WO1994013828A1 - Arylpropionates chiraux et leur utilisation - Google Patents

Arylpropionates chiraux et leur utilisation Download PDF

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Publication number
WO1994013828A1
WO1994013828A1 PCT/GB1993/002530 GB9302530W WO9413828A1 WO 1994013828 A1 WO1994013828 A1 WO 1994013828A1 GB 9302530 W GB9302530 W GB 9302530W WO 9413828 A1 WO9413828 A1 WO 9413828A1
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WO
WIPO (PCT)
Prior art keywords
enantiomer
excess
respect
formula
process according
Prior art date
Application number
PCT/GB1993/002530
Other languages
English (en)
Inventor
Raymond Mccague
Shouming Wang
Stephen John Clifford Taylor
Original Assignee
Chiroscience Limited
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
Priority claimed from GB929225792A external-priority patent/GB9225792D0/en
Priority claimed from GB939318036A external-priority patent/GB9318036D0/en
Application filed by Chiroscience Limited filed Critical Chiroscience Limited
Priority to AU56569/94A priority Critical patent/AU5656994A/en
Publication of WO1994013828A1 publication Critical patent/WO1994013828A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • 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
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters

Definitions

  • the present invention relates to compounds that are useful as chiral synthons, in particular in the synthesis of the anti-hypertensive agent diltiazem, and processes for making those synthons.
  • Diltiazem is the compound of formula (I) , below. It is a calcium-channel blocking agent used for the treatment of hypertension.
  • the compound is desirably in the form of a single enantiomer.
  • Intermediate (II) can be made by reaction of o-aminobenzenethiol with the corresponding epoxide (V; see Scheme 1) . While the intermediate (II) can be resolved, such as by forming the R- ⁇ -methylbenzylamine salt, e.g. as described in EP-A- 0381570, such an approach suffers from the unwanted enantiomer, i.e. that is not a precursor of diltiazem, being unusable, thereby creating waste and requiring twice the amount of materials than is theoretically possible.
  • a process for preparing an enantiomer of a compound having the formula III comprises biotransformation of the corresponding racemate with a material having stereoselective esterase activity.
  • the process provides a simple and efficient resolution technique, and allows the other, unwanted, enantiomer to be converted into a usable form, thereby reducing waste.
  • a process for preparing a thiazepinone of formula (VII) in enantio eric form comprises dehydrohalogenation of the corresponding enantiomer, described above, by reaction with alkoxide to form the epoxide, with subsequent addition of o-aminobenzenethiol and subsequent acid cyclisation, and proceeds without isolation of the intermediates from the enantiomer to the thiazepinone being necessary.
  • R can be H or acyl, and in some instances is preferably acyl for reasons described below.
  • Suitable acyl groups include optionally-substituted (C 1-6 alkyl)carbonyl groups.
  • R can be H or an esterifying group, suitable examples of which include optionally-substituted C 1 . 6 alkyl groups.
  • Ar represents an aryl group, including heterocyclic aryl, e.g. optionally-substituted phenyl.
  • the nature of Ar is not critical to the invention, but will be chosen according to the desired final product.
  • the most preferred aryl group is 4- methoxypheny1.
  • Hal represents a halogen atom, which with regard to the process economy is preferably chlorine or bromine, and is more preferably bromine, for reasons outlined below.
  • Scheme 1 outlines the processes of the invention and indicates how enantiomers of the invention may be prepared and used.
  • the starting material a cinnamic acid ester
  • halohydrin-forming reagents e.g. N-bromosuccinimide for a bromohydrin
  • Known procedures may be used.
  • the racemate (III) is then subjected to a biotransformation with a material having stereoselective esterase activity.
  • a material having stereoselective esterase activity is chosen so as to react with a single enantiomer only and in so doing convert it to a species that is separable from the unreacted enantiomer by a technique such as solvent partitioning.
  • the biotransformation can be a hydrolysis reaction (as shown in Scheme 1) or an esterification reaction, depending upon the esterase and/or the reaction conditions chosen.
  • R is acyl, it is generally that group that undergoes the hydrolytic biotransformation shown in Scheme
  • R 1 is hydrogen, i.t is the ester group R2 that undergoes hydrolytic biotransformation. It is essential that R is not hydrogen in the substrate (III) , for hydrolytic biotransformation, since the reaction would not provide separable species. An esterification reaction, however, would provide such separable species.
  • the biocatalyst that carries out the biotransformation can be an enzyme such as a lipase, for example Mucor mieheii or Candida cylindracea lipase, or it can be a microorganism such as a bacterium, fungus or yeast that has the appropriate esterase activity.
  • Biocatalysts that can act on either one of the enantiomers (III) can be simply selected by the skilled man. Following the biotrans ormation, the desired enantiomer, e.g.
  • An acylation reaction can be carried out on the thiazepinone through its hydroxyl function, depending on the desired final product. Known procedures can be used. It is possible to carry out the acylation reaction immediately after the acid cyclisation described above, without isolation of the thiazepinone.
  • the unwanted enantiomer from the biotransformation can be cyclised to its corresponding epoxide, which is then inverted by acidic hydrolysis to the diol, followed by regioselective tosylation at C-2, as described by Rama Rao et aJ , J. Chem. Soc. Chem/Commun. (1992), 859-860, and then elimination using alkoxide to give epoxide (V) .
  • the procedure may give a mixture of epi ers at C-3, but this does not affect the stereochemistry in any subsequently formed thiazepinone and/or diltiazem, as this is determined only by the configuration at C-2.
  • Methyl 2-bromo-3-hydroxy-3- (4-methoxyphenyl) - propionate (33 g, 0.114 mol) , prepared in a similar manner to that described in Example 3, in diethyl ether (300 ml) , was cooled on ice with stirring. To this were added butyric anhydride (18.6 ml, 0.114 mol), triethylamine (16 ml, 0.114 mol) and 4-dimethylaminopyridine (1 g, 8 mol) , allowing the mixture to warm to room temperature. After stirring for 40 min.
  • Example 2 The bromohydrin diester of Example 1 (30 g, 0.08 mol) was dissolved in toluene (200 ml) and 0.1M pH 7 Tris buffer (500 ml) .
  • Candida cylindracea lipase (A ano MY; 6 g) was added.
  • the mixture was stirred and maintained at pH 7 by addition of 1M NaOH, of which 40 ml (0.04 mol) had been added after 23 hours. Conversion was calculated at 25% from enantio eric excess (ee) measurements (see below) .
  • the ee of the substrate diester was determined by HPLC (Daicel Chiracel-OJ column, 25 cm x 4 mm, eluent 10% 2- propanol in n-heptane, 1 ml/min, 254 n , retention times 16.7 and 19.7 in.).
  • the ee of the product was determined by derivatisation to the epoxide, by reaction of a sample in methanol with 10% sodium methoxide.
  • the toluene phase was filtered through Celite (registered Trade Mark) and dried over anhydrous magnesium sulphate, and then concentrated under vacuum to yield optically-active bromohydrin (76 g) .
  • This was dissolved in methanol (950 ml) , cooled in ice and sodium methoxide (13.8 g) was added. After stirring the mixture for 20 min, the solution was neutralised with 1 M potassium dihydrogen phosphate, then the methanol was removed by evaporation in vacuo. The aqueous solution was then extracted with an equal volume of dichloromethane and the organic phase was dried over anhydrous magnesium sulphate and concentrated to yield 52 g crude epoxide as a yellow oil.
  • This epoxide was heated to reflux in a solution of o-aminobenzenethiol (26 ml) in xylene (500 ml) and reflux was maintained for 4- ⁇ h. After cooling, methanesulphonic acid (3.5 ml) was added, and the solution was then heated at reflux for a further 3 h.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

L'invention se rapporte à des composés ayant la formule Ar-CHOR1-CHHal-COOR2 qui sont utilisés comme synthons chiraux, par exemple dans la synthèse de l'agent hypertensif diltiazem, et des agents de blocage des canaux calciques apparentés. Les synthons peuvent être préparés sous une forme purifiée énantiomériquement sans perte de l'énantiomère non désiré.
PCT/GB1993/002530 1992-12-10 1993-12-10 Arylpropionates chiraux et leur utilisation WO1994013828A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56569/94A AU5656994A (en) 1992-12-10 1993-12-10 Chiral arylpropionates and their use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB929225792A GB9225792D0 (en) 1992-12-10 1992-12-10 Chiral compounds and atheir use
GB9225792.2 1992-12-10
GB9318036.2 1993-08-31
GB939318036A GB9318036D0 (en) 1993-08-31 1993-08-31 Chiral compounds and their use

Publications (1)

Publication Number Publication Date
WO1994013828A1 true WO1994013828A1 (fr) 1994-06-23

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AU (1) AU5656994A (fr)
WO (1) WO1994013828A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0808824A2 (fr) * 1996-05-24 1997-11-26 Tanabe Seiyaku Co., Ltd. Procédé de préparation d'esters de l'acide 2-halogéno-3-hydroxypropionique optiquement actif
WO2004040098A1 (fr) 2002-10-25 2004-05-13 Baker Hughes Incorporated Centreurs telescopiques destines a des elements tubulaires extensibles
CN114874156A (zh) * 2022-06-20 2022-08-09 巨鑫生物制药股份有限公司 一种合成地尔硫卓中间体(2s)-顺-羟基内酰胺的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989005291A1 (fr) * 1987-11-30 1989-06-15 Ici Australia Operations Proprietary Limited Preparation enantioselective de derives d'aminothiophenol substitue
GB2229721A (en) * 1989-04-01 1990-10-03 Arakawa Chem Ind Optically active compounds useful as chiral dopants or intermediates
EP0447938A1 (fr) * 1990-03-22 1991-09-25 Tanabe Seiyaku Co., Ltd. Procédé pour la fabrication de composés esters de l'acide propionique-halogéno-2-hydroxy-3-phényle-3
EP0451668A2 (fr) * 1990-04-12 1991-10-16 Chisso Corporation Alkyl-3-aryl-hydroxypropionates optiquement actives et leur méthode de préparation
EP0472336A1 (fr) * 1990-08-13 1992-02-26 Suntory Limited Procédé de préparation de dérivés de 3-hydroxybutane optiquement actifs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989005291A1 (fr) * 1987-11-30 1989-06-15 Ici Australia Operations Proprietary Limited Preparation enantioselective de derives d'aminothiophenol substitue
GB2229721A (en) * 1989-04-01 1990-10-03 Arakawa Chem Ind Optically active compounds useful as chiral dopants or intermediates
EP0447938A1 (fr) * 1990-03-22 1991-09-25 Tanabe Seiyaku Co., Ltd. Procédé pour la fabrication de composés esters de l'acide propionique-halogéno-2-hydroxy-3-phényle-3
EP0451668A2 (fr) * 1990-04-12 1991-10-16 Chisso Corporation Alkyl-3-aryl-hydroxypropionates optiquement actives et leur méthode de préparation
EP0472336A1 (fr) * 1990-08-13 1992-02-26 Suntory Limited Procédé de préparation de dérivés de 3-hydroxybutane optiquement actifs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MERCEDES C. CABALEIRO ET AL.: "Mechanism of dehydroacetoxylation of methyl 3-acetoxy-3-aryl-2-halogenopropanoates.", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 2, no. 7, July 1986 (1986-07-01), LETCHWORTH GB, pages 1091 - 1095 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0808824A2 (fr) * 1996-05-24 1997-11-26 Tanabe Seiyaku Co., Ltd. Procédé de préparation d'esters de l'acide 2-halogéno-3-hydroxypropionique optiquement actif
EP0808824A3 (fr) * 1996-05-24 1998-04-08 Tanabe Seiyaku Co., Ltd. Procédé de préparation d'esters de l'acide 2-halogéno-3-hydroxypropionique optiquement actif
WO2004040098A1 (fr) 2002-10-25 2004-05-13 Baker Hughes Incorporated Centreurs telescopiques destines a des elements tubulaires extensibles
CN114874156A (zh) * 2022-06-20 2022-08-09 巨鑫生物制药股份有限公司 一种合成地尔硫卓中间体(2s)-顺-羟基内酰胺的方法

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