-264071 |
Claims
1-11. (canceled)
12. A process for producing a 3-alkoxy-2-amino-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative represented
by the formula (I) or a salt thereof, the process comprising:
##STR00051## (in the formula (I), R.sup.1 and R.sup.2, which may be
the same or different from each other, each represent a hydrogen
atom, a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a
phenyl group, a naphthyl group, a naphthyl group substituted with 1
to 7 halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure), (A) converting a
compound represented by the formula (II) or a salt thereof to a
compound represented by the formula (III) or a salt thereof,
##STR00052## (in the formula (II), R.sup.3 represents a C.sub.1-6
alkoxy group, an amino group, or a hydroxyl group) ##STR00053## (in
the formula (III), R.sup.4 represents --SiR.sup.41R.sup.42R.sup.43
wherein R.sup.41, R.sup.42, and R.sup.43, which may be the same or
different from each other, each represent a C.sub.1-6 alkyl group.
R.sup.5 represents a C.sub.1-6 alkoxy group, an amino group, or a
hydroxyl group) (B) converting the compound represented by the
formula (III) or a salt thereof to a compound represented by the
formula (IV) or a salt thereof, ##STR00054## (in the formula (IV),
R.sup.6 represents a hydrogen atom, a benzoyl group, a benzoyl
group substituted with a halogen atom, or
--SiR.sup.61R.sup.62R.sup.63 wherein R.sup.61, R.sup.62, and
R.sup.63, which may be the same or different from each other, each
represent a C.sub.1-6 alkyl group. R.sup.7 represents a C.sub.1-6
alkoxy group, an amino group, or a hydroxyl group) (C) converting
the compound represented by the formula (IV) or a salt thereof to a
compound represented by the formula (V) or a salt thereof,
##STR00055## (in the formula (V), R.sup.1 and R.sup.2 are as
defined in the above and R.sup.8 represents a C.sub.1-6 alkoxy
group, an amino group, or a hydroxyl group) (H) converting the
compound represented by the formula (V) or a salt thereof to a
compound represented by the formula (IX) or a salt thereof,
##STR00056## (in the formula (IX), R.sup.1 and R.sup.2 are as
defined in the above and R.sup.12 represents a C.sub.1-6 alkoxy
group, an amino group, or a hydroxyl group), and (I) converting the
compound represented by the formula (IX) or a salt thereof to the
compound represented by the formula (I) or a salt thereof.
13. A compound represented by the formula (IV) or a salt thereof
##STR00057## (in the formula (IV), R.sup.6 represents a hydrogen
atom, a benzoyl group, a benzoyl group substituted with a halogen
atom, or --SiR.sup.61R.sup.62R.sup.63 wherein R.sup.61, R.sup.62,
and R.sup.63, which may be the same or different from each other,
each represent a C.sub.1-6 alkyl group. R.sup.7 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
14. A compound represented by the formula (V) or a salt thereof
##STR00058## (in the formula (V), R.sup.1 and R.sup.2, which may be
the same or different from each other, each represent a hydrogen
atom, a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a
phenyl group, a naphthyl group, a naphthyl group substituted with 1
to 7 halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.8 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
15. A compound represented by the formula (VI) or a salt thereof
##STR00059## (in the formula (VI), R.sup.1 and R.sup.2, which may
be the same or different from each other, each represent a hydrogen
atom, a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a
phenyl group, a naphthyl group, a naphthyl group substituted with 1
to 7 halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.9 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
16. A compound represented by the formula (VIII) or a salt thereof
##STR00060## (in the formula (VIII), R.sup.1 and R.sup.2, which may
be the same or different from each other, each represent a hydrogen
atom, a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a
phenyl group, a naphthyl group, a naphthyl group substituted with 1
to 7 halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.13 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
17. A compound represented by the formula (VII) or a salt thereof
##STR00061## (in the formula (VII), R.sup.1 and R.sup.2, which may
be the same or different from each other, each represent a hydrogen
atom, a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a
phenyl group, a naphthyl group, a naphthyl group substituted with 1
to 7 halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.10 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group.
R.sup.11 represents a C.sub.1-6 alkoxy group, an amino group, or a
hydroxyl group, with the proviso that, R.sup.10 and R.sup.11 do not
simultaneously represent a hydroxyl group and do not simultaneously
represent a C.sub.1-6 alkoxy group. When any one of R.sup.10 and
R.sup.11 is a hydroxyl group, the other is not a C.sub.1-6 alkoxy
group).
18. A compound represented by the formula (IX) or a salt thereof
##STR00062## (in the formula (IX), R.sup.1 and R.sup.2, which may
be the same or different from each other, each represent a hydrogen
atom, a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a
phenyl group, a naphthyl group, a naphthyl group substituted with 1
to 7 halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.12 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
19. A compound represented by the formula (X) or a salt thereof
##STR00063## (in the formula (X), R.sup.1 and R.sup.2, which may be
the same or different from each other, each represent a hydrogen
atom, a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a
phenyl group, a naphthyl group, a naphthyl group substituted with 1
to 7 halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.14 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
Description
TECHNICAL FIELD
[0001] The present invention relates to a process for producing a
3-alkoxy-2-amino-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxylic
acid derivative useful as a pharmaceutical. The invention also
relates to a novel intermediate compound produced in the production
process.
BACKGROUND ART
[0002] An excitatory amino acid such as glutamic acid modulates
various physiological processes such as long term potentiation
(learning and memory), synaptic plasticity development, motion
control, respiration, cardiovascular modulation, and perception in
the central nervous system (CNS) of a mammal.
[0003] Presently, glutamate receptors are classified into two major
groups, that is, "an ionotropic type in which the receptor has an
ion channel structure": ion channel type glutamate receptor
(iGluR), and "a metabotropic type in which the receptor is coupled
to a G protein": metabotropic glutamate receptor (mGluR) (see,
Non-Patent Document 1). It appears that receptors of either class
mediate normal synaptic transmission in accordance with an
excitatory pathway. It also appears that they are involved in
modification of synaptic binding from the development stage
throughout the lifetime (see, Non-Patent Document 2).
[0004] Eight subtypes of the metabotropic glutamate receptor that
have been identified so far are classified into three groups (group
I, II, and III) depending on pharmacological characteristics and
intracellular second messengers to which they are coupled. Among
them, group II receptor (mGluR2/mGluR3) binds with adenylate
cyclase, and inhibits the accumulation of cyclic
adenosine-1-phosphate (cAMP) stimulated by forskolin (see,
Non-Patent Document 3). Thus, it is suggested that compounds that
antagonize the activity of group II metabotropic glutamate
receptors are effective for the treatment or prevention of acute
and chronic psychiatric disorders and neurological diseases.
[0005] It is recognized that a 2-amino-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative having a
substituent group on position 3 has a strong antagonistic effect on
group II metabotropic glutamate receptor. As such, it is effective
for the treatment and prevention of psychiatric disorders such as
schizophrenia, anxiety and related ailments thereof, bipolar
disorder, or epilepsy, and also of neurological diseases such as
drug dependence, cognitive disorders, Alzheimer's disease,
Huntington's disease, Parkinson's disease, dyskinesia associated
with muscular rigidity, cerebral ischemia, cerebral failure,
encephalopathy, or head trauma (see, Patent Documents 1 to 3 and
Non-Patent Documents 4 to 6).
[0006] For example, as an antagonist substance of group II
metabotropic glutamate receptor, 3-alkoxy-2-amino-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative represented
by the following formula (IA), a pharmaceutically acceptable salt
thereof, or a hydrate thereof is disclosed (see, Patent Document
1).
##STR00002##
[0007] (in the formula (IA), R.sup.A and R.sup.B, which may be the
same or different, each represent a hydroxyl group, a C.sub.1-10
alkoxy group, a phenoxy group, a naphthyloxy group, a C.sub.1-6
alkoxy group which is substituted with one or two phenyl groups, a
C.sub.1-6 alkoxy C.sub.1-6 alkoxy group, a hydroxy C.sub.2-6alkoxy
group, an amino group, an amino group which is substituted with the
same or different one or two C.sub.1-6 alkyl groups, an amino group
which is substituted with the same or different one or two
C.sub.1-6 alkoxy C.sub.1-6 alkyl groups, an amino group which is
substituted with the same or different one or two hydroxy C.sub.2-6
alkyl groups, an amino group which is substituted with the same or
different one or two C.sub.1-6 alkoxycarbonyl C.sub.1-6 alkyl
groups, or a native or non-native amino acid residue represented by
NR.sup.F--CHR.sup.G-A-CO.sub.2R.sup.H (wherein R.sup.F and R.sup.G,
which may be the same or different, each represent a hydrogen atom,
a hydroxy C.sub.1-6 alkyl group, a hydroxycarbonyl C.sub.1-6 alkyl
group, a C.sub.1-10 alkyl group, a phenyl group, a phenyl C.sub.1-6
alkyl group, a hydroxyphenyl group, a hydroxyphenyl C.sub.1-6 alkyl
group, a naphthyl group, a naphthyl C.sub.1-6 alkyl group, an
aromatic heterocyclic C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy
C.sub.1-6 alkyl group, an amino C.sub.2-6 alkyl group, a guanidino
C.sub.2-6 alkyl group, a mercapto C.sub.2-6 alkyl group, a
C.sub.1-6 alkylthio C.sub.1-6 alkyl group or an aminocarbonyl
C.sub.1-6 alkyl group, or R.sup.F and R.sup.G may bind to each
other to represent a group capable of forming a methylene group, an
ethylene group or a propylene group, or may together form a cyclic
amino group; R.sup.H represents a hydrogen atom or a protecting
group for carboxy group; and A represents a single bond, a
methylene group, an ethylene group or a propylene group); R.sup.C
represents a C.sub.2-10 acyl group, a C.sub.1-6 alkoxy C.sub.1-6
acyl group, a hydroxy C.sub.2-10 acyl group, a C.sub.1-6
alkoxycarbonyl C.sub.1-6 acyl group, a hydroxycarbonyl C.sub.1-6
acyl group, or an amino acid residue represented by
R.sup.I--NH-A-CH--R.sup.G--CO (wherein R.sup.G and A are as defined
above, and R.sup.I represents a hydrogen atom or a protecting group
for amino group); and R.sup.D and R.sup.E, which may be the same or
different, each represent a hydrogen atom, a C.sub.1-10 alkyl
group, a C.sub.2-10 alkenyl group, a phenyl group, a naphthyl
group, a 5-membered heteroaromatic ring containing one or more
heteroatoms, or a phenyl group substituted with 1 to 5 substituent
groups selected from the group consisting of a halogen atom, a
C.sub.1-10 alkyl group, a C.sub.1-10 alkoxy group, a
trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an
amino group, a nitro group, a cyano group and a phenoxy group, or
R.sup.D and R.sup.E may bind to each other to form a cyclic
structure).
[0008] With respect to a lab-scale synthesis of an antagonist
substance of group II metabotropic glutamate receptor that is
represented by the formula (IA) and synthetic intermediate thereof,
several studies have been made (see, Patent Documents 1 and 3 and
Non-Patent Documents 4 and 6).
RELATED DOCUMENT
Patent Document
[0009] [Patent Document 1] Pamphlet of International Publication
No. 2003/061698 [0010] [Patent Document 2] Pamphlet of
International Publication No. 2005/000790 [0011] [Patent Document
3] Pamphlet of International Publication No. 2005/000791
Non-Patent Document
[0011] [0012] [Non-Patent Document 1] Science, 258, 597-603 (1992)
[0013] [Non-Patent Document 2] Trends Pharmacol. Sci., 11, 508-515
(1990) [0014] [Non-Patent Document 3] Trends Pharmacol. Sci., 14,
13-20 (1993) [0015] [Non-Patent Document 4] J. Med. Chem., 47,
4570-4587 (2004) [0016] [Non-Patent Document 5] Bioorg. Med. Chem.,
14, 3405-3420 (2006) [0017] [Non-Patent Document 6] Bioorg. Med.
Chem., 14, 4193-4207 (2006)
DISCLOSURE OF THE INVENTION
Problem to be Solved by the Invention
[0018] According to the conventional synthetic process disclosed in
Patent Documents 1 and 3 and Non-Patent Documents 4 and 6, the
antagonist substance of group II metabotropic glutamate receptor
having the formula (IA) wherein R.sup.A and R.sup.B are a hydroxyl
group and R.sup.C is a hydrogen atom is synthesized by performing
many reaction steps, that is, nine to ten reaction steps, from
6-fluoro-2-oxo bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester
(intermediate (IIA)) as a synthetic intermediate shown with the
following formula (IIA).
##STR00003##
[0019] From the viewpoint that reduction in total yield is caused
due to having a large number of reaction steps and lowering the
production cost and shortening the production period are difficult
to achieve, the synthetic route described above strongly requires
an improvement. Further, since the conventional synthetic process
needs to use sodium azide having potential explosion problem and to
undergo a synthetic intermediate having an azide functional group
with the same problem, it is necessary to use highly toxic osmium
tetraoxide or carbon monoxide. Therefore, from the viewpoint of
ensuring safety in preparation, an improved process is also in
need.
[0020] Since the antagonist substance of group II metabotropic
glutamate receptor that is represented by the formula (IA) as
disclosed in Patent Document 1 is useful as a therapeutic agent, in
relation to a process for producing the compound, a production
process which has no safety problem like run away reaction, can be
easily scaled up, uses a reagent that is safe and effective in
terms of cost, is effective as having fewer number of reaction
steps, and is appropriate for mass production is in need.
[0021] To solve all at once the problems of the conventional
synthetic processes described above, the inventors of the present
application found a novel synthetic route and a novel synthetic
intermediate compound which allow the synthesis of the antagonist
substance of group II metabotropic glutamate receptor, that is
represented by the following formula (I), from an intermediate
represented by the following formula (II) by performing only 5 to 6
reaction steps.
[0022] Specifically, the present invention relates to the
followings;
(1) A process for producing a 3-alkoxy-2-amino-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative represented
by the formula (I) or a salt thereof, which includes:
##STR00004##
[0023] (in the formula (I), R.sup.1 and R.sup.2, which may be the
same or different from each other, each represent a hydrogen atom,
a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a phenyl
group, a naphthyl group, a naphthyl group substituted with 1 to 7
halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure),
[0024] (A) converting a compound represented by the formula (II) or
a salt thereof to a compound represented by the formula (III) or a
salt thereof,
##STR00005##
[0025] (in the formula (II), R.sup.3 represents a C.sub.1-6 alkoxy
group, an amino group, or a hydroxyl group)
##STR00006##
[0026] (in the formula (III), R.sup.4 represents
--SiR.sup.41R.sup.42R.sup.43 wherein R.sup.41, R.sup.42, and
R.sup.43, which may be the same or different from each other, each
represent a C.sub.1-6 alkyl group. R.sup.5 represents a C.sub.1-6
alkoxy group, an amino group, or a hydroxyl group)
[0027] (B) converting the compound represented by the formula (III)
or a salt thereof to a compound represented by the formula (IV) or
a salt thereof,
##STR00007##
[0028] (in the formula (IV), R.sup.6 represents a hydrogen atom, a
benzoyl group, a benzoyl group substituted with a halogen atom, or
--SiR.sup.61R.sup.62R.sup.63 wherein R.sup.61, R.sup.62, and
R.sup.63, which may be the same or different from each other, each
represent a C.sub.1-6 alkyl group. R.sup.7 represents a C.sub.1-6
alkoxy group, an amino group, or a hydroxyl group)
[0029] (C) converting the compound represented by the formula (IV)
or a salt thereof to a compound represented by the formula (V) or a
salt thereof,
##STR00008##
[0030] (in the formula (V), R.sup.1 and R.sup.2 are as defined in
the above and R.sup.8 represents a C.sub.1-6 alkoxy group, an amino
group, or a hydroxyl group)
[0031] (D) converting the compound represented by the formula (V)
or a salt thereof to a compound represented by the formula (VI) or
a salt thereof,
##STR00009##
[0032] (in the formula (VI), R.sup.1 and R.sup.2 are as defined in
the above and R.sup.9 represents a C.sub.1-6 alkoxy group, an amino
group, or a hydroxyl group), and
[0033] (E) converting the compound represented by the formula (VI)
or a salt thereof to the compound represented by the formula (I) or
a salt thereof.
(2) A process for producing a 3-alkoxy-2-amino-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative represented
by the formula (I) or a salt thereof, which includes converting a
compound represented by the formula (VI) or a salt thereof to the
compound represented by the formula (I) or a salt thereof
##STR00010##
[0034] (in the formula (I), R.sup.1 and R.sup.2, which may be the
same or different from each other, each represent a hydrogen atom,
a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a phenyl
group, a naphthyl group, a naphthyl group substituted with 1 to 7
halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure),
##STR00011##
[0035] (in the formula (VI), R.sup.1 and R.sup.2 are as defined in
the above and R.sup.9 represents a C.sub.1-6 alkoxy group, an amino
group, or a hydroxyl group).
(3) The process described in (1) or (2) above, wherein the
converting the compound represented by the formula (VI) or a salt
thereof to the compound represented by the formula (I) or a salt
thereof includes following steps;
[0036] (F) converting the compound represented by the formula (VI)
or a salt thereof to a compound represented by the formula (VII) or
a salt thereof
##STR00012##
[0037] (in the formula (VII), R.sup.1 and R.sup.2 are as defined in
the above. R.sup.10 represents a C.sub.1-6 alkoxy group, an amino
group or a hydroxyl group, and R.sup.11 represents a C.sub.1-6
alkoxy group, an amino group, or a hydroxyl group, with the proviso
that R.sup.10 and R.sup.11 do not simultaneously represent a
hydroxyl group), and
[0038] (G) converting the compound represented by the formula (VII)
or a salt thereof to the compound represented by the formula (I) or
a salt thereof.
(4) A process for producing a 3-alkoxy-2-amino-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative represented
by the formula (I) or a salt thereof, which includes:
##STR00013##
[0039] (in the formula (I), R.sup.1 and R.sup.2, which may be the
same or different from each other, each represent a hydrogen atom,
a C.sub.1-6 alkyl group, a C.sub.2-10 alkenyl group, a phenyl
group, a naphthyl group, a naphthyl group substituted with 1 to 7
halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure),
[0040] (A) converting a compound represented by the formula (II) or
a salt thereof to a compound represented by the formula (III) or a
salt thereof,
##STR00014##
[0041] (in the formula (II), R.sup.3 represents a C.sub.1-6 alkoxy
group, an amino group, or a hydroxyl group)
##STR00015##
[0042] (in the formula (III), R.sup.4 represents
--SiR.sup.41R.sup.42R.sup.43 wherein R.sup.41, R.sup.42, and
R.sup.43, which may be the same or different from each other, each
represent a C.sub.1-6 alkyl group. R.sup.5 represents a C.sub.1-6
alkoxy group, an amino group, or a hydroxyl group)
[0043] (B) converting the compound represented by the formula (III)
or a salt thereof to a compound represented by the formula (IV) or
a salt thereof,
##STR00016##
[0044] (in the formula (IV), R.sup.6 represents a hydrogen atom, a
benzoyl group, a benzoyl group substituted with a halogen atom, or
--SiR.sup.61R.sup.62R.sup.63 wherein R.sup.61, R.sup.62, and
R.sup.63, which may be the same or different from each other, each
represent a C.sub.1-6 alkyl group. R.sup.7 represents a C.sub.1-6
alkoxy group, an amino group, or a hydroxyl group)
[0045] (C) converting the compound represented by the formula (IV)
or a salt thereof to a compound represented by the formula (V) or a
salt thereof,
##STR00017##
[0046] (in the formula (V), R.sup.1 and R.sup.2 are as defined in
the above and R.sup.8 represents a C.sub.1-6 alkoxy group, an amino
group, or a hydroxyl group)
[0047] (H) converting the compound represented by the formula (V)
or a salt thereof to a compound represented by the formula (IX) or
a salt thereof,
##STR00018##
[0048] (in the formula (IX), R.sup.1. and R.sup.2 are as defined in
the above and R.sup.12 represents a C.sub.1-6 alkoxy group, an
amino group, or a hydroxyl group), and
[0049] (I) converting the compound represented by the formula (IX)
or a salt thereof to the compound represented by the formula (I) or
a salt thereof.
(5) A compound represented by the formula (IV) or a salt
thereof
##STR00019##
[0050] (in the formula (IV), R.sup.6 represents a hydrogen atom, a
benzoyl group, a benzoyl group substituted with a halogen atom, or
--SiR.sup.61R.sup.62R.sup.63 wherein R.sup.61, R.sup.62, and
R.sup.63, which may be the same or different from each other, each
represent a C.sub.1-6 alkyl group. R.sup.7 represents a C.sub.1-6
alkoxy group, an amino group, or a hydroxyl group).
(6) A compound represented by the formula (V) or a salt thereof
##STR00020##
[0051] (in the formula (V), R.sup.1 and R.sup.2, which may be the
same or different from each other, each represent a hydrogen atom,
a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a phenyl
group, a naphthyl group, a naphthyl group substituted with 1 to 7
halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.8 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
(7) A compound represented by the formula (VI) or a salt
thereof
##STR00021##
[0052] (in the formula (VI), R.sup.1 and R.sup.2, which may be the
same or different from each other, each represent a hydrogen atom,
a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a phenyl
group, a naphthyl group, a naphthyl group substituted with 1 to 7
halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.9 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
(8) A compound represented by the formula (VIII) or a salt
thereof
##STR00022##
[0053] (in the formula (VIII), R.sup.1 and R.sup.2, which may be
the same or different from each other, each represent a hydrogen
atom, a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a
phenyl group, a naphthyl group, a naphthyl group substituted with 1
to 7 halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.13 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
(9) A compound represented by the formula (VII) or a salt
thereof
##STR00023##
[0054] (in the formula (VII), R.sup.1 and R.sup.2, which may be the
same or different from each other, each represent a hydrogen atom,
a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a phenyl
group, a naphthyl group, a naphthyl group substituted with 1 to 7
halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.10 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group.
R.sup.11 represents a C.sub.1-6 alkoxy group, an amino group, or a
hydroxyl group, with the proviso that, R.sup.10 and R.sup.11 do not
simultaneously represent a hydroxyl group and do not simultaneously
represent a C.sub.1-6 alkoxy group. When any one of R.sup.10 and
R.sup.11 is a hydroxyl group, the other is not a C.sub.1-6 alkoxy
group).
(10) A compound represented by the formula (IX) or a salt
thereof
##STR00024##
[0055] (in the formula (IX), R.sup.1 and R.sup.2, which may be the
same or different from each other, each represent a hydrogen atom,
a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a phenyl
group, a naphthyl group, a naphthyl group substituted with 1 to 7
halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.12 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
(11) A compound represented by the formula (X) or a salt
thereof
##STR00025##
[0056] (in the formula (X), R.sup.1 and R.sup.2, which may be the
same or different from each other, each represent a hydrogen atom,
a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a phenyl
group, a naphthyl group, a naphthyl group substituted with 1 to 7
halogen atoms, a heteroaromatic group, or a phenyl group
substituted with 1 to 5 substituent groups selected from a group
consisting of a halogen atom, a C.sub.1-10 alkyl group, a
C.sub.1-10 alkoxy group, a trifluoro methyl group, a phenyl group,
a hydroxy carbonyl group, an amino group, a nitro group, a cyano
group, and a phenoxy group. Further, R.sup.1 and R.sup.2 may bind
to each other to form a cyclic structure. R.sup.14 represents a
C.sub.1-6 alkoxy group, an amino group, or a hydroxyl group).
[0057] By using the production process of the present invention,
synthesis of an antagonist substance of group II metabotropic
glutamate receptor that is represented by the formula (I) can be
obtained from the intermediate represented by the formula (II) with
reduced number of reaction steps, that is, five to six reaction
steps. At the same time, the total yield is significantly increased
compared to conventional synthetic processes. In addition, not only
the use of a sodium azide having potential explosion problem and
the intervention of a synthetic intermediate containing an azide
functional group with the same problem can be avoided, but also the
use of highly toxic osmium tetraoxide or carbon monoxide can be
avoided.
[0058] In other words, according to the production process of the
present invention which has no safety problem like run away
reaction, can be easily scaled up, uses a reagent that is safe and
effective in terms of cost, is effective as having few number of
reaction steps, and is appropriate for mass production compared to
conventional synthetic processes, 3-alkoxy-2-amino-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative represented
by the formula (I), which is an antagonist substance of group II
metabotropic glutamate receptor, can be efficiently produced.
DESCRIPTION OF EMBODIMENTS
[0059] In the specification, the numerical range described with "-"
or "to" includes the value of both ends, unless specifically
described otherwise.
[0060] The "C.sub.1-10 alkyl group" means a straight-chain alkyl
group having one to ten carbon atoms, a branched chain alkyl group
having three to ten carbon atoms or a cyclic alkyl group having
three to ten carbon atoms.
[0061] Examples of the straight-chain alkyl group include a methyl
group, an ethyl group, a propyl group, a butyl group, a pentyl
group, a hexyl group, a heptyl group, an octyl group, a nonyl group
and a decyl group.
[0062] Examples of the branched chain alkyl group include an
isopropyl group, an isobutyl group, a 1-methyl propyl group, a
tert-butyl group, a 1-methyl butyl group, a 2-methyl butyl group, a
3-methyl butyl group, a 1-ethyl propyl group, a 1,1-dimethyl propyl
group, a 2,2-dimethyl propyl group, a 1,2-dimethyl propyl group, a
1-methyl pentyl group, a 2-methyl pentyl group, a 3-methyl pentyl
group, a 4-methyl pentyl group, a 1-ethyl butyl group, a 2-ethyl
butyl group, a 1,1-dimethyl butyl group, a 1,2-dimethyl butyl
group, a 1,3-dimethyl butyl group, a 2,2-dimethyl butyl group, a
2,3-dimethyl butyl group, a 3,3-dimethyl butyl group, a 5-methyl
hexyl group, a 3-ethyl pentyl group, a 1-propyl butyl group, a
1,4-dimethyl pentyl group, a 3,4-dimethyl pentyl group, a
1,2,3-trimethyl butyl group, a 1-isopropyl butyl group, a
4,4-dimethyl pentyl group, a 5-methyl heptyl group, a 6-methyl
heptyl group, a 4-ethyl hexyl group, a 2-propyl pentyl group, a
2,5-dimethyl hexyl group, a 4,5-dimethyl hexyl group, a
2-ethyl-3-methyl pentyl group, a 1,2,4-trimethyl pentyl group, a
2-methyl-1-isopropyl butyl group, a 3-methyl octyl group, a
2,5-dimethyl heptyl group, a 1-(1-methyl propyl)-2-methyl butyl
group, a 1,4,5-trimethyl hexyl group, a 1,2,3,4-tetramethyl pentyl
group, a 7-methyl octyl group, a 6-methyl nonyl group, a 8-methyl
nonyl group, a 5-ethyl-2-methyl heptyl group, a
2,3-dimethyl-1-(1-methyl propyl)butyl group, a cyclopropyl methyl
group, a 2-(cyclopropyl)ethyl group, a 3,7-dimethyl octyl group, a
3-(cyclobutyl)pentyl group, a cyclopentyl methyl group, and a
cyclohexyl methyl group.
[0063] Examples of the cyclic alkyl group include a cyclopropyl
group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group,
a cycloheptyl group, and a cyclooctyl group.
[0064] The "C.sub.2-10 alkenyl group" means a straight-chain
alkenyl group having two to ten carbon atoms, a branched chain
alkenyl group having three to ten carbon atoms or a cyclic alkenyl
group having five to ten carbon atoms, all with at least one double
bond, and examples of which include a vinyl group, an allyl group,
a 3-butenyl group, a 4-pentenyl group, a 5-hexenyl group, a
6-heptenyl group, a 7-octenyl group, a 8-noneyl group, a 9-decenyl
group, a 1-methyl-2-butenyl group, a 2-methyl-2-butenyl group, a
2-methyl-3-butenyl group, a 2-pentenyl group, a 2-methyl-2-hexenyl
group and a 2-cyclopentenyl group.
[0065] The "naphthyl group substituted with one to seven halogen
atoms" means a naphthyl group which is substituted with the same or
different one to seven fluorine atom, chlorine atom, bromine atom
or iodine atom, and examples of which include a 1-fluoro-2-naphthyl
group, a 2-fluoro-1-naphthyl group, a 1-chloro-2-naphthyl group, a
2-chloro-1-naphthyl group, a 1-bromo-2-naphthyl group, a
2-bromo-1-naphthyl group, a 1-iodo-2-naphthyl group, a
2-iodo-1-naphthyl group, and a 1,3-difluoro-2-naphthyl group.
[0066] The "heteroaromatic group" means a monocyclic aromatic 5
membered or 6 membered ring containing at least one atom selected
from an oxygen atom, a nitrogen atom or a sulfur atom; a monocyclic
ring such as above which is fused with a benzene ring; or a
bicyclic aromatic ring which is fused with one another. Examples of
the hetero aromatic group include furyl, pyrrolyl, thiophenyl,
oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxadiazolyl, thiadiazolyl, benzofuranyl, indolyl,
benzothiophenyl, indazolyl, benzoisooxazolyl, benzoisothiazolyl,
benzoimidazolyl, benzooxazolyl, benzothiazolyl, pyridinyl,
quinolynyl, isoquinolynyl, pyridazinyl, pyrimidinyl, pyrazinyl,
cinnolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.
[0067] The "C.sub.1-10 alkoxy group" means a straight-chain or
branched chain alkoxy group having one to ten carbon atoms, and
examples of which include a methoxy group, an ethoxy group, a
propoxy group, an isopropoxy group, a butoxy group, an isobutoxy
group, a tert-butoxy group, a pentyloxy group and an isopentyloxy
group.
[0068] The "phenyl group substituted with one to five substituent
groups selected from a group consisting of a halogen atom, a phenyl
group, a C.sub.1-10 alkyl group, a C.sub.1-10 alkoxy group, a
trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an
amino group, a nitro group, a cyano group and a phenoxy group"
means a phenyl group substituted with one to five substituent
groups selected from a fluorine atom, a chlorine atom, a bromine
atom, an iodine atom, a C.sub.1-10 alkyl group, a cyclic C.sub.3-10
alkyl group, a C.sub.1-10 alkoxy group, a cyclic C.sub.3-10 alkoxy
group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl
group, an amino group, a nitro group, a cyano group, or a phenoxy
group.
[0069] Examples of the phenyl group substituted with one
substituent group include a 2-fluoro phenyl group, a 3-fluoro
phenyl group, a 4-fluoro phenyl group, a 2-chloro phenyl group, a
3-chloro phenyl group, a 4-chloro phenyl group, a 2-bromo phenyl
group, a 3-bromo phenyl group, a 4-bromo phenyl group, a 2-iodo
phenyl group, a 3-iodo phenyl group, a 4-iodo phenyl group, a
2-methyl phenyl group, a 3-methyl phenyl group, a 4-methyl phenyl
group, a 2-ethyl phenyl group, a 3-ethyl phenyl group, a 4-ethyl
phenyl group, a 2-isopropyl phenyl group, a 3-isopropyl phenyl
group, a 4-isopropyl phenyl group, a 2-cyclopropyl phenyl group, a
3-cyclopropyl phenyl group, a 4-cyclopropyl phenyl group, a
2-cyclohexyl phenyl group, a 3-cyclohexyl phenyl group, a
4-cyclohexyl phenyl group, a 2-methoxy phenyl group, a 3-methoxy
phenyl group, a 4-methoxy phenyl group, a 2-isopropoxy phenyl
group, a 3-isopropoxy phenyl group, a 4-isopropoxy phenyl group, a
2-cyclobutyloxy phenyl group, a 3-cyclobutyloxy phenyl group, a
4-cyclobutyloxy phenyl group, a 2-cyclohexyl oxy phenyl group, a
3-cyclohexyl oxy phenyl group, a 4-cyclohexyl oxy phenyl group, a
2-trifluoro methyl phenyl group, a 3-fluoro methyl phenyl group, a
4-trifluoro methyl phenyl group, a 2-phenyl phenyl group, a
3-phenyl phenyl group, a 4-phenyl phenyl group, a 2-hydroxy
carbonyl phenyl group, a 3-hydroxy carbonyl phenyl group, a
4-hydroxy carbonyl phenyl group, a 2-amino phenyl group, a 3-amino
phenyl group, a 4-amino phenyl group, a 2-nitro phenyl group, a
3-nitro phenyl group, a 4-nitro phenyl group, a 2-cyano phenyl
group, a 3-cyano phenyl group, a 4-cyano phenyl group, a 2-phenoxy
phenyl group, a 3-phenoxy phenyl group, and a 4-phenoxy phenyl
group.
[0070] Examples of the phenyl group substituted with two
substituent groups include a 2,3-difluoro phenyl group, a
2,4-difluoro phenyl group, a 2,5-difluoro phenyl group, a
2,6-difluoro phenyl group, a 3,4-difluoro phenyl group, a
3,5-difluoro phenyl group, a 2,3-dichloro phenyl group, a
2,4-dichloro phenyl group, a 2,5-dichloro phenyl group, a
2,6-dichloro phenyl group, a 3,4-dichloro phenyl group, a
3,5-dichloro phenyl group, a 2,3-dibromo phenyl group, a
2,4-dibromo phenyl group, a 2,5-dibromo phenyl group, a 2,6-dibromo
phenyl group, a 3,4-dibromo phenyl group, a 3,5-dibromo phenyl
group, a 2,3-diiodo phenyl group, a 2,4-diiodo phenyl group, a
2,5-diiodo phenyl group, a 2,6-diiodo phenyl group, a 3,4-diiodo
phenyl group, a 3,5-diiodo phenyl group, a 3-chloro-4-fluoro phenyl
group, a 4-chloro-3-fluoro phenyl group, a 3-bromo-4-fluoro phenyl
group, a 4-bromo-3-fluoro phenyl group, a 4-bromo-3-chloro phenyl
group, a 3-bromo-4-chloro phenyl group, a 3-chloro-4-methyl phenyl
group, a 4-chloro-3-methyl phenyl group, a 3-fluoro-4-methyl phenyl
group, a 4-fluoro-3-methyl phenyl group, a 3-fluoro-4-methoxy
phenyl group, a 4-fluoro-3-methoxy phenyl group, a
3-bromo-4-methoxy phenyl group, a 4-bromo-3-methoxy phenyl group, a
3-chloro-4-phenoxy phenyl group, a 4-chloro-3-phenoxy phenyl group,
a 3-chloro-4-nitro phenyl group, a 4-chloro-3-nitro phenyl group, a
4-bromo-3-nitro phenyl group, a 3-bromo-4-nitro phenyl group, a
3-amino-4-bromo phenyl group, a 4-amino-3-bromo phenyl group, a
3-bromo-4-hydroxy carbonyl group, a 4-bromo-3-hydroxy carbonyl
phenyl group, a 4-fluoro-3-hydroxy carbonyl phenyl group, a
3-fluoro-4-hydroxy carbonyl phenyl group, a 4-fluoro-3-hydroxy
carbonyl phenyl group, a 3-cyano-4-fluoro phenyl group, a
3-cyano-4-fluoro phenyl group, a 4-cyano-3-methyl phenyl group, a
3-cyano-4-methyl phenyl group, a 3-cyano-4-methoxy phenyl group,
and a 4-cyano-3-methoxy phenyl group.
[0071] Examples of the phenyl group substituted with three
substituent groups include a 2,3,4-trifluorophenyl group, a
3,4,5-trifluorophenyl group, a 3,4,5-trichlorophenyl group, a
3-chloro-2,6-difluorophenyl group, a 3,5-dichloro-4-methoxyphenyl
group, and a 3,5-dibromo-4-methoxyphenyl group.
[0072] Examples of the phenyl group substituted with four
substituent groups include a 2,5-dibromo-3,4-dimethoxyphenyl group,
and a 3,4-dibromo-2,4-dimethoxyphenyl group.
[0073] Examples of the phenyl group substituted with five
substituent groups include a 2,3,4,5,6-pentafluorophenyl group.
[0074] The term "form wherein R.sup.1 and R.sup.2 bind to each
other to form a cyclic structure" includes form to have a
cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a
cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a
cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a
cyclooctenyl group, an oxa cyclobutyl group, an oxa cyclopentyl
group, an oxa cyclohexyl group, an oxa cycloheptyl group, an oxa
cyclooctyl group, an azacyclobutyl group, an azacyclopentyl group,
an azacyclohexyl group, an azacycloheptyl group, or an
azacyclooctyl group.
[0075] The "C.sub.1-6 alkoxy group" means a straight-chain alkoxy
group having one to six carbon atoms, a branched chain alkoxy group
having three to six carbon atoms, or a cyclic alkoxy group having
three to six carbon atoms, and examples of which include a methoxy
group, an ethoxy group, a propoxy group, a butoxy group, a
pentyloxy group, a hexyloxy group, an isopropoxy group, an iso
butoxy group, a 1-methyl propoxy group, a tert-butoxy group, a
1-methyl butoxy group, a 2-methyl butoxy group, an isopentyl oxy
group, a neopentyl oxy group, a 1,1-dimethyl propoxy group, a
1,2-dimethyl propoxy group, a 1-methyl pentyloxy group, a 2-methyl
pentyloxy group, a 3-methyl pentyloxy group, an iso hexyloxy group,
a 1-ethyl butoxy group, a 2-ethyl butoxy group, a 1,1-dimethyl
butoxy group, a 1,2-dimethyl butoxy group, a 1,3-dimethyl butoxy
group, a 2,2-dimethyl butoxy group, a 2,3-dimethyl butoxy group, a
3,3-dimethyl butoxy group, a cyclopropyl oxy group, a cyclobutyl
oxy group, a cyclopentyl oxy group, and a cyclohexyl oxy group.
[0076] The "C.sub.1-6 alkyl group" means a straight-chain alkyl
group having one to six carbon atoms, a branched chain alkyl group
having three to six carbon atoms, or a cyclic alkyl group having
three to six carbon atoms, and examples of which include a methyl
group, an ethyl group, a propyl group, a butyl group, a pentyl
group, a hexyl group, an isopropyl group, an isobutyl group, a
1-methyl propyl group, a tert-butyl group, a 1-methyl butyl group,
a 2-methyl butyl group, an isopentyl group, a neopentyl group, a
1,1-dimethyl propyl group, a 1,2-dimethyl propyl group, a 1-methyl
pentyl group, a 2-methyl pentyl group, a 3-methyl pentyl group, an
iso hexyl group, a 1-ethyl butyl group, a 2-ethyl butyl group, a
1,1-dimethyl butyl group, a 1,2-dimethyl butyl group, a
1,3-dimethyl butyl group, a 2,2-dimethyl butyl group, a
2,3-dimethyl butyl group, a 3,3-dimethyl butyl group, a cyclopropyl
group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl
group.
[0077] The "benzoyl group substituted with a halogen atom" means a
benzoyl group substituted with at least one fluorine atom, a
chlorine atom, a bromine atom, or an iodine atom. Examples thereof
include a 3-chloro benzoyl group, a 4-fluoro benzoyl group, a
4-bromo benzoyl group, and a 4-iodo benzoyl group.
[0078] The "salt" includes, for example, a salt with an inorganic
acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,
nitric acid, phosphoric acid, or boric acid, a salt with an organic
acid such as formic acid, acetic acid, propionic acid, 2-ethyl
hexanoic acid, trifluoroacetic acid, trichloroacetic acid, pyruvic
acid, diphenyl acetic acid, cinnamic acid, glycolic acid, D-lactic
acid, L-lactic acid, D-mandelic acid, L-mandelic acid, D-glucuronic
acid, D-gluconic acid, lactobionic acid, oxalic acid, malonic acid,
succinic acid, glutaric acid, adipic acid, fumaric acid, maleic
acid, (+)-camphoric acid, 2-ketoglutaric acid, glutamic acid,
asparaginic acid, pyroglutamic acid, D-tartaric acid, L-tartaric
acid, D-malic acid, L-malic acid, citric acid, benzoic acid,
4-hydroxybenzoic acid, salicylic acid, phthalic acid, isophthalic
acid, terephthalic acid, methane sulfonic acid, trifluoromethane
sulfonic acid, ethane sulfonic acid, benzene sulfonic acid,
p-toluene sulfonic acid, (+)-10-camphor sulfonic acid,
(-)-10-camphor sulfonic acid, and isethionic acid;
[0079] a salt with one or more types of metal ions such as lithium
ion, sodium ion, potassium ion, magnesium ion, calcium ion, barium
ion, zinc ion, or aluminum ion;
[0080] a salt with an amine such as ammonia, triethyl amine,
trimethyl amine, diethyl amine, morpholine, N-methyl morpholine,
piperidine, piperazine, pyrrolidine, dicyclohexyl amine, 4-phenyl
cyclohexyl amine, 2-amino ethanol, arginine, lysine, or N,
N'-dibenzyl ethylene diamine, and;
a salt with quaternary ammonium ion such as tetramethyl ammonium
ion, tetraethyl ammonium ion, tetrabutyl ammonium ion, or
choline.
[0081] The "inert solvent" specifically indicates a solvent that is
not involved with a target reaction.
[0082] A specific example of the combination of R.sup.1 and R.sup.2
in the compound represented by the formula (I) or a salt thereof in
the present invention include a combination wherein one of R.sup.1
and R.sup.2 is a hydrogen atom and the other is a phenyl group
substituted with 1 to 5 halogen atoms like a 3,4-dichloro phenyl
group.
[0083] In a preferred embodiment of the process for producing a
compound represented by the formula (I) or a salt thereof in the
present invention, the compound represented by the formula (II) or
a salt thereof is used as a starting material. Preferably, R.sup.3
is a methoxy group or an ethoxy group. More preferably, R.sup.3 is
an ethoxy group.
[0084] In a preferred embodiment of the process for producing a
compound represented by the formula (I) or a salt thereof in the
present invention, specifically in a combination of substituent
group in a compound represented by the formula (III) as an
intermediate or a salt thereof, R.sup.4 is a trimethylsilyl group
or a triethyl silyl group and R.sup.5 is a methoxy group or an
ethoxy group. More preferably, R.sup.4 is a trimethylsilyl group
and R.sup.5 is an ethoxy group.
[0085] In a preferred embodiment of the process for producing a
compound represented by the formula (I) or a salt thereof in the
present invention, specifically in a combination of substituent
group in a compound represented by the formula (IV) as an
intermediate or a salt thereof, R.sup.6 is a hydrogen atom, a
benzoyl group, a benzoyl group substituted with a halogen atom, or
--SiR.sup.61R.sup.62R.sup.63 wherein R.sup.61, R.sup.62, and
R.sup.63, which may be the same or different from each other, each
represent a C.sub.1-6 alkyl group, and R.sup.7 is a methoxy group
or an ethoxy group. More preferably, R.sup.6 is a hydrogen atom and
R.sup.7 is an ethoxy group.
[0086] In a preferred embodiment of the process for producing a
compound represented by the formula (I) or a salt thereof in the
present invention, specifically in a combination of substituent
group in a compound represented by the formula (V) as an
intermediate or a salt thereof, R.sup.8 is a methoxy group, an
ethoxy group, or an amino group, R.sup.1 is a hydrogen atom and
R.sup.2 is a 3,4-dichloro phenyl group. More preferably, R.sup.8 is
an ethoxy group or an amino group.
[0087] In a preferred embodiment of the process for producing a
compound represented by the formula (I) or a salt thereof in the
present invention, specifically in a combination of substituent
group in a compound represented by the formula (VI) as an
intermediate or a salt thereof, R.sup.9 is a methoxy group, an
ethoxy group or an amino group, R.sup.1 is a hydrogen atom, and
R.sup.2 is a 3,4-dichloro phenyl group. More preferably, R.sup.9 is
an amino group.
[0088] In a combination of substituent group in a compound
represented by the formula (VIII) or a salt thereof, which is a
diastereomer of the compound represented by the formula (VI) or a
salt thereof, it is preferable that R.sup.13 is a methoxy group, an
ethoxy group or an amino group, R.sup.1 is a hydrogen atom, and
R.sup.2 is a 3,4-dichloro phenyl group. More preferably, R.sup.13
is an amino group.
[0089] Further, preferred examples of a salt of the compound
represented by the formula (VI) or the formula (VIII) include a
salt with an organic acid like citric acid, L-tartaric acid, oxalic
acid, and p-toluene sulfonic acid.
[0090] In a preferred embodiment of the process for producing a
compound represented by the formula (I) or a salt thereof in the
present invention, specifically in a combination of substituent
group in a compound represented by the formula (VII) as an
intermediate or a salt thereof, R.sup.10 is an amino group, a
hydroxyl group, a methoxy group or an ethoxy group, R.sup.11 is an
amino group, a hydroxyl group, a methoxy group or an ethoxy group,
R.sup.1 is an a hydrogen atom, and R.sup.2 is a 3,4-dichloro phenyl
group (with the proviso that R.sup.10 and R.sup.11 are not
simultaneously a hydroxyl group). More preferably, R.sup.10 is an
amino group and R.sup.11 is an amino group or a hydroxyl group.
[0091] In a preferred embodiment of the process for producing a
compound represented by the formula (I) or a salt thereof in the
present invention, a compound represented by the formula (VI) or a
salt thereof is used as a starting material. In a combination of
substituent group, it is preferable that R.sup.9 is a methoxy
group, an ethoxy group, or an amino group, R.sup.1 is a hydrogen
atom and R.sup.2 is a 3,4-dichloro phenyl group. More preferably,
R.sup.9 is an amino group.
[0092] In a preferred embodiment of the process for producing a
compound represented by the formula (I) or a salt thereof in the
present invention, specifically in a combination of substituent
group in a compound represented by the formula (IX) as an
intermediate or a salt thereof, R.sup.12 is an amino group, a
hydroxyl group, a methoxy group or an ethoxy group, R.sup.1 is an a
hydrogen atom, and R.sup.2 is a 3,4-dichloro phenyl group. More
preferably, R.sup.12 is a hydroxyl group.
[0093] In a combination of substituent group in a compound
represented by the formula (X) or a salt thereof, which is a
diastereomer of the compound represented by the formula (IX) or a
salt thereof, it is preferable that R.sup.14 is an amino group, a
hydroxyl group, a methoxy group or an ethoxy group, R.sup.1 is a
hydrogen atom, and R.sup.2 is a 3,4-dichloro phenyl group. More
preferably, R.sup.14 is a hydroxyl group.
[0094] The present invention relates to a process for producing a
compound represented by the formula (I) or a salt thereof, that is,
a process for producing the compound represented by the formula (I)
or a salt thereof starting from a compound represented by the
formula (II) or a salt thereof with the intervention of a compound
represented by the formula (VI) or a salt thereof as an
intermediate, a process for producing the compound represented by
the formula (I) or a salt thereof starting from the compound
represented by the formula (VI) or a salt thereof as an
intermediate, and a process for producing the compound represented
by the formula (I) or a salt thereof starting from the compound
represented by the formula (II) or a salt thereof with the
intervention of a compound represented by the formula (IX) or a
salt thereof as an intermediate. The invention also relates to a
compound represented by the formula (IV), the formula (V), the
formula (VI), the formula (VII), the formula (VIII), the formula
(IX), or the formula (X) and a salt thereof, which is a synthetic
intermediate of the compound of the formula (I).
[0095] The invention can be carried out according to the process
described below. One embodiment of the present invention is shown
in the following Scheme 1, Scheme 2, and Scheme 3.
##STR00026##
[0096] In the formulae of the Scheme 1 above,
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 R.sup.13 areas
defined above.
[0097] The compound represented by the formula (II) as a starting
material can be produced according to the processes described in
literatures (reference literatures: Org. Lett., 6, 3775-3777
(2004), J. Med. Chem., 43, 4893-4909 (2000), Org. Biomol. Chem.,
2,168-174 (2004), Tetrahedron, 57, 7487-7493 (2001), and the
pamphlet of International Publication No. WO 02/00595).
[0098] (Step 1): A compound represented by the formula (III) is
obtained by reacting a compound represented by the formula (II)
with a silylating agent in an inert solvent in the presence of a
base.
[0099] Examples of the inert solvent that can be used include
hydrocarbon type solvents such as toluene, xylene, benzene,
heptane, hexane, or petroleum ether;
[0100] halogen type solvents such as dichloro methane, chloroform,
1,2-dichloro ethane, carbon tetrachloride, chloro benzene, or
benzotrifluoride;
[0101] ether type solvents such as tetrahydrofuran, 2-methyl
tetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether,
tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxy
ethane, diethoxy methane, or 1,4-dioxane;
[0102] acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
dimethyl sulfoxide (DMSO), or a mixture of these solvents.
[0103] Examples of the base that can be used include an organic
amine like triethyl amine, diisopropyl ethyl amine, N-methyl
morpholine, diazabicycloundecene, diazabicyclononene, and pyridine,
a metal amide base like lithium diisopropyl amide, lithium
hexamethyl disilazide, sodium hexamethyl disilazide, and potassium
hexamethyl disilazide, and an alkali metal hydride base like sodium
hydride and potassium hydride.
[0104] Examples of the silylating agent that can be used include
chloro trimethyl silane, bromo trimethyl silane, iodo trimethyl
silane, trimethyl silyl trifluoro methane sulfonic acid, chloro
triethyl silane, chloro triisopropyl silane, and tert-butyl chloro
dimethyl silane. Further, as an additive for a combination with
chloro trimethyl silane, sodium iodide, potassium iodide,
tetrabutyl ammonium iodide, sodium bromide, and potassium bromide
can be used.
[0105] The reaction temperature may be usually from -80.degree. C.
to the boiling point of the solvent used, is preferably in the
range of -60.degree. C. to 100.degree. C., and is more preferably
in the range of 0.degree. C. to 60.degree. C.
[0106] The amount of base that can be used may be in the range of
0.5 to 5 molar equivalents relative to the compound represented by
the formula (II) as a raw material, preferably in the range of 1 to
3 molar equivalents, and more preferably in the range of 1 to 1.5
molar equivalents.
[0107] The amount of silylating agent that can be used may be in
the range of 1 to 5 molar equivalents relative to the compound
represented by the formula (II) as a raw material, preferably in
the range of 1 to 3 molar equivalents, and more preferably in the
range of 1 to 1.5 molar equivalents.
[0108] With regard to the amount of reaction solvent, it may be
used at 1 to 100 times by mass relative to the compound represented
by the formula (II) as a raw material, preferably in the range of 1
to 30 times by mass, and more preferably in the range of 1 to 10
times by mass.
[0109] The compound represented by the formula (III) may be used as
a raw material for next step without purifying concentrated
residues after the post-reaction treatment or concentrating the
solution after post-treatment (reference literature: J. Med. Chem.,
43, 4893-4909 (2000) and Bioorg. Med. Chem., 10, 433-436
(2002)).
[0110] (Step 2): A compound represented by the formula (IV) is
obtained by reacting a compound represented by the formula (III)
with an oxidizing agent in an inert solvent in the presence or
absence of an additive.
[0111] Herein, by reacting in a solvent like methanol and ethanol
in the presence of a base like potassium carbonate, sodium
carbonate, sodium hydrogen carbonate, and potassium hydrogen
carbonate, the compound represented by the formula (IV) of the
present invention wherein R.sup.6 is a benzoyl group or a benzoyl
group substituted with a halogen atom can be converted into the
compound represented by the formula (IV) of the present invention
wherein R.sup.6 is a hydrogen atom.
[0112] Further, by treating under acidic condition (dilute
hydrochloric acid, aqueous solution of acetic acid, or the like) or
basic condition (potassium carbonate, tetrabutyl ammonium fluoride,
or the like), the compound represented by the formula (IV) of the
present invention wherein R.sup.6 is --SiR.sup.61R.sup.62R.sup.63
(R.sup.61, R.sup.62, and R.sup.63, which may be the same or
different from each other, each represent a C.sub.1-6 alkyl group)
can be converted into the compound represented by the formula (IV)
of the present invention wherein R.sup.6 is a hydrogen atom.
[0113] Further, in the oxidation reaction of the compound
represented by the formula (III), by treating under post-treatment
condition (acid treatment, base treatment, or treatment with
aqueous solution of sodium thiosulfate, aqueous solution of sodium
sulfite, or aqueous solution of sodium hydrogen sulfite), the
compound represented by the formula (IV) of the present invention
wherein R.sup.6 is --SiR.sup.61R.sup.62R.sup.63 (R.sup.61,
R.sup.62, and R.sup.63, which may be the same or different from
each other, each represent a C.sub.1-6 alkyl group), that is
produced together with the compound represented by the formula (IV)
of the present invention wherein R.sup.6 is a hydrogen atom, can be
converted into the compound represented by the formula (IV) of the
present invention wherein R.sup.6 is a hydrogen atom.
[0114] Examples of the oxidizing agent that can be used include
peracid like 3-chloro perbenzoic acid, perbenzoic acid, mono peroxy
phthalic acid, magnesium salt of mono peroxy phthalic acid, and
peracetic acid;
[0115] hydrogen peroxide in the presence of a catalyst like methyl
trioxo rhenium or tris(cetyl pyridinium)peroxo tungstophosphate
(PCWP);
[0116] hydrogen peroxide in the presence of a nitrile compound like
trichloroacetonitrile and acetonitrile;
[0117] hydrogen peroxide in the presence of a nitrile compound like
trichloroacetonitrile and acetonitrile and a ketone compound like
acetone;
[0118] oxone (2 KHSO.sub.5.KHSO.sub.4.K.sub.2SO.sub.4) in the
presence of a ketone compound like acetone;
[0119] dimethyldioxirane, tert-butyl hydroperoxide, osmium
tetraoxide, N-methyl morpholine-N-oxide, lead tetraacetate, iodosyl
benzene and boron trifluoride diethyl ether complex, chromyl
chloride, and ozone (reference literature: Organic Reactions, 62,
1-356 (2003)).
[0120] Examples of the inert solvent that can be used include
hydrocarbon type solvents such as toluene, xylene, benzene,
heptane, hexane, or petroleum ether;
[0121] halogen type solvents such as dichloro methane, chloroform,
1,2-dichloro ethane, carbon tetrachloride, chloro benzene, or
benzotrifluoride;
[0122] ether type solvents such as tetrahydrofuran, 2-methyl
tetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether,
tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxy
ethane, diethoxy methane, or 1,4-dioxane;
[0123] alcohol type solvents such as methanol, ethanol, 2-propanol,
or tert-butyl alcohol;
[0124] ketone type solvents such as acetone, 2-butanone, or methyl
isobutyl ketone;
[0125] ester type solvents such as ethyl acetate or isopropyl
acetate;
[0126] acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
dimethyl sulfoxide, acetic acid, water, or a mixture of these
solvents.
[0127] Examples of the additive include sodium hydrogen carbonate,
potassium hydrogen carbonate, potassium carbonate, sodium
carbonate, calcium hydroxide, potassium dihydrogen phosphate,
dipotassium hydrogen phosphate, sodium dihydrogen phosphate,
disodium hydrogen phosphate, pyridine, and acetic acid.
[0128] The reaction temperature may be usually from -80.degree. C.
to the boiling point of the solvent used, is preferably in the
range of 0 to 100.degree. C., and is more preferably in the range
of 0 to 50.degree. C.
[0129] The amount of oxidizing agent that can be used may be in the
range of 0.5 to 5 molar equivalents relative to the compound
represented by the formula (III) as a raw material, preferably in
the range of 1 to 3 molar equivalents, and more preferably in the
range of 1 to 1.5 molar equivalents.
[0130] The amount of the catalyst that can be used may be in the
range of 0.001 to 0.5 molar equivalents relative to the compound
represented by the formula (III) as a raw material, preferably in
the range of 0.002 to 0.1 molar equivalents, and more preferably in
the range of 0.01 to 0.05 molar equivalents.
[0131] With regard to the amount of solvent, it may be used at 1 to
100 times by mass relative to the compound represented by the
formula (III) as a raw material, preferably in the range of 1 to 30
times by mass, and more preferably in the range of 1 to 10 times by
mass.
[0132] Compound represented by the formula (IV) can be obtained as
a purified product or unpurified product according to the process
like chromatography, re-crystallization, re-slurry, neutralization
crystal precipitation, and distillation.
[0133] (Step 3): A compound represented by the formula (V) of the
present invention wherein R.sup.8 is a C.sub.1-6 alkoxy group is
obtained by reacting a compound represented by the formula (IV)
wherein R.sup.7 is a C.sub.1-6 alkoxy group and R.sup.6 is a
hydrogen atom with a compound represented by the formula
R.sup.1R.sup.2CHOC(.dbd.NH)CCl.sub.3 (R.sup.1 and R.sup.2 are as
defined above) in an inert solvent in the presence of an acid
(reference literature: J. Chem. Soc., Chem. Commun., 1240-1241
(1981) and J. Chem. Soc., Perkin Trans. 1, 2247-2250 (1985)).
[0134] Examples of the inert solvent that can be used include
hydrocarbon type solvents such as toluene, xylene, benzene,
heptane, hexane, cyclohexane, or petroleum ether;
[0135] halogen type solvents such as dichloro methane, chloroform,
1,2-dichloro ethane, carbon tetrachloride, chloro benzene,
1,2-dichlorobenzene, or benzotrifluoride;
[0136] ether type solvents such as tetrahydrofuran, 2-methyl
tetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether,
tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxy
ethane, diethoxy methane, or 1,4-dioxane;
[0137] ketone type solvents such as acetone, 2-butanone, or methyl
isobutyl ketone;
[0138] ester type solvents such as ethyl acetate or isopropyl
acetate;
[0139] acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
dimethyl sulfoxide, or a mixture of these solvents.
[0140] Examples of the acid that can be used include Broensted acid
like trifluoromethane sulfonic acid, bistrifluoro methane
sulfonimide, trifluoro acetic acid, hydrochloric acid, and
perchloric acid or Lewis acid like boron trifluoride diethyl ether
complex, zinc chloride, tin chloride, trifluoro methane sulfonic
acid trimethyl silyl, scandium (III) trifluoro methane sulfonic
acid, and ytterbium (III) trifluoro methane sulfonic acid.
[0141] The reaction temperature may be usually from -80.degree. C.
to the boiling point of the solvent used, is preferably in the
range of -30 to 50.degree. C., and is more preferably in the range
of -10 to 20.degree. C.
[0142] The amount of the compound represented by the formula
R.sup.1R.sup.2CHOC(.dbd.NH)CCl.sub.3 (R.sup.1 and R.sup.2 are as
defined in the above) used may be in the range of 1 to 5 molar
equivalents relative to the compound represented by the formula
(IV) as a reacting compound, preferably in the range of 1 to 3
molar equivalents, and more preferably in the range of 1 to 1.5
molar equivalents.
[0143] The amount of acid that can be used may be in the range of
0.01 to 2 molar equivalents relative to the compound represented by
the formula (IV) as a raw material, preferably in the range of 0.1
to 1.5 molar equivalents, and more preferably in the range of 0.3
to 1 molar equivalents.
[0144] With regard to the amount of solvent, it may be used at 1 to
100 times by mass relative to the compound represented by the
formula (IV) as a raw material, preferably in the range of 1 to 30
times by mass, and more preferably in the range of 5 to 15 times by
mass.
[0145] The compound represented by the formula
R.sup.1R.sup.2CHOC(.dbd.NH)CCl.sub.3 (R.sup.1 and R.sup.2 are as
defined in the above) can be obtained by reacting an alcohol
represented by the formula R.sup.1R.sup.2CHOH with
trichloroacetonitirle in the presence of a base according to a
process described in the literature (reference literature: J. Chem.
Soc., Perkin Trans. 1, 2247-2250 (1985) and Tetrahedron Lett., 37,
1481-1484 (1996)).
[0146] Further, by reacting the compound represented by the formula
(IV) wherein R.sup.7 is a C.sub.1-6 alkoxy group and R.sup.6 is a
hydrogen atom with a compound represented by the formula
R.sup.1R.sup.2CHX (R.sup.1 and R.sup.2 are as defined in the above)
in an inert solvent in the presence of abase, a compound
represented by the formula (V) of the present invention wherein
R.sup.8 is a C.sub.1-6 alkoxy group can be obtained. Herein, X
represents a leaving group other than OC(.dbd.NH)CCl.sub.3 and
examples thereof include a chlorine atom, a bromine atom, an iodine
atom, a p-toluene sulfonyl oxy group, a p-bromo benzene sulfonyl
oxy group, a p-nitro benzene sulfonyl oxy group, a benzene sulfonyl
oxy group, a methane sulfonyloxy group, and a trifluoro methane
sulfonyl oxy group.
[0147] Examples of the inert solvent that can be used include
hydrocarbon type solvents such as toluene, xylene, benzene,
heptane, hexane, cyclohexane, cyclohexane, or petroleum ether;
[0148] halogen type solvents such as dichloro methane, chloroform,
1,2-dichloro ethane, carbon tetrachloride, chloro benzene,
1,2-dichloro benzene, or benzotrifluoride;
[0149] ether type solvents such as tetrahydrofuran, 2-methyl
tetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether,
tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxy
ethane, diethoxy methane, or 1,4-dioxane;
[0150] ketone type solvents such as acetone, 2-butanone, or methyl
isobutyl ketone;
[0151] ester type solvents such as ethyl acetate or isopropyl
acetate;
[0152] acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
dimethyl sulfoxide, or a mixture of these solvents.
[0153] Examples of the base include inorganic bases like sodium
hydride, potassium hydride, potassium carbonate, sodium carbonate,
cesium carbonate, potassium hydrogen carbonate, sodium hydrogen
carbonate, sodium hydroxide, potassium hydroxide, and silver (I)
oxide;
[0154] metal amide bases like lithium diisopropyl amide, lithium
hexamethyl disilazide, sodium hexamethyl disilazide, and potassium
hexamethyl disilazide;
[0155] organic amine bases like triethyl amine, diisopropyl ethyl
amine, N-methyl morpholine, diazabicycloundecene,
diazabicyclononene, pyridine, and 4-dimethyl amino pyridine,
and;
[0156] alkoxide bases like potassium tert-butoxide, sodium
tert-pentoxide, and potassium tert-pentoxide.
[0157] The reaction temperature may be usually from -80.degree. C.
to the boiling point of the solvent used, is preferably in the
range of -30 to 100.degree. C., and is more preferably in the range
of 0 to 50.degree. C.
[0158] The amount of the compound represented by the formula
R.sup.1R.sup.2CHX (R.sup.1, R.sup.2 and X are as defined in the
above) used may be in the range of 1 to 5 molar equivalents
relative to the compound represented by the formula (IV) as a raw
material, preferably in the range of 1 to 3 molar equivalents, and
more preferably in the range of 1 to 1.5 molar equivalents.
[0159] The amount of base that can be used may be in the range of 1
to 5 molar equivalents relative to the compound represented by the
formula (IV) as a raw material, preferably in the range of 1 to 3
molar equivalents, and more preferably in the range of 1 to 1.5
molar equivalents.
[0160] With regard to the amount of solvent, it may be used at 1 to
100 times by mass relative to the compound represented by the
formula (IV) as a raw material, preferably in the range of 1 to 30
times by mass, and more preferably in the range of 5 to 15 times by
mass.
[0161] Further, by reacting the compound represented by the formula
(V) of the present invention wherein R.sup.8 is a C.sub.1-6 alkoxy
group under a common condition for hydrolysis (reference
literature: T. W. Greene, P. G. M. Wuts, "Protective Groups in
Organic Synthesis"), a compound represented by the formula (V) of
the present invention wherein R.sup.8 is a hydroxyl group or a salt
thereof can be obtained.
[0162] Further, by reacting the compound represented by the formula
(V) of the present invention wherein R.sup.8 is a C.sub.1-6 alkoxy
group with ammonia in an inert solvent, a compound represented by
the formula (V) of the present invention wherein R.sup.8 is an
amino group can be obtained.
[0163] Examples of the inert solvent that can be used include
alcohol type solvents such as methanol, ethanol, 2-propanol, or
tert-butyl alcohol;
[0164] hydrocarbon type solvents such as toluene, xylene, benzene,
heptane, hexane, cyclohexane, or petroleum ether;
[0165] halogen type solvents such as dichloro methane, chloroform,
1,2-dichloro ethane, carbon tetrachloride, chloro benzene, or
benzotrifluoride;
[0166] ether type solvents such as tetrahydrofuran, 2-methyl
tetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether,
tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxy
ethane, diethoxy methane, or 1,4-dioxane;
[0167] acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
dimethyl sulfoxide, or a mixture of these solvents.
[0168] The reaction temperature may be usually from -80.degree. C.
to the boiling point of the solvent used, is preferably in the
range of -20 to 100.degree. C., and is more preferably in the range
of 0 to 50.degree. C.
[0169] The amount of ammonia that can be used may be in the range
of 1 to 100 molar equivalents relative to the compound represented
by the formula (V) of the present invention wherein R.sup.8 is a
C.sub.1-6 alkoxy group, preferably in the range of 5 to 50 molar
equivalents, and more preferably in the range of 3 to 10 molar
equivalents.
[0170] With regard to the amount of solvent, it may be used at 1 to
100 times by mass relative to the compound represented by the
formula (IV) of the present invention wherein R.sup.8 is a
C.sub.1-6 alkoxy group, preferably in the range of 1 to 30 times by
mass, and more preferably in the range of 1 to 10 times by
mass.
[0171] Compound represented by the formula (V) of the present
invention can be obtained as a purified product or unpurified
product according to the process like chromatography,
re-crystallization, re-slurry, neutralization crystal
precipitation, and distillation.
[0172] (Step 4): A compound represented by the formula (VI) of the
present invention or a salt thereof and a compound represented by
the formula (VIII) of the present invention or a salt thereof can
be obtained by reacting the compound represented by the formula (V)
with ammonia in an inert solvent in the presence of a Lewis acid
followed by reaction with a cyanating agent in the presence or
absence of a Lewis acid (reference literature: Tetrahedron Lett.,
41, 6403-6406 (2000), Tetrahedron Lett., 42, 1499-1502 (2001), J.
Org. Chem., 69, 843-856 (2004), J. Org. Chem., 70, 8027-8034
(2005), and Synlett, 1875-1878 (2006)).
[0173] Alternatively, the compound represented by the formula (VI)
of the present invention or a salt thereof and the compound
represented by the formula (VIII) of the present invention or a
salt thereof can be obtained by reacting the compound represented
by the formula (V) in an inert solvent with ammonia and a cyanating
agent in the presence of a Lewis acid.
[0174] Examples of the inert solvent that can be used include
alcohol type solvents such as methanol, ethanol, 2-propanol,
tert-butyl alcohol, 2,2,2-trifluoro ethanol, or [0175]
1,1,1,3,3,3-hexafluoro-2-propanol;
[0176] hydrocarbon type solvents such as toluene, xylene, benzene,
heptane, hexane, cyclohexane, or petroleum ether;
[0177] halogen type solvents such as dichloro methane, chloroform,
1,2-dichloro ethane, carbon tetrachloride, chloro benzene, or
benzotrifluoride;
[0178] ether type solvents such as tetrahydrofuran, 2-methyl
tetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether,
tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxy
ethane, diethoxy methane, or 1,4-dioxane;
[0179] acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
dimethyl sulfoxide, acetic acid, water, or a mixture of these
solvents.
[0180] Examples of the Lewis acid that can be used include titanium
(IV) isopropoxide, titanium (IV) methoxide, titanium (IV) ethoxide,
titanium (IV) propoxide, titanium (IV) butoxide, lithium bromide,
lithium perchloric acid, magnesium bromide, magnesium bromide,
diethyl ether complex, magnesium acetate, magnesium
trifluoromethane sulfonic acid, magnesium perchloric acid,
ferrocenium hexafluoro phosphate, cobalt (II) chloride, nickel (II)
chloride, copper (II) trifluoromethane sulfonic acid, zinc
chloride, zinc bromide, zinc iodide, zinc (II) trifluoromethane
sulfonic acid, gallium (III) trifluoromethane sulfonic acid,
niobium (V) chloride, molybdenum (VI) oxide, ruthenium (III)
chloride, rhodium (III) iodide hydrate, indium (III) chloride,
indium (III) bromide, indium (III) iodide, vanadyl triflate, tin
chloride (II), tin (IV) chloride, iodine, hafnium (IV)
trifluoromethane sulfonic acid, thallium (III) chloride, bismuth
(III) chloride, scandium (III) trifluoromethane sulfonic acid,
yttrium (III) trifluoromethane sulfonic acid, lanthanum (III)
trifluoromethane sulfonic acid, lanthanum (III) isopropoxide,
lanthanum (III) nitrate hexahydrate, cerium (III) chloride,
praseodymium (III) trifluoromethane sulfonic acid, neodymium (III)
trifluoromethane sulfonic acid, samarium (III) trifluoromethane
sulfonic acid, gadolinium (III) trifluoromethane sulfonic acid,
gadolinium (III) chloride hexahydrate, and ytterbium (III)
trifluoromethane sulfonic acid.
[0181] Examples of the cyanating agent that can be used include
trimethylsilyl cyanide, hydrogen cyanide, sodium cyanide, potassium
cyanide, acetone cyanohydrin, diethylcyano phosphonate, diethyl
aluminum cyanide, tert-butyl dimethyl silyl cyanide, and tributyl
tin cyanide.
[0182] The reaction temperature may be usually from -80.degree. C.
to the boiling point of the solvent used. However, for the reaction
between the compound represented by the formula (V) and ammonia, it
is preferably in the range of 0 to 30.degree. C. For the subsequent
reaction with a cyanating agent, it is preferably in the range of
-40 to 30.degree. C. For the reaction between the compound
represented by the formula (V) and ammonia and a cyanating agent,
it is preferably in the range of -40 to 30.degree. C.
[0183] The amount of ammonia that can be used may be in the range
of 1 to 100 molar equivalents relative to the compound represented
by the formula (V), preferably in the range of 5 to 50 molar
equivalents, and more preferably in the range of 5 to 15 molar
equivalents.
[0184] The amount of Lewis acid that can be used may be in the
range of 0.01 to 10 molar equivalents relative to the compound
represented by the formula (V), preferably in the range of 0.1 to 5
molar equivalents, and more preferably in the range of 0.1 to 2
molar equivalents.
[0185] The amount of cyanating agent that can be used may be in the
range of 1 to 5 molar equivalents relative to the compound
represented by the formula (V), preferably in the range of 1 to 3
molar equivalents, and more preferably in the range of 1 to 1.5
molar equivalents.
[0186] With regard to the amount of solvent, it may be used at 1 to
100 times by mass relative to the compound represented by the
formula (V), preferably in the range of 1 to 30 times by mass, and
more preferably in the range of 1 to 10 times by mass.
[0187] Further, the compound represented by the formula (VI) of the
present invention or a salt thereof and the compound represented by
the formula (VIII) of the present invention or a salt thereof can
be obtained by reacting the compound represented by the formula
[0188] (V) in an inert solvent with ammonia, ammonium salt, or a
mixture of ammonia and ammonium salts, and a cyanating agent.
[0189] Examples of the inert solvent that can be used include
alcohol type solvents such as methanol, ethanol, 2-propanol,
tert-butyl alcohol, 2,2,2-trifluoro ethanol, or
1,1,1,3,3,3-hexafluoro-2-propanol;
[0190] hydrocarbon type solvents such as toluene, xylene, benzene,
heptane, hexane, cyclohexane, or petroleum ether;
[0191] halogen type solvents such as dichloro methane, chloroform,
1,2-dichloro ethane, carbon tetrachloride, chloro benzene, or
benzotrifluoride;
[0192] ether type solvents such as tetrahydrofuran, 2-methyl
tetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether,
tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxy
ethane, diethoxy methane, or 1,4-dioxane;
[0193] acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
dimethyl sulfoxide, acetic acid, water, or a mixture of these
solvents.
[0194] Examples of the ammonium salt that can be used include
ammonium chloride, ammonium carbonate, ammonium hydrogen carbonate,
ammonium formate, ammonium acetate, and ammonium carbamate.
[0195] Examples of the cyanating agent that can be used include
trimethylsilyl cyanide, hydrogen cyanide, sodium cyanide, potassium
cyanide, acetone cyanohydrin, diethylcyano phosphonate, diethyl
aluminum cyanide, tert-butyl dimethyl silyl cyanide, and tributyl
tin cyanide.
[0196] The reaction temperature may be usually from -80.degree. C.
to the boiling point of the solvent used, is preferably in the
range of 0 to 100.degree. C., and is more preferably in the range
of 20 to 60.degree. C.
[0197] The amount of ammonia that can be used may be in the range
of 1 to 100 molar equivalents relative to the compound represented
by the formula (V), preferably in the range of 5 to 50 molar
equivalents, and more preferably in the range of 3 to 10 molar
equivalents.
[0198] The amount of ammonium salt that can be used may be in the
range of 1 to 10 molar equivalents relative to the compound
represented by the formula (V), and preferably in the range of 2 to
5 molar equivalents.
[0199] The amount of cyanating agent that can be used may be in the
range of 1 to 5 molar equivalents relative to the compound
represented by the formula (V), preferably in the range of 1 to 3
molar equivalents, and more preferably in the range of 1 to 1.5
molar equivalents.
[0200] With regard to the amount of solvent, it may be used at 1 to
100 times by mass relative to the compound represented by the
formula (V), preferably in the range of 1 to 30 times by mass, and
more preferably in the range of 1 to 10 times by mass.
[0201] Further, by reacting the compound represented by the formula
(VI) of the present invention wherein R.sup.9 is a C.sub.1-6 alkoxy
group or an amino group or a salt thereof under a common condition
for ester hydrolysis (reference literature: T. W. Greene, P. G. M.
Wuts, "Protective Groups in Organic Synthesis"), or a common
condition for carbamoyl group hydrolysis (reference literature: R.
C. Larock, "Comprehensive Organic Transformations"), a compound
represented by the formula (VI) of the present invention wherein
R.sup.9 is a hydroxyl group or a salt thereof can be obtained.
[0202] Similarly, by reacting the compound represented by the
formula (VIII) of the present invention wherein R.sup.13 is a
C.sub.1-6 alkoxy group or an amino group or a salt thereof under a
common condition for ester hydrolysis (reference literature: T. W.
Greene, P. G. M. Wuts, "Protective Groups in Organic Synthesis"),
or a common condition for carbamoyl group hydrolysis (reference
literature: R. C. Larock, "Comprehensive Organic Transformations"),
a compound represented by the formula (VIII) of the present
invention wherein R.sup.13 is a hydroxyl group or a salt thereof
can be obtained.
[0203] By reacting the compound represented by the formula (VI) of
the present invention wherein R.sup.9 is a C.sub.1-6 alkoxy group
or an amino group, the compound represented by the formula (VIII)
of the present invention wherein R.sup.13 is a C.sub.1-6 alkoxy
group or an amino group, or a mixture containing them at an
arbitrary ratio with acid in an inert solvent, an acid salt of a
compound represented by the formula (VI) of the present invention
wherein R.sup.9 is a C.sub.1-6 alkoxy group or an amino group, an
acid salt of a compound represented by the formula (VIII) of the
present invention wherein R.sup.13 is a C.sub.1-6 alkoxy group or
an amino group, or a mixture containing them at an arbitrary ratio
can be obtained.
[0204] Further, by selecting a combination of a solvent and an
acid, an acid salt of the compound represented by the formula (VI)
of the present invention wherein R.sup.9 is a C.sub.1-6 alkoxy
group or an amino group or an acid salt of the compound represented
by the formula (VIII) of the present invention wherein R.sup.13 is
a C.sub.1-6 alkoxy group or an amino group can be obtained as a
solid with high purity from a mixture containing at an arbitrary
ratio the compound represented by the formula (VI) of the present
invention wherein R.sup.9 is a C.sub.1-6 alkoxy group or an amino
group and the compound represented by the formula (VIII) of the
present invention wherein R.sup.13 is a C.sub.1-6 alkoxy group or
an amino group.
[0205] By appropriately selecting a combination of acid and solvent
for the salt formation reaction described above, solubility
difference in a solvent between an acid salt of the compound
represented by the formula (VI) of the present invention and an
acid salt of the compound represented by the formula (VIII) of the
present invention can be increased. By utilizing such difference in
solubility, an acid salt of the compound represented by the formula
(VI) of the present invention can be obtained as a highly pure
solid (crystal) by performing a simple filtration process only.
Alternatively, it is also possible that an acid salt of the
compound represented by the formula (VI) can be separated as a
filtrate with high purity from an acid salt of the compound
represented by the formula (VIII) of the present invention. When
the salt formation reaction is appropriately performed, the
compound represented by the formula (V) as a raw material of the
present invention is not necessarily required to be a purified
product, and it may be an unpurified product. The process can be
applied for a large scale production, and favorable separation
efficiency is also expected.
[0206] Preferred examples of an acid and a solvent include a
combination of organic acid and acetic acid solvent or ester
solvent. Preferred examples of the organic acid include citric
acid, L-tartaric acid, oxalic acid, and p-toluene sulfonic acid.
Preferred examples of the ester solvent include ethyl acetate.
[0207] As for the compound represented by the formula (VI) of the
present invention wherein R.sup.9 is a C.sub.1-6 alkoxy group or an
amino group, compound represented by the formula (VIII) of the
present invention wherein R.sup.13 is a C.sub.1-6 alkoxy group or
an amino group, or a mixture containing them at an arbitrary ratio
for the salt formation reaction described above, purified product
of each of them or a mixture containing purified products at an
arbitrary ratio, or unpurified product of each of them or a mixture
containing unpurified products at an arbitrary ratio can be
used.
[0208] Examples of the inert solvent that can be used include
alcohol type solvents such as methanol, ethanol, 2-propanol,
tert-butyl alcohol, 2,2,2-trifluoro ethanol, or
1,1,1,3,3,3-hexafluoro-2-propanol;
[0209] hydrocarbon type solvents such as toluene, xylene, benzene,
heptane, hexane, cyclohexane, or petroleum ether;
[0210] halogen type solvents such as dichloro methane, chloroform,
1,2-dichloro ethane, carbon tetrachloride, chloro benzene, or
benzotrifluoride;
[0211] ether type solvents such as tetrahydrofuran, 2-methyl
tetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether,
tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxy
ethane, diethoxy methane, or 1,4-dioxane;
[0212] ketone type solvents such as acetone, 2-butanone, or methyl
isobutyl ketone;
[0213] ester type solvents such as ethyl acetate or isopropyl
acetate; acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
dimethyl sulfoxide, formic acid, acetic acid, water, or a mixture
of these solvents.
[0214] Examples of the acid include an inorganic acid such as
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, nitric acid, or boric acid, and;
[0215] an organic acid such as formic acid, acetic acid, propionic
acid, 2-ethyl hexanoic acid, trifluoroacetic acid, trichloroacetic
acid, pyruvic acid, diphenyl acetic acid, cinnamic acid, glycolic
acid, D-lactic acid, L-lactic acid, D-mandelic acid, L-mandelic
acid, D-glucuronic acid, D-gluconic acid, lactobionic acid, oxalic
acid, malonic acid, succinic acid, glutaric acid, adipic acid,
fumaric acid, maleic acid, (+)-camphoric acid, 2-ketoglutaric acid,
glutamic acid, asparaginic acid, pyroglutamic acid, D-tartaric
acid, L-tartaric acid, D-malic acid, L-malic acid, citric acid,
benzoic acid, 4-hydroxybenzoic acid, salicylic acid, phthalic acid,
isophthalic acid, terephthalic acid, methane sulfonic acid,
trifluoromethane sulfonic acid, ethane sulfonic acid, benzene
sulfonic acid, p-toluene sulfonic acid, (+)-10-camphor sulfonic
acid, (-)-10-camphor sulfonic acid, and isethionic acid.
[0216] The reaction temperature may be usually from -80.degree. C.
to the boiling point of the solvent used, is preferably in the
range of 0 to 50.degree. C., and is more preferably in the range of
0 to 30.degree. C.
[0217] The amount of acid that can be used may be in the range of
0.33 to 50 molar equivalents relative to a compound represented by
the formula (VI), a compound represented by the formula (VIII), or
a mixture containing them, preferably in the range of 1 to 10 molar
equivalents, and more preferably in the range of 1 to 5 molar
equivalents.
[0218] With regard to the amount of solvent, it may be used at 1 to
100 times by mass relative to a compound represented by the formula
(VI), a compound represented by the formula (VIII), or a mixture
containing them, preferably in the range of 1 to 30 times by mass,
and more preferably in the range of 1 to 20 times by mass.
[0219] The compound represented by the formula (VI) of the present
invention or a salt thereof and compound represented by the formula
(VIII) of the present invention or a salt thereof can be obtained
as a purified product of each of them or a mixture containing
purified products at an arbitrary ratio, or unpurified product of
each of them or a mixture containing unpurified products at an
arbitrary ratio according to the process like chromatography,
re-crystallization, re-slurry, isoelectric precipitation,
isoelectric crystallization, neutralization crystal precipitation,
and distillation.
[0220] (Step 5): A compound represented by the formula (VII) of the
present invention or a salt thereof (provided that R.sup.10 and
R.sup.11 are not simultaneously a hydroxyl group) can be obtained
by reacting the compound represented by the formula (VI) or a salt
thereof under an acidic condition or a basic condition. In
particular, a compound represented by the formula (VII) of the
present invention wherein R.sup.10 is an amino group or a salt
thereof can be also obtained by reacting the compound represented
by the formula (VI) or a salt thereof under an oxidizing condition
(reference literature: R. C. Larock, "Comprehensive Organic
Transformations").
[0221] Examples of the acidic condition include performing the
reaction at the temperature of 0 to 100.degree. C. by using acid
like hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric
acid, polyphosphoric acid, methane sulfonic acid, p-toluene
sulfonic acid, trifluoromethane sulfonic acid, formic acid, acetic
acid, trifluoroacetic acid, and boron trifluoride.cndot.diethyl
ether complex and a solvent like water, methanol, ethanol,
2-propanol, formic acid, acetic acid, acetone, ethyl acetate,
tetrahydrofuran, and 1,4-dioxane, or a mixture solvent thereof.
[0222] Examples of the basic condition include performing the
reaction at the temperature of 0 to 100.degree. C. by using base
like lithium hydroxide, sodium hydroxide, potassium hydroxide, and
barium hydroxide and a solvent like water, methanol, ethanol,
2-propanol, tert-butyl alcohol, ethylene glycol, diethylene glycol,
ethylene glycol monomethyl ether, ethylene glycol monoethyl ether,
tetrahydrofuran, or a mixture solvent thereof.
[0223] Examples of the oxidizing condition include performing the
reaction at the temperature of 0 to 50.degree. C. by using hydrogen
peroxide, a base like lithium hydroxide, sodium hydroxide,
potassium hydroxide, potassium carbonate, sodium carbonate,
ammonium hydroxide and sodium phosphate, or an aqueous solution
thereof, and a solvent like dimethyl sulfoxide (reference
literature: Synthesis, 949-950 (1989) and Bull. Chem. Soc. Jpn.,
54, 793-799 (1981)).
[0224] The amount of hydrogen peroxide used for oxidizing condition
may be in the range of 1 to 5 molar equivalents relative to the
compound represented by the formula (VI) or a salt thereof, and
preferably in the range of 1 to 2 molar equivalents.
[0225] The amount of base that can be used for oxidizing condition
may be in the range of 0.1 to 5 molar equivalents relative to the
compound represented by the formula (VI), and preferably in the
range of 0.1 to 1 molar equivalents. Regarding an acid salt of the
compound represented by the formula (VI), an amount of base
required for converting the salt into free base form is preferably
added to the use amount of base described above. When an aqueous
solution of base is used, it may be used in the range of 0.1 to 10
molar (M) concentration, and preferably in the range of 1 to 10
molar concentrations.
[0226] With regard to the amount of solvent used like dimethyl
sulfoxide under an oxidizing condition, it may be used at 1 to 100
times by mass relative to the compound represented by the formula
(VI) or a salt thereof, preferably in the range of 1 to 10 times by
mass, and more preferably in the range of 1 to 5 times by mass.
[0227] The compound represented by the formula (VII) of the present
invention or a salt thereof may be obtained as a single compound or
a mixture thereof.
[0228] The compound represented by the formula (VII) of the present
invention or a salt thereof can be obtained as a purified product
or a unpurified product according to the process like
chromatography, re-crystallization, re-slurry, isoelectric
precipitation, isoelectric crystallization, neutralization crystal
precipitation, and distillation.
[0229] The compound represented by the formula (VII) of the present
invention or a salt thereof can be used as a reaction mixture for
the next Step 6 without being isolated or purified.
[0230] (Step 6): A compound represented by the formula (I) of the
present invention or a salt thereof can be obtained by hydrolyzing
the compound represented by the formula (VII) or a salt thereof
under an acid condition or a basic condition (reference literature:
R. C. Larock, "Comprehensive Organic Transformations").
[0231] Examples of the acidic condition include performing the
reaction at the temperature of 0 to 100.degree. C. by using acid
like hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric
acid, polyphosphoric acid, methane sulfonic acid, p-toluene
sulfonic acid, trifluoromethane sulfonic acid, formic acid, acetic
acid, trifluoroacetic acid, and boron trifluoride diethyl ether
complex and a solvent like water, methanol, ethanol, 2-propanol,
formic acid, acetic acid, acetone, ethyl acetate, tetrahydrofuran,
and 1,4-dioxane, or a mixture solvent thereof.
[0232] Examples of the basic condition include performing the
reaction at the temperature of 0 to 100.degree. C. by using base
like lithium hydroxide, sodium hydroxide, potassium hydroxide, and
barium hydroxide and a solvent like water, methanol, ethanol,
2-propanol, tert-butyl alcohol, ethylene glycol, diethylene glycol,
ethylene glycol monomethyl ether, ethylene glycol monoethyl ether,
tetrahydrofuran, or a mixture solvent thereof.
[0233] The compound represented by the formula (I) of the present
invention or a salt thereof can be obtained as a purified product
or a unpurified product according to the process like isoelectric
precipitation, isoelectric crystallization, chromatography,
re-crystallization, re-slurry, neutralization crystal
precipitation, distillation and sublimation.
[0234] (Step 7): A compound represented by the formula (I) of the
present invention or a salt thereof can be obtained by reacting the
compound represented by the formula (VI) or a salt thereof under an
acidic condition, a basic condition, a basic condition which
follows an oxidizing condition, or an oxidizing basic
condition.
[0235] Examples of the acidic condition include performing the
reaction at the temperature of 0 to 100.degree. C. by using acid
like hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric
acid, polyphosphoric acid, methane sulfonic acid, p-toluene
sulfonic acid, trifluoromethane sulfonic acid, formic acid, acetic
acid, and trifluoroacetic acid and a solvent like water, methanol,
ethanol, 2-propanol, formic acid, acetic acid, acetone, ethyl
acetate, tetrahydrofuran, and 1,4-dioxane, or a mixture solvent
thereof.
[0236] Examples of the basic condition include performing the
reaction at the temperature of 0 to 100.degree. C. by using base
like lithium hydroxide, sodium hydroxide, potassium hydroxide, and
barium hydroxide and a solvent like water, methanol, ethanol,
2-propanol, tert-butyl alcohol, ethylene glycol, diethylene glycol,
ethylene glycol monomethyl ether, ethylene glycol monoethyl ether,
tetrahydrofuran, or a mixture solvent thereof.
[0237] Examples of the basic condition which follows the oxidizing
condition include performing the reaction under oxidizing condition
at the temperature of 0 to 50.degree. C. by using hydrogen
peroxide, a base like lithium hydroxide, sodium hydroxide,
potassium hydroxide, potassium carbonate, sodium carbonate,
ammonium hydroxide, and sodium phosphate, or an aqueous solution
thereof, and a solvent like dimethyl sulfoxide (reference
literature: Synthesis, 949-950 (1989) and Bull. Chem. Soc. Jpn.,
54, 793-799 (1981)) followed by reaction under basic condition by
performing the reaction at the temperature of 0 to 100.degree. C.
by adding, to the reaction liquid, base like lithium hydroxide,
sodium hydroxide, potassium hydroxide, and barium hydroxide, or an
aqueous solution thereof, and a solvent like water, methanol,
ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol,
diethylene glycol, ethylene glycol monomethyl ether, ethylene
glycol monoethyl ether, tetrahydrofuran, or a mixture solvent
thereof.
[0238] The amount of hydrogen peroxide used for oxidizing condition
may be in the range of 1 to 5 molar equivalents relative to the
compound represented by the formula (VI) or a salt thereof, and
preferably in the range of 1 to 2 molar equivalents.
[0239] The amount of base that can be used for oxidizing condition
may be in the range of 0.1 to 5 molar equivalents relative to the
compound represented by the formula (VI), and preferably in the
range of 0.1 to 1 molar equivalents. Regarding an acid salt of the
compound represented by the formula (VI), an amount of base
required for converting the salt into free base form is preferably
added to the use amount of base described above. When an aqueous
solution of base is used, it may be used in the range of 0.1 to 10
molar (M) concentration, and preferably in the range of 1 to 10
molar concentrations.
[0240] With regard to the amount of solvent used like dimethyl
sulfoxide under an oxidizing condition, it may be used at 1 to 100
times by mass relative to the compound represented by the formula
(VI) or a salt thereof, preferably in the range of 1 to 10 times by
mass, and more preferably in the range of 1 to 5 times by mass.
[0241] The reaction time for the oxidizing condition is the time
until the loss of the compound represented by the formula (VI) as a
raw material is identified by high performance liquid
chromatography (HPLC) or thin layer chromatography (TLC), and it is
generally in the range of 0.1 to 24 hours.
[0242] The amount of base that can be used for basic condition
following the oxidizing condition may be in the range of 3 to 30
molar equivalents relative to the compound represented by the
formula (VI), and preferably in the range of 3 to 10 molar
equivalents. When an aqueous solution of base is used, it may be
used in the range of 0.1 to 10 molar (M) concentration, and
preferably in the range of 1 to 10 molar concentrations.
[0243] The amount of solvent for basic condition following the
oxidizing condition may be used at 1 to 100 times by mass relative
to the compound represented by the formula (VI) or a salt thereof,
preferably in the range of 1 to 10 times by mass, and more
preferably in the range of 1 to 5 times by mass. However, the
solvent may not be used.
[0244] Examples of the oxidizing basic condition include performing
the reaction at the temperature of 0 to 40.degree. C. by using
hydrogen peroxide, a base like lithium hydroxide, sodium hydroxide,
potassium hydroxide, potassium carbonate, sodium carbonate,
ammonium hydroxide, and sodium phosphate, or an aqueous solution
thereof, and a solvent like dimethyl sulfoxide followed by reaction
at the temperature of 50 to 100.degree. C.
[0245] The amount of hydrogen peroxide used for oxidizing basic
condition may be in the range of 1 to 5 molar equivalents relative
to the compound represented by the formula (VI) or a salt thereof,
and preferably in the range of 1 to 2 molar equivalents.
[0246] The amount of base that can be used for oxidizing basic
condition may be in the range of 3 to 30 molar equivalents relative
to the compound represented by the formula (VI), and preferably in
the range of 5 to 15 molar equivalents. Regarding an acid salt of
the compound represented by the formula (VI), an amount of base
required for converting the salt into free base form is preferably
added to the use amount of base described above. When an aqueous
solution of base is used, it may be used in the range of 0.1 to 10
molar (M) concentration, and preferably in the range of 1 to 10
molar concentrations.
[0247] The amount of solvent like dimethyl sulfoxide used for
oxidizing basic condition may be used at 1 to 100 times by mass
relative to the compound represented by the formula (VI) or a salt
thereof, preferably in the range of 1 to 10 times by mass, and more
preferably in the range of 1 to 5 times by mass.
[0248] The reaction time for the oxidizing basic condition at the
temperature of 0 to 40.degree. C. is the time until the loss of the
compound represented by the formula (VI) as a raw material is
identified by high performance liquid chromatography (HPLC) or thin
layer chromatography (TLC), and it is generally in the range of 0.1
to 24 hours.
[0249] The compound represented by the formula (I) of the present
invention or a salt thereof can be obtained as a purified product
or a unpurified product according to the process like isoelectric
precipitation, isoelectric crystallization, chromatography,
re-crystallization, re-slurry, distillation, and sublimation.
##STR00027##
[0250] In the formulae of the above Scheme 2, R.sup.1, R.sup.2,
R.sup.8, R.sup.9, and R.sup.13 are as defined in the above.
[0251] (Step 8): A compound represented by the formula (V) of the
present invention or a salt thereof can be obtained by reacting the
compound represented by the formula (VI) of the present invention
or a salt thereof, the compound represented by the formula (VIII)
of the present invention or a salt thereof, or a mixture containing
them at an arbitrary ratio under an acidic condition.
[0252] Examples of the acidic condition include performing the
reaction at the temperature of 0 to 150.degree. C. by using acid
like hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric
acid, polyphosphoric acid, methane sulfonic acid, p-toluene
sulfonic acid, trifluoromethane sulfonic acid, formic acid, acetic
acid, trifluoroacetic acid, and boron trifluoride.diethyl ether
complex and a solvent like water, methanol, ethanol, 2-propanol,
formic acid, acetic acid, acetone, ethyl acetate, tetrahydrofuran,
and 1,4-dioxane, or a mixture solvent thereof.
[0253] The compound represented by the formula (VI) of the present
invention or a salt thereof, the compound represented by the
formula (VIII) of the present invention or a salt thereof, or a
mixture containing them at an arbitrary ratio can be used as a
purified product of each of them or a mixture containing purified
products at an arbitrary ratio, or unpurified product of each of
them or a mixture containing unpurified products at an arbitrary
ratio.
[0254] For example, a mixture fraction generated during isolation
or purification of the compound during the Step 4, mother liquor of
recrystallization or concentrated residue thereof, or filtrate
obtained by filtering solids that is generated during isolation or
purification of an acid salt of the compound or concentrated
residues thereof can be also used. Specifically, by performing the
present reaction step, the compound represented by the formula
(VIII) of the present invention or a salt thereof, which is a
byproduct not having stereochemistry desired for synthesis of the
compound represented by the formula (I) or a salt thereof, is
converted into the compound represented by the formula (V) of the
present invention or a salt thereof as a synthetic intermediate of
the compound represented by the formula (I) or a salt thereof, and
therefore can be effectively used without being discarded.
[0255] The compound represented by the formula (V) of the present
invention or a salt thereof can be obtained as a purified product
or a unpurified product according to the process like
chromatography, re-crystallization, re-slurry, neutralization
crystal precipitation, and distillation.
##STR00028##
[0256] In the formulae of the above Scheme 3, 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.12, and
R.sup.14 are as defined in the above.
[0257] Further, the Step 1, Step 2, and Step 3 are as defined in
the above Scheme 1.
[0258] (Step 9): A compound represented by the formula (IX) of the
present invention or a salt thereof, a compound represented by the
formula (X) of the present invention or a salt thereof, or a
mixture containing compound represented by the formula (IX) of the
present invention or a salt thereof and the compound represented by
the formula (X) of the present invention or a salt thereof can be
obtained by reacting the compound represented by the formula (V) or
a salt thereof with ammonium carbonate, and potassium cyanide or
sodium cyanide in an inert solvent (reference literature:
Tetrahedron: Asymmetry, 8, 511-514 (1997), J. Med. Chem., 43,
4893-4909 (2000), J. Org. Chem., 69, 4516-4519 (2004), Tetrahedron
60, 6711-6745 (2004), Tetrahedron: Asymmetry, 20, 1-63 (2009), and
Org. Proc. Res. Dev., 10, 28-32 (2006)).
[0259] Examples of the inert solvent that can be used include
alcohol type solvents such as methanol, ethanol, propanol,
2-propanol, or ethylene glycol, and;
[0260] N,N-dimethyl formamide, dimethyl sulfoxide, water, or a
mixture of these solvents. Preferably, a mixture of water and an
alcohol type solvent is used.
[0261] The reaction temperature may be usually from 0.degree. C. to
the boiling point of the solvent used, is preferably in the range
of 20 to 80.degree. C., and is more preferably in the range of 40
to 70.degree. C.
[0262] The amount of ammonium carbonate used may be in the range of
2 to 20 molar equivalents relative to the compound represented by
the formula (V), preferably in the range of 3 to 10 molar
equivalents, and more preferably in the range of 3 to 5 molar
equivalents.
[0263] The amount of potassium cyanide or sodium cyanide used may
be in the range of 1 to 10 molar equivalents relative to the
compound represented by the formula (V), preferably in the range of
1 to 5 molar equivalents, and more preferably in the range of 1 to
3 molar equivalents.
[0264] With regard to the amount of solvent, it may be used at 1 to
100 times by mass relative to the compound represented by the
formula (V), preferably in the range of 1 to 30 times by mass, and
more preferably in the range of 1 to 10 times by mass.
[0265] A compound represented by the formula (IX) of the present
invention wherein R.sup.12 is a hydroxyl group or a salt thereof, a
compound represented by the formula (X) of the present invention
wherein R.sup.14 is a hydroxyl group or a salt thereof, or a
mixture containing compound represented by the formula (IX) of the
present invention wherein R.sup.12 is a hydroxyl group or a salt
thereof and a compound represented by the formula (X) of the
present invention wherein R.sup.14 is a hydroxyl group or a salt
thereof can be obtained by reacting a compound represented by the
formula (V) wherein R.sup.8 is a C.sub.1-6 alkoxy group with a base
like an aqueous solution of sodium hydroxide or potassium hydroxide
in a solvent such as methanol or ethanol for conversion into a
compound represented by the formula (V) wherein R.sup.8 is a
hydroxyl group or a salt thereof and adding ammonium carbonate and
potassium cyanide or sodium cyanide to the reaction mixture.
[0266] A compound represented by the formula (IX) of the present
invention wherein R.sup.12 is a methoxy group or an ethoxy group or
a salt thereof, a compound represented by the formula (X) of the
present invention wherein R.sup.14 is a methoxy group or an ethoxy
group or a salt thereof, or a mixture containing the compound
represented by the formula (IX) of the present invention wherein
R.sup.12 is a methoxy group or an ethoxy group or a salt thereof
and the compound represented by the formula (X) of the present
invention wherein R.sup.14 is a methoxy group or an ethoxy group or
a salt thereof can be obtained by reacting a compound represented
by the formula (IX) of the present invention wherein R.sup.12 is a
hydroxyl group or a salt thereof, a compound represented by the
formula (X) of the present invention wherein R.sup.14 is a hydroxyl
group or a salt thereof, or a mixture containing the compound
represented by the formula (IX) of the present invention wherein
R.sup.12 is a hydroxyl group or a salt thereof and the compound
represented by the formula (X) of the present invention wherein
R.sup.14 is a hydroxyl group or a salt thereof with methanol or
ethanol, a base like 4-dimethylaminopyridine, and a condensing
agent like 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in a
solvent like N,N-dimethyl formamide.
[0267] A compound represented by the formula (IX) of the present
invention wherein R.sup.12 is a hydroxyl group or a salt thereof, a
compound represented by the formula (X) of the present invention
wherein R.sup.14 is a hydroxyl group or a salt thereof, or a
mixture containing the compound represented by the formula (IX) of
the present invention wherein R.sup.12 is a hydroxyl group or a
salt thereof and the compound represented by the formula (X) of the
present invention wherein R.sup.14 is a hydroxyl group or a salt
thereof can be obtained by hydrolyzing a compound represented by
the formula (IX) of the present invention wherein R.sup.12 is a
C.sub.1-6 alkoxy group or a salt thereof, a compound represented by
the formula (X) of the present invention wherein R.sup.14 is a
C.sub.1-6 alkoxy group or a salt thereof, or a mixture of the
compound represented by the formula (IX) of the present invention
wherein R.sup.12 is a C.sub.1-6 alkoxy group or a salt thereof and
the compound represented by the formula (X) of the present
invention wherein R.sup.14 is a C.sub.1-6 alkoxy group or a salt
thereof in an aqueous solution of sodium hydroxide or an aqueous
solution of potassium hydroxide.
[0268] A compound represented by the formula (IX) of the present
invention or a salt thereof, the compound represented by the
formula (X) of the present invention or a salt thereof, or a
mixture of the compound represented by the formula (IX) of the
present invention or a salt thereof and the compound represented by
the formula (X) of the present invention or a salt thereof can be
obtained as a purified product or a unpurified product according to
the process like chromatography, re-crystallization, re-slurry,
neutralization crystal precipitation, and distillation.
[0269] (Step 10): A compound represented by the formula (I) of the
present invention or a salt thereof can be obtained by reacting a
compound represented by the formula (IX) of the present invention
or a salt thereof or a mixture of the compound represented by the
formula (IX) of the present invention or a salt thereof and a
compound represented by the formula (X) of the present invention or
a salt thereof under an acidic condition or a basic condition.
[0270] Examples of the basic condition include performing the
reaction at the temperature of 0.degree. C. to reflux temperature
by using base like lithium hydroxide, sodium hydroxide, potassium
hydroxide, and barium hydroxide and a solvent like water, methanol,
ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol,
diethylene glycol, ethylene glycol monomethyl ether, ethylene
glycol monoethyl ether, tetrahydrofuran, or a mixture solvent
thereof.
[0271] Examples of the acidic condition include performing the
reaction at the temperature of 0.degree. C. to reflux temperature
by using acid like hydrochloric acid, hydrogen bromide, sulfuric
acid, methane sulfonic acid, p-toluene sulfonic acid,
trifluoromethane sulfonic acid, and trifluoroacetic acid, and a
solvent like water, methanol, ethanol, 2-propanol, formic acid,
acetic acid, tetrahydrofuran, and 1,4-dioxane, or a mixture solvent
thereof.
[0272] The compound represented by the formula (I) of the present
invention or a salt thereof can be obtained as a purified product
or a unpurified product according to the process like isoelectric
precipitation, isoelectric crystallization, chromatography,
re-crystallization, re-slurry, distillation, and sublimation.
EXAMPLES
[0273] Hereinbelow, the present invention is specifically explained
in greater detail with reference to the examples given below.
However, the present invention is not construed to be limited to
the descriptions of the examples. The yield described in the
examples below is sometimes affected by reaction condition, thus
higher yield can be obtained by selecting an optimized reaction
condition.
Example 1
Synthesis of
ethyl(1R,5R,6R)-6-fluoro-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hex-2-ene-6-
-carboxylate (3a)
##STR00029##
[0275] 205 g of triethyl amine was added to a toluene (1251 g)
solution containing 250 g of ethyl(1R,5R,6R)-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (2a). The solution obtained was
cooled to the temperature of 5.degree. C. or less, and 359 g of
trimethylsilyl trifluoromethane sulfonic acid was added dropwise to
the solution while keeping the internal temperature at 5.degree. C.
or less. When the dropwise addition is completed, 1253 g of water
was added for liquid separation. The organic layer was washed with
1252 g of 5 wt % aqueous solution of sodium hydrogen carbonate and
1251 g of water in order. The organic layer was concentrated under
reduced pressure, and the resulting residues were added with 631 g
of toluene and concentrated again under reduced pressure to give
concentrated residues of
ethyl(1R,5R,6R)-6-fluoro-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hexa-2-ene--
6-carboxylate (3a).
[0276] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta.: 0.22 (s, 9H),
1.32 (t, J=7.2 Hz, 3H), 2.28-2.32 (m, 1H), 2.42-2.48 (m, 1H),
2.54-2.57 (m, 1H), 2.65-2.71 (m, 1H), 4.27 (q, J=7.2 Hz, 2H),
4.62-4.64 (m, 1H). MS (EI) m/z: 258 (le), 223 (base).
Example 2
Synthesis of ethyl(1R,3R,5R,6R)-6-fluoro-3-hydroxy-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4a)
##STR00030##
[0278] To the concentrated residues of
ethyl(1R,5R,6R)-6-fluoro-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hexa-2-ene--
6-carboxylate (3a) obtained from the Example 1, 2577 g of toluene
and 111 g of tris(cetyl pyridinium)peroxo tungstophosphate (PCWP)
(reference literature: J. Org. Chem., 53, 3587-3593 (1988) and J.
Org. Chem., 62, 7174-7177 (1997)) were added and heated to
30.degree. C. 183 g of 30 wt % hydrogen peroxide was added dropwise
to the solution over 1 hr and 10 min while keeping the internal
temperature at 45.degree. C. or less and stirred for 10 min. The
reaction solution was cooled in an ice batch and added with 347 g
of 5 wt % aqueous solution of sodium hydrogen carbonate and 1420 g
of 30 wt % aqueous solution of sodium thiosulfate in order. After
removing the solvent by distillation under reduced pressure, 114 g
of cellulose powder (KC-flock) and 1745 g of ethyl acetate were
added to the residues and stirred overnight. After filtering the
suspension, the solid was washed with 1737 g of ethyl acetate. The
filtrate and washing solution were combined and subjected to liquid
separation. The aqueous layer was extracted with 1728 g of ethyl
acetate. The organic layer was combined and concentrated under
reduced pressure. The resulting residues were purified by silica
gel column chromatography (eluent solution; hexane:ethyl
acetate=5:1, followed by 1:1), 201 g of
ethyl(1R,3R,5R,6R)-6-fluoro-3-hydroxy-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4a) was obtained as a light
brown oily material.
[0279] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta.: 1.34 (t, J=7.2
Hz, 3H), 2.31-2.37 (m, 1H), 2.58 (br s, 1H, exchangeable with
D.sub.2O), 2.61-2.64 (m, 1H), 2.72-2.77 (m, 2H), 4.05-4.10 (m, 1H),
4.31 (q, J=7.2 Hz, 2H). MS (EI) m/z: 202 (M.sup.+), 125 (base).
Example 3
Synthesis of ethyl(1RS,3RS,5RS,6RS)-6-fluoro-3-hydroxy-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4a') and
ethyl(1RS,3RS,5RS,6RS)-3-[(3-chlorobenzoyl)oxy]-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4b')
##STR00031##
[0281] A chloroform (302.1 g) solution containing 41.35 g (content:
84.2 wt %) of
ethyl(1RS,5RS,6RS)-6-fluoro-2-[(trimethylsilyl)oxy]bicyclo[3.1.0-
]hexa-2-ene-6-carboxylate (3a') was cooled to 6.degree. C., added
with 22.94 g of sodium hydrogen carbonate, and further added with
39.50 g (content: 65 wt %) of 3-chloro perbenzoic acid (mCPBA) at
the temperature of 11.degree. C. or less over 44 min. The mixture
was warmed to 25.degree. C. over 4.5 hrs under stirring. The
reaction solution was added with an aqueous solution of sodium
thiosulfate (anhydrous sodium thiosulfate 7.48 g and water 75.61 g)
and stirred for 25 min. After keeping it for 10 min, it was
separated into an organic layer and an aqueous layer. The aqueous
layer was extracted again with 151.6 g and 151.1 g of chloroform.
The organic layer was combined, washed with 96 g of water, and
added with 30.26 g of anhydrous magnesium sulfate. After stirring
for 5 min, insoluble materials were removed by filtration. The
filtrate was concentrated under reduced pressure and the residues
were purified by silica gel column chromatography (eluent solution;
hexane:ethyl acetate=4:1 to 3:1) to obtain 7.436 g of
ethyl(1RS,3RS,5RS,6RS)-6-fluoro-3-hydroxy-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4a') as a colorless oily
material and 19.33 g of
ethyl(1RS,3RS,5RS,6RS)-3-[(3-chlorobenzoyl)oxy]-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4b') as a colorless solid.
19.33 g of the compound (4b') was recrystallized with ethyl
acetate-hexane to obtain 10.74 g of the compound (4b') as a
colorless solid.
[0282] (4b'): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 1.35 (t,
J=7.2 Hz, 3H), 2.52-2.63 (m, 1H), 2.72-2.77 (m, 1H), 2.82-2.94 (m,
2H), 4.33 (q, J=7.2 Hz, 2H), 5.17-5.26 (m, 1H), 7.40 (t, J=7.9 Hz,
1H), 7.54-7.59 (m, 1H), 7.92-7.96 (m, 1H), 8.01-8.04 (m, 1H). MS
(ESI/APCI Dual) m/z: 341 [(M+H).sup.+], 343 {[(M+2)+H].sup.+}, 363
[(M+Na).sup.+], 365 {[(M+2)+Na].sup.+}. IR (KBr) cm.sup.-1: 3072,
2968, 1756, 1722, 1324, 1290, 1255, 1218, 1128, 1105, 1086, 1012,
748. Anal. Calcd. for C.sub.16H.sub.14ClFO.sub.5: C, 56.40; H,
4.14; Cl, 10.41; F, 5.58. Found: C, 56.41; H, 4.18; Cl, 10.36; F,
5.58.
Example 4
Synthesis of methyl(1RS,3RS,5RS,6RS)-6-fluoro-3-hydroxy-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4c') and
methyl(1RS,3RS,5RS,6RS)-3-[(3-chlorobenzoyl)oxy]-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4d')
##STR00032##
[0284] To a methanol (10.75 g) solution containing 1.072 g of ethyl
(1RS,3RS,5RS,6RS)-3-[(3-chlorobenzoyl)oxy]-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4b'), 0.031 g of potassium
carbonate was added. The mixture was then stirred for four hrs and
further added with 0.012 g of potassium carbonate. After stirring
for 1 hr, the liquid was adjusted to pH 6 by adding 0.322 g of 1 M
hydrochloric acid and stirred for 15 hrs. The reaction solution was
concentrated under reduced pressure and added with chloroform and
water to dissolve the residues. 1 M Hydrochloric acid was added to
the mixture solution obtained so that the aqueous layer has pH 1
followed by extraction with chloroform. The organic layer was
concentrated under reduced pressure and the residues were purified
by silica gel column chromatography (eluent solution; hexane:ethyl
acetate=4:1) to obtain 0.476 g of
methyl(1RS,3RS,5RS,6RS)-6-fluoro-3-hydroxy-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4c') as a colorless oily
material and 0.008 g of
methyl(1RS,3RS,5RS,6RS)-3-[(3-chlorobenzoyl)oxy]-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4d') as a colorless foamy
solid.
[0285] (4c'): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 2.30-2.41
(m, 1H), 2.61-2.66 (m, 1H), 2.68 (br s, 1H, exchangeable with
D.sub.2O), 2.70-2.81 (m, 2H), 3.87 (s, 3H), 4.03-4.13 (m, 1H).
[0286] (4d'): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 2.53-2.64
(m, 1H), 2.73-2.78 (m, 1H), 2.82-2.94 (m, 2H), 3.88 (s, 3H),
5.17-5.27 (m, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.53-7.60 (m, 1H),
7.91-7.97 (m, 1H), 8.01-8.04 (m, 1H).
Example 5
Synthesis of ethyl(1RS,3RS,5RS,6RS)-6-fluoro-3-hydroxy-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4a'),
ethyl(1RS,3RS,5RS,6RS)-6-fluoro-2-oxo-3-[(trimethylsilyl)oxy]bicyclo[3.1.-
0]hexane-6-carboxylate (4e'), and ethyl(1RS,5RS,6RS)-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (2a')
##STR00033##
[0288] 0.310 mL of Trichloro acetonitrile, 0.445 mL of acetone, and
0.105 g of dipotassium hydrogen phosphate were added to a toluene
(3 mL) solution containing 0.44 g (content: 89.0 wt %) of
ethyl(1RS,5RS,6RS)-6-fluoro-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hexa-2-e-
ne-6-carboxylate (3a') and cooled in an ice bath. To the mixture,
0.347 g of 30 wt % hydrogen peroxide was added dropwise and stirred
at 0 to 3.degree. C. for 1 hr and subsequently at 19 to 22.degree.
C. for 3 hrs and 20 min. The reaction solution was cooled in an ice
bath and added with 8 mL of 5 wt % aqueous solution of sodium
sulfite followed by extraction with toluene. The organic layer was
washed with saturated aqueous solution of sodium chloride and dried
over anhydrous magnesium sulfate. The residues (0.480 g) that are
obtained by removing the solvent by distillation under reduced
pressure were purified by silica gel column chromatography (eluent
solution; hexane:ethyl acetate=8:1, 5:1, 3:1) to obtain, in elution
order, 0.014 g of
ethyl(1RS,3RS,5RS,6RS)-6-fluoro-2-oxo-3-[(trimethylsilyl)oxy]bicyclo[3.1.-
0]hexane-6-carboxylate (4e') as a colorless oily material, 0.124 g
of ethyl(1RS,5RS,6RS)-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (2a') as a colorless oily
material, and 0.034 g of
ethyl(1RS,3RS,5RS,6RS)-6-fluoro-3-hydroxy-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4a') as a colorless oily
material.
[0289] (4e'): .sup.1H NMR (600 MHz, CDCl.sub.3) .delta.: 0.16 (s,
9H), 1.33 (t, J=7.2 Hz, 3H), 2.30-2.36 (m, 1H), 2.52-2.55 (m, 1H),
2.61-2.69 (m, 2H), 4.03-4.08 (m, 1H), 4.29 (q, J=7.2 Hz, 2H). MS
(ESI/APCI Dual) m/z: 297 [(M+Na).sup.+].
Example 6
Synthesis of ethyl(1R,3R,5R,6R)-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro-2-oxo bicyclo[3.1.0]hexane-6-carboxylate
(5a)
##STR00034##
[0291] 33.7 g (content: 85 wt %) of 3,4-dichloro benzyl
2,2,2-trichloroacetimidate was added to tetrahydropyran (120 g)
solution containing 11.98 g of
ethyl(1R,3R,5R,6R)-6-fluoro-3-hydroxy-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (4a). The solution obtained was
added with tetrahydropyran (12 g) solution containing 4.44 g of
trifluoromethane sulfonic acid over 15 min at 24 to 31.degree. C.
After stirring for 1.5 hr at 24 to 30.degree. C., the reaction
solution was poured over 120 g of saturated aqueous solution of
sodium hydrogen carbonate and the organic layer was washed with 134
g of 10% aqueous solution of sodium chloride. The organic layer was
concentrated under reduced pressure and the residues were purified
by silica gel column chromatography (eluent solution; hexane:ethyl
acetate=4:1) to obtain 16.51 g of
ethyl(1R,3R,5R,6R)-3-[(3,4-dichloro benzyl)oxy]-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (5a) as a yellow oily
material.
[0292] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 1.33 (t, J=7.2
Hz, 3H), 2.34-2.45 (m, 1H), 2.57-2.75 (m, 3H), 3.84-3.93 (m, 1H),
4.30 (q, J=7.2 Hz, 2H), 4.56 (d, J=11.9 Hz, 1H), 4.95 (d, J=11.9
Hz, 1H), 7.18 (dd, J=8.2 and 2.1 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H),
7.46 (d, J=2.1 Hz, 1H). MS (ESI/APCI Dual) m/z: 378
[(M+NH.sub.4).sup.+].
Example 7
Synthesis of (1R,3R,5R,6R)-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro-2-oxo bicyclo[3.1.0]hexane-6-carboxamide
(5b)
##STR00035##
[0294] 2.14 g of ethyl(1R,3R,5R,6R)-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro-2-oxo bicyclo[3.1.0]hexane-6-carboxylate (5a)
was dissolved in 8 mL of 7 M ammonia-methanol solution and stirred
at room temperature for 1 hr. The reaction solution was
concentrated under reduced pressure to obtain 1.956 g of residues.
1.8 g of the residues were purified by silica gel column
chromatography (eluent solution; chloroform:methanol=20:1) to
obtain 1.02 g of solid. The solid was suspended in 3 mL of ethyl
acetate, filtered, collected, and dried to obtain 0.4709 g of
(1R,3R,5R,6R)-3-[(3,4-dichloro benzyl)oxy]-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxamide (5b) as a colorless solid.
[0295] mp 157-160.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta.: 2.29-2.39 (m, 1H), 2.40-2.45 (m, 1H), 2.55-2.64 (m, 1H),
2.67-2.74 (m, 1H), 3.85-3.94 (m, 1H), 4.61 (d, J=12.3 Hz, 1H), 4.79
(d, J=12.3 Hz, 1H), 7.34 (dd, J=8.2 and 2.2 Hz, 1H), 7.61 (d, J=2.2
Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.86 (br s, 1H, exchangeable with
D.sub.2O), 8.07 (br s, 1H, exchangeable with D.sub.2O). MS
(ESI/APCI Dual) m/z: 354 [(M+Na).sup.+]. IR (KBr) cm.sup.-1: 3374,
3176, 1747, 1694, 1472, 1436, 1272, 1235, 1099, 986. Anal. Calcd
for C.sub.14H.sub.12Cl.sub.2FNO.sub.3: C, 50.62; H, 3.64; N, 4.22;
Cl, 21.35; F, 5.72. Found: C, 50.51; H, 3.67; N, 4.14; Cl, 21.24;
F, 5.57.
Example 8
Synthesis of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a) and
(1R,2R,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (8a)
##STR00036##
[0297] 4.03 g of ethyl(1R,3R,5R,6R)-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro-2-oxo bicyclo[3.1.0]hexane-6-carboxylate (5a)
was added to 13.9 mL of 8 M ammonia-methanol and 4.0 mL of titanium
(IV) isopropoxide was added to the mixture solution under nitrogen
atmosphere followed by stirring for 7 hrs at 25.degree. C. The
reaction solution was cooled in an ice bath, added with 1.66 mL of
trimethylsilyl cyanide, and stirred at 0.degree. C. for 6 hrs and
subsequently at 0 to 19.degree. C. for 12 hrs. To a crude product
obtained by concentrating the reaction solution under reduced
pressure, 50 mL of ethyl acetate was added to give a suspension.
After filtration, the resulting solid was washed with 50 mL of
ethyl acetate. The filtrate and washing solution were concentrated
under reduced pressure to give residues, which were then purified
by performing twice the silica gel column chromatography (first
eluent solution; [0298] ethyl acetate:chloroform=4:1, second eluent
solution; chloroform:ethyl acetate=1:2 to 1:4, followed by ethyl
acetate) to give a fraction (1.06 g) which represents a spot in a
less polar region in thin layer chromatography (silica gel
60F.sub.254 plate, developed with chloroform:methanol=10:1), a
fraction (1.75 g) which represents a spot in more polar region, and
a mixture of the fractions (0.36 g).
[0299] 1.75 g of the fraction representing a spot in a more polar
region was recrystallized with ethyl acetate and hexane to obtain
1.67 g of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a) as a
colorless solid. Further, 1.06 g of the fraction representing a
spot in a less polar region was suspended with ethyl acetate and
hexane, and filtered to obtain 1.01 g of
(1R,2R,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (8a) as a
colorless solid. 0.48 g of the concentrated residues obtained by
combining each filtrate and the mixture fraction described above
was suspended with ethyl acetate-hexane and filtered to obtain
0.371 g of a mixture of the compounds (6a) and (8a) as a colorless
solid.
[0300] (6a): mp 121-125.degree. C. .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta.: 1.98-2.02 (m, 1H), 2.12-2.18 (m, 1H),
2.26-2.29 (m, 1H), 2.34-2.39 (m, 1H), 3.68-3.73 (m, 1H), 4.62 (d,
J=12.6 Hz, 1H), 4.73 (d, J=12.6 Hz, 1H), 7.38 (dd, J=8.4 and 2.0
Hz, 1H), 7.63 (d, =8.4 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.65 (br s,
1H, exchangeable with D.sub.2O), 7.84 (br s, 1H, exchangeable with
D.sub.2O). MS (ESI/APCI Dual) m/z: 380 [(M+Na).sup.+], 382
{[(M+2)+Na].sup.+}. IR (KBr) cm.sup.-1: 3420, 3364, 3304, 3193,
2233, 1672, 1604, 1474, 1377, 1129, 1031. Anal. Calcd for
C.sub.15H.sub.14Cl.sub.2FN.sub.3O.sub.2: C, 50.30; H, 3.94; N,
11.73; Cl, 19.80; F, 5.30. Found: C, 50.25; H, 3.99; N, 11.52; Cl,
19.68; F, 5.08.
[0301] (8a): mp 183-186.degree. C. .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta.: 1.94-1.98 (m, 1H), 2.15-2.21 (m, 1H),
2.24-2.31 (m, 2H), 3.97-4.02 (m, 1H), 4.59 (d, J=12.2 Hz, 1H), 4.72
(d, J=12.2 Hz, 1H), 7.38 (dd, J=8.3 and 1.8 Hz, 1H), 7.63 (d, J=8.3
Hz, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.68 (br s, 1H, exchangeable with
D.sub.2O), 7.92 (br s, 1H, exchangeable with D.sub.2O). MS
(ESI/APCI Dual) m/z: 380 [(M+Na).sup.+], 382 {[(M+2)+Na].sup.+}. IR
(KBr) cm.sup.-1: 3405, 3211, 2228, 1643, 1238, 1122, 1104. Anal.
Calcd for C.sub.15H.sub.14Cl.sub.2FN.sub.3O.sub.2: C, 50.30; H,
3.94; N, 11.73; Cl, 19.80; F, 5.30. Found: C, 50.32; H, 3.96; N,
11.63; Cl, 19.77; F, 5.15.
Example 9
Synthesis of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxmide citrate
(6b)
##STR00037##
[0303] 51.0 mL suspension of 8 M ammonia-methanol containing 15.0 g
(content: 97.1 wt %) of
ethyl(1R,3R,5R,6R)-3-[(3,4-dichlorobenzyl)oxy]-6-fluoro-2-oxo
bicycle[3.1.0]hexane-6-carboxylate (5a) was stirred for 69 min at
17 to 25.degree. C. under argon atmosphere. The reaction solution
was cooled in an ice bath and added dropwise with 14.5 g (content:
95.0 wt o) of titanium (IV) isopropoxide at 0 to 6.degree. C. over
8 min. The ice bath was removed and the mixture was stirred at room
temperature for 4.5 hrs (temperature was increased to 25.degree.
C.), and then cooled to -6.degree. C. in a cooling incubator. 4.58
g (content: 96.0 wt %) of trimethylsilyl cyanide was added dropwise
to the mixture at -6 to -4.degree. C. for 10 min, and stirred for
17 hrs and 50 min at -5.degree. C. and for 2 hrs and 35 min at
0.degree. C.
[0304] To a suspension in which 73 mL of ethyl acetate is added to
14.7 g of Silica gel 60N (spherical and neutral), the reaction
solution described above was added under stirring. While washing
the vessel containing the reaction solution with 292 mL of ethyl
acetate, the washing solution was added to the suspension of silica
gel. The resulting suspension was stirred for 30 min at 14 to
20.degree. C., filtered by suction, and washed with 365 mL of ethyl
acetate. The filtrate and washing solution were combined and
concentrated under reduced pressure, and the resulting residues
were dried under reduced pressure to obtain 15.0 g of a crude
product.
[0305] The crude product obtained was dissolved in 165 mL of acetic
acid, and 7.76 g (content: 98.0 wt %) of citric acid (anhydrous)
was added thereto followed by stirring for 15 hrs and 50 min at 26
to 27.degree. C. The resulting slurry was filtered by suction and
the solid was washed with 40 mL of acetic acid. The resulting solid
was dried under reduced pressure at 50.degree. C. to obtain 12.9 g
of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide citrate
(6b) as a colorless solid.
[0306] mp 144.degree. C. (hydrolysis). .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta.: 1.98-2.03 (m, 1H), 2.12-2.18 (m, 1H),
2.26-2.30 (m, 1H), 2.34-2.39 (m, 1H), 2.66 (d, J=15.1 Hz, 2H), 2.75
(d, J=15.1 Hz, 2H), 3.68-3.74 (m, 1H), 4.62 (d, J=12.4 Hz, 1H),
4.73 (d, J=12.4 Hz, 1H), 7.38 (dd, J=8.3 and 2.3 Hz, 1H), 7.63 (d,
J=8.3 Hz, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.66 (br s, 1H, exchangeable
with D.sub.2O), 7.85 (br s, 1H, exchangeable with D.sub.2O). MS
(ESI/APCI Dual) m/z: 380 [(M+Na).sup.+]. IR (KBr) cm.sup.-1: 3498,
3426, 3190, 2541, 1716, 1571, 1433, 1244, 1190, 1125. Anal. Calcd
for C.sub.21H.sub.22Cl.sub.2FN.sub.3O.sub.9: C, 45.83; H, 4.03; N,
7.64; Cl, 12.88; F, 3.45. Found: C, 45.69; H, 4.09; N, 7.55; Cl,
12.72; F, 3.38.
Example 10
Synthesis of
(1R,3R,5R,6R)-3-[(3,4-dichlorobenzyl)oxy]-6-fluoro-2-oxybicyclo[3,1,0]hex-
ane-6-carboxamide (5b)
##STR00038##
[0308] 174.84 g [containing 0.351 g of
(1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide citrate
(6b) and 3.853 g of
(1R,2R,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluorobicyclo[3.1.0]hexane-6-carboxamide citrate
(8b)] of the 190.36 g of the filtrate and washing solution (acetic
acid solution) obtained from the Example 9 was added with 174 mL of
water and stirred for 4.5 hrs under heating at 90 to 93.degree. C.
The reaction solution was cooled to room temperature, added with
ethyl acetate and water, and extracted. The organic layer was
washed with water, a saturated aqueous solution of sodium hydrogen
carbonate, and a saturated aqueous solution of sodium chloride in
order, and dried over anhydrous magnesium sulfate. The solvent was
removed by distillation under reduced pressure to give a crude
product, which was then subjected to silica gel column
chromatography (eluent solution: chloroform:methanol=20:1). The
concentrated residues obtained were crystallized with
chloroform-hexane to obtain 2.07 g of
(1R,3R,5R,6R)-3-[(3,4-dichloro benzyl)oxy]-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxamide (5b) as a colorless solid.
Example 11
Synthesis of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide citrate
(6b)
##STR00039##
[0310] 61.7 g (content: 49.5 wt %) of
ethyl(1R,3R,5R,6R)-3-[(3,4-dichloro benzyl)oxy]-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (5a) was added with 106 mL of 8
M ammonia-methanol solution and stirred at room temperature. Under
cooling, 30.4 g of titanium (IV) isopropoxide was added to the
mixture and stirred for 1 hr while keeping the internal temperature
at 20.degree. C. or less. Subsequently, under cooling, 9.62 g of
trimethyl silyl cyanide was added dropwise while keeping the
internal temperature at 5.degree. C. or less and stirred for 12
hrs. 271 g of ethyl acetate was added to the reaction solution. In
a separate vessel, 31 g of Silica gel 60N (spherical and neutral)
and 139 g of ethyl acetate were mixed under stirring, and then the
above reaction solution diluted with ethyl acetate was added
dropwise to the suspension. After stirring for 30 min at room
temperature, solids were filtered and washed with 690 g of ethyl
acetate. The filtrate and washing solution were combined and the
residues obtained by concentrating them under reduced pressure were
dissolved in 446 g of acetic acid and added with 19.4 g of citric
acid (anhydrous). The mixture was stirred for 13 hrs at room
temperature, and the precipitated solids were collected by
filtration and washed with 163 g of acetic acid. The resulting
solids were dried under reduced pressure at 50.degree. C. to obtain
23.4 g of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide citrate
(6b) as a light brown solid.
Example 12
Synthesis of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide L-tartarate
(6c)
##STR00040##
[0312] To ethyl acetate (5 mL) solution containing 250.2 mg of the
mixture of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a) and
(1R,2R,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (8a)
[containing (6a): 168.6 mg and (8a): 74.8 mg], 107.9 mg (content:
99 wt %) of L-tartaric acid was added and stirred for 19 hrs and 15
min at room temperature. The resulting slurry was filtered under
suction, washed with 2 mL of ethyl acetate, and dried under reduced
pressure at room temperature. 254.6 mg of the resulting colorless
powder (265.9 mg obtained) was suspended in 2.5 mL of ethyl
acetate, and stirred at room temperature for 15.5 hrs. The
resulting slurry was filtered under suction, washed with 2 mL of
ethyl acetate, and dried under reduced pressure at room temperature
to obtain 206.9 mg of
(1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide L-tartarate
(6c) as a colorless solid.
[0313] mp 154-157.degree. C. (hydrolysis). .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta.: 1.98-2.03 (m, 1H), 2.11-2.18 (m, 1H),
2.26-2.30 (m, 1H), 2.34-2.39 (m, 1H), 3.68-3.73 (m, 1H), 4.31 (s,
2H), 4.62 (d, J=12.4 Hz, 1H), 4.73 (d, J=12.4 Hz, 1H), 7.38 (dd,
J=8.3 and 2.1 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.65 (d, J=2.1 Hz,
1H), 7.66 (br s, 1H, exchangeable with D.sub.2O), 7.85 (br s, 1H,
exchangeable with D.sub.2O). MS (ESI/APCI Dual) m/z: 380
[(M+Na).sup.+]. IR (KBr) cm.sup.-1: 3325, 1679, 1601, 1426, 1380,
1131, 1068, 683. Anal. Calcd for
C.sub.19H.sub.20Cl.sub.2FN.sub.3O.sub.8 (adhesion of 0.5 H.sub.2O):
C, 44.12; H, 4.09; N, 8.12; Cl, 13.71; F, 3.67. Found: C, 44.22; H,
3.97; N, 7.98; Cl, 13.57; F, 3.71.
Example 13
Synthesis of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide oxalate
(6d)
##STR00041##
[0315] To ethyl acetate (5 mL) solution containing 251.0 mg of the
mixture of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a) and
(1R,2R,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (8a)
[containing (6a): 171.5 mg and (8a): 75.1 mg], 67.7 mg (content: 98
wt o) of oxalic acid was added and stirred for 17 hrs and 50 min at
room temperature. The resulting slurry was filtered under suction,
washed with 2 mL of ethyl acetate, and dried under reduced pressure
at room temperature. 217.0 mg of the resulting colorless powder
(229.1 mg obtained) was suspended in 2.5 mL of ethyl acetate, and
stirred at room temperature for 15.5 hrs. The resulting slurry was
filtered under suction, washed with 2 mL of ethyl acetate, and
dried under reduced pressure at room temperature to obtain 193.5 mg
of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluorobicyclo[3.1.0]hexane-6-carboxamide oxalate (6d)
as a colorless solid.
[0316] mp 156-159.degree. C. (hydrolysis). .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta.: 1.99-2.04 (m, 1H), 2.12-2.19 (m, 1H),
2.27-2.31 (m, 1H), 2.35-2.40 (m, 1H), 3.69-3.75 (m, 1H), 4.62 (d,
J=12.4 Hz, 1H), 4.73 (d, J=12.4 Hz, 1H), 7.38 (dd, J=8.3 and 1.8
Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.67 (br
s, 1H, exchangeable with D.sub.2O), 7.85 (br s, 1H, exchangeable
with D.sub.2O). MS (ESI/APCI Dual) m/z: 380 [(M+Na).sup.+]. IR
(KBr) cm.sup.-1: 3431, 1765, 1710, 1694, 1599, 1244, 1139, 722.
Anal. Calcd for C.sub.17H.sub.16Cl.sub.2FN.sub.3O.sub.6: C, 45.55;
H, 3.60; N, 9.37; Cl, 15.82; F, 4.24. Found: C, 45.43; H, 3.65; N,
9.21; Cl, 15.62; F, 4.16.
Example 14
Synthesis of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide p-toluene
sulfonate (6e)
##STR00042##
[0318] To ethyl acetate (5 mL) solution containing 251.7 mg of the
mixture of ((1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a) and
(1R,2R,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (8a)
[containing (6a): 172.0 mg and (8a): 75.3 mg], 139.4 mg (content:
98 wt %) of p-toluene sulfonic acid was added and stirred for 18
hrs and 20 min at room temperature. The resulting slurry was
filtered under suction, washed with 2 mL of ethyl acetate, and
dried under reduced pressure at room temperature. 233.2 mg of the
resulting colorless powder (248.0 mg obtained) was suspended in 2.5
mL of ethyl acetate, and stirred at room temperature for 15.5 hrs.
The resulting slurry was filtered under suction, washed with 2 mL
of ethyl acetate, and dried under reduced pressure at room
temperature to obtain 220.6 mg of
(1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide p-toluene
sulfonate (6e) as a colorless solid.
[0319] mp 198-202.degree. C. (hydrolysis). .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta.: 2.25-2.31 (m, 2H), 2.29 (s, 3H), 2.51-2.57
(m, 2H), 4.08-4.15 (m, 1H), 4.65 (s, 2H), 7.11 (d, J=8.0 Hz, 2H),
7.39 (dd, J=8.3 and 1.8 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.66 (d,
J=8.3 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.86 (br s, 1H, exchangeable
with D.sub.2O), 7.96 (br s, 1H, exchangeable with D.sub.2O). MS
(ESI/APCI Dual) m/z: 380 [(M+Na).sup.+]. IR (KBr) cm.sup.-1: 3391,
3165, 1688, 1544, 1207, 1168, 1158, 1132, 1011, 687, 564. Anal.
Calcd for C.sub.22H.sub.22Cl.sub.2FN.sub.3O.sub.5S: C, 49.82; H,
4.18; N, 7.92; Cl, 13.37; F, 3.58; S, 6.05. Found: C, 49.68; H,
4.16; N, 7.82; Cl, 13.27; F, 3.81; S, 5.98.
Example 15
Synthesis of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxylic acid
(6f)
##STR00043##
[0321] A mixture containing 22.5 mg of
(1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a), 0.1
mL of acetic acid, 0.1 mL of water, and 0.2 mL of concentrated
hydrochloric acid was stirred for 6 hrs approximately under heating
at 75.degree. C. (external temperature). The reaction mixture was
concentrated under reduced pressure to obtain 24.6 mg of
(1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxylic acid (6f) as
a light brown solid.
[0322] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: 2.21-2.32 (m,
1H), 2.33-2.42 (m, 1H), 2.52-2.59 (m, 1H), 2.59-2.65 (m, 1H),
4.00-4.13 (m, 1H), 4.63 (d, J=12.1 Hz, 1H), 4.72 (d, J=12.1 Hz,
1H), 7.03 (br s, 0.62H, exchangeable with D.sub.2O), 7.06 (br s,
0.38H, exchangeable with D.sub.2O), 7.20 (br s, 0.62H, exchangeable
with D.sub.2O), 7.23 (br s, 0.38H, exchangeable with D.sub.2O),
7.37 (br s, 0.62H, exchangeable with D.sub.2O), 7.39 (dd, J=8.4 and
2.1 Hz, 1H), 7.40 (br s, 0.38H, exchangeable with D.sub.2O), 7.66
(d, J=8.4 Hz, 1H), 7.69 (d, J=2.1 Hz, 1H). MS (ESI/APCI Dual) m/z:
357 [(M-H).sup.-].
Example 16
Synthesis of (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxamide
(7a)
##STR00044##
[0324] To a dimethyl sulfoxide (1.2 mL) solution containing 303.0
mg of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a), 35.5
mg of potassium carbonate was added under cooling in water bath
(13.degree. C. approximately). Subsequently, 0.2 mL of 30 wt %
hydrogen peroxide was added thereto and stirred for 30 min. After
stirring for 67.5 hrs at room temperature, 3 mL of water was added
to the reaction solution and the precipitated solids were filtered
and washed with 1.2 mL of water. The resulting solids were dried
under reduced pressure at room temperature to obtain 313.2 mg of
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro benzyl)oxy]-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxamide (7a) as a colorless
solid.
[0325] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta.: 1.87-1.91 (m,
1H), 1.91-1.94 (m, 1H), 2.09-2.15 (m, 2H, exchangeable with
D.sub.2O), 2.19-2.24 (m, 2H), 3.60-3.66 (m, 1H), 4.49 (d, J=12.6
Hz, 1H), 4.68 (d, J=12.6 Hz, 1H), 7.21 (br s, 1H, exchangeable with
D.sub.2O), 7.25 (br s, 1H, exchangeable with D.sub.2O), 7.20 (br s,
0.62H, exchangeable with D.sub.2O), 7.23 (br s, 0.38H, exchangeable
with D.sub.2O), 7.29 (dd, J=8.3 and 2.3 Hz, 1H), 7.52 (br s, 1H,
exchangeable with D.sub.2O), 7.54 (d, J=2.3 Hz, 1H), 7.58 (d, J=8.3
Hz, 1H), 7.71 (br s, 1H, exchangeable with D.sub.2O). MS (ESI/APCI
Dual) m/z: 376 [(M+H).sup.+].
[0326] HPLC retention time of the compound (7a) was about 8.1 min
[HPLC retention time of the compound (6a) was about 19.3 min]. HPLC
measurement was carried out under the condition described
below.
[0327] Column: CAPCELL PAK C18 UG 120 5 .mu.m 150.times.4.6 mm ID,
column oven temperature: 40.degree. C.,
[0328] Flow rate: 1 mL/min, Detection wavelength: 205 nm (UV),
[0329] Mobile phase: liquid A: methanol, liquid B: 0.1% aqueous
solution of phosphoric acid
[0330] Gradient condition: liquid A/liquid B=30/70 is switched to
liquid A/liquid B=80/20 over 25 min, and then liquid A/liquid
B=80/20 is maintained for 5 min.
Example 17
Synthesis of (1R,2R,3R,5R, 6R)-2-amino-2-carbamoyl-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxylic acid
(7b)
##STR00045##
[0332] To a dimethyl sulfoxide (1 mL) solution containing 500.1 mg
of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide citrate
(6b), 0.15 mL of 30 wt % hydrogen peroxide was added at room
temperature (20.degree. C. approximately). Subsequently, 2.5 mL of
6.25 M aqueous solution of sodium hydroxide was added (temperature
has risen to 51.degree. C.) and stirred for 3 hrs and 45 min at
25.degree. C. To the reaction solution, 4.3 mL of 3 M hydrochloric
acid was added dropwise under ice cooling to adjust pH to pH 4. The
slurry obtained was stirred at room temperature for 1 hr, filtered
under suction, and washed with ethanol. The resulting solids were
dried under reduced pressure to obtain 307.4 mg of (1R,2R,3R,5R,
6R)-2-amino-2-carbamoyl-3-[(3,4-dichloro benzyl)oxy]-6-fluoro
bicyclo[3.1.0]hexane-6-carboxylic acid (7b) as a colorless
solid.
[0333] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta.: 2.00-2.04 (m,
1H), 2.07-2.11 (m, 1H), 2.21-2.32 (m, 2H), 3.84-3.90 (m, 1H), 4.46
(d, J=12.2 Hz, 1H), 4.60 (d, J=12.2 Hz, 1H), 7.28 (dd, J=8.3 and
2.1 Hz, 1H), 7.31 (br s, 1H, exchangeable with D.sub.2O), 7.54 (d,
J=2.1 Hz, 1H), 7.56 (br s, 1H, exchangeable with D.sub.2O), 7.59
(d, J=8.3 Hz, 1H). MS (ESI/APCI Dual) m/z: 377 [(M+H).sup.+].
[0334] HPLC retention time of the compound (7b) was about 12.9 min
[HPLC retention time of the compound (6b) was about 19.3 min]. HPLC
measurement condition was the same as the condition described in
the Example 16.
Example 18
Synthesis of (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxylic acid
(1a)
##STR00046##
[0336] A mixture of 0.195 g of (1R,2S,3R,5R,
6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro
bicyclo[3.1.0]hexane-6-carboxamide (6a), 1.9 mL of acetic acid, and
1.9 ml of concentrated hydrochloric acid was stirred for 31 hrs
under heating in an oil bath at 75.degree. C. The reaction solution
was cooled to room temperature and the precipitated solids were
collected by filtration. The solids were washed with 5.28 g of
water and dried by air to obtain 0.094 g of (1R,2R,3R,5R,
6R)-2-amino-3-[(3,4-dichloro benzyl)oxy]-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1a) as a solid. The
compound exhibited the proton nuclear resonance spectrum (.sup.1H
NMR) and the HPLC retention time that are the same as those of the
compound (1a) synthesized according to conventional process (that
is, Compound 34 described in the pamphlet of International
Publication No. 03/061698).
[0337] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: 2.07-2.14 (m,
2H), 2.25-2.41 (m, 2H), 3.87-3.99 (m, 1H), 4.43 (d, J=12.2 Hz, 1H),
4.54 (d, J=12.2 Hz, 1H), 7.30 (dd, J=8.2 and 1.9 Hz, 1H), 7.57 (d,
J=1.9 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H). MS (ESI/APCI Dual) m/z: 376
[(M-H).sup.-].
[0338] HPLC retention time of the compound (1a) was about 11.9 min
[HPLC retention time of the compound (6a) was about 16.5 min]. HPLC
measurement was carried out under the condition described
below.
[0339] Column: CAPCELL PAK C18 UG 120 5 .mu.m 150.times.4.6 mm ID,
column oven temperature: 40.degree. C.,
[0340] Flow rate: 1 mL/min, Detection wavelength: 205 nm (UV),
[0341] Mobile phase: liquid A: acetonitrile, liquid B: 0.1% aqueous
solution of phosphoric acid
[0342] Gradient condition: liquid A/liquid B=10/90 is switched to
liquid A/liquid B=80/20 over 25 min, and then liquid A/liquid
B=80/20 is maintained for 5 min.
Example 19
Synthesis of (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxylic acid
(1a)
##STR00047##
[0344] To a dimethyl sulfoxide (0.3 mL) containing 99.2 mg of (1R,
2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro
bicyclo[3.1.0]hexane-6-carboxamide (6a), 13 .mu.L of 25 wt %
aqueous solution of sodium hydroxide was added under cooling in
water bath. Subsequently, 1.0 mL of 30 wt % hydrogen peroxide was
added. After stirring for 30 min at room temperature, part of the
reaction solution was collected and subjected to HPLC measurement.
As a result, it was found that the peak at about 19.3 min, which
corresponds to the retention time of the reacting material (6a),
has disappeared and only the peak at about 8.1 min, which
corresponds to the retention time of (1R,2R,3R,5R,
6R)-2-amino-3-[(3,4-dichloro benzyl)oxy]-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxamide (7a), is appeared (condition
for HPLC measurement is the same as the condition described in the
Example 16).
[0345] Subsequently, after stirring for 45 min at room temperature,
0.6 mL of ethanol and 1 mL of 25 wt % aqueous solution of sodium
hydroxide were added to the reaction solution and stirred for 4 hrs
at 75.degree. C. and for 18 hrs at room temperature. 3.0 mL of 3 M
hydrochloric acid was added to the reaction solution under ice
cooling and stirred for 4 hrs at room temperature. The resulting
slurry was filtered under suction and dried under reduced pressure
to obtain 80.3 mg of (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxylic acid
(1a) as a light yellow solid.
Example 20
Synthesis of (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxylic acid
(1a)
##STR00048##
[0347] To a dimethyl sulfoxide (0.4 mL) containing 200.3 mg of (1R,
2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro
bicyclo[3.1.0]hexane-6-carboxamide citrate (6b), 0.06 mL of 30 wt %
hydrogen peroxide was added at room temperature. Subsequently, 1 mL
of 6.25 M aqueous solution of sodium hydroxide was added. After
stirring for 1 hr at room temperature, part of the reaction
solution was collected and subjected to HPLC measurement. As a
result, it was found that the peak at about 19.3 min, which
corresponds to the retention time of the reacting material (6b),
has disappeared and only the peak at about 12.7 min, which
corresponds to the retention time of (1R,
2R,3R,5R,6R)-2-amino-2-carbamoyl-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxylic acid (7b),
is appeared (condition for HPLC measurement is the same as the
condition described in the Example 16).
[0348] Subsequently, after stirring for 30 min at room temperature,
the reaction solution was stirred for 2 hrs at 92 to 100.degree.
C., 16 hrs at room temperature, and 1 hr at 100.degree. C. After
cooling to room temperature, the reaction solution was added
dropwise with 0.22 mL of 3 M hydrochloric acid (pH 1), stirred for
2 hrs and 25 min at room temperature, and cooled for 10 min on ice.
The resulting slurry was filtered under suction and dried under
reduced pressure to obtain 141.4 mg of
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro benzyl)oxy]-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1a) as a light yellow
solid.
Example 21
Synthesis of (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxylic acid
(1a)
##STR00049##
[0350] To 32.5 g of (1R,2S,3R,5R,
6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro
bicyclo[3.1.0]hexane-6-carboxamide citrate (6b), 63.9 g of dimethyl
sulfoxide and 9.88 g of 30 wt % hydrogen peroxide were added and
stirred for 10 min. To the mixture, 202 g of 20 wt % aqueous
solution of sodium hydroxide was added dropwise over 1 hr, and
stirred for 10 min after completing the dropwise addition. The
reaction mixture was heated and stirred for about 13 hrs at the
internal temperature of 80.degree. C. or more. The reaction
solution was cooled in an ice bath until the internal temperature
reaches 16.degree. C., and pH was adjusted to approximately 1 to 2
with hydrochloric acid. The precipitated solids were filtered and
collected to yield solids, which are then washed with 290 mL of a
mixture solution of ethanol:water=1:1 (v/v) and 90 mL of ethanol in
order. The resulting solids were dried under reduced pressure at
50.degree. C. to obtain 21.1 g of
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro benzyl)oxy]-6-fluoro
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1a) as a light yellow
to light brown solid.
Example 22
Synthesis of (1R,2R,3R,5R,6R)-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro-2',5'-dioxospiro[bicyclo[3.1.0]hexane-2,4'-imidazoli-
dine]-6-carboxylic acid (9a) and (1R,2S,3R, 5R,6R)-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro-2',5'-dioxospiro[bicyclo[3.1.0]hexane-2,4'-imidazoli-
dine]-6-carboxylic acid (10a)
##STR00050##
[0352] To a mixture containing 0.928 g of ethyl(1R,3R,5R,
6R)-3-[(3,4-dichloro benzyl)oxy]-6-fluoro-2-oxo
bicyclo[3.1.0]hexane-6-carboxylate (5a), 4.70 g of methanol, and
4.66 g of water, 0.1073 g (content: 96 wt %) of sodium hydroxide
was added and stirred for 2 hrs and 40 min at room temperature. One
hour and ten minutes after starting the reaction, part of the
reaction solution was collected and subjected to HPLC measurement.
As a result, it was found that the peak at about 27.5 min, which
corresponds to the retention time of the reacting material (5a),
has disappeared and the peak at about 25.7 min, which is believed
to be the retention time of the carboxylate resulting from
hydrolysis of the ester, is observed (condition for HPLC
measurement is the same as the condition described in the Example
16, ditto for the followings). To the reaction solution, 2.042 g
(content: 97 wt %) of ammonium carbonate and 0.55 g (content: 97 wt
o) of sodium cyanide were added and stirred for 6 hrs under heating
in an oil bath at 65.degree. C. followed by stirring for about 14
hrs at room temperature. Part of the reaction solution was
collected and subjected to HPLC measurement. As a result, it was
found that the peak at retention time of about 25.7 min has
disappeared, and the peak at about 19.6 min, which corresponds to
(1R,2R,3R,5R,6R)-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro-2',5'-dioxospiro[bicyclo[3.1.0]hexane-2,4'-imidazoli-
dine]-6-carboxylic acid (9a), is appeared and the peak at about
18.8 min, which corresponds to (1R,2S,3R, 5R,6R)-3-[(3,4-dichloro
benzyl)oxy]-6-fluoro-2',5'-dioxospiro[bicyclo[3.1.0]hexane-2,4'-imidazoli-
dine]-6-carboxylic acid (10a), is appeared, with the peak area
ratio of (9a)/(10a)=2.2.
[0353] To the reaction solution, 3.49 g (content: 35 wt %) of
concentrated hydrochloric acid was added. The resulting suspension
was filtered to give a solid. The solid obtained was subjected to
HPLC measurement, and as a result, it was confirmed that it is a
mixture of the compounds of (9a) and (10a) with the peak area ratio
of (9a)/(10a)=6.6.
INDUSTRIAL APPLICABILITY
[0354] With respect to the process of producing
3-alkoxy-2-amino-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxylic
acid derivative which is useful as an antagonist for a metabotropic
glutamate receptor or a salt thereof, it becomes possible by the
present invention to provide a production process which solves the
problems relating to safety issue, can be easily scaled up, is
effective in terms of cost, has good efficiency as having fewer
reaction steps, and therefore is suitable for large scale
production.
* * * * *