U.S. patent application number 14/975427 was filed with the patent office on 2016-04-14 for substituted n-pentanamide compounds, preparation method and the use thereof.
The applicant listed for this patent is SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES, TOPHARMAN SHANGHAI CO., LTD.. Invention is credited to Xiangrui JIANG, Jianfeng LI, Guanghui TIAN, Qiang ZHANG, Rongxia ZHANG, Fuqiang ZHU.
Application Number | 20160102047 14/975427 |
Document ID | / |
Family ID | 46557763 |
Filed Date | 2016-04-14 |
United States Patent
Application |
20160102047 |
Kind Code |
A1 |
ZHANG; Qiang ; et
al. |
April 14, 2016 |
SUBSTITUTED N-PENTANAMIDE COMPOUNDS, PREPARATION METHOD AND THE USE
THEREOF
Abstract
The present invention relates to a (2R,3R)-3-(3-substituted
phenyl)-2-methyl n-pentanamide compounds as shown in the formula I
and the preparation method thereof, wherein, the substituents are
as defined in the specification, the present invention further
relates to a use of the above compounds for the preparation of
tapentadol II or its pharmaceutically acceptable salt, and the
intermediates involved in the preparation process ##STR00001##
Inventors: |
ZHANG; Qiang; (Shanghai,
CN) ; ZHANG; Rongxia; (Shanghai, CN) ; TIAN;
Guanghui; (Shanghai, CN) ; LI; Jianfeng;
(Shanghai, CN) ; ZHU; Fuqiang; (Shanghai, CN)
; JIANG; Xiangrui; (Shanghai, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF
SCIENCES
TOPHARMAN SHANGHAI CO., LTD. |
Shanghai
Shanghai |
|
CN
CN |
|
|
Family ID: |
46557763 |
Appl. No.: |
14/975427 |
Filed: |
December 18, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13982733 |
Sep 20, 2013 |
9249084 |
|
|
PCT/CN2012/070781 |
Jan 31, 2012 |
|
|
|
14975427 |
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Current U.S.
Class: |
562/465 ;
564/170; 564/171 |
Current CPC
Class: |
C07C 59/64 20130101;
C07D 263/26 20130101; C07C 213/02 20130101; C07C 17/16 20130101;
C07C 217/62 20130101; C07C 22/04 20130101; C07C 309/73 20130101;
C07C 43/23 20130101; C07C 59/68 20130101; C07C 215/54 20130101;
C07C 41/26 20130101; Y02P 20/582 20151101; C07C 43/225 20130101;
C07D 263/52 20130101; C07C 235/34 20130101; C07C 17/16 20130101;
C07C 41/26 20130101; C07C 309/75 20130101; C07C 309/66 20130101;
C07C 43/23 20130101 |
International
Class: |
C07C 235/34 20060101
C07C235/34; C07C 59/64 20060101 C07C059/64; C07C 59/68 20060101
C07C059/68 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 31, 2011 |
CN |
201110034202.4 |
Claims
1-23. (canceled)
24. A compound represented by any one of the follows: ##STR00130##
wherein R is a protecting group of the phenolic hydroxyl.
Description
RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. application Ser.
No. 13/982,733, filed Sep. 20, 2013, which claims priority to
International Patent Application No. PCT/CN2012/070781, filed Jan.
31, 2012, which claims priority to China patent Application No.
201110034202.4, filed Jan. 31, 2011. The entirety of the
aforementioned applications is incorporated herein by
reference.
FIELD
[0002] The invention relates to the field of pharmaceutical
chemistry and organic chemistry, specifically, the present
invention relates to (2R,3R)-3-(3-substituted
phenyl)-2-methyl-n-pentanamide compounds representing by the
following structure formula (I), the preparation method thereof,
and the use thereof for preparation of tapentadol (II) or its
pharmaceutically acceptable salt.
##STR00002##
BACKGROUND
[0003] Tapentadol is central analgesic with a dual action mechanism
developed by Johnson & Johnson, since it is both the p-type
opioid receptor agonist and norepinephrine reuptake inhibitor, up
to now it is the first single-molecule drug which has both above
pharmacological effects. It was approved for marketing on Nov. 21,
2008 by the U.S. Food and Drug Administration, for the treatment of
moderate to severe acute pain. Studies show that tapentadol is
independent of metabolism activation and has no active metabolite;
moreover, it has curative effect on all of the acute, inflammatory
and chronic neuropathic pain models, and its effectiveness is
between morphine and tramadol; in addition, the satisfactory plasma
concentration can be obtained by both intravenous and oral
administration of tapentadol, it is not easier to cause analgesic
tolerance and physical dependence than morphine, and its clinical
application shows mild side effects and well tolerance. Its
chemical name is:
(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol,
whose structure is represented by the following formula (II):
##STR00003##
[0004] It is recorded in European Patent No. EP693475 a method for
preparing compound (II) from 3-pentanone through the Mannich
reaction, Grignard reaction, crystallization to separate
diastereoisomer, column chromatography to separate diastereoisomer,
chloridization, elimination and demethylation reaction, the method
is shown as Reaction Scheme 1:
##STR00004##
[0005] It is recorded in European Patent No. EP2049464 and U.S.
Patent No. US2009326271 a method for preparing compound (II) from
3'-benzyloxyphenyl ethyl ketone through Mannich reaction, chiral
separation, Grignard reaction, dehydration, and debenzylation
together with stereoselective hydrogenation, the method is shown as
Reaction Scheme 2:
##STR00005##
[0006] It is recorded in European Patent No. EP2046724 a method for
preparing the hydrochloride of compound (II) from 3'-methoxyphenyl
ethyl ketone through Mannich reaction, chiral separation, Grignard
reaction, dehydration, stereoselective hydrogenation, demethylation
reaction, and directly adding hydrochloric acid without separation,
the method is shown as Reaction Scheme 3:
##STR00006##
[0007] It is recorded in European Patent No. EP2046726 and U.S.
Patent No. US2009312578 an improved method of the dehydration
reaction in the above Reaction Scheme 3, that is, after dehydration
using trifluoroacetic anhydride or acylating hydroxy compound,
hydrogenation and deprivation are performed, the method is shown as
Reaction Scheme 4:
##STR00007##
[0008] The existing synthesis methods of tapentadol adopt the
column chromatography or resolution methods, which have a high cost
and low yield, and are not suitable for industrial production.
Therefore, it is eager to find a method which has simple process,
high yield, low cost and is suitable for industrial production.
SUMMARY
[0009] In order to overcome the disadvantages of high cost and low
yield etc. of the method for preparation of tapentadol in the prior
art, the present invention provides (2R,3R)-3-(3-substituted
phenyl)-2-methyl n-pentanamide compounds having a structure
represented by the following formula I, and the compounds of
formula I may be used to synthesize tapentadol or its
pharmaceutically acceptable salt economically, conveniently and
with a high yield.
##STR00008##
[0010] It is one object of the present invention to provide
(2R,3R)-3-(3-substituted phenyl)-2-methyl n-pentanamide compounds
represented by formula I.
[0011] It is another object of the present invention to provide a
method for preparing (2R,3R)-3-(3-substituted phenyl)-2-methyl
n-pentanamide compounds represented by formula I.
[0012] It is still another object of the present invention to
provide a use of (2R,3R)-3-(3-substituted phenyl)-2-methyl
n-pentanamide compounds represented by formula I for preparing
tapentadol.
[0013] It is yet another object of the present invention to provide
the intermediates involved in the above preparation method.
[0014] To achieve the above object, the present invention provides
(2R,3R)-3-(3-substituted phenyl)-2-methyl n-pentanamide compounds
represented by formula I.
##STR00009##
[0015] wherein, R is the protecting group of the phenolic hydroxy,
R may form an ether group or an ester group with the phenolic
hydroxy; R may be one selected from the group consisting of C1-C6
linear or branched alkyl group, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, alkylsilyl, C1-C6
alkoxymethyl, C1-C6 alkyloyl, substituted or unsubstituted aryloyl;
wherein the substituent may be hydroxy, halogen, C1-C6 alkyl, C1-C6
alkoxy, etc.; the aryl may be phenyl, naphthyl, etc.;
##STR00010##
is the residue of chiral auxiliaries, which is defined as
follows:
##STR00011##
[0016] wherein, X is O, S or NR.sub.7, wherein R.sub.7 is hydrogen,
C1-C6 branched or linear alkyl;
[0017] Y is O or S;
[0018] R.sub.1 is C1-C6 alkyl, substituted or unsubstituted phenyl
(Ph), substituted or unsubstituted naphthyl, substituted or
unsubstituted benzyl (Bn), C1-C6 alkoxycarbonyl, wherein the
substituent on phenyl, naphthyl or benzyl is 1 to 3 substituent(s)
selected from hydroxy, halogen, C1-C6 alkyl and C1-C6 alkoxy;
[0019] R.sub.2 and R.sub.3 are each independently selected from H;
C1-C6 alkyl; phenyl; phenyl substituted with 1 to 3 substituent(s)
selected from hydroxy, halogen, C1-C6 alkyl and C1-C6 alkoxy.
[0020] In a preferred embodiment of the present invention, in
formula I, R may form an ether group or an ester group with the
phenolic hydroxy; R may be selected from the group consisting of
C1-C6 linear or branched alkyl group, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, alkylsilyl, C1-C6
alkoxymethyl, C1-C6 alkyloyl, substituted or unsubstituted aryloyl;
wherein the substituent may be hydroxy, halogen, C1-C6 alkyl, C1-C6
alkoxy, etc.; the aryl may be phenyl, naphthyl, etc.
[0021] X is O; and Y is O;
[0022] R.sub.1 is C1-C6 alkyl, substituted or unsubstituted phenyl
(Ph), or substituted or unsubstituted benzyl (Bn), wherein the
substituent on phenyl or benzyl is 1 to 3 substituent(s) selected
from hydroxy, halogen, C1-C6 alkyl and C1-C6 alkoxy;
[0023] R.sub.2 and R.sub.3 are each independently selected from H,
C1-C6 alkyl and phenyl.
[0024] In a further preferred embodiment of the present invention,
in formula I,
[0025] R is benzyl, methyl, t-butyl, triphenylmethyl,
methoxymethyl, trimethylsilyl, t-butyldimethylsilyl, acetyl or
benzoyl;
[0026] X is O; and Y is O;
[0027] R.sub.1 is phenyl; phenyl substituted with 1 to 3
substituent(s) selected from hydroxy, halogen, C1-C6 alkyl and
C1-C6 alkoxy; or benzyl;
[0028] R.sub.2 and R.sub.3 are each independently selected from H,
C1-C6 alkyl and phenyl.
[0029] Still in a further preferred embodiment of the present
invention, the compound represented by formula I is: [0030] (1)
3-[(2R,3R)-2-methyl-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4R-phenyl-2--
Oxazolidinone
[0030] ##STR00012## [0031] (2)
3-[(2R,3R)-2-methyl-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4R,5S-diphen-
yl-2-Oxazolidinone
[0031] ##STR00013## [0032] (3)
3-[(2R,3R)-3-(3-methoxyphenyl)-2-methyl-1-oxopentyl]-4R,5S-diphenyl-2-Oxa-
zolidinone
[0032] ##STR00014## [0033] (4)
3-[(2R,3R)-3-(3-methoxyphenyl)-2-methyl-1-oxopentyl]-4R-phenyl-2-Oxazolid-
inone
##STR00015##
[0034] The present invention provides a method for preparing
(2R,3R)-3-(3-substituted phenyl)-2-methyl n-pentanamide compounds
as shown in formula I, said method comprises:
##STR00016##
[0035] wherein, R is a protecting group of the phenolic hydroxy, R
may form an ether group or an ester group with the phenolic
hydroxy; R may be selected from C1-C6 linear or branched alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, alkylsilyl, C1-C6 alkoxymethyl, C1-C6 alkyloyl,
substituted or unsubstituted aryloyl; wherein, the said substituent
may be hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, etc.; the said
aryl may be phenyl, naphthyl, etc.;
##STR00017##
is the residue of chiral auxiliaries, which is defined as
follows:
##STR00018##
[0036] wherein, X is O, S or NR.sub.7, in which R.sub.7 is
hydrogen, C1-C6 branched or linear alkyl; Y is O or S;
[0037] R.sub.1 is C1-C6 alkyl group, substituted or unsubstituted
phenyl (Ph), substituted or unsubstituted naphthyl, substituted or
unsubstituted benzyl (Bn), C1-C6 alkoxycarbonyl, wherein, the
substituent on phenyl, naphthyl or benzyl is 1 to 3 substituent(s)
selected from hydroxy, halogen, C1-C6 alkyl and C1-C6 alkoxy;
[0038] R.sub.2 and R.sub.3 are each independently selected from H;
C1-C6 alkyl; phenyl; phenyl substituted with 1 to 3 substituent(s)
selected from hydroxy, halogen, C1-C6 alkyl and C1-C6 alkoxy.
[0039] The .alpha.-methylation reaction is conducted between a
compound of formula II and hydrocarbylation reagent in the presence
of strong base or Lewis acid, and a post-treatment is performed by
a conventional method to give the compound I; the said
hydrocarbylation reagent is any one of methyl iodide, methyl
bromide, methyl chloride, methyl trifluoromethanesulfonate, methyl
benzenesulfonate and methyl fluorosulfonate; the said strong base
is any one of sodium hexamethyldisilylamide (NaHMDS), lithium
hexamethyldisilylamide (LiHMDS), potassium hexamethyldisilylamide
(KHMDS), lithium amide, sodium amide, potassium amide, lithium
diisopropylamide (LDA) and n-butyl lithium; the said Lewis acid is
any one of titanium tetrachloride, aluminum trichloride, ferric
trichloride, zinc chloride and antimony pentafluoride.
[0040] The method for preparing (2R,3R)-3-(3-substituted
phenyl)-2-methyl n-pentanamide compounds shown as formula I
comprises: firstly, 3-(3-hydroxy protected phenyl)acrylic acid (IV)
is reacted with a chiral auxiliary
##STR00019##
under the activation of a carboxylic acid activating agent to
obtain a compound V; the compound V is subjected to asymmetric
Michael addition with ethyl magnesium halide under the condition of
organic metal reagent in an inert solvent, then the resultant is
post-treated by a conventional method to give Compound III;
compound III and hydrocarbylation reagent are conducted the
.alpha.-methylation reaction in the presence of strong base or
Lewis acid, then the resultant is post-treated by a conventional
method to give the compound I. The method is shown as Reaction
Scheme 5:
##STR00020##
[0041] Wherein, R and
##STR00021##
are as defined above.
[0042] The method comprises the following steps:
[0043] (1) In step a, 3-(3-hydroxy protected phenyl)acrylic acid
(IV) is reacted in the presence of carboxylic acid activating
agent, chiral auxiliaries
##STR00022##
and base, and with the suitable organic solvent and suitable
temperatures to form Compound V.
[0044] The carboxylic acid activating agent is any one of thionyl
chloride, oxalyl chloride, pivaloyl chloride, chloroformate,
carbodiimides such as dicyclohexyl carbodiimide (DCC),
4-dimethylaminopyridine (DMAP) and carbonyldiimidazole (CDI);
[0045] said base is inorganic base or organic base, and may be any
one selected from sodium hydride, potassium hydride, alkyl lithium
(n-butyl lithium or t-butyl lithium), lithium amide, sodium amide,
potassium amide, lithium diisopropylamide (LDA), lithium
hexamethyldisilylamide (LiHMDS), sodium hexamethyldisilylamide
(NaHMDS), sodium methoxide, sodium ethoxide, potassium
tert-butoxide, sodium hydroxide, potassium hydroxide, calcium
hydroxide, triethylamine, ethylenediamine, sodium carbonate,
potassium carbonate, sodium bicarbonate and potassium
bicarbonate;
[0046] Said organic solvents include: hydrocarbons, such as
benzene, xylene, toluene, dichloromethane, chloroform; ethers such
as tetrahydrofuran, diethyl ether, dipropyl ether, 1,4-dioxane;
amides such as N,N-dimethylformamide, N,N-diethylformamide,
N,N-dimethylacetamide; nitriles such as acetonitrile; and the
mixtures of the above solvents, wherein, the preferred solvent is
tetrahydrofuran, toluene, N,N-dimethylformamide or
acetonitrile;
[0047] The reaction temperature is usually in the range of
-100.degree. C. to 50.degree. C., preferably -80.degree. C. to
30.degree. C.
[0048] (2) In step b, the inert solution of the compound V was
slowly added to the mixed solution of Grignard reagent ethyl
magnesium halide and organic metal reagent at the suitable
temperature, after the reaction was complete, the resultant was
post-treated by a conventional method to give the Compound III.
[0049] Said organic metal reagent is any one of cuprous bromide
dimethylsulfide, cuprous bromide, cuprous chloride and cuprous
iodide. Said Grignard reagent ethyl magnesium halide is any one of
ethyl magnesium bromide, ethyl magnesium iodide and ethyl magnesium
chloride. The amount of the Grignard reagent is 1 to 10 times
(molar ratio), preferably 1 to 4 times that of the compound V. The
amount of the organic metal reagent is 0.1 to 5 times (molar
ratio), preferably 0.5 to 2 times that of the compound V. The
reacting temperature of the above reaction may be vary in the range
of a certain width, typically from -50.degree. C. to 50.degree. C.,
preferably from -40.degree. C. to 25.degree. C. The reaction time
may vary depending on the solvent and reaction temperature, and is
usually preferably 2 to 10 hours.
[0050] Said inert solvent is C1-C4 halogenated hydrocarbons, C6-C8
aromatic hydrocarbons, C2-C6 ether, C2-C6 nitrile, preferably
dichloromethane, tetrahydrofuran, acetonitrile.
[0051] (3) In step c, the .alpha.-methylation reaction is conducted
between a compound of formula III and hydrocarbylation reagent in
the presence of strong base or Lewis acid, and the resultant is
post-treated by a conventional method to give the compound I; said
hydrocarbylation reagent is any one of methyl iodide, methyl
bromide, methyl chloride, methyl trifluoromethanesulfonate, methyl
benzenesulfonate, methyl fluorosulfonate; said strong base is any
one of sodium hexamethyldisilylamide (NaHMDS), lithium
hexamethyldisilylamide (LiHMDS), potassium hexamethyldisilylamide
(KHMDS), lithium amide, sodium amide, potassium amide, lithium
diisopropylamide (LDA), n-butyl lithium; said Lewis acid is any one
of titanium tetrachloride, aluminum trichloride, ferric
trichloride, zinc chloride, antimony pentafluoride.
[0052] A preferred embodiment of the present invention is as
follows:
##STR00023##
[0053] Another preferred embodiment of the present invention is as
follows:
##STR00024##
[0054] The present invention also provides another method for
preparing (2R,3R)-3-(3-substituted phenyl)-2-methyl n-pentanamide
compound of formula I, said method comprises: trans-pent-2-enoic
acid VI is reacted with a chiral auxiliary
##STR00025##
under the activation of a carboxylic acid activating agent to
obtain a compound VII; the compound VII is subjected to an
asymmetric Michael addition with 3-hydroxy protected phenyl
magnesium halide under the condition of organic metal reagent in an
inert solvent, then the resultant is post-treated by a conventional
method to give a compound VIII; the chiral auxiliary
##STR00026##
is removed from the compound VIII to give a compound IX; then the
compound IX is reacted with a chiral auxiliary
##STR00027##
under the activation of a carboxylic acid activating agent to
obtain a compound III; the compound III and hydrocarbylation
reagent are conducted the .alpha.-methylation reaction in the
presence of strong base or Lewis acid, then the resultant is
post-treated by a conventional method to give the compound I. The
method is shown as Reaction Scheme 6:
##STR00028##
Wherein, R and
##STR00029##
[0055] are as defined above;
##STR00030##
is the residue of chiral auxiliaries, which is defined as
follows:
##STR00031##
[0056] wherein, Z is O, S or NR.sub.8, wherein R.sub.8 is hydrogen,
C1-C6 branched or linear alkyl;
[0057] W is O or S;
[0058] R.sub.4 is C1-C6 alkyl, substituted or unsubstituted phenyl
(Ph), substituted or unsubstituted naphthyl, substituted or
unsubstituted benzyl (Bn), C1-C6 alkoxycarbonyl, wherein, the
substituent on phenyl, naphthyl or benzyl group is 1 to 3
substituent(s) selected from hydroxy, halogen, C1-C6 alkyl and
C1-C6 alkoxy;
[0059] R.sub.5 and R.sub.6 are each independently selected from H;
C1-C6 alkyl; phenyl; phenyl substituted with 1 to 3 substituent(s)
selected from hydroxy, halogen, C1-C6 alkyl and C1-C6 alkoxy.
[0060] The method comprises the following steps:
[0061] (1) In step d, trans-pent-2-enoic acid VI is reacted in the
presence of carboxylic acid activating agent, chiral
auxiliaries
##STR00032##
and base, and with a suitable organic solvent and suitable
temperature to form Compound VII.
[0062] The carboxylic acid activating agent is any one of thionyl
chloride, oxalyl chloride, pivaloyl chloride, chloroformate and
carbodiimides such as dicyclohexyl carbodiimide (DCC),
4-dimethylaminopyridine (DMAP) and carbonyldiimidazole (CDI);
[0063] said base may be inorganic base or organic base, and may be
any one selected from sodium hydride, potassium hydride, alkyl
lithium (n-butyl lithium or t-butyl lithium), lithium amide, sodium
amide, potassium amide, lithium diisopropylamide (LDA), lithium
hexamethyldisilylamide (LiHMDS), sodium hexamethyldisilylamide
(NaHMDS), sodium methoxide, sodium ethoxide, potassium
tert-butoxide, sodium hydroxide, potassium hydroxide, calcium
hydroxide, triethylamine, ethylenediamine, sodium carbonate,
potassium carbonate, sodium bicarbonate and potassium
bicarbonate;
[0064] Said organic solvent includes: hydrocarbons, such as
benzene, xylene, toluene, dichloromethane, chloroform; ethers such
as tetrahydrofuran, diethyl ether, dipropyl ether, 1,4-dioxane;
amides such as N,N-dimethylformamide, N,N-diethylformamide,
N,N-dimethylacetamide; nitriles such as acetonitrile; and the
mixtures of the above solvents, wherein, the preferred solvent is
tetrahydrofuran, toluene, N,N-dimethylformamide or
acetonitrile;
[0065] The reaction temperature is usually in the range of
-100.degree. C. to 50.degree. C., preferably -80.degree. C. to
30.degree. C.
[0066] (2) In step e, the inert solution of the compound VII is
slowly added to the mixed solution of Grignard reagent 3-hydroxy
protected phenyl magnesium halide and organic metal reagent at a
suitable temperature, after the reaction was complete, the
resultant was post-treated by a conventional method to give the
product VIII.
[0067] Said organic metal reagent is any one of cuprous bromide
dimethylsulfide, cuprous bromide, cuprous chloride and cuprous
iodide. The Grignard Reagent 3-hydroxy protected phenyl magnesium
halide is any one selected from 3-hydroxy protected phenyl
magnesium bromide, 3-hydroxy protected phenyl magnesium iodide and
3-hydroxy protected phenyl magnesium chloride. The amount of the
Grignard reagent is 1 to 10 times (molar ratio), preferably 1 to 4
times that of the compound VII. The amount of the organic metal
reagent is 0.1 to 5 times (molar ratio), preferably 0.5 to 2 times
that of the compound VII. The reacting temperature of the above
reaction may be vary in a certain range, typically from -50.degree.
C. to 50.degree. C., preferably from -40.degree. C. to 25.degree.
C. The reaction time may vary depending on the solvent and reaction
temperature, and is usually preferably 2 to 10 hours.
[0068] Said inert solvent is C1-C4 halogenated hydrocarbon, C6-C8
aromatic hydrocarbon, C2-C6 ether, C2-C6 nitrile, preferably
dichloromethane, tetrahydrofuran, acetonitrile.
[0069] (3) In step f, the chiral auxiliary residue
##STR00033##
is removed from the compound VIII in the presence of hydrogen
peroxide and an alkali metal hydroxide, said alkali metal hydroxide
is any one selected from lithium hydroxide, sodium hydroxide and
potassium hydroxide.
[0070] (4) In step g, the compound IX is reacted in the presence of
carboxylic acid activating agent, chiral auxiliaries
##STR00034##
and base, and with a suitable organic solvent and suitable
temperature to form Compound III.
[0071] The carboxylic acid activating agent is any one of thionyl
chloride, oxalyl chloride, pivaloyl chloride, chloroformate and
carbodiimides such as dicyclohexyl carbodiimide (DCC),
4-dimethylaminopyridine (DMAP) and carbonyldiimidazole (CDI);
[0072] said base may be inorganic base or organic base, and may be
any one selected from sodium hydride, potassium hydride, alkyl
lithium (n-butyl lithium or t-butyl lithium), lithium amide, sodium
amide, potassium amide, lithium diisopropylamide (LDA), lithium
hexamethyldisilylamide (LiHMDS), sodium hexamethyldisilylamide
(NaHMDS), sodium methoxide, sodium ethoxide, potassium
tert-butoxide, sodium hydroxide, potassium hydroxide, calcium
hydroxide, triethylamine, ethylenediamine, sodium carbonate,
potassium carbonate, sodium bicarbonate and potassium
bicarbonate;
[0073] Said organic solvent includes: hydrocarbons, such as
benzene, xylene, toluene, dichloromethane, chloroform; ethers such
as tetrahydrofuran, diethyl ether, dipropyl ether, 1,4-dioxane;
amides such as N,N-dimethylformamide, N,N-diethylformamide,
N,N-dimethylacetamide; nitriles such as acetonitrile; and the
mixtures of the above solvents, wherein, the preferred solvent is
tetrahydrofuran, toluene, N,N-dimethylformamide or
acetonitrile;
[0074] The reaction temperature is usually in the range of
-100.degree. C. to 50.degree. C., preferably -80.degree. C. to
30.degree. C.
[0075] (5) In step c, a .alpha.-methylation reaction is conducted
between a compound of formula III and hydrocarbylation reagent in
the presence of strong base or Lewis acid, and the resultant is
post-treated by a conventional method to give the compound I;
[0076] said hydrocarbylation agent is any one of methyl iodide,
methyl bromide, methyl chloride, methyl trifluoromethanesulfonate,
methyl benzenesulfonate, methyl fluorosulfonate; said strong base
is any one of sodium hexamethyldisilylamide (NaHMDS), lithium
hexamethyldisilylamide (LiHMDS), potassium hexamethyldisilylamide
(KHMDS), lithium amide, sodium amide, potassium amide, lithium
diisopropylamide (LDA), n-butyl lithium; said Lewis acid is any one
of titanium tetrachloride, aluminum trichloride, ferric
trichloride, zinc chloride, antimony pentafluoride.
[0077] A preferred embodiment of the present invention is as
follows:
##STR00035##
[0078] Another preferred embodiment of the present invention is as
follows:
##STR00036##
[0079] The invention also relates to a use of
(2R,3R)-3-(3-substituted phenyl)-2-methyl n-pentanamide compound as
shown in formula I, characterized in that, (2R,3R)-3-(3-substituted
phenyl)-2-methyl n-pentanamide compound as shown in formula I can
be used for preparing tapentadol or its pharmaceutically acceptable
salt according to the following method.
[0080] (1) The chiral auxiliary residue
##STR00037##
of the compounds as shown in formula I is removed to give compound
X; compound X is subjected to the amidation reaction with
dimethylamine or its salt under the activation of a carboxylic acid
activating agent to give compound XI; compound XI is subjected to
carbonyl reduction in a suitable reducing agent and a suitable
solvent to give compound XII, then the protection group of the
phenolic hydroxy group thereon is removed to give tapentadol II; if
necessary, the tapentadol may be dissolved in a solvent, and then a
suitable acid may be added therein to give a pharmaceutically
acceptable salt of tapentadol; or after the protection group of the
phenolic hydroxy group is removed, an appropriate acid is directly
added therein without separation to give a pharmaceutically
acceptable salt of tapentadol, as shown in Reaction Scheme 7:
##STR00038##
[0081] or:
[0082] (2) The chiral auxiliary residue
##STR00039##
of the compounds as shown in formula I is removed to give compound
X; compound X is subjected to the amidation reaction with
dimethylamine or its salt under the activation of a carboxylic acid
activating agent to give compound XI; the protection group of the
phenolic hydroxy group on compound XI is removed to give compound
XIII, compound XIII is reacted in a suitable reducing agent and a
suitable solvent to give tapentadol II; if necessary, the
tapentadol may be dissolved in a solvent, and then a suitable acid
is added to give a pharmaceutically acceptable salt of tapentadol;
or after the carbonyl group is reduced, an appropriate acid is
directly added therein without separation to give a
pharmaceutically acceptable salt of tapentadol, as shown in
Reaction Scheme 8:
##STR00040##
[0083] or:
[0084] (3) In case of
##STR00041##
the substituents R1 to R3 is the same as those defined in the
compounds of the formula I, the lactone in the chiral auxiliary
residue in the compounds of formula I is hydrolyzed to give
compound XIV, and carbonyl group on compound XIV IS reduced to give
compound XV, then the protection group on phenolic hydroxy group
and the substituents on the amino group are removed to give a
primary amine compound XVI, finally it is methylated to give
tapentadol; if necessary, the tapentadol may be dissolved in a
solvent, and then a suitable acid is added to give a
pharmaceutically acceptable salt of tapentadol; or after the
methylation reaction, an appropriate acid is directly added therein
without separation to give a pharmaceutically acceptable salt of
tapentadol, as shown in Reaction Scheme 9:
##STR00042##
or:
[0085] (4) In case of
##STR00043##
the lactone in the chiral auxiliary residue in the compounds of
formula I is hydrolyzed to give compound XVII, and carbonyl group
on compound XVII is reduced to give compound XVIII, then the
protection group on phenolic hydroxy group and the substituents on
the amino group are removed to give a primary amine compound XVI,
finally it is methylated to give tapentadol; if necessary, the
tapentadol may be dissolved in a solvent, and then a suitable acid
is added to give a pharmaceutically acceptable salt of tapentadol;
or after the methylation reaction, an appropriate acid is directly
added without separation to give a pharmaceutically acceptable salt
of tapentadol, as shown in Reaction Scheme 10:
##STR00044##
or:
[0086] (5) The compounds of formula I are reduced to give compound
XIX, the hydroxy of compound XIX is converted to a leaving group LV
to give compound XX, and compound XX is reacted with dimethylamine
or its salt to give compound XII, then the protection group of the
phenolic hydroxy group is removed to give tapentadol II; if
necessary, the tapentadol may be dissolved in a solvent, and then a
suitable acid is added to give a pharmaceutically acceptable salt
of tapentadol; or after removing the protection group of the
phenolic hydroxy group, an appropriate acid is directly added
therein without separation to give a pharmaceutically acceptable
salt of tapentadol, as shown in Reaction Scheme 11:
##STR00045##
[0087] Wherein, LV represents a leaving group such as halogen,
mesyl, phenylsulfonyl, substituted phenylsulfonyl (such as
p-tolylsulfonyl) and the like;
[0088] In the above method of preparing the tapentadol or its
pharmaceutically acceptable salt, the condition of removing the
chiral auxiliary residue may be in the presence of hydrogen
peroxide and an alkali metal hydroxide. Said alkali metal hydroxide
is any one of lithium hydroxide, sodium hydroxide and potassium
hydroxide. The condition of amidation reaction may be: compound X
is reacted with dimethylamine or its salt under the action of a
carboxylic acid activating agent to give compound XI. The used
carboxylic acid activating agent is any one of thionyl chloride,
oxalyl chloride, pivaloyl chloride, chloroformate, carbodiimides
such as dicyclohexyl carbodiimide (DCC), 4-dimethylaminopyridine
(DMAP) and carbonyldiimidazole (CDI); said reduction conditions may
be: the reducing agent is any one of lithium aluminum tetrahydride,
sodium borohydride/cobaltic chloride, boron trifluoride diethyl
ether and zinc chloride; the solvent is diethyl ether,
tetrahydrofuran, methanol and the like; said reaction of removing
the protection group of phenolic hydroxy group is conducted as the
conventional methods depending on the protection groups. For
example: when R is benzyl or substituted benzyl, it may be removed
in hydrochloric acid, the concentration range of the hydrochloric
acid is selected from 5% to 36%; or it may be removed in the
presence of palladium on carbon, formic acid and ammonium formate;
alternatively, it may be removed by hydrogenation in an organic
solvent in the presence of a metal catalyst, and the metal catalyst
may be palladium on carbon, Raney nickel or platinum dioxide; and
when R is methyl, it may be removed with hydrobromic acid or boron
tribromide. The hydrolysis of lactone is under the alkaline
condition, the base may be selected from an inorganic or organic
base, for example, the inorganic base may be lithium hydroxide,
potassium hydroxide, sodium hydroxide, etc.; the organic base may
be sodium methoxide, sodium ethoxide, etc.; substituents on the
amino group may be removed by hydrogenation in an organic solvent
and in the presence of a metal catalyst, the metal catalyst may be
palladium on carbon, Raney nickel or platinum dioxide; said
methylation reaction may be conducted in the presence of
formaldehyde and formic acid; the reaction conditions of converting
the hydroxy of the compound XIX to a leaving group is as the
conventional methods depending on the protection groups. For
example, when the LV is halogen, the reaction is conducted using
the corresponding halogenated reagent, such as thionyl chloride,
hydrobromic acid, etc.; when the LV is a sulfonyl group, the
reaction is conducted using the corresponding sulfonyl chloride
under alkaline conditions; the reaction of said compound XX with
dimethylamine or its salt is carried out under alkaline conditions.
The acid radical of said pharmaceutically acceptable salt of
tapentadol may be from inorganic or organic acid, it is
characterized in that, the inorganic acid is one of hydrochloric
acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid
and hydroiodic acid; the organic acid is one of formic acid, acetic
acid, propionic acid, butyric acid, malic acid, tartaric acid,
amino acid, methanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic
acid, taurine, fumaric acid, maleic acid, citric acid, succinic
acid, cholic acid and deoxycholic acid.
[0089] A preferred embodiment of the present invention is as
follows:
##STR00046##
[0090] Another preferred embodiment of the present invention is as
follows:
##STR00047##
[0091] Another preferred embodiment of the present invention is as
follows:
##STR00048##
[0092] Another preferred embodiments of the present invention is as
follows:
##STR00049##
[0093] Another preferred embodiment of the present invention is as
follows:
##STR00050##
[0094] Another preferred embodiments of the present invention is as
follows:
##STR00051##
[0095] Another preferred embodiment of the present invention is as
follows:
##STR00052##
[0096] The most preferred embodiment of the present invention is as
follows:
##STR00053##
[0097] Another most preferred embodiment of the present invention
is as follows:
##STR00054##
[0098] Another most preferred embodiment of the present invention
is as follows:
##STR00055##
[0099] Another most preferred embodiment of the present invention
is as follows:
##STR00056##
[0100] The present invention also provides the compounds of the
following formula III to XX:
##STR00057## ##STR00058##
[0101] wherein, R is the protecting group of the phenolic hydroxy,
R can form an ether group or an ester group with the phenolic
hydroxy; R may be selected from C1-C6 linear or branched alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, alkylsilyl, C1-C6 alkoxymethyl, C1-C6 alkyloyl,
substituted or unsubstituted aryloyl; wherein, said substituents
may be hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy etc.; said aryl
may be phenyl, naphthyl etc.;
[0102] LV represents a leaving group such as halogen, mesyl,
phenylsulfonyl, substituted phenylsulfonyl and the like;
##STR00059##
is the chiral auxiliary residue, which is defined as follows:
##STR00060##
[0103] wherein, X is O, S or NR.sub.7, wherein R.sub.7 is hydrogen,
C1-C6 branched or linear alkyl; Y is O or S;
[0104] R.sub.1 is C1-C6 alkyl group, substituted or unsubstituted
phenyl (Ph), substituted or unsubstituted naphthyl, substituted or
unsubstituted benzyl (Bn), C1-C6 alkoxycarbonyl, wherein, the
substituent on phenyl, naphthyl or benzyl group is 1 to 3
substituent(s) selected from C1-C6 alkyl and hydroxy;
[0105] R.sub.2 and R.sub.3 are each independently selected from H,
C1-C6 alkyl and phenyl;
##STR00061##
is chiral auxiliary residue, which is defined as follows:
##STR00062##
[0106] wherein, Z is O, S or NRs, wherein R.sub.1 is hydrogen,
C1-C6 branched or linear alkyl; W is O or S;
[0107] R.sub.4 is C1-C6 alkyl group, substituted or unsubstituted
phenyl (Ph), substituted or unsubstituted naphthyl, substituted or
unsubstituted benzyl (Bn), C1-C6 alkoxycarbonyl, wherein the
substituent on phenyl, naphthyl or benzyl group is 1 to 3
substituent(s) selected from hydroxy, halogen, C1-C6 alkyl and
C1-C6 alkoxy;
[0108] R.sub.5 and R.sub.6 are each independently selected from H;
C1-C6 alkyl; phenyl; phenyl substituted with 1 to 3 substituent(s)
selected from hydroxy, halogen, C1-C6 alkyl and C1-C6 alkoxy.
[0109] In the preferred compound of the present invention, R is
benzyl, methyl, t-butyl, triphenylmethyl, methoxymethyl,
trimethylsilyl, t-butyldimethylsilyl, acetyl or benzoyl; LV is
bromine, iodine, chlorine, mesyl, phenylsulfonyl, substituted
phenylsulfonyl and the like;
[0110] X is O; and Y is O;
[0111] R.sub.1 is C1-C6 alkyl group, substituted or unsubstituted
phenyl (Ph), substituted or unsubstituted benzyl (Bn), wherein the
substituent on phenyl or benzyl group is 1 to 3 substituent(s)
selected from hydroxy, halogen, C1-C6 alkyl and C1-C6 alkoxy;
[0112] R.sub.2 and R.sub.3 are each independently selected from H,
C1-C6 alkyl and phenyl;
[0113] W is O; Z is O;
[0114] R.sub.4 is C1-C6 alkyl group, substituted or unsubstituted
phenyl (Ph), substituted or unsubstituted benzyl (Bn), wherein the
substituent on phenyl or benzyl group is 1 to 3 substituent(s)
selected from hydroxy, halogen, C1-C6 alkyl and C1-C6 alkoxy;
[0115] R.sub.5 and R.sub.6 are each independently selected from H,
C1-C6 alkyl and phenyl.
[0116] In a further preferred compound of the present invention, R
is benzyl or methyl;
[0117] LV is bromine, iodine, chlorine, mesyl, p-tolylsulfonyl and
the like;
[0118] X is O; and Y is O;
[0119] R.sub.1 is phenyl; phenyl substituted with 1 to 3
substituent(s) selected from hydroxy, halogen, C1-C6 alkyl and
C1-C6 alkoxy; or benzyl;
[0120] R.sub.2 and R.sub.3 are each independently selected from H,
C1-C6 alkyl and phenyl;
[0121] W is O; Z is O;
[0122] R.sub.4 is phenyl; phenyl substituted with 1 to 3
substituent(s) selected from hydroxy, halogen, C1-C6 alkyl and
C1-C6 alkoxy; or benzyl;
[0123] R.sub.5 and R.sub.6 are each independently selected from H,
C1-C6 alkyl and phenyl.
[0124] More preferably, the compounds of the present invention are
as follows: [0125] (1)
3-[(3R)-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4R-phenyl-2-Oxazolidinon-
e
[0125] ##STR00063## [0126] (2)
3-[(3R)-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4R,5S-diphenyl-2-Oxazoli-
dinone
[0126] ##STR00064## [0127] (3)
3-[(3R)-3-(3-methoxyphenyl)-1-oxopentyl]-4R-phenyl-2-Oxazolidinone
[0127] ##STR00065## [0128] (4)
3-[(3R)-3-(3-methoxyphenyl)-1-oxopentyl]-4R,5S-diphenyl-2-Oxazolidinone
[0128] ##STR00066## [0129] (5)
3-[(3R)-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4S-phenyl-2-Oxazolidinon-
e
[0129] ##STR00067## [0130] (6)
3-[(3R)-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4S,5R-diphenyl-2-Oxazoli-
dinone
[0130] ##STR00068## [0131] (7)
(.beta.R)-ethyl-3-(phenylmethoxy)benzenepropanoic acid
[0131] ##STR00069## [0132] (8)
(.beta.R)-ethyl-3-methoxybenzenepropanoic acid
[0132] ##STR00070## [0133] (9)
(.alpha.R,.beta.R)-.beta.-ethyl-.alpha.-methyl-3-(phenylmethoxy)benzenepr-
opanoic acid
[0133] ##STR00071## [0134] (10)
(.alpha.R,.beta.R)-.beta.-ethyl-3-methoxy-.alpha.-methylbenzenepropanoic
acid
[0134] ##STR00072## [0135] (11)
(.alpha.R,.beta.R)-.beta.-ethyl-N,N,.alpha.-trimethyl-3-(phenylmethoxy)be-
nzenepropanamide
[0135] ##STR00073## [0136] (12)
(.alpha.R,.beta.R)-.beta.-ethyl-3-methoxy-N,N,.alpha.-trimethyl
benzenepropanamide
[0136] ##STR00074## [0137] (13)
(.alpha.R,.beta.R)-.beta.-ethyl-3-hydroxy-N,N,.alpha.-trimethylbenzenepro-
panamiide
[0137] ##STR00075## [0138] (14)
(.beta.R,.gamma.R)-.gamma.-ethyl-N,N,.beta.-trimethyl-3-(phenylmethoxy)be-
nzenepropanamnine
[0138] ##STR00076## [0139] (15)
3-[(1R,2R)-3-amino-1-ethyl-2-methylpropyl]phenol
[0139] ##STR00077## [0140] (16)
(.beta.R,.gamma.R)-.gamma.-ethyl-.beta.-methyl-3-(phenylmethoxy)benzenepr-
opanol
[0140] ##STR00078## [0141] (17)
(.beta.R,.gamma.R)-.gamma.-ethyl-3-methoxy-.beta.-methylbenzenepropanol
[0141] ##STR00079## [0142] (18)
(.beta.R,.gamma.R)-.gamma.-ethyl-.beta.-methyl-3-(phenylmethoxy)benzenepr-
opanol 1-methanesulfonate
[0142] ##STR00080## [0143] (19)
(.beta.R,.gamma.R)-.gamma.-ethyl-3-methoxy-.beta.-methylbenzenepropanol
1-methanesulfonate
[0143] ##STR00081## [0144] (20)
(.beta.R,.gamma.R)-.gamma.-ethyl-.beta.-methyl-3-(phenylmethoxy)benzenepr-
opanol 1-(4-methylbenzenesulfonate)
[0144] ##STR00082## [0145] (21)
1-[(1R,2R)-3-chloro-1-ethyl-2-methylpropyl]-3-(phenylmethoxy)benzene
[0145] ##STR00083## [0146] (22)
1-[(1R,2R)-3-bromo-1-ethyl-2-methylpropyl]-3-(phenylmethoxy)benzene
##STR00084##
[0147] According to present invention, the new chiral centers is
introduced via the stereoselective alkylation in a asymmetric
Michael addition reaction controlled by chiral auxiliaries, to form
a product which is easily purified by crystallization. The
resulting intermediate and the final product have a high optical
purity, and chiral auxiliaries have the characteristic of easy to
be removed, configuration retention, and easier to recycle and use.
The present method has the advantages of good reactivity, high
stereo selectivity, high yield, simple operatation, cheap and
easy-to-get reagents, recyclable chiral auxiliaries etc., and it
can be economically and conveniently used to realize industrial
production of tapentadol or the pharmaceutically acceptable salt
thereof.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0148] Now the present invention is further described with
reference to the following Examples, however, the Examples are not
intended for any limitation of the invention.
Example 1
(R,E)-3-(3-(3-benzyloxy)phenyl)acryloyl)-4-phenyl
oxazolidin-2-one
##STR00085##
[0150] m-benzyloxy cinnamic acid (9.0 g, 35.4 mmol) was dissolved
in thionyl chloride (25 ml) and refluxed for 1 hour, and the
mixture was concentrated to remove thionyl chloride for further
use. 4R-phenyl-2-oxazolidinone (5.6 g, 34.4 mmol) was placed in a
three-necked flask, after it was purged with nitrogen,
tetrahydrofuran (25 ml) was added and when it was cooled to
-78.degree. C., n-butyl lithium (1.6M, 22 ml, 35.4 mmol) was added
dropwise, and the reaction was carried out for 30 minutes. Then the
solution (35 ml) of m-benzyloxy cinnamoyl chloride in
tetrahydrofuran as prepared above was added dropwise and the
reaction was continued for 30 minutes. After that, it was slowly
raised to 0.degree. C., the reaction was continued for 2 hours,
then it was quenched with saturated ammonium chloride solution. The
resulted mixture was then concentrated to remove tetrahydrofuran
and extracted with ethyl acetate for three times, then the organic
phases were combined, washed with saturated brine, dried over
anhydrous sodium sulfate, concentrated and recrystallized with
petroleum ether and ethyl acetate to give a white solid 14 g,
yield: 93%. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.9 (1H, d,
J=15.5), 7.7 (1H, d, J=15.3), 7.3-7.5 (11H, m), 7.2 (2H, m), 7.0
(1H, dd, J=2.3, 8.6), 5.6 (1H, dd, J=4.0, 9.0), 5.1 (2H, s), 4.8
(1H, t, J=8.9, 17.7), 4.3 (1H, dd, J=3.9, 8.8). ESI-MS: 422.2
(M+Na).
Example 2
3-[(3R)-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4R-phenyl-2-Oxazolidinone
##STR00086##
[0152] Cuprous bromide dimethyl sulfide complex (7.7 g, 37.5 mmol)
was placed in a three-necked flask, after it was purged with
nitrogen, tetrahydrofuran (25 ml) was added therein. When it was
cooled to -40.degree. C., ethyl magnesium bromide (2.5M, 30 ml, 75
mmol) was added dropwise, the reaction was carried out with
stirring for 10 minutes, and the reaction solution became yellow;
boron trifluoride diethyl ether (4.8 ml, 37.5 mmol) was added
dropwise and the reaction was continued for 10 minutes; then the
solution of the product of Example 1 (10 g, 25 mmol) in
tetrahydrofuran was added dropwise, after the addition was
complete, it was warmed to -15.degree. C., and then gradually
warmed to room temperature, the reaction was continued for 2 hours
and quenched with saturated ammonium chloride solution, then the
resulted mixture was concentrated to remove tetrahydrofuran. The
reaction solution was diluted with ethyl acetate, filtered to
remove insoluble material and separated, then the aqueous phase was
extracted twice with ethyl acetate, the organic phases were
combined and washed with 1N ammonia twice, then washed with water
and saturated brine, dried over anhydrous sodium sulfate,
concentrated and recrystallized with petroleum ether and ethyl
acetate to obtain the target 9 g, yield: 85%, d.r.=99:1.
[0153] .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.3-7.5 (8H, m),
7.1-7.2 (3H, m), 6.7-6.9 (3H, m), 5.2 (1H, dd, J=3.7, 8.6), 5.1
(2H, s), 4.5 (1H, t, J=8.9, 17.1), 4.2 (1H, dd, J=3.5, 8.6), 3.5
(1H, dd, J=8.9, 16.4), 3.2 (1H, d, J=5.6), 3.1 (1H, m), 1.5-1.7
(2H, m), 0.9 (3H, t, J=7.3, 14.7). ESI-MS: 430.5 (M+H).
Example 3
3-[(2R,3R)[3-(phenylmethoxy)phenyl]pentyl]-4R-phenyl-2-Oxazolidinone
##STR00087##
[0155] The product of Example 2 (8.6 g, 20 mmol) was placed in a
double-necked flask, after it was purged with nitrogen, it was
cooled to -78.degree. C., then tetrahydrofuran (25 ml) was added.
The solution of sodium hexamethyldisilylamide (NaHMDS) in
tetrahydrofuran (2M, 10 ml, 20 mmol) was slowly added dropwise, and
the reaction was carried out at -78.degree. C. for 30 min; methyl
iodide (2.5 ml, 40 mmol) was added, and the reaction was continued
at -78.degree. C. for 30 min, then it was slowly warmed to
-50.degree. C., and the reaction was continued for 1 hour and
quenched with saturated ammonium chloride solution. Then the
resulted mixture was concentrated to remove tetrahydrofuran and
extracted with ethyl acetate for three times. The organic phases
were combined, washed with saturated brine, dried over anhydrous
sodium sulfate, concentrated and recrystallized with petroleum
ether and ethyl acetate to give a white solid 7.5 g, yield: 85%,
d.r.=99.9:0.1. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.2-7.5
(11H, m), 6.7-6.9 (3H, m), 5.1 (2H, s), 4.8 (1H, dd, J=3.5, 7.5),
4.2-4.3 (1H, m), 3.9-4.0 (2H, m), 2.6 (1H, dt, J=3.7, 10.3),
1.8-2.0 (1H, m), 1.4-1.6 (1H, m), 1.2 (3H, d, J=7.2), 0.9 (3H, t,
J=7.4, 14.7). ESI-MS: 444.4 (M+H).
Example 4
(.alpha.R,.beta.R)-.beta.-ethyl-.alpha.-methyl-3-(phenylmethoxy)benzenepro-
panoic acid
##STR00088##
[0157] The product of Example 3 (6.6 g, 15 mmol) was dissolved in
tetrahydrofuran/water (v/v=4/1), in an ice-water bath, hydrogen
peroxide (30%, 1.9 ml, 60 mmol) and lithium hydroxide (574 mg, 24
mmol) aqueous solution were added dropwise in sequence, then it was
slowly warmed to room temperature and the reaction was continued
for 4 hours. Sodium sulfite aqueous solution (2.5M, 24 ml) was
added dropwise to the reaction solution which was stirred for 10
minutes, concentrated to remove tetrahydrofuran, extracted with
dichloromethane for three times, washed with water and saturated
brine, dried over anhydrous sodium sulfate, concentrated and
recovered to give 4R-phenyl oxazolidin-2-one 2.3 g. The pH of the
aqueous phase was adjusted to appropreate 2 with 1N hydrochloric
acid, and extracted with dichloromethane for three times, then the
organic phases were combined, washed with saturated sodium
bicarbonate solution and saturated brine, dried over anhydrous
sodium sulfate, concentrated and recrystallized with petroleum
ether and ethyl acetate to give a white solid 3.8 g, yield: 91%.
.sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.3-7.5 (5H, m), 7.2 (1H,
t, J=7.6, 15.3), 6.7-6.9 (3H, m), 5.0 (2H, s), 2.8 (1H, m), 2.7
(1H, m), 1.7-1.8 (1H, m), 1.5-1.6 (1H, m), 1.1 (3H, d, 6.8), 0.9
(3H, t, J=7.3, 14.5). ESI-MS: 297.0 (M-H).
Example 5
(.alpha.R,.beta.R)-.beta.-ethyl-N,N,.alpha.-trimethyl-3-(phenylmethoxy)ben-
zenepropanamide
##STR00089##
[0159] The product of Example 4 (3 g, 10 mmol) was dissolved in
dichloromethane (10 ml), oxalyl chloride (2.6 ml, 30 mmol) was
added dropwise, and it was reacted at room temperature for 1 hr,
then the reaction solution was concentrated to give a pale yellow
oil which was further dissolved in dichloromethane. And then the
resulted solution was added dropwise to an ice-water bath cooled
solution of dimethylamine hydrochloride (1.6 g, 20 mmol) and
triethylamine (4.3 ml, 30 mmol) in dichloromethane, then the
mixture was slowly warmed to room temperature to react for 1 hour.
The pH thereof was adjusted to about 7 with 1N hydrochloric acid,
then it was extracted with dichloromethane. The organic phases were
combined, washed with saturated sodium bicarbonate solution and
saturated brine, dried over anhydrous sodium sulfate, concentrated
and recrystallized with petroleum ether and ethyl acetate to give a
white solid 3.1 g, yield: 95%. .sup.1HNMR (300 MHz, CDCl.sub.3):
.delta. 7.3-7.5 (5H, m), 7.2 (1H, m), 6.7-6.8 (3H, m), 5.0 (2H, s),
2.8-2.9 (1H, m), 2.7-2.8 (1H, m), 2.6 (3H, s), 2.5 (3H, s), 1.8-1.9
(1H, m), 1.4-1.6 (1H, m), 1.1 (3H, d, J=6.2), 0.8 (3H, t, J=6.8,
14.1). ESI-MS: 326.4 (M+H).
Example 6
(.beta.R,.gamma.R)-.gamma.-ethyl-N,N,.beta.-trimethyl-3-(phenylmethoxy)ben-
zenepropanamine
##STR00090##
[0161] Lithium aluminum tetrahydride (730 mg, 20 mmol) was
suspended in tetrahydrofuran (10 ml), then it was cooled in an
ice-water bath and the solution of product of Example 5 (3 g, 9.2
mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction
was carried out for 2 hours and quenched by adding 10% NaOH aqueous
solution, Then the reaction solution was extracted with ethyl
acetate for three times, and the organic phases were combined,
washed with saturated brine, dried over anhydrous sodium sulfate
and concentrated to give a pale yellow oil 2.7 g, yield: 93%.
.sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.3-7.5 (5H, m), 7.2 (1H,
t, J=7.6, 15.1), 6.8 (1H, d, J=8.5), 6.7 (2H, m), 5.0 (2H, s),
2.2-2.3 (2H, m), 2.2 (3H, s), 2.1 (3H, s), 1.8-1.9 (1H, m), 1.7-1.8
(1H, m), 1.5-1.6 (1H, m), 1.4-1.5 (1H, m), 1.0 (3H, d, J=6.2), 0.8
(3H, t, J=7.4, 14.7). ESI-MS: 312.3 (M+H).
Example 7
3-((1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl) phenol
hydrochloride
##STR00091##
[0163] The product of Example 6 (2.5 g, 8 mmol) was dissolved in
methanol, 5% Pd--C (250 mg) was added, and it was purged with
hydrogen for three times, then the reaction was carried out with
stirring at room temperature for 1 hr. The reaction solution was
filtered to remove Pd--C, the residue was washed with methanol for
3 times, then the organic phases are combined and concentrated to 2
ml. After that, the concentrated hydrochloric acid (670 ml, 8 mmol)
was added dropwise, then the resulted solution was concentrated and
recrystallized with isopropanol and ethyl acetate to give the
target 1.9 g, yield: 90%. [.alpha.].sub.D=+.sup.24.3.degree.
(c=1.10, CH.sub.3OH). .sup.1HNMR (300 MHz, CD.sub.3OD): .delta. 7.2
(1H, t, J=7.9, 15.6), 6.6-6.8 (3H, m), 2.8-2.9 (2H, m), 2.7-2.8
(6H, br s), 2.2-2.3 (1H, m), 2.1-2.2 (1H, m), 1.8-1.9 (1H, m),
1.5-1.6 (1H, m), 1.2 (3H, d, J=6.7), 0.8 (3H, t, J=7.4, 14.4).
ESI-MS: 222.4 (M+H).
Example 8
(4R,5S)-3-(((E)-3-(3-(benzyloxy)phenyl)acryloyl)-4,5-diphenyl
oxazolidin-2-one
##STR00092##
[0165] The (4R,5S)-diphenyl oxazolidin-2-one (4.8 g, 20 mmol) was
put in a double-necked flask, after purged with nitrogen,
tetrahydrofuran was added and it was cooled to -78.degree. C., then
n-butyl lithium (2.5M, 8 ml, 20 mmol) was added dropwise, and the
reaction was carried out for 30 minutes. After that, a solution of
m-benzyloxy cinnamoyl chloride (6.0 g, 22 mmol) in tetrahydrofuran
was added dropwise, the reaction was continued for 30 minutes, then
it was slowly raised to 0.degree. C., the reaction was continued
for 2 hours, then quenched with saturated ammonium chloride
solution. The reaction solution was concentrated to remove
tetrahydrofuran and washed with ethyl acetate 3 times, then the
organic phases were combined, washed with saturated sodium
bicarbonate aqueous solution twice and saturated brine once, dried
over anhydrous sodium sulfate, concentrated and recrystallized with
petroleum ether and ethyl acetate to give a white solid 8.6 g,
yield: 90%. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 8.0 (1H, d,
J=15.5), 7.8 (1H, d, J=15.6), 7.3-7.5 (6H, m), 7.2-7.3 (2H, m),
7.1-7.2 (6H, m), 7.0-7.1 (3H, m), 6.9-7.0 (2H, m), 6.0 (1H, d,
J=7.4), 5.8 (1H, d, J=7.3), 5.1 (2H, s). ESI-MS: 476.4 (M+H).
Example 9
3-[(3R)-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4R,5S-diphenyl-2-Oxazolid-
inone
##STR00093##
[0167] Cuprous bromide dimethyl sulfide complex (5.5 g, 26.8 mmol)
was placed in a three-necked flask, after purged with nitrogen,
tetrahydrofuran was added and it was cooled to -40.degree. C., then
ethyl magnesium bromide (2.5M, 21.5 ml) was added dropwise, the
reaction was carried out with stirring for 10 minutes. After that,
the boron trifluoride diethyl ether (3.4 ml, 26.8 mmol) was added
dropwise, and the reaction was continued for 10 minutes; then the
solution of the product of Example 8 (8.0 g, 17.9 mmol) in
tetrahydrofuran was added dropwise, after the addition was
complete, it was warmed to -15.degree. C., and then gradually
warmed to room temperature. The reaction was continued for 2 hours
and quenched with saturated ammonium chloride solution. The
reaction solution was then concentrated to remove tetrahydrofuran,
then the resultant was diluted with ethyl acetate, filtered to
remove insoluble material and extracted with ethyl acetate twice,
then the organic phases were combined, washed with 1N ammonia
twice, then washed with water and saturated brine, dried over
anhydrous sodium sulfate, concentrated and recrystallized with
petroleum ether and ethyl acetate to obtain a white solid 7.6 g,
yield: 84%, d.r.=99:1. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta.
7.3-7.5 (5H, m), 7.2 (1H, t, J=7.9, 15.7), 7.0-7.1 (6H, m), 6.9-7.0
(3H, m), 6.8-6.9 (4H, m), 5.7 (1H, d, J=8.1), 5.5 (1H, d, J=8.2),
5.0 (2H, s), 3.6 (1H, dd, J=7.4, 14.9), 3.2 (1H, dd, J=9.6, 16.9),
3.0-3.1 (1H, m), 1.6-1.8 (2H, m), 0.8 (3H, t, J=7.3, 14.6). ESI-MS:
506.4 (M+H).
Example 10
3-[(2R,3R)-2-methyl-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4R,5S-dipheny-
l-2-Oxazolidinone
##STR00094##
[0169] The product of Example 9 (7.5 g, 14.9 mmol) was placed in a
double-necked flask, after it was purged with nitrogen and cooled
to -78.degree. C., tetrahydrofuran was added, and the solution of
sodium hexamethyldisilylamide (NaHMDS) in tetrahydrofuran (2M, 7.5
ml, 15 mmol) was slowly added dropwise, and the reaction was kept
at -78.degree. C. for 30 min; after methyl iodide (1.9 ml, 30 mmol)
was added, the reaction was continued at -78.degree. C. for 30 min,
then it was slowly warmed to -20.degree. C., and the reaction was
continued for 2 hour, then quenched with saturated ammonium
chloride solution, and then the mixture was concentrated to remove
tetrahydrofuran and extracted with ethyl acetate for three times,
the organic phases were combined, washed with saturated brine,
dried over anhydrous sodium sulfate, concentrated, and
recrystallized with petroleum ether and ethyl acetate to give a
white solid 7.0 g, yield: 90%, d.r.=99.9:0.1. .sup.1HNMR (300 MHz,
CDCl.sub.3): .delta. 7.4-7.5 (2H, m), 7.2-7.4 (4H, m), 7.0-7.1 (6H,
m), 6.8-6.9 (3H, m), 6.8 (2H, m), 6.7 (2H, m), 5.2 (1H, d, J=8.2),
5.1 (2H, s), 5.0 (1H, d, J=7.8), 4.2-4.3 (1H, m), 2.6-2.7 (1H, dt,
J=3.1, 13.0), 1.9-2.0 (1H, m), 1.5-1.7 (1H, m), 1.3 (3H, d, J=6.6),
0.8 (3H, t, J=7.5, 14.8). ESI-MS: 542.2 (M+Na).
Example 11
(R,E)-3-(3-(3-methoxy)phenyl)acryloyl)-4-phenyl
oxazolidin-2-one
##STR00095##
[0171] The 4R-phenyl-2-oxazolidinone (5.6 g, 34.4 mmol) was placed
in a three-necked flask, after it was purged with nitrogen,
tetrahydrofuran was added and it was cooled to -78.degree. C., then
n-butyl lithium (1.6M, 22 ml, 35.4 mmol) was added dropwise, and
the reaction was carried out for 30 minutes. After a solution of
m-methoxy cinnamoyl chloride (10.3 g, 37.8 mmol) in tetrahydrofuran
was added dropwise, the reaction was continued for 30 minutes, then
it was slowly raised to 0*C, the reaction was continued for 2 hours
and quenched with saturated ammonium chloride solution. The mixture
was concentrated to remove tetrahydrofuran and extracted with ethyl
acetate 3 times, then the organic phases were combined, washed with
saturated brine, dried over anhydrous sodium sulfate, concentrated,
and recrystallized with petroleum ether and ethyl acetate to give a
white solid 10.3 g, yield: 92%. .sup.1HNMR (300 MHz, CDCl.sub.3):
.delta. 8.0 (1H, d, J=15.3), 7.8 (1H, d, J=15.7), 7.2-7.4 (6H, m),
7.1-7.2 (2H, m), 7.0 (1H, d, J=8.6), 5.6 (1H, dd, J=4.0, 9.0), 4.8
(1H, t, J=8.8, 17.5), 4.3 (1H, dd, J=4.0, 8.8), 3.8 (3H, s).
ESI-MS: 346.3 (M+Na).
Example 12
3-[(3R)-3-(3-methoxyphenyl)-1-oxopentyl]-4R-phenyl-2-Oxazolidinone
##STR00096##
[0173] Cuprous bromide dimethyl sulfide complex (7.7 g, 37.5 mmol)
was placed in a three-necked flask, and it was purged with
nitrogen, then tetrahydrofuran was added and it was cooled to
-40.degree. C. After ethyl magnesium bromide (2.5M, 30 ml, 75 mmol)
was added dropwise, the reaction was carried out with stirring for
10 minutes, and the reaction solution turned yellow; the boron
trifluoride diethyl ether (4.8 ml, 37.5 mmol) was added dropwise,
and the reaction was continued for 10 minutes; the solution of the
product of Example 11 (8 g, 25 mmol) in tetrahydrofuran was added
dropwise, after the addition was complete, it was warmed to
-15.degree. C., and then gradually warmed to room temperature,
after the reaction was continued for 2 hours, it was quenched with
saturated ammonium chloride solution, and the reaction solution was
concentrated to remove tetrahydrofuran, then diluted with ethyl
acetate, filtered to remove insoluble material and separated, after
the aqueous phase was extracted twice with ethyl acetate, the
organic phases were combined, washed with 1N ammonia twice, washed
with water and saturated brine, dried over anhydrous sodium
sulfate, concentrated, and recrystallized with petroleum ether and
ethyl acetate to obtain the target 7.4 g, yield: 84%, d.r.=99:1.
.sup.1HNMR (300 MHz, CDCl.sub.3): .delta.7.2-7.4 (6H, m), 7.1-7.2
(2H, m), 7.0 (1H, d, J=8.6), 5.3 (1H, dd, J=4.0, 9.0), 4.5 (1H, t,
J=8.8, 17.5), 4.2 (1H, dd, J=4.0, 8.8), 3.8 (3H, s), 3.5 (1H, dd,
J=8.9, 16.3), 3.2 (1H, d, J=5.6), 3.1 (1H, m), 1.6-1.7 (2H, m), 0.9
(3H, t, J=7.3, 14.7). ESI-MS: 354.5 (M+H).
Example 13
3-[(2R,3R)-3-(3-methoxyphenyl)-2-methyl-1-oxopentyl]-4R-phenyl-2-Oxazolidi-
none
##STR00097##
[0175] The product of Example 12 (7.1 g, 20 mmol) was placed in a
double-necked flask, after it was purged with nitrogen and cooled
to -78.degree. C., tetrahydrofuran was added, and the solution of
sodium hexamethyldisilylamide (NaHMDS) in tetrahydrofuran (2M, 10
ml, 20 mmol) was slowly added dropwise, and the reaction was kept
at -78.degree. C. for 30 min; methyl iodide (2.5 ml, 40 mmol) was
added, and the reaction was continued at -78.degree. C. for 30 min,
then it was slowly warmed to -50.degree. C., and the reaction was
continued for 1 hour, then quenched with saturated ammonium
chloride solution. After the reaction solution was concentrated to
remove tetrahydrofuran and extracted with ethyl acetate for three
times, the organic phases were combined, washed with saturated
brine, dried over anhydrous sodium sulfate concentrated, and
recrystallized with petroleum ether and ethyl acetate to give a
white solid 5.9 g, yield: 81%, d.r.=99.9:0.1. .sup.1HNMR (300 MHz,
CDCl.sub.3): .delta. 7.2-7.4 (6H, m), 7.1-7.2 (2H, m), 7.0 (1H, d,
J=8.4), 4.9 (1H, dd, J=3.5, 7.6), 4.2-4.3 (1H, m), 3.9-4.0 (2H, m),
3.8 (3H, s), 2.7 (1H, dt, J=3.7, 10.4), 1.8-1.9 (1H, m), 1.4-1.6
(1H, m), 1.2 (3H, d, J=7.2), 0.8 (3H, t, J=7.5, 14.7). ESI-MS:
368.4 (M+H).
Example 14
(.alpha.R,.beta.R)-.beta.-ethyl-3-methoxy-.alpha.-methylbenzenepropanoic
acid
##STR00098##
[0177] The product of Example 13 (5.5 g, 15 mmol) was dissolved in
tetrahydrofuran/water (v/v=4/1), when it was cooled in an ice bath,
30% hydrogen peroxide (1.9 ml, 60 mmol) and lithium hydroxide (574
mg, 24 mmol) aqueous solution was added dropwise in sequence, then
it was slowly warmed to room temperature and the reaction was
continued for 4 hours. Sodium sulfite aqueous solution (2.5M, 24
ml) was added dropwise to the reaction liquid, which was stirred
for 10 minutes and concentrated to remove tetrahydrofuran, then
extracted with dichloromethane for three times, washed with water
and saturated brine, dried over anhydrous sodium sulfate,
concentrated, and recovered to give 4R-phenyl oxazolidin-2-one 2.3
g. The pH of the aqueous phase was adjusted to appropreate 2 with
1N hydrochloric acid, then extracted with dichloromethane for three
times, and then the organic phases were combined, washed with
saturated sodium bicarbonate solution and saturated brine, dried
over anhydrous sodium sulfate concentrated, and recrystallized with
petroleum ether and ethyl acetate to give a white solid 3.0 g,
yield: 90%. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.2 (1H, t,
J=7.9, 15.6), 6.6-6.8 (3H, m), 3.7 (3H, s), 2.7 (1H, m), 2.6 (1H,
m), 1.7-1.8 (1H, m), 1.5-1.6 (1H, m), 1.1 (3H, d, 6.7), 0.8 (3H, t,
J=7.4, 14.7). ESI-MS: 221.0 (M-H).
Example 15
(.alpha.R,.beta.R)-.beta.-ethyl-3-methoxy-N,N,.alpha.-trimethylbenzeneprop-
anamide
##STR00099##
[0179] The product of Example 14 (2.2 g, 10 mmol) was dissolved in
dichloromethane (10 ml), oxalyl chloride (2.6 ml, 30 mmol) was
added dropwise, and the reaction was carried out at room
temperature for 1 hr, then the reaction solution was concentrated
to give a pale yellow oil which was thereafter dissolved in
dichloromethane, and then the resulted solution was added dropwise
to an ice bath cooled solution of dimethylamine hydrochloride (1.6
g, 20 mmol) and triethylamine (4.3 ml, 30 mmol) in dichloromethane.
Then it was slowly warmed to room temperature to make the reaction
carry out for 1 hour. The pH was adjusted to about 7 with 1N
hydrochloric acid, then the reaction solution was extracted with
dichloromethane, and the organic phases were combined, washed with
saturated sodium bicarbonate solution and saturated brine, dried
over anhydrous sodium sulfate concentrated, and recrystallized with
petroleum ether and ethyl acetate to give a white solid 2.3 g,
yield: 92%. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.2 (1H, t,
J=7.9, 15.6), 6.6-6.8 (3H, m), 3.7 (3H, s), 2.8-2.9 (1H, m),
2.7-2.8 (1H, m), 2.6 (3H, s), 2.5 (3H, s), 1.7-1.8 (1H, m), 1.4-1.6
(1H, m), 1.1 (3H, d, J=6.2), 0.8 (3H, t, J=6.8, 14.3). ESI-MS:
250.4 (M+H).
Example 16
(.beta.R,.gamma.R)-.gamma.-ethyl-N,N,.beta.-trimethyl-3-methoxybenzeneprop-
anamine
##STR00100##
[0181] Lithium aluminum tetrahydride (730 mg, 20 mmol) was
suspended in tetrahydrofuran (10 ml), after the mixture was cooled
in an ice-water bath, the solution of product of Example 15 (2.2 g,
9.0 mmol) in tetrahydrofuran (10 ml) was added dropwise, then the
reaction was carried out for 2 hours, and quenched by adding 10%
NaOH aqueous solution, after the reaction solution was extracted
with ethyl acetate for three times, the organic phases were
combined, washed with saturated brine, dried over anhydrous sodium
sulfate and concentrated to give a pale yellow oil 1.9 g, yield:
90%. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.2 (1H, t, J=7.9,
15.6), 6.6-6.8 (3H, m), 3.7 (3H, s), 2.2-2.3 (2H, m), 2.2 (3H, s),
2.1 (3H, s), 1.8-1.9 (1H, m), 1.7-1.8 (1H, m), 1.5-1.6 (1H, m),
1.4-1.5 (1H, m), 1.0 (3H, d, J=6.3), 0.8 (3H, t, J=7.4, 14.5).
ESI-MS: 236.3 (M+H).
Example 17
3-((1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl)-phenol
hydrochloride
##STR00101##
[0183] The product of Example 16 (1.9 g, 8 mmol) was dissolved in
dichloromethane, the mixture was cooled in an ice-water bath, and a
solution of boron tribromide (1.9 ml, 20 mmol) in dichloromethane
was slowly added dropwise, then it was gradually raised to room
temperature to make it react for 15 hrs. After it was cooled in an
ice-water bath, methanol was slowly added dropwise to quench the
reaction, and the organic phase was washed with water and saturated
brine, dried over anhydrous sodium sulfate, and concentrated to 2
mL, then the concentrated hydrochloric acid (670M1, 8 mmol) was
added dropwise, and the mixture was concentrated and recrystallized
with isopropanol and ethyl acetate to obtain the target 1.8 g,
yield: 90%. [.alpha.].sub.D=+24.3.degree. (c=1.10,CH.sub.3OH).
.sup.1HNMR (300 MHz, CD.sub.3OD): .delta. 7.2 (1H, t, J=7.9, 15.6),
6.6-6.8 (3H, m), 2.8-2.9 (2H, m), 2.7-2.8 (6H, br s), 2.2-2.3 (1H,
m), 2.1-2.2 (1H, m), 1.8-1.9 (1H, m), 1.5-1.6 (1H, m), 1.2 (3H, d,
J-=6.7), 0.8 (3H, t, J=7.4, 14.4). ESI-MS: 222.4 (M+H).
Example 18
(4R,5S)-3-(((E)-3-(3-(methoxy)phenyl)acryloyl)-4,5-diphenyl
oxazolidin-2-one
##STR00102##
[0185] The (4R,5S)-diphenyl oxazolidin-2-one (4.8 g, 20 mmol) was
placed in a double-necked flask, after it was purged with nitrogen,
tetrahydrofuran was added and the mixture was cooled to -78.degree.
C., then n-butyl lithium (2.5M, 8 ml, 20 mmol) was added dropwise,
and the reaction was carried out for 30 minutes. Then a solution of
m-methoxy cinnamoyl chloride (4.3 g, 22 mmol) in tetrahydrofuran
was added dropwise, the reaction was continued for 30 minutes, then
it was slowly raised to 0.degree. C., and the reaction was
continued for 2 hours, then quenched with saturated ammonium
chloride solution. After that, the reaction solution was
concentrated to remove tetrahydrofuran and washed with ethyl
acetate 3 times, then the organic phases were combined, washed with
saturated sodium bicarbonate aqueous solution twice and saturated
brine once, dried over anhydrous sodium sulfate concentrated, and
recrystallized with petroleum ether and ethyl acetate to give a
white solid 7.3 g, yield: 92%. .sup.1HNMR (300 MHz, CDCl.sub.3):
.delta. 8.0 (1H, d, J=15.8), 7.8 (1H, d, J=15.8), 7.3-7.4 (1H, m),
7.2-7.3 (1H, m), 7.1-7.2 (7H, m), 6.8-7.0 (5H, m), 6.0 (1H, d,
J=7.6), 5.8 (1H, d, J=7.7), 3.8 (3H, s). ESI-MS: 400.4 (M+H).
Example 19
3-[(3R)-3-(3-methoxyphenyl)-1-oxopentyl]-4R,5S-diphenyl-2-Oxazolidinone
##STR00103##
[0187] Cuprous bromide dimethyl sulfide complex (5.5 g, 26.8 mmol)
was placed in a three-necked flask, after it was purged with
nitrogen, tetrahydrofuran was added and the mixture was cooled to
-40.degree. C., then ethyl magnesium bromide (2.5M, 21.5 ml) was
added dropwise, and the reaction was carried out with stirring for
10 minutes. After the boron trifluoride diethyl ether (3.4 ml, 26.8
mmol) was added dropwise, the reaction was continued for 10
minutes. The solution of the product of Example 18 (7.1 g, 17.9
mmol) in tetrahydrofuran was added dropwise, after the addition was
complete, it was warmed to -15.degree. C., and then gradually
warmed to room temperature, then the reaction was continued for 2
hours and quenched with saturated ammonium chloride solution. The
reaction solution was concentrated to remove tetrahydrofuran, then
diluted with ethyl acetate and filtered to remove insoluble
material. The filtration was then extracted with ethyl acetate
twice, and the organic phases were combined, washed with 1N ammonia
twice, then washed with water and saturated brine, dried over
anhydrous sodium sulfate, concentrated and recrystallized with
petroleum ether and ethyl acetate to obtain a white solid 6.2 g,
yield: 81%, d.r.=99:1. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta.
7.2 (1H, m), 7.0-7.2 (6H, m), 6.9-7.0 (2H, m), 6.8-6.9 (5H, m), 5.7
(1H, d, J=8.1), 5.5 (1H, d, J=7.8), 3.8 (3H, s), 3.6 (1H, dd,
J=9.2, 16.4), 3.2 (1H, dd, J=5.5, 16.8), 3.0-3.1 (1H, m), 1.6-1.8
(2H, m), 0.8 (3H, t, J=7.4, 14.9). ESI-MS: 430.4 (M+H).
Example 20
3-[(2R,3R)-3-(3-methoxyphenyl)-2-methyl-1-oxopentyl]-4R,5S-diphenyl-2-Oxaz-
olidinone
##STR00104##
[0189] The product of Example 19 (6.2 g, 14.5 mmol) was placed in a
double-necked flask, and it was purged with nitrogen and cooled to
-78.degree. C., then tetrahydrofuran was added, and the solution of
sodium hexamethyldisilylamide in tetrahydrofuran (2M, 7.5 ml, 15
mmol) was slowly added dropwise, and then the reaction was kept at
-78.degree. C. for 30 min; after that, methyl iodide (1.9 ml, 30
mmol) was added, and the reaction was continued at -78.degree. C.
for 30 min, then it was slowly warmed to -20.degree. C., and the
reaction was continued for 2 hour, and then quenched with saturated
ammonium chloride solution. The reaction solution was then
concentrated to remove tetrahydrofuran and extracted with ethyl
acetate for three times, then the organic phases were combined,
washed with saturated brine, dried over anhydrous sodium sulfate,
concentrated, and recrystallized with petroleum ether and ethyl
acetate to give a white solid 5.7 g, yield: 89%, d.r.=99.9:0.1.
.sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.2 (1H, m), 7.0-7.2 (6H,
m), 6.9-7.0 (2H, m), 6.8-6.9 (5H, m), 5.5 (1H, d, J=8.1), 5.3 (1H,
d, J=7.8), 4.0-4. (1H, m), 3.8 (3H, s), 2.6-2.7 (1H, dt, J=3.1,
13.0), 1.9-2.0 (1H, m), 1.5-1.7 (1H, m), 1.3 (3H, d, J=6.6), 0.8
(3H, t, J=7.5, 14.8). ESI-MS: 444.5 (M+H).
Example 21
(S,E)-3-(pent-2-enoyl)-4-phenyl oxazolidin-2-one
##STR00105##
[0191] The 4S-phenyl-2-oxazolidinone (5.6 g, 34.4 mmol) was placed
in a three-necked flask, after it was purged with nitrogen,
tetrahydrofuran was added and it was cooled to -78.degree. C., then
n-butyl lithium (1.6M, 22 ml, 35.4 mmol) was added dropwise, and
the reaction was carried out for 30 minutes. After that, a solution
of 2-pentenoyl chloride (4.2 g, 35.5 mmol) in tetrahydrofuran was
added dropwise, and the reaction was continued for 30 minutes, then
it was slowly raised to 0.degree. C., the reaction was continued
for 2 hours and quenched with saturated ammonium chloride solution.
The reaction solution was then concentrated to remove
tetrahydrofuran and extracted with ethyl acetate 3 times, then the
organic phases were combined, washed with saturated brine, dried
over anhydrous sodium sulfate, concentrated, and recrystallized
with petroleum ether and ethyl acetate to give a white solid 8 g,
yield: 95%. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.3-7.4 (5H,
m), 7.1-7.2 (1H, m), 6.9-7.1 (1H, m), 5.5 (1H, dd, J=4.2, 19.0),
4.8 (1H, t, J=9.6, 18.7), 4.2 (1H, dd, J=3.7, 18.9), 2.2 (2H, m),
1.0 (3H, t, J=7.4, 14.9). ESI-MS: 246.4 (M+H).
Example 22
3-[(3R)-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4S-phenyl-2-Oxazolidinone
##STR00106##
[0193] Cuprous bromide dimethyl sulfide complex (10.0 g, 48.9 mmol)
was placed in a three-necked flask, after it was purged with
nitrogen, tetrahydrofuran was added and it was cooled to
-40.degree. C., then 3-benzyloxy phenyl magnesium bromide (2.5M, 39
ml, 97.8 mmol) was added dropwise, the reaction was carried out
with stirring for 10 minutes, and the reaction solution turned
yellow; after that, the boron trifluoride diethyl ether (6.2 ml,
48.9 mmol) was added dropwise and the reaction was continued for 10
minutes; then the solution of the product of Example 21 (8 g, 32.6
mmol) in tetrahydrofuran was added dropwise, after the addition was
complete, it was warmed to -15.degree. C., and then gradually
warmed to room temperature. After that, the reaction was continued
for 2 hours, then quenched with saturated ammonium chloride
solution. The reaction solution was concentrated to remove
tetrahydrofuran, diluted with ethyl acetate, filtered to remove
insoluble material, and separated, then the aqueous phase was
extracted twice with ethyl acetate, and the organic phases were
combined, washed with 1N ammonia twice, then washed with water and
saturated brine, dried over anhydrous sodium sulfate, concentrated,
and recrystallized with petroleum ether and ethyl acetate to obtain
the target 12 g, yield: 86%, d.r.=99:1. .sup.1HNMR (300 MHz,
CDCl.sub.3): .delta. 7.3-7.5 (8H, m), 7.1-7.2 (3H, m), 6.7-6.9 (3H,
m), 5.1 (1H, dd, J=3.7, 8.6), 5.0 (2H, s), 4.6 (1H, t, J=8.9,
17.1), 4.1 (1H, dd, J=3.5, 8.6), 3.6 (1H, dd, J=8.9, 16.3), 3.2
(1H, d, J=5.6), 3.1 (1H, m), 1.5-1.7 (2H, m), 0.8 (3H, t, J=7.3,
14.9). ESI-MS: 430.5 (M+H).
Example 23
(.beta.R)-ethyl-3-(phenylmethoxy)benzenepropanoic acid
##STR00107##
[0195] The product of Example 22 (11 g, 25.6 mmol) was dissolved in
tetrahydrofuran/water (v/v=4/1) in an ice-water bath, 30% hydrogen
peroxide (3.2 ml, 100 mmol) and lithium hydroxide (1.0 g, 43.5
mmol) aqueous solution were added dropwise in sequence, then it was
slowly warmed to room temperature and the reaction was continued
for 4 hours. After that, sodium sulfite aqueous solution (2.5M, 40
ml) was added dropwise to the reaction liquid, the reaction was
carried out with stirring for 10 minutes, the reaction solution was
concentrated to remove tetrahydrofuran, then extracted with
dichloromethane for 3 times, washed with water and saturated brine,
dried over anhydrous sodium sulfate, concentrated, and recovered to
give 4S-phenyl oxazolidin-2-one 3.9 g. The pH of the aqueous phase
was adjusted to appropreate 2 with 1N hydrochloric acid, then
extracted with dichloromethane for three times, after that, the
organic phases were combined, washed with saturated sodium
bicarbonate solution and saturated brine, dried over anhydrous
sodium sulfate, concentrated, and recrystallized with petroleum
ether and ethyl acetate to give a white solid 6.7 g, yield: 92%.
.sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.3-7.5 (5H, m), 7.2 (1H,
t, J=7.6, 15.2), 6.8-6.9 (3H, m), 5.0 (2H, s), 3.0 (1H, m), 2.6-2.7
(2H, m), 1.7-1.8 (1H, m), 1.6-1.7 (1H, m), 0.8 (3H, t, J=7.3,
14.7). ESI-MS: 283.1 (M-H).
Example 24
3-[(3R)-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4R-phenyl-2-Oxazolidinone
##STR00108##
[0197] The 4R-phenyl-2-oxazolidinone (3.5 g, 21.4 mmol) was placed
in a three-necked flask, after it was purged with nitrogen,
tetrahydrofuran was added and it was cooled to -78.degree. C., then
n-butyl lithium (1.6M, 13.8 ml, 22 mmol) was added dropwise, and
the reaction was carried out for 30 minutes. After that, a solution
of (R)-3-(3-(benzyloxy)phenyl) pentanoyl chloride (7.1 g, 23.6
mmol) in tetrahydrofuran was added dropwise, the reaction was
continued for 30 minutes, then it was slowly raised to 0.degree.
C., the reaction was continued for 2 hours, and then quenched with
saturated ammonium chloride solution. The reaction solution was
then concentrated to remove tetrahydrofuran and extracted with
ethyl acetate 3 times, then the organic phases were combined,
washed with saturated brine, dried over anhydrous sodium sulfate,
concentrated, and recrystallized with petroleum ether and ethyl
acetate to give a white solid 8.6 g, yield: 85%.
.sup.1HNMR(CDCl.sub.3): .delta. 7.3-7.5 (8H, m), 7.1-7.2 (3H, m),
6.7-6.9 (3H, m), 5.2 (1H, dd, J=3.7, 8.6), 5.1 (2H, s), 4.5 (1H, t,
J=8.9, 17.1), 4.2 (1H, dd, J=3.5, 8.6), 3.5 (1H, dd, J=8.9, 16.4),
3.2 (1H, d, J=5.6), 3.1 (1H, m), 1.5-1.7 (2H, m), 0.9 (3H, t,
J=7.3, 14.7). ESI-MS: 430.5 (M+H).
Example 25
3-[(2R,3R)[3-(phenylmethoxy)phenyl]pentyl]-4R-phenyl-2-Oxazolidinone
##STR00109##
[0199] The product of Example 24 (8.6 g, 20 mmol) was placed in a
double-necked flask, and it was purged with nitrogen and cooled to
-78.degree. C., then tetrahydrofuran was added, and the solution of
sodium hexamethyldisilylamide (NaHMDS) in tetrahydrofuran (2M, 10
ml, 20 mmol) was slowly added dropwise, and the reaction was kept
at -78.degree. C. for 30 min; after that, methyl iodide (2.5 ml, 40
mmol) was added, and the reaction was continued at -78.degree. C.
for 30 min, then it was slowly warmed to -50.degree. C., and the
reaction was continued for 1 hour, and then quenched with saturated
ammonium chloride solution. The reaction solution was then
concentrated to remove tetrahydrofuran and extracted with ethyl
acetate for three times, then the organic phases were combined,
washed with saturated brine, dried over anhydrous sodium sulfate,
concentrated, and recrystallized with petroleum ether and ethyl
acetate to give a white solid 7.5 g, yield: 85%, d.r.=99.9:0.1.
.sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.2-7.5 (11H, m), 6.7-6.9
(3H, m), 5.1 (2H, s), 4.8 (1H, dd, J=3.5, 7.5), 4.2-4.3 (1H, m),
3.9-4.0 (2H, m), 2.6 (1H, dt, J=3.7, 10.3), 1.8-2.0 (1H, m),
1.4-1.6 (1H, m), 1.2 (3H, d, J=7.2), 0.9 (3H, t, J=7.4, 14.7).
ESI-MS: 444.4 (M+H).
Example 26
(.alpha.R,.beta.R)-3-ethyl-3-hydroxy-N,N,.alpha.-trimethylbenzenepropanami-
de
##STR00110##
[0201] The product of Example 5 (3.0 g, 9 mmol) was dissolved in
methanol, 5% Pd--C (300 mg) was added therein, after it was purged
with hydrogen for three times, the reaction was carried out with
stirring at room temperature for 1 hr. Then the reaction solution
was filtered to remove Pd--C, the residue was washed with methanol
for 3 times, and the organic phases are combined and concentrated
to give the target 2.0 g, yield: 95%. .sup.1HNMR (300 MHz,
CDCl.sub.3): .delta. 7.2 (1H, m), 6.7-6.8 (3H, m), 2.8-2.9 (1H, m),
2.7-2.8 (1H, m), 2.6 (3H, s), 2.5 (3H, s), 1.8-1.9 (1H, m), 1.4-1.6
(1H, m), 1.1 (3H, d, J-=6.2), 0.8 (3H, t, J-=6.8, 14.1). ESI-MS:
236.4 (M+H).
Example 27
3-((1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl)-phenol
hydrochloride
##STR00111##
[0203] Lithium aluminum tetrahydride (730 mg, 20 mmol) was
suspended in tetrahydrofuran (10 ml), and it was cooled in an
ice-water bath, then the solution of product of Example 26 (2 g,
8.5 mmol) in tetrahydrofuran (10 ml) was added dropwise, the
reaction was carried out for 2 hours and then quenched by adding
10% NaOH aqueous solution. The reaction solution was then extracted
with ethyl acetate for three times, and the organic phases were
combined, washed with saturated brine, dried over anhydrous sodium
sulfate and concentrated to 2 mL, then the concentrated
hydrochloric acid (710 .mu.l, 8.5 mmol) was added dropwise therein,
and the resulted solution was concentrated and recrystallized with
isopropanol-ethyl acetate to obtain the target 1.97 g, yield: 90%.
[.alpha.].sub.D=+24.3.degree. (c=1.10, CH.sub.3OH). .sup.1HNMR (300
MHz, CD.sub.3OD): .delta. 7.2 (1H, t, J=7.9, 15.6), 6.6-6.8 (3H,
m), 2.8-2.9 (2H, m), 2.7-2.8 (6H, br s), 2.2-2.3 (1H, m), 2.1-2.2
(1H, m), 1.8-1.9 (1H, m), 1.5-1.6 (1H, m), 1.2 (3H, d, J=6.7), 0.8
(3H, t, J=7.4, 14.4). ESI-MS: 222.4 (M+H).
Example 28
(2R,3R)-3-(3-(benzyloxy)phenyl-N--((R)-2-hydroxy-1-phenylethyl)-2-methyl
pentanamide
##STR00112##
[0205] The product of Example 3 (6.6 g, 15 mmol) was dissolved in
tetrahydrofuran/water (v/v=4/1), and it was cooled in an ice-water
bath, then the lithium hydroxide (574 mg, 24 mmol) aqueous solution
was added dropwise, the mixture was slowly warmed to room
temperature, and the reaction was continued for 6 hours. After
that, the reaction solution was concentrated to remove
tetrahydrofuran, extracted with dichloromethane 3 times, washed
with water and saturated brine, dried over anhydrous sodium
sulfate, concentrated, and then separated through silica gel column
chromatography to obtain target 5.0 g, yield: 80%. .sup.1HNMR (300
MHz, CDCl.sub.3): .delta. 7.2-7.5 (11H, m), 6.8-6.9 (3H, m), 5.6
(1H, d, J=6.9), 5.1 (2H, s), 4.8 (1H, m), 3.4 (1H, dd, J=5.4,
11.4), 3.3 (1H, dd, J=3.7, 11.5), 2.7 (1H, dt, J=3.5, 11.0),
1.8-2.0 (1H, m), 1.4-1.5 (1H, m), 1.2 (3H, d, J=6.5), 0.7 (3H, t,
J=7.3, 14.6). ESI-MS: 418.3 (M+H).
Example 29
(R)-2-((2R,3R)-3-(3-(benzyloxy)phenyl)-2-methyl
pentylamine)-2-phenylethanol
##STR00113##
[0207] The product of Example 28 (5.0 g, 12 mmol) was dissolved in
tetrahydrofuran, lithium aluminum tetrahydride (2.3 g, 60 mmol) was
added, and the reaction was conducted under reflux for 8 hours,
then it was cooled in ice-water bath, and water was added dropwise
to quench the reaction. After that, 10% sodium hydroxide aqueous
solution was added therein, the reaction solution was filtered, and
the filtrate was extracted with ethyl acetate three times, then the
organic phases were combined, washed with saturated brine, dried
over anhydrous sodium sulfate, concentrated, and then separated
through silica gel column chromatography to give the target 4.3 g,
yield: 90%. .sup.1HNMR (300 MHz, CD.sub.3Cl): .delta. 7.3-7.5 (8H,
m), 7.1-7.2 (3H, m), 6.8 (1H, m), 6.6 (2H, m), 5.0 (2H, s), 3.6-3.8
(3H, m), 2.4 (1H, dd, J=3.8, 12.0), 2.3 (1H, d, J=8.1), 2.2 (1H,
m), 1.9-2.0 (1H, m), 1.7-1.8 (1H, m), 1.4-1.5 (1H, m), 1.1 (3H, d,
J=6.9), 0.8 (3H, t, J=7.4, 14.5). ESI-MS: 404.4 (M+H).
Example 30
3-[(1R,2R)methylpropyl]phenol
##STR00114##
[0209] The product of Example 29 (4.0 g, 10 mmol) was dissolved in
methanol, 10% Pd--C (400 mg) was added therein, after it was purged
with hydrogen three times, the reaction was carried out with
stirring at room temperature for 12 hours. Then the reaction
solution was filtered, the residue was washed with methanol three
times, and the filtrate was concentrated to give the target 1.74 g,
yield: 90%. .sup.1HNMR (300 MHz, CD.sub.3OD): .delta. 7.2 (H, t,
J=7.9, 15.6), 6.6-6.8 (3H, m), 2.8-2.9 (2H, m), 2.2-2.3 (1H, m),
2.1-2.2 (1H, m), 1.8-1.9 (1H, m), 1.5-1.6 (1H, m), 1.2 (3H, d,
J=6.7), 0.8 (3H, t, J=7.4, 14.4). ESI-MS: 194.4 (M+H).
Example 31
3-((1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl)-phenol
hydrochloride
##STR00115##
[0211] The product of Example 30 (1.7 g, 9 mmol) was dissolved in a
formaldehyde aqueous solution, 98% formic acid (1.6 ml, 45 mmol)
was added thereto, and the reaction was conducted at 80.degree. C.
for 2 hours, then the reaction solution was poured into ice-water,
after that, the pH was adjusted to 8 with 10% sodium hydroxide
solution, and the solution was extracted with dichloromethane three
times, then the organic phases were combined, washed with water and
saturated brine, dried over anhydrous sodium sulfate and
concentrated to obtain an oil. The oil was dissolved in methanol,
the mixture was cooled in an ice-water bath, 12N hydrochloric acid
(0.7 ml, 8.4 mmol) was added and it was stirred for 10 minutes,
then the ethyl acetate was added to recrystallize to obtain the
target 1.4 g, yield: 60%. [.alpha.]o=+24.3.degree. (c=1.10,
CH.sub.3OH). .sup.1HNMR (300 MHz, CD.sub.3OD): .delta. 7.2 (1H, t,
J=7.9, 15.6), 6.6-6.8 (3H, m), 2.8-2.9 (2H, m), 2.7-2.8 (6H, brs),
2.2-2.3 (1H, m), 2.1-2.2 (1H, m), 1.8-1.9 (1H, m), 1.5-1.6 (1H, m),
1.2 (3H, d, J=6.7), 0.8 (3H, t, J=7.4, 14.4). ESI-MS: 222.4
(M+H).
Example 32
(.beta.R,.gamma.R)-.gamma.-ethyl-.beta.-methyl-3-(phenylmethoxy)benzenepro-
panol
##STR00116##
[0213] The product of Example 3 (4.5 g, 10 mmol) was dissolved in
tetrahydrofuran, lithium aluminum tetrahydride (760 mg, 20 mmol)
was added, and the mixture was stirred at room temperature for 3
hours, then water was added to quench the reaction. After that, 10%
sodium hydroxide solution was added, the resulted solution was
filtered, and the filtrate was extracted with ethyl acetate three
times, then the organic phases were combined, washed with saturated
brine, dried over anhydrous sodium sulfate, concentrated, and then
separated through silica gel column chromatography to give the
target 2.6 g, yield: 90%. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta.
7.3-7.5 (5H, m), 7.2 (1H, t, J=7.6, 15.3), 6.7-6.9 (3H, m), 5.0
(2H, s), 3.3-3.5 (2H, m), 2.8 (1H, m), 2.7 (1H, m), 1.7-1.8 (1H,
m), 1.5-1.6 (1H, m), 1.1 (3H, d, 6.8), 0.9 (3H, t, J=7.3, 14.5).
ESI-MS: 285.2 (M-H).
Example 33
(.beta.R,.gamma.R)-.gamma.-ethyl-3-methyl-3-(phenylmethoxy)benzenepropanol-
, 1-methanesulfonate
##STR00117##
[0215] The product of Example 32 (2.6 g, 9 mmol) was dissolved in
dichloromethane, triethylamine (1.9 ml, 13.5 mmol) was added
therein, then it was cooled in ice-water bath, and methanesulfonyl
chloride (0.77 ml, 10 mmol) was slowly added dropwise, after the
addition was complete, the reaction was continued for 1 hour, and
then quenched by adding water. The reaction solution was separated,
the aqueous phase was extracted with dichloromethane three times,
and the organic phases were combined, washed with saturated brine,
dried over anhydrous sodium sulfate, and concentrated to give the
target compound 3.0 g, yield: 91%.
[0216] .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.3-7.5 (5H, m),
7.2 (1H, t, J=7.6, 15.3), 6.7-6.9 (3H, m), 5.0 (2H, s), 3.4 (1H,
m), 3.5 (1H, m), 3.1 (3H, s), 2.8 (1H, m), 2.7 (1H, m), 1.7-1.8
(1H, m), 1.5-1.6 (1H, m), 1.1 (3H, d, 6.8), 0.9 (3H, t, J=7.3,
14.5). ESI-MS: 363.5 (M-H).
Example 34
(.beta.R,.gamma.R)-.gamma.-ethyl-N,N,.beta.-trimethyl-3-(phenylmethoxy)ben-
zenepropanamine
##STR00118##
[0218] The product of Example 33 (2.9 g, 8 mmol) was dissolved in
dichloromethane, triethylamine (4.6 ml, 2 mmol) and dimethylamine
hydrochloride (1.3 g, 16 mmol) were added therein, the reaction was
conducted at room temperature for 8 hours, and the water was add to
separate the liquid, then the aqueous phase was extracted with
dichloromethane twice, and the organic phases were combined, washed
with saturated brine, dried over anhydrous sodium sulfate,
concentrated, and then separated through silica gel column
chromatography to give target 2.2 g, yield: 90%. .sup.1HNMR (300
MHz, CDCl.sub.3): .delta. 7.3-7.5 (5H, m), 7.2 (1H, t, J=7.6,
15.1), 6.8 (1H, d, J=8.5), 6.7 (2H, m), 5.0 (2H, s), 2.2-2.3 (2H,
m), 2.2 (3H, s), 2.1 (3H, s), 1.8-1.9 (1H, m), 1.7-1.8 (1H, m),
1.5-1.6 (1H, m), 1.4-1.5 (1H, m), 1.0 (3H, d, J=6.2), 0.8 (3H, t,
J=7.4, 14.7). ESI-MS: 312.3 (M+H).
Example 35
(R,E)-3-(3-(3-benzyloxy)phenyl)acryloyl)-4-phenyl
oxazolidin-2-one
##STR00119##
[0220] The m-benzyloxy cinnamic acid (90 g, 354 mmol) was dissolved
in dichloromethane (25 ml), oxalyl chloride (45 ml) was added
therein and it was reacted at room temperature for 5 hours, then
the reaction solution was concentrated to remove the solvent and
oxalyl chloride for further use; 4(R)-phenyl-2-oxazolidinone (57 g,
350 mmol) was dissolved in dichloromethane, the mixture was cooled
to 0.degree. C., and 4-dimethylamino pyridine (4.3 g, 35 mmol) and
triethylamine (76 mL, 525 mmol) was added, then the solution of
m-benzyloxy cinnamic acid in dichloromethane was added. After that,
the reaction was continued for 8 hours and quenched with saturated
ammonium chloride solution, then the reaction solution was
separated, the dichloromethane layer was washed with water and
saturated brine, dried over anhydrous sodium sulfate, concentrated
and recrystallized with petroleum ether and ethyl acetate to give a
white solid 144 g, yield: 95%. The HNMR spectrum data is the same
as that in Example 1.
Example 36
3-[(3R)-1-oxo-3-[3-(phenylmethoxy)phenyl]pentyl]-4R-phenyl-2-Oxazolidinone
##STR00120##
[0222] Cuprous bromide (7 g, 48.9 mmol) was placed in a
three-necked flask, after it was purged with nitrogen,
tetrahydrofuran was added and it was cooled to -20.degree. C., the
solution of ethyl magnesium bromide in tetrahydrofuran (2.5M, 39
ml, 97.8 mmol) was added dropwise, the reaction was carried out
with stirring for 10 minutes, and the reaction solution turned
yellow; after that, boron trifluoride diethyl etherate (6.2 ml,
48.9 mmol) was added dropwise, and the reaction was continued for
10 minutes; then the solution of the product of Example 35 (13 g,
32.6 mmol) in tetrahydrofuran was added dropwise, after the
addition was complete, the temperature was raised to -5.degree. C.,
then the reaction was continued for 2 hours and quenched with
saturated ammonium chloride solution. Then the reaction solution
was concentrated to remove tetrahydrofuran, diluted with ethyl
acetate, filtered to remove insoluble material and separated, the
aqueous phase was re-extracted with ethyl acetate twice, the
organic phases were combined, washed with 1N ammonia twice, washed
with water and saturated brine, dried over anhydrous sodium
sulfate, concentrated and recrystallized with petroleum ether and
ethyl acetate to give the target 12 g, yield: 85%, d.r.=98:1. The
HNMR spectrum data is the same as that in Example 2.
Example 37
3-[(2R,3R)[3-(phenylmethoxy)phenyl]pentyl]-4R-phenyl-2-Oxazolidinone
##STR00121##
[0224] The product of Example 36 (8.58 g, 20 mmol) was placed in a
double-necked flask, then it was purged with nitrogen and cooled to
-20.degree. C., after that, tetrahydrofuran was added, the solution
of sodium hexamethyldisilylamide (NaHMDS) in tetrahydrofuran (2M,
10 ml, 20 mmol) was slowly added dropwise, and the reaction was
kept at -20.degree. C. for 30 min; and then the solution of
bromomethane in tetrahydrofuran (2.5M, 16 mL, 40 mmol) was added,
the reaction was continued at -20.degree. C. for 30 min, after it
was slowly warmed to 0.degree. C., the reaction was continued for 1
hour and quenched with saturated ammonium chloride solution. The
reaction solution was concentrated to remove tetrahydrofuran and
extracted with ethyl acetate for three times, then the organic
phases were combined, washed with saturated brine, dried over
anhydrous sodium sulfate, concentrated and recrystallized with
petroleum ether and ethyl acetate to give a white solid 7.5 g,
Yield: 85%, d.r.=99.9:0.1. The HNMR spectrum data is the same as
that in Example 3.
Example 38
(.beta.R,.gamma.R)-.gamma.-ethyl-N,N,.beta.-trimethyl-3-(phenylmethoxy)ben-
zenepropanamine
##STR00122##
[0226] Lithium aluminum tetrahydride (730 mg, 20 mmol) was
suspended in tetrahydrofuran (10 ml), the product of Example 5 (3.2
g, 10 mmol) was dissolved in toluene, cooled in an ice-water bath,
the solution of red aluminum in toluene (9 mL, 30 mmol) was added
dropwise, the reaction was carried out for 2 hours and then
quenched by adding 10% NaOH aqueous solution. After the reaction
solution was separated, the organic phase was washed with saturated
brine, dried over anhydrous sodium sulfate, and concentrated to
give a pale yellow oil 2.8 g, yield: 90%. The HNMR spectrum data is
the same as that in Example 6.
Example 39
3-((1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl)-phenol
hydrochloride
##STR00123##
[0228] 20 mL of water and 20 mL of concentrated hydrochloric acid
were added to the product of Example 38 (2.5 g, 8 mmol), then it
was reacted at 80.degree. C. for 17 hours, after that, the reaction
solution was concentrated and recrystallized with isopropanol and
isopropyl ether to give the target 1.9 g, yield: 90%. The HNMR
spectrum data is the same as that in Example 7.
Example 40
(.beta.R,.gamma.R)-.gamma.-ethyl-.beta.-methyl-.beta.-(phenylmethoxy)benze-
nepropanol, 1-(4-methylbenzenesulfonate)
##STR00124##
[0230] The product of Example 32 (2.6 g, 9 mmol) was dissolved in
dichloromethane, triethylamine (1.9 ml, 13.5 mmol) was added
therein, and the mixture was cooled in an ice-water bath, then
p-toluenesulfonyl chloride (1.9 g, 10 mmol) was slowly added
dropwise, after the addition was complete, the reaction was
continued for 1 hour and then quenched by adding water. After the
reaction solution was separated, the aqueous phase was extracted
with dichloromethane three times, and the organic phases were
combined, washed with saturated brine, dried over anhydrous sodium
sulfate, and concentrated to give the target compound 3.0 g, yield:
91%. .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.7 (4H, m), 7.5-7.4
(5H, m), 7.4-7.3 (4H, m), 7.2 (1H, t, J=7.6, 15.3), 6.7-6.9 (3H,
m), 5.0 (2H, s), 3.4 (1H, m), 3.5 (1H, m), 3.1 (3H, s), 2.8 (1H:
m), 2.7 (1H, m), 1.7-1.8 (1H, m), 1.5-1.6 (1H, m), 1.1 (3H, d,
6.8), 0.9 (3H, t, J=7.3, 14.5). ESI-MS: 337.5 (M-H).
Example 41
(.beta.R,.gamma.R)-.gamma.-ethyl-N,N,.beta.-trimethyl-3-(phenylmethoxy)ben-
zenepropanamine
##STR00125##
[0232] The product of Example 40 (3.7 g, 8 mmol) was dissolved in
dichloromethane, triethylamine (4.6 ml, 20 mmol) and dimethylamine
hydrochloride (1.3 g, 16 mmol) were added therein, and it was
reacted at room temperature for 8 hours, then water was added for
separating, the aqueous phase was extracted twice with
dichloromethane, and the organic phases were combined, washed with
saturated brine, dried over anhydrous sodium sulfate, concentrated,
and seperated through silica gel column chromatography to give
target 2.2 g, yield: 90%.
Example 42
1-[(1R,2R)-3-chloro-1-ethyl-2-methylpropyl]-3-(phenylmethoxy)benzene
##STR00126##
[0234] The product of Example 32 (2.6 g, 9 mmol) was dissolved in
dichloromethane, the mixture was cooled in an ice-water bath, then
N, N-dimethylformamide (2 drops) was added and thionyl chloride
(0.64 mL, 10 mmol) was added dropwise, after the addition was
complete, the reaction was conducted under reflux for 6 hours and
quenched by adding water. After the reaction solution was
separated, the aqueous phase was extracted with dichloromethane
three times, and the organic phases were combined, washed with
saturated brine, dried over anhydrous sodium sulfate, and
concentrated to give the target compound 2.4 g, yield: 90%.
.sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.3-7.5 (5H, m), 7.2 (1H,
t, J=7.6, 15.3), 6.7-6.9 (3H, m), 5.0 (2H, s), 3.4 (1H, m), 3.3
(1H, m), 2.8 (1H, m), 2.7 (1H, m), 1.7-1.8 (1H, m), 1.5-1.6 (1H,
m), 1.1 (3H, d, 6.8), 0.9 (3H, t, J=7.3, 14.5). ESI-MS: 301.2
(M-H).
Example 43
(.beta.R,.gamma.R)-.gamma.-ethyl-N,N,.beta.-trimethyl-3-(phenylmethoxy)ben-
zenepropanamine
##STR00127##
[0236] The product of Example 42 (2.4 g, 8 mmol) was dissolved in
N,N-dimethylformamide, potassium carbonate (2.7 g, 20 mmol) and
dimethylamine hydrochloride (0.7 g, 8 mmol) were added therein,
then it was reacted at room temperature for 12 hours. After that,
the reaction solution was poured into water, the aqueous phase was
extracted with dichloromethane twice, then the organic phases were
combined, washed with saturated brine, dried over anhydrous sodium
sulfate, concentrated, and separated through silica gel column
chromatography to give target 2.2 g, yield: 90%.
Example 44
1-[(1R,2R)-3-bromo-1-ethyl-2-methylpropyl]-3-(phenylmethoxy)benzene
##STR00128##
[0238] The product of Example 32 (2.6 g, 9 mmol) was dissolved in
dichloromethane, and the mixture was cooled in an ice-water bath,
then 48% hydrobromic acid (0.54 mL, 10 mmol) was added dropwise,
after the addition was complete, it was reacted at room temperature
for 16 hours. After that, water was added therein for separating,
the aqueous phase was extracted with dichloromethane three times,
then the organic phases were combined, washed with saturated brine,
dried over anhydrous sodium sulfate, and concentrated to give the
target compound 2.7 g, yield: 87%. .sup.1HNMR (300 MHz,
CDCl.sub.3): .delta. 7.3-7.5 (5H, m), 7.2 (1H, t, J=7.6, 15.3),
6.7-6.9 (3H, m), 5.0 (2H, s), 3.4 (1H, m), 3.2 (1H, m), 2.8 (1H,
m), 2.7 (1H, m), 1.7-1.8 (1H, m), 1.5-1.6 (1H, m), 1.1 (3H, d,
6.8), 0.9 (3H, t, J=7.3, 14.5). ESI-MS: 346.2 (M-H).
Example 45
(.beta.R,.gamma.R)-.gamma.-ethyl-N,N,.beta.-trimethyl-3-(phenylmethoxy)ben-
zenepropanamine
##STR00129##
[0240] The product of Example 44 (2.7 g, 8 mmol) was dissolved in
N,N-dimethylformamide, potassium carbonate (2.7 g, 20 mmol) and
dimethylamine hydrochloride (0.7 g, 8 mmol) were added therein, and
it was reacted at room temperature for 12 hours. After the reaction
solution was poured into water, the aqueous phase was extracted
with dichloromethane twice, then the organic phases were combined,
washed with saturated brine, dried over anhydrous sodium sulfate,
concentrated, and separated through silica gel column
chromatography to give target 2.1 g, yield: 89%.
* * * * *