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WO1989010350A1 - Preparation d'un epoxyde - Google Patents

Preparation d'un epoxyde Download PDF

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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
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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
Application number
PCT/AU1989/000176
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English (en)
Inventor
Graham Bird
Keith Watson
Helen Gountzos
San Thang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orica Australia Pty Ltd
Original Assignee
ICI Australia Operations Pty Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by ICI Australia Operations Pty Ltd filed Critical ICI Australia Operations Pty Ltd
Publication of WO1989010350A1 publication Critical patent/WO1989010350A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

On a mis au point un procédé stéréosélectif de préparation d'un epoxyde de formule (I), dans laquelle Ar est choisi dans le groupe composé d'aryle, hétéroaryle, aryle substitué et hétéroaryle substitué, et R représente un groupe ou un ester d'acide carboxylique ou un groupe que l'on peut transformer en un groupe ou un ester d'acide carboxylique. Ledit procédé consiste à faire réagir un diol de formule (III) avec un agent de sulfonation de formule (IV) pour former un composé de formule (V), et à éliminer le groupe sulfonyloxy du composé de formule (V) pour former l'époxyde de formule (I), dans lequel dans le composé de formule (IV), L est un groupe labile et dans les composés de formule (IV) et (V) le groupe X, qui peut être différent lorsqu'on a plus d'un X, est choisi dans le groupe composé d'alkyle et d'halogène comportant 1 à 6 atomes de carbone, et représente un nombre entier compris entre 1 et 5.
PCT/AU1989/000176 1988-04-21 1989-04-21 Preparation d'un epoxyde Ceased WO1989010350A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPI7846 1988-04-21
AUPI784688 1988-04-21

Publications (1)

Publication Number Publication Date
WO1989010350A1 true WO1989010350A1 (fr) 1989-11-02

Family

ID=3773038

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1989/000176 Ceased WO1989010350A1 (fr) 1988-04-21 1989-04-21 Preparation d'un epoxyde

Country Status (1)

Country Link
WO (1) WO1989010350A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
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 (zh) * 2017-03-01 2017-06-27 郭彦超 一种选择性合成地尔硫卓手性中间体的方法

Citations (3)

* Cited by examiner, † Cited by third party
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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 (zh) * 2017-03-01 2017-06-27 郭彦超 一种选择性合成地尔硫卓手性中间体的方法

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