WO1989010350A1 - Preparation of an epoxide - Google Patents
Preparation of an epoxide Download PDFInfo
- Publication number
- WO1989010350A1 WO1989010350A1 PCT/AU1989/000176 AU8900176W WO8910350A1 WO 1989010350 A1 WO1989010350 A1 WO 1989010350A1 AU 8900176 W AU8900176 W AU 8900176W WO 8910350 A1 WO8910350 A1 WO 8910350A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- formula
- compound
- alkyl
- alkoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/39—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing halogen atoms bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
Definitions
- the present invention relates to an epoxide useful in stereoselective preparation of benzothiazepine type pharmaceuticals, to methods for preparation of such epoxides and to sulphinate ester intermediate to the epoxide.
- Ar is selected from the groups consisting of aryl heteroaryl, substituted aryl, and substituted heteroaryl and R is a carboxylic acid group or ester or a group capable of being converted to a carboxylic acid group or ester; are useful intermediates for preparation of biologically active compounds in which the stereochemistry of the final compound is controlled entirely or in part by the configuration of the chiral carbons (marked *).
- Diltiazem a benzothiazepine derivative which is well known as a vasodilator is one of four possible optical isomers.
- Diltiazem isomer of commercial interest as a vasodilator.
- the desired (2S,3S) isomer can be obtained in at most a 25% yield, and hence workers in the area have concentrated on stereoselective synthetic routes which require the intermediates such as the epoxide of formula I, to have a high optical purity.
- the compound of formula I may be prepared with high stereoselectivity via formation of a sulphonate ester intermediate.
- Ar is selected from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl, and R is a carboxylic acid group or ester or a group capable of being converted to a carboxylic acid group or ester; the process comprising reacting a diol of formula III with a sulfonating agent of formula IV to form a compound of formula V and eliminating the sulfonyloxy group from the compound of formula V to form the epoxide of formula I
- L is a leaving group such as halogen and preferably chlorine or bromine.
- the group X which may be different when there is more than one X, is preferably selected from the group consisting of C 1 to C 6 alkyl and halogen, and preferably n is an integer from 1 to 5 and preferably 1 to 3.
- the group Ar is preferably selected from the group of formula VI
- A is independently selected from the group consisting of halogen, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylthio, and more preferably C 1 to C 4 alkyl and C 1 to C 4 alkoxy, and m is an integer of from 0 to 3 inclusive and preferably m is 0 or 1.
- Ar is p-(C 1 to C 6 alkoxy)phenyl, for example p-methoxyphenyl;
- R is selected from the group
- G is chosen from the group consisting of: hydrogen, hydroxy, mercapto, C 1 to C 10 alkoxy, C 1 to C 10 haloalkoxy, C 2 to C 10 alkenyloxy, C 3 to C 10 alkynyloxy, C 3 to C 10 alkynylthio, C 3 to C 7 cycloalkoxy, C 3 to C 7 cycloalkoxy substituted with one or two C 1 to C 4 alkyl groups, phenoxy, phenylthio, benzyloxy, benzylthio, the group C 1 to
- C 6 alkoxy substituted with a substituent chosen from the group consisting of C 1 to C 6 alkoxy, amino, ammonic, cyano, N-(C 1 to C 6 alkyl)amino and N,N,N-tri(C 1 to C 6 alkyl)ammonio, the groups phenoxy, phenylthio, benzyloxy and benzylthio wherein in each group the phenyl ring is substituted with front 1 to 3 substituents chosen from the group consisting of halogen, nitro, cyano, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl and C 1 to C 6 alkoxy, the group - NHSO 2 R 6 wherein R 6 is chosen from C 1 to C 10 alkyl and C 1 to C 6 haloalkyl, the group -NR 7 R 8 wherein R 7 and R 8 are independently chosen from the group consisting of hydrogen, C 1 to C 6 alkyl, phenyl and benzyl or R
- Preferred R is cyano, the group wherein
- G is selected from hydrogen, hydroxy, C 1 to C 6 alkyl, C 1 to C 6 alkoxy and the group CH 2 Z wherein Z is hydroxy, chloro or C 1 to C 6 alkoxy.
- R are the group where G is hydroxy or C 1 to C 6 alkoxy (e.g. methoxy).
- G is hydroxy or C 1 to C 6 alkoxy (e.g. methoxy).
- the sulfonation stage is carried out at a temperature in the range -10 to 40oC.
- the sulfonyloxy group elimination from the compound V is carried out at a temperature of from -10 to 60oC.
- the composition of the diol of formula III is enriched in a one enantiomer and typically will comprise a high proportion, for example at least 80% (more preferably at least 90% w/w), of one enantiomer.
- the epoxide product will comprise at least 80% (preferably at least 90%) of one isomer.
- the invention further provides a composition comprising an epoxide of formula I wherein at least 80% (and preferably at least 90%) of said epoxide is in the form of one isomer.
- the diol of formula I is enriched in the 2S, 3R enantiomer.
- the enantiomerically enriched diol may be prepared by a variety of methods including classical resolution techniques however, as described in our copending International Patent Application No.PCT/AU88/00345 it is advantageous in most cases to prepare the diol in an enantioselective manner from the alkene of formula VII
- composition of the compound of formula V will comprise at least 80% w/w and preferably at least
- An enantiomerically enriched composition of the epoxide of formula I may be used in enantioselective preparation of the key intermediate to benzothiazepine compounds which intermediate has the formula VIII
- Y is oxygen or sulfur and G is chosen from nitro, C 1 to C 6 alkyl, amino, C 1 to C 6 alkylamino, N,N-di(C 1 to C 6 alkyl)amino, and N-(C 1 to C 6 alkyl)amino-substituted (C 1 to C 6 alkylamino such as 2-diethylaminoethylamino.
- the compound of formula VIII may be prepared by reaction of the epoxide of formula I with a phenol/thiophenol of formula IX preferably in the presence of a base. Generally the reaction is carried out in non-aqueous solution with a mild base such as sodium bicarbonate which is conveniently present in catalytic amounts.
- a mild base such as sodium bicarbonate which is conveniently present in catalytic amounts.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Accordingly we provide a stereoselective process for preparation of an epoxide of formula (I), wherein Ar is selected from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl, and R is a carboxylic acid group or ester or a group capable of being converted to a carboxylic acid group or ester; the process comprising reacting a diol of formula (III) with a sulfonating agent of formula (IV) to from a compound of formula (V) and eliminating the sulfonyloxy group form the compound of formula (V) to form the epoxide of formula (I), wherein in the compound of formula (IV), L is a leaving group and in the compounds of formula (IV and V), the group X, which may be different when there is more than one X, is selected from the group consisting of C1 to C6 alkyl and halogen, and n is an integer from 1 to 5.
Description
PREPARATION OF AN EPOXIDE
The present invention relates to an epoxide useful in stereoselective preparation of benzothiazepine type pharmaceuticals, to methods for preparation of such epoxides and to sulphinate ester intermediate to the epoxide.
Compounds of formula I
Ar is selected from the groups consisting of aryl heteroaryl, substituted aryl, and substituted heteroaryl and R is a carboxylic acid group or ester or a group capable of being converted to a carboxylic acid group or ester; are useful intermediates for preparation of biologically active compounds in which the stereochemistry of the final compound is controlled entirely or in part by the configuration of the chiral carbons (marked *). For example, Diltiazem, a benzothiazepine derivative which is well known as a vasodilator is one of four possible optical isomers. There is a wide variation in biological activity between Diltiazem and its three related optical isomers, Diltiazem being the isomer of commercial interest as a vasodilator. In a nonstereospecific synthesis of Diltiazem, the desired (2S,3S) isomer can be obtained in at most a 25% yield, and hence workers in the area have concentrated on stereoselective synthetic routes which require the intermediates such as the epoxide of formula I, to have a high optical purity.
We have now found that the compound of formula I may be prepared with high stereoselectivity via formation of a sulphonate ester intermediate.
Accordingly we provide a stereoselective process for preparation of an epoxide of formula I
Ar is selected from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl, and R is a carboxylic acid group or ester or a group capable of being converted to a carboxylic acid group or ester; the process comprising reacting a diol of formula III with a sulfonating agent of formula IV to form a compound of formula V and eliminating the sulfonyloxy group from the compound of formula V to form the epoxide of formula I
In the compound of formula IV L is a leaving group such as halogen and preferably chlorine or bromine. In the compounds of formula IV and V, the group X, which may be different when there is more than one X, is preferably selected from the group consisting of C1 to C6 alkyl and halogen, and preferably n is an integer from 1 to 5 and preferably 1 to 3.
In the compounds of formula I, III and V the group Ar is preferably selected from the group of formula VI
wherein A is independently selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, and more preferably C1 to C4 alkyl and C1 to C4 alkoxy, and m is an integer of from 0 to 3 inclusive and preferably m is 0 or 1.
Most preferred Ar is p-(C1 to C6 alkoxy)phenyl, for example p-methoxyphenyl;
Preferably R is selected from the group
consisting of cyano, thiocarbomoyl,
and CH2Z, wherein: G is chosen from the group consisting of: hydrogen, hydroxy, mercapto, C1 to C10 alkoxy, C1 to C10 haloalkoxy, C2 to C10 alkenyloxy, C3 to C10 alkynyloxy, C3 to C10 alkynylthio, C3 to C7 cycloalkoxy, C3 to C7 cycloalkoxy substituted with one or two C1 to C4 alkyl groups, phenoxy, phenylthio, benzyloxy, benzylthio, the group C1 to
C6 alkoxy substituted with a substituent chosen from the group consisting of C1 to C6 alkoxy, amino, ammonic, cyano, N-(C1 to C6 alkyl)amino and N,N,N-tri(C1 to C6 alkyl)ammonio, the groups phenoxy, phenylthio, benzyloxy and benzylthio wherein in each group the phenyl ring is substituted with front 1 to 3 substituents chosen from the group consisting of halogen, nitro, cyano, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy, the group -
NHSO2R6 wherein R6 is chosen from C1 to C10 alkyl and C1 to C6 haloalkyl, the group -NR 7R8 wherein R7 and R8 are independently chosen from the group consisting of hydrogen, C1 to C6 alkyl, phenyl and benzyl or R 7 and R8 together form a heterocyclic ring, and the group -O-N=R 9 wherein R9 is a C1 to C10 alkylidene group; Z is chosen from the group consisting of halogen, hydroxy, mercapto, C1 to C10 alkoxy, C1 to C10 haloalkoxy, C1 to C10 alkylthio and the group -NR7R8 wherein R7 and R8 are as hereinbefore defined.
Preferred R is cyano, the group
wherein
G is selected from hydrogen, hydroxy, C1 to C6 alkyl, C1 to C6 alkoxy and the group CH2Z wherein Z is hydroxy, chloro or C1 to C6 alkoxy.
Particularly preferred R are the group
where G is hydroxy or C1 to C6 alkoxy (e.g. methoxy). Specific examples of compounds of formula
I which may be prepared according to the present invention include the following:
Accordingly the invention further provides a composition comprising an epoxide of formula I wherein at least 80% (and preferably at least 90%) of said epoxide is in the form of one isomer.
For preparation of Diltiazem it is preferred to proceed via the cis-epoxide and to prepare the cis-epoxide it is preferred that the diol of formula I is enriched in the 2S, 3R enantiomer.
The enantiomerically enriched diol may be prepared by a variety of methods including classical resolution techniques however, as described in our copending International Patent Application No.PCT/AU88/00345 it is advantageous in most cases to prepare the diol in an enantioselective manner from the alkene of formula VII
Ar CH = CHR VII
In a further embodiment we provide a compound of formula V as hereinbefore defined. Preferably the composition of the compound of formula V will comprise at least 80% w/w and preferably at least
90% w/w of one enantiomer.
An enantiomerically enriched composition of the epoxide of formula I may be used in enantioselective preparation of the key intermediate to benzothiazepine compounds which intermediate has the formula VIII
OH Ar CH - CHR
wherein:
Y is oxygen or sulfur and G is chosen from nitro, C1 to C6 alkyl, amino, C1 to C6 alkylamino, N,N-di(C1 to C6 alkyl)amino, and N-(C1 to C6 alkyl)amino-substituted (C1 to C6 alkylamino such as 2-diethylaminoethylamino. The compound of formula VIII may be prepared by reaction of the epoxide of formula I with a phenol/thiophenol of formula IX
preferably in the presence of a base. Generally the reaction is carried out in non-aqueous solution with a mild base such as sodium bicarbonate which is conveniently present in catalytic amounts. The invention will now be described by but is in no way limited to the following examples.
Example A
Preparation of 2,4,6 trichlorobenzenesulphonyl chloride Chlorosulphonic acid (20 ml) was added to
1,3,5-trichlorobenzene (10 g) via a dropping funnel over 15 min. with stirring at room temperature. The reaction mixture was then heated (oil bath) at 110°C for 2h. The resulting dark mixture was cooled to room temperature, poured into ice water (150 ml) , the crude product collected by filtration and washed thoroughly with cold water (500 ml) giving beige coloured crystals (12.0 g, 80%). The crude was recrystallised from hexane resulting in pure sulphonyl chloride m.p. 47-49°C (lit ref. 90°C). Ref: Farrer, W.V., J. Chem. Soc 1960, 3063.
Example 1
(a) Preparation of methyl-2(S)-(2'.4',6' - trichlorobenzenesulphonyloxy)-3(R)-hydroxy -3-(4'-methoxyphenyl)propionate
To a solution of (2S, 3R)-methyl 2,3-dihydroxy-3-(4-methoxyphenyl)propionate (0.2 g , 0.88 mmol) in pyridine (2 ml) was added 2,4,6-trichlorobenzene sulphonyl
chloride (0.27 g, 0.97 mmol), and the combined mixture was kept at 0-4°C for 18 h.
The resulting pale yellow solution was then poured into water (20 ml), extracted with ethyl acetate (3 × 20 ml) washed with 10% HCl
(20 ml ), water (20 ml) and finally dried
(Na2SO4). The solvent was removed invacuo leaving a white solid residue (0.39. g, 96%) which analysed correctly for a C2 monosubstituted sulphonate ester, m.p; 127-129°C (ethanol).
Preparation of methyl (2R,3R) cis-3-(4- methoxyphenyl)glycidate
To a solution of sulfonate ester of step (a) (0.30 g, 0.65 mmol) in THF (4 ml) was added
NaH (0.017 g, 1.1 mol equivalents), and the mixture was left to stir for 5 h. After this time TLC indicated completion of reaction. The reaction mixture was then poured into water (20 ml) and extracted with ethyl acetate (3 × 20 ml) washed with water (2 × 20 ml) and finally dried (Na2SO4). The solvent was removed in vacuo giving a pale yellow oil (0.130 g, 97%). The oil was not purified further as it analysed correctly for the cis isomer of -3-(4-methoxyphenyl)glycidate.
Ref: Hashiyama, T., Inoue, H., et .al,
J. Chem.Soc. Perkin Trans.1, 1725, (1984).
(c) Addition of 2-nitrothiophenol to the cis glycidate
To a mixture of 2-nitrothiophenol (0.079 g, 0.52 mmol) and NaHCO3 (15 mg - 20 mg) in dry ethanol (5 ml) was added the cis glycidate prepared in step (b) (0.10 g 0.48 mmol). The reaction mixture was stirred at room temperature overnight. The resulting yellow suspension was then poured into water (20 ml), extracted with ethyl acetate (3 × 20 ml), washed with sat. NaHCO3 (20 ml) water (20 ml), brine (20 ml) and finally dried (NaHCO3). The solvent was removed in vacuo giving a yellow oil (0.15 g). The crude was purified by flash column chromatography (eluant CH2Cl2: Et2O 20:1). Evaporation of the second eluant gave a yellow oil (0.10 g, 60%) which analysed correctly for 2R, 3S methyl-2-hydroxy-3-(2-nitrophenylthio)-3- (4-methoxyphenyl)propionate (threo thioether) Ref.
Ref. Hashiyama T., Inoue, H., et.al,
J. Chem Soc. Perkin Trans. 1, 1725, (1984).
A small portion of this yellow oil was acetylated by heating with acetic anhydride and pyridine for 1.5 h on a water bath.
Excess anhydride, acetic acid and pyridine were removed under reduced pressure.
Analysis of the resulting oil by H n.m.r. spectroscopy indicated a single isomer with the methyl signal for the OCOCH, group appearing at 2.10 ppm. This is correct for the threo isomer Ref
Ref. Hashiyama T., Inoue, H., et.al, J. Chem Soc. Perkin Trans. 1, 1725, (1984).
Claims
1 . Accordingly we provide a stereoselective process for preparation of an epoxide of formula I
wherein :
Ar is selected from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl, and R is a carboxylic acid group or ester or a group capable of being converted to a carboxylic acid group or ester; the process comprising reacting a diol of formula
I I I with a sulfonating agent of formula IV to form a compound of formula V and eliminating the sulfonyloxy group from the compound of formula V to form the epoxide of formula I
2. A process according to claim 1 wherein: Ar is the group of formula VI
R is selected from the group consisting of cyano,
thiocarbamoyl, 
and CH2Z, wherein: G is chosen from the group consisting of: hydrogen, hydroxy, mercapto, C1 to C10 alkoxy, C1 to C10 haloalkoxy, C2, to C10 alkenyloxy, C3 to C10 alkynyloxy, C3 to C7, cycloalkoxy, C3 to C7 cycloalkoxy substituted with one or two C1 to C4 alkyl groups, phenoxy, phenylthio, benzyloxy, benzylthio, the group C1 to C6 alkoxy substituted with a substituent chosen from the group consisting of C1 to C6 alkoxy, amino, ammonio, cyano, N-(C1 to C6 alkyl)amino and N,N,N-tri(C1 to C6 alkyl)ammonio, the groups phenoxy, phenylthio, benzyloxy and benzylthio wherein in each group the phenyl ring is substituted with from 1 to 3 substituents chosen from the group consisting of halogen, nitro, cyano, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy, the group - NHSO2R6 wherein R6 is chosen from C1 to C10 alkyl and C1 to C6 haloalkyl, the group -NR 7R8 wherein R7 and R8 are independently chosen from the group consisting of hydrogen, C1 to C6 alkyl, phenyl and benzyl or R 7 and R8 together form a heterocyclic ring, and the group -O-N=R 9 wherein R9 is a C1 to
C10 alkylidene group; Z is chosen from the group consisting of halogen, hydroxy, mercapto, C1 to C10 alkoxy, C1 to C10 haloalkoxy, C 1 to C10 alkylthio and the group -NR 7R8 wherein R7 and R8 are as hereinbefore defined.
3. A process according to claim 1 or claim 2 wherein: Ar is the group of formula VI
R is selected from the group consisting of cyano,
the group 
wherein G is selected from hydrogen, hydroxy, C1 to C6 alkyl, C1 to C6 alkoxy and the group CH2Z wherein Z is hydroxy, chloro or C1 to C6 alkoxy;
X is selected from the group consisting of C1 to C6 alkyl and halogen and n is an integer from 1 to 3; and
L is chlorine or bromine.
4. A process according to any one of claims 1 to 3 wherein: Ar is p-(C1 to C6 alkoxy) phenyl; R is the group 
where G is hydroxy or C1, to C6 alkoxy;
X is halogen and n is 3; and
L is chlorine.
5. A process according to any one of claims 1 to
4 wherein Ar is p-methoxyphenyl and R is the group 
where G is methoxy.
6. A process according to any one of claims 1 to
5 wherein the compound of formula III is reacted with the compound IV in the presence of a solvent selected from aromatic hydrocarbons, aliphitic hydrocarbons, alcohols, ketones, esters and heteroaromatic compounds.
7. A process according to any one of claims 1 to
6 wherein the sulfonyloxy group is eliminated from the compound of formula V in the presence of a base catalyst and a polar aprotic solvent.
8. a process according to claim 7 wherein the bas catalyst is selected from sodium hydride and potassium-t-butoxide and the solvent is selected from tetrahydrofuran, dimethylformamide and dimethysulfoxide.
9. A process according to any one of claims 1 to 8 wherein the compound of formula III is reacted with the compound of formula IV at a temperature of from -10 to 40ºC and the sulfonyloxy group elimination is carried out at a temperature in the range of from -10 to 60ºC.
10. A process according to any one of claims 1 to 9 wherein the compound of formula III comprises at least 80% of one enantiomer.
11. A composition comprising an epoxde of formula I as defined according to any one of claims 1 to 8 wherein at least 80% of said compound is in the form of one isomer.
12. A composition according to claim 11 wherein at least 80% of said compound is the 2S, 3R enantiomer.
13. A compound of formula V
14. A composition comprising a component consisting of the compound of formula V wherein at least 80% of said component a one enantiomer.
15. A process according to any one of claims 1 to 10 wherein the compound of formula I is subsequently reacted with a compound of formula
IX
wherein:
Y is oxyger, or sulphur G is selected from the group consisting of nitro, C1 to C6 alkyl, amino, C1 to C6 alkylamino, N, N-di(C1 to C6 alkyl) amino, and N-(C1 to C6 alkyl) amino substituted (C1 to C6 alkyl) amino; to provide a compound of formula VIII.
16. A process according to claim 15 wherein G is nitro.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AUPI784688 | 1988-04-21 | ||
| AUPI7846 | 1988-04-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1989010350A1 true WO1989010350A1 (en) | 1989-11-02 |
Family
ID=3773038
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/AU1989/000176 Ceased WO1989010350A1 (en) | 1988-04-21 | 1989-04-21 | Preparation of an epoxide |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1989010350A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296618A (en) * | 1992-05-14 | 1994-03-22 | Orion-Yhtyma Oy Fermion | Method for the manufacture of the derivatives of propionic acid |
| US5488118A (en) * | 1993-12-06 | 1996-01-30 | Nippon Kayaku Kabushiki Kaisha | Process for producing optically active erythro-3-amino-1,2-epoxy compound |
| US5629423A (en) * | 1994-05-16 | 1997-05-13 | Cell Therapeutics, Inc. | Asymmetric synthesis of chiral secondary alcohols |
| US5998637A (en) * | 1997-02-27 | 1999-12-07 | Tanabe Seiyaku Co., Ltd. | Process for preparing optically active trans-3-substituted glycidic acid ester |
| CN106892881A (en) * | 2017-03-01 | 2017-06-27 | 郭彦超 | A kind of method of selectivity synthesis diltiazem chiral intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3674771A (en) * | 1971-12-10 | 1973-06-14 | William H. Rorer, Inc | Substituted alkanoic acids and their derivatives, and process |
| AU3094077A (en) * | 1976-11-25 | 1979-05-31 | Ciba Geigy Ag | 2-sulphonyl (or-sulphinyl)-2'aminoacetophenones |
| AU9146482A (en) * | 1981-12-11 | 1983-06-16 | Syntex Pharmaceuticals International Ltd. | Preparation of alpha-arylalkanoic acids |
-
1989
- 1989-04-21 WO PCT/AU1989/000176 patent/WO1989010350A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3674771A (en) * | 1971-12-10 | 1973-06-14 | William H. Rorer, Inc | Substituted alkanoic acids and their derivatives, and process |
| AU3094077A (en) * | 1976-11-25 | 1979-05-31 | Ciba Geigy Ag | 2-sulphonyl (or-sulphinyl)-2'aminoacetophenones |
| AU9146482A (en) * | 1981-12-11 | 1983-06-16 | Syntex Pharmaceuticals International Ltd. | Preparation of alpha-arylalkanoic acids |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296618A (en) * | 1992-05-14 | 1994-03-22 | Orion-Yhtyma Oy Fermion | Method for the manufacture of the derivatives of propionic acid |
| US5488118A (en) * | 1993-12-06 | 1996-01-30 | Nippon Kayaku Kabushiki Kaisha | Process for producing optically active erythro-3-amino-1,2-epoxy compound |
| US5629423A (en) * | 1994-05-16 | 1997-05-13 | Cell Therapeutics, Inc. | Asymmetric synthesis of chiral secondary alcohols |
| US5998637A (en) * | 1997-02-27 | 1999-12-07 | Tanabe Seiyaku Co., Ltd. | Process for preparing optically active trans-3-substituted glycidic acid ester |
| US6197953B1 (en) | 1997-02-27 | 2001-03-06 | Tanabe Seiyaku Co., Ltd. | Process for preparing optically active trans-3-substituted glycidic acid ester |
| CN106892881A (en) * | 2017-03-01 | 2017-06-27 | 郭彦超 | A kind of method of selectivity synthesis diltiazem chiral intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4582918A (en) | Preparation of intermediates for (threo)-1-aryl-2-acylamido-3-fluoro-1-propanols | |
| US4973750A (en) | Preparation of (threo)-1-aryl-2-acylamido-3-fluoro-1-propanols | |
| EP0380144B1 (en) | Process for producing optically active benzene-sulfonamide derivatives | |
| KR0157610B1 (en) | Preparation of (S) -α-ethyl-2-oxo-1-pyrrolidineacetamide | |
| KR101100064B1 (en) | Method for preparing nitrooxy derivatives of naproxen | |
| WO1989010350A1 (en) | Preparation of an epoxide | |
| RU2045530C1 (en) | (+) form of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6h- pyrano (2,3-f) benz-2,1-3-oxadiazole showing right-hand rotation in ethanol | |
| US4677214A (en) | Intermediates for preparation of (threo)-1-aryl-2-acylamido-3-fluoro-1-propanols | |
| EP0233432A1 (en) | Polyfluoralkylthiomethyl compounds, processes for their preparation and their use as tensio-active compounds or as precursors therefor | |
| US4499294A (en) | Process for production of methyl 2-tetradecylgycidate | |
| EA001518B1 (en) | Intermediates for the preparation of 2-imidazoline-5-ones | |
| US4423225A (en) | Process for the preparation of pyrazole | |
| AU748477B2 (en) | Process for the preparation of 2-alkylthio benzoic acid derivatives | |
| KR0163770B1 (en) | Method for preparing 3,4-epoxybutyrate and intermediates therefor | |
| JP3361334B2 (en) | Method for producing trans- (5R) -2,4,5-trisubstituted 2-oxazoline | |
| US5654461A (en) | Sulfamate compound containing carbamoyl group | |
| KR920000375B1 (en) | Process for preparing substituted guanylthioureas | |
| AU3382499A (en) | Improved process for the manufacture of n-(1-cyanoalkyl)-2-phenoxypropionamide derivatives | |
| KR0141657B1 (en) | Optically active 1-phenylpyrrolidone derivatives | |
| EP0242001A1 (en) | Process for the manufacture of n-(sulfonylmethyl) formamides and sulfonylmethylisocyanides | |
| EP0802193B1 (en) | Process for the preparation of substituted pyrimidines | |
| Shimizugawa et al. | EFFECTIVE AND PREFERENTIAL TRANSFORMATION OF COMPOUNDS HAVING 2-HALOETHYL GROUPS ON POSITIVE SULFUR INTO ETHENYL COMPOUNDS UNDER PTC CONDITIONS | |
| FR2491069A1 (en) | ||
| JP4123540B2 (en) | Process for producing 2-oxo-3-oxabicyclo [3,1,0] hexane | |
| KR100209298B1 (en) | New amine ring compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): JP US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LU NL SE |