EP0434743A4 - Methods for preparing captopril and its analogues - Google Patents

Methods for preparing captopril and its analogues

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Publication number
EP0434743A4
EP0434743A4 EP19890910744 EP89910744A EP0434743A4 EP 0434743 A4 EP0434743 A4 EP 0434743A4 EP 19890910744 EP19890910744 EP 19890910744 EP 89910744 A EP89910744 A EP 89910744A EP 0434743 A4 EP0434743 A4 EP 0434743A4
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European Patent Office
Prior art keywords
formula
group
diastereomer
compound
solution
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EP19890910744
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EP0434743A1 (fr
Inventor
Charles M. Zepp
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Sunovion Pharmaceuticals Inc
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Sepracor Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to novel methods for converting a diastereomeric mixture of S-protected derivatives of an orally active inhibitor of an angiotensin-converting enzyme (ACE) and its analogues into its separate optically resolved diastereomeric components.
  • ACE angiotensin-converting enzyme
  • the invention relates to methods for the preparation of optically purified captopril for the preparation of optically purified captopril and its analogs from racemic precursors.
  • This resolution process is achieved through the fractional crystallization of S- protected derivatives of captopril and its precursors, which derivatives are useful for the reason that they are (1) easily prepared from novel precursors, (2) resolvable to their optically purified stereoisomeric species and (3) convertible to non-derivatized stereoisomeric species which correspond to the pharmacologically active inhibitor and its analogues.
  • novel methods for preparing the derivatives and their precursors are also noted herein.
  • novel derivatives and their precursors are also described herein.
  • optically active forms i.e. , they have the ability to rotate the plane of plane-polarized light.
  • the property of optical activity is due to molecular asymmetry about carbon atoms that are linked to four different atoms or chemical groups.
  • D and L or R and S are used to denote the configuration of the molecule about its chiral center(s).
  • the prefixes (+) and (-) or and 1 are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 ⁇ meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • stereoisomers Compounds of a given chemical structure, which differ from one another only in the configuration of chemical groups about one asymmetric carbon atom, or chiral center as it is sometimes called, are called stereoisomers. Where there are n asymmetric carbons or chiral centers, the number of potential stereoisomers increases to 2 n . Thus, a molecule with three chiral centers would have eight possible stereoisomers.
  • stereoisomers are identical except that they are non-superimposable mirror images of one another, the molecules are referred to as enantiomers.
  • Stereoisomers which are not non-superimposable mirror images of other stereoisomers of the same compound are described as diastereomers (e.g. 2R,3R-tartaric acid and 2R,3£3-tartaric acid are diastereomers whereas 2R,3R- tartaric acid and 2 ,3 ⁇ -tartaric acid are enantiomers).
  • a mixture of enantiomers is called an enantiomeric or racemic mixture, and as used herein this term is applied to mixtures of enantiomers in any proportion.
  • diastereomers is referred to as a diastereomeric mixture, where as the term is used herein the diastereomers may be present in any proportion.
  • Stereochemical purity is of equal importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality.
  • a case in point is provided by naproxen, or (+)-£>-2-(6-methoxy-2- naphthyDpropanoic acid, which is one of the two most important members of a class of 2-arylpropanoic acids with non-steroidal anti-inflammatory activity used, for instance, in the management of arthritis.
  • the ⁇ 3(+) enantiomer of the drug is known to be 28 times more therapeutically potent than its R(-) counterpart.
  • Still another example of chiral pharmaceuticals is provided by the family of beta-blockers; the L-form of propranolol is known to be 100 times more potent than the D-enantiomer.
  • captopril belongs to a new class of antihypertensive agents. Its specific action resides in its acting as a specific competitive inhibitor of angiotensin I-converting enzyme (ACE) which converts angiotensin I to angiotensin II. Although the actual mechanism of its action is not fully elucidated, it has been shown that captopril reduces blood pressure and results in beneficial hemodynamic effects in patients with congestive heart failure. More specifically, captopril (commercially available from Squibb as CAPOTENTM) , contains a 2-methyl-3-thiolpropanoyl segment linked via an amide bond to L-proline.
  • CAPOTENTM 2-methyl-3-thiolpropanoyl segment linked via an amide bond to L-proline.
  • certain isomers may actually be deleterious rather than simply inert.
  • the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy.
  • its L-thalidomide counterpart was discovered to be a potent teratogen.
  • racemic mixture and "diastereomeric mixture” as used herein, refer to mixtures of a first and a second stereoisomer in any proportions, such that the first and second stereoisomers are enantiomers or diastereomers, respectively.
  • solution as used herein will- refer to the transformation of a racemic or diastereomeric mixture, as defined above, into two product mixtures, in each of which the proportions of the two above defined stereoisomers may be different from both the starting racemic or diastereomeric mixture and from each other, the proportion being greater in one and necessarily smaller in the other.
  • resolved is intended to refer to a quantity of any compound, capable of resolution, which has undergone the process of resolution defined above to yield an optically active product material.
  • stereospecific and “stereoselective” as used herein are synonymous.
  • a widely used approach has been the selective precipitation of desired stereoisomeric compounds from diastereomeric mixtures.
  • diastereomeric mixtures are created by addition of a chiral and optically purified resolving agent to a racemic mixture, which then induces fractional crystallization.
  • Such chiral and optically purified resolving agents form complexes, salts or covalent compounds with the racemic species to be resolved.
  • Said diastereomeric complexes, salts and covalent compounds now possess two or more chiral centers wherein one chiral center in one diastereomer has the same configuration as the corresponding chiral center in another diastereomer, while the diastereomers-' other corresponding chiral centers have the opposite configuration.
  • the individual diasteromers have different physical properties (e.g. , solubility) and are hence readily separable from one another.
  • Yoshioka et al. [U.S. Patent No. 3,879,451] treated a mixture of ( ⁇ )-cis- and ( ⁇ )-trans- chrysanthemic acids with an optically active aromatic amine and recovered the resulting diastereomeric amine salts of (i)-ci>s- and (i)-trans-chrysanthemic acids by crystallization.
  • captopril fractional crystallization methods have been noted in resolving captopril, captopril analogues and their precursors, generally based on the use of optically active amines capable of forming diastereomers with the acid precursors of captopril (e.g. , 2-methyl-3- thiolpropanoic acid) and its analogues.
  • acid precursors of captopril e.g. , 2-methyl-3- thiolpropanoic acid
  • benzyl- ⁇ -phenethylamine is used as one of the fractional crystallization reagents (i.e. , resolving agents) .
  • De Heij also discloses in European Patent Application No. 0,008,831 Al that cinchonidine is a suitable resolving agent as described in his Dutch Patent Application No. 7,809,121.
  • 1,2-diphenylethylamine and 2-amino-l- butanol have been employed in resolutions (J.
  • racemic- ⁇ -methyl- ⁇ -acylthiopropanoic acids are not given to fractional crystallization using standard optically active amines such as quinidine, ephedrine, -methylbenzylamine and brucine (Col. 1, lines 44 to Col. 2, line 2).
  • optically active amines such as quinidine, ephedrine, -methylbenzylamine and brucine
  • N. Ohashi, et al. of optically active amines such as l-( ⁇ -naphthyl)-ethylamine and ⁇ / S-diphenylethylamine proved to be more successful, it was noted that the procedures were very expensive, cumbersome to effect, and capable of producing only relatively low yields (CJ. Sih, PCT No. WO87/05328 p. 2) .
  • non-optically active amines have been employed in fractional crystallization resolution steps to prepare captopril.
  • D.H. Naur, et al., J. Phar . Sci. 73(12): 1843-4 (1984) used dicyclohexylamine to resolve the diastereomers of racemic N-(L-proline)-3-halo- 2-methylpropanamide precursor used in a captopril synthesis.
  • the amide can be converted to the corresponding diastereomeric S-protected derivatives _ g _
  • captopril by treating the amide with either a sodium dialkyldithiocarbamate or potassium xanthogenate, as demonstrated by D.K. Kim in U.K. patent No. 2,170,806A.
  • Dicyclohexylamine was also used by I. Castellet-Linan, Spain Patent No. 548154, to resolve the benzoylthio- protected captopril.
  • the use of non-optically active amines also incurs an added expense and additional synthetic steps in using the amine.
  • hydrolases especially the lipases, proteases and esterases such as chymotrypsin
  • lyases and oxidoreductases e.g. , amino acid oxidases and alcohol reductases
  • captopril enzymatic resolution procedures have been preferably undertaken since there have been problems with fractional crystallization methods.
  • M. Shimazaki, et al. Chem. Pharm. Bull. 30(9): 3139-45 (1982) used a microbiological step developed by Cohen et al. , J. Org. Chem. 41, 3505 (1976) to convert isobutyric acid by a bacterial hydroxylation to D-3-hydroxy-2- 32 _ 10 _ .
  • Y is an alkyl group, preferably C, g alkyl group, an aralkyl group, preferably C , g aralkyl group or an aryl group, preferably C g _ 6 aryl group;
  • Y. is an alkyl group, preferably C, 6 alkyl group; and Y is 1 or 2, by allowing a source containing an enzyme capable of asymmetrically hydrolyzing an ester to act on the ester represented by the formula,
  • Y 2 , Y_, and Y have the same meanings as those mentioned above; and R_ is an alkyl group, preferably C_ 6 alkyl group.
  • R_ is an alkyl group, preferably C_ 6 alkyl group.
  • Y_ was either an acyl radical in straight chain, branched chain or cyclic configuration having 1 to about 12 carbon atoms; cycloalkane radicals having 5 to 7 carbon atoms; or benzoyl, naphthoyl, biphenoyl and carbobenzoxy radicals containing substituents such as nitro, halogen, methyl or alkoxy groups on the aromatic ring.
  • This invention relates to novel methods for converting a diastereomeric mixture of S-protected derivatives of an orally active inhibitor of an angiotensin-converting enzyme (ACE) and its analogues into its separate optically resolved diastereomeric components.
  • ACE angiotensin-converting enzyme
  • the invention relates to methods for the preparation of optically purified captopril and its analogs from racemic precursors. This resolution process is achieved through the fractional crystallization of S- protected derivatives of captopril and its precursors, which derivatives are useful for the reason that they are (1) easily prepared from novel precursors, (2) resolvable to their optically purified stereoisomeric species and (3) convertible to non-derivatized stereoisomeric species which correspond to the pharmacologically active inhibitor and its analogues.
  • novel methods for preparing the derivatives and their precursors are also noted herein.
  • novel derivatives and their precursors are also described herein.
  • FIG. 1 is a schematic representation of (1) the methods for preparing S-protected captopril and its analogues, (2) the use of the precursors of the S-protected captopril and its analogues and (3) the methods for preparing captopril and its analogues from their S- protected derivatives.
  • the undesired protected diastereomeric amide can be hydrolyzed to isolate the amide's amine for recycling to the coupling (a idization) step.
  • compositions of matter regarding the S-protected derivatives and their precursors, and methods of producing these compositions of matter are also noted herein.
  • the amide compounds which are the primary subject matter of this invention contain two chiral centers wherein one of the chiral centers is located alpha to the carboxyl carbon in the thiol alkanoyl segment of the amide and the other chiral center is alpha to the nitrogen which forms the amide. Consequently, the compounds may be produced as mixtures of diastereomers.
  • the compounds are useful in that they directly, without further chemical modification, undergo fractional crystallization to allow separation of their component diastereomers. This property of the subject compounds is described herein as "self- fractional crystallization".
  • Self-fractional crystallization is to be distinguished from the usual practice of fractional crystallization to resolve stereoisomers whereby the desired stereoisomer is separated as a diastereomeric derivative (for example, resolution of a racemic mixture of a carboxylic acid by fractional crystallization of a diastereomeric mixture of salts formed between the former and an optically active amine) .
  • This usual practice requires regeneration of the underivatized compound and recovery of the amine "resolving agent".
  • This self-fractional crystallization behavior is attributed to the physical properties resulting from the novel thiol protecting group.
  • racemic S-functionalized carboxylic acid compounds precursors
  • S-functionalized amide compounds which result from their reactions with alpha-amino acids or alpha-a ino acid derivatives.
  • Said S-functionalized amide compounds may undergo self-fractional crystallization and be further converted by removal of the thiol protecting group to the desired single optical iso er of the desired compound.
  • reaction of the claimed racemic S- functionalized carboxylic acid compound (after conversion to a suitable acylating agent) with L-proline results in formation of a diastereomeric mixture of amide compounds which undergoes self-fractional crystallization and is further converted by de-protection to captopril.
  • Embodiments of this invention pertain to novel methods for preparing optically purified captopril and its analogues from a diastereomeric mixture of the S-protected derivatives, which resolved derivatives are de-protected to form captopril and its analogues.
  • R 5 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, phenoxy, hydroxy, thiol, alkylthio, halide, phenyl and substituted phenyl, and p is 2, 3, or 4;
  • R is selected from the group consisting of hydroxy, amino and lower alkoxy
  • R 3 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, phenoxy, hydroxy, thiol, alkylthio, arylthio, halide, phenyl and substituted phenyl
  • m is 2, 3, or 4, both of the formulae represent rings ranging in sizes from four to six.
  • m is 3 regarding formula II it corresponds to the substituent group R_ described later herein as being selected from the group consisting of L- proline (where R is hydroxy1 and R_ is hydrogen) and substituted L-proline selected from the group consisting of 423-(phenylthio)-L-proline, 4£3-hydroxy L-proline, lower alkyl ester of L-proline and amide of L-proline.
  • R 5 and R_ groups are each represented as such to note that they can substitute for any methylene (-CH,-) hydrogen(s) of the ring.
  • substitutions pertain to those replacements which either provide a heterocyclic amine which is non-optically active or which replacement involves a single stereoconfiguration at that chiral carbon which is the site of substitution.
  • Examples of the former are geminal substitutions or those which provide eso compounds (i.e. , having a plane of symmetry) .
  • An example of the latter is provided by substituted L-proline wherein the substituent group R_ is 4S-(phenylthio) .
  • One of the novel compositions of matter prepared herein is a compound of the formula III 2732 _ , . _
  • R is selected from the group consisting of hydroxy, amino and lower alkoxy;
  • R. is selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halide, phenyl and substituted phenyl;
  • R 2 is selected from the group consisting of 0, S and i ino;
  • R is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, phenoxy, hydroxy, thiol, alkylthio, arylthio, halide, phenyl and substituted phenyl;
  • R. is a cyclic secondary amino;
  • m is 2, 3 or 4;
  • C has an or R configuration;
  • C. has a D or L configuration;
  • n is 1, 2 or 3; and basic salts thereof.
  • the compound of formula III also encompasses the compound wherein said cyclic secondary amino has the formula I as described above; said R_ is an imino which has the formula NR ⁇ wherein R ⁇ is selected from the group consisting of hydrogen, hydroxy, lower alkoxy, lower alkyl, phenyl and substituted phenyl; said phenyl substituent is selected from the group consisting of halide, lower alkyl, hydroxy and lower alkoxy; and said lower alkoxy and lower alkyl groups have up to seven carbon atoms.
  • R is hydroxy
  • R. is lower alkyl wherein said lower alkyl is methyl
  • R 2 is S
  • R_ is hydrogen, 4£-hydroxy or 4 ⁇ S-phenylthio
  • n is 1, m is 3
  • R. is a cyclic secondary amino of the formula I above wherein R- is hydrogen and p is 3, and C, has an L configuration; _ 1? _
  • R is lower alkoxy wherein said lower alkoxy is methoxy or t-butoxy
  • R. is lower alkyl wherein said lower alkyl is methyl
  • R 2 is S
  • R 3 is hydrogen, 4S-hydroxy or 4S-phenylthio
  • n is 1, m is 3
  • R. is a cyclic secondary amino of the formula of I above wherein R 5 is hydrogen and p is 3, and C. has an L configuration;
  • R is lower alkoxy wherein said lower alkoxy is methoxy
  • R. is lower alkyl wherein said lower alkyl is methyl
  • R 2 is O
  • 3 is hydrogen, 4 ⁇ 3-hydroxy or 4S-phenylthio
  • n is 1, m is 3
  • R. is a cyclic secondary amino of the formula of I above, wherein R g is hydrogen and p is 3, and C. has an L configuration.
  • compositions of matter also cover a compound of the formula IV
  • R 2 is S
  • R. is a cyclic secondary amino of formula I above wherein R 5 is hydrogen and p is 3
  • R_ is a) L-proline or b) substituted L-(proline) wherein the substituted L-proline is
  • novel compositions of matter pertain to a compound of the formula V
  • R Thallium is selected from the group consisting of O and S; Rg is pyrrolidino; and basic salts thereof wherein all the other substituents are defined as above.
  • R g is S
  • R_ is a) L-proline or b) substituted L-proline wherein the substituted L-proline is
  • the S-protected precursor provides a novel and simple substrate for forming S-protected derivatives (thiol- protected captopril and its analogues) which undergo self- fractional crystallization upon their formation from that precursor.
  • amidization of the precursor with optically active amines other than proline or its analogues is useful for forming amides which also undergo self-fractional crystallization to separate diastereomeric amide species. More specifically, these resulting individual diastereomeric amides are separately hydrolyzable to the corresponding optically resolved amine species. Consequently, the precursor has utility for preparing individual diastereomeric amide species of which it is part.
  • Novel compositions of matter therefore, pertain to a compound of the formula VI 732 _ 20 _ .
  • R 1Q is selected from the group consisting of lower alkoxy or hydroxy, and basic salts thereof wherein the other substituents are defined as above.
  • this compound include the compound of the formula VI wherein: - is lower alkyl wherein said lower alkyl is methyl, R 2 is S, n is 1, R. is a cyclic secondary amino of the formula I as defined above wherein R 5 is hydrogen and p is 3, and R 10 is hydroxy.
  • Novel compositions of matter also pertain to a compound of the formula VII
  • compositions of matter pertinent to this invention comprise a compound of the formula VIII
  • step b) converting said compound of the formula XV of step a) to an acylating agent by reacting it, for example, with the acid chloride of an inorganic acid; c) reacting said formed acylating agent of step b) with a compound of the formula II to form said compound of the formula XIII; and d) isolating said compound of the formula XIII.
  • R 12 is lower alkoxy, with a compound of the formula XI and a cyclic secondary amine to form the compound of the formula XX
  • the methods also pertain to the preparation of compounds wherein the protecting group portion of the compound is variable as noted regarding the compositions of matter, whereas the alkanoyl and amino portions of the amide compound are limited respectively to 2-methyl-3- thiopropanoyl and to L-proline and substituted L-proline, including but not limited to the case wherein the substituted L-proline is 4S-(phenylthio)-L-proline.
  • the methods are useful in the situation wherein the protecting group is limited to pyrrolidinocarbonyl or pyrrolidinothioxomethyl, and the thioalkylcarboxamide portion of the compound is limited as just noted.
  • Compound III may also be prepared by alternating the preparative sequences noted in prior methods.
  • the initial step again necessitates condensing the carboxylic acid compounds of step (a) of the prior noted methods with an amine using known methods to produce an amide.
  • one such method involves reacting the carboxylic acid compounds of step (a) with the acid halide of an inorganic acid to convert the carboxylic acid to an acylating agent.
  • the order of subsequent reaction steps can be changed.
  • the formed acylating agent is then subjected to an amidization reaction as noted in the prior noted preparative methods.
  • the carboxylic acid portion of the amide undergoes reaction steps as noted in the prior discussed preparative methods whereby the S-functionalized thiol group is incorporated in the carboxylic acid portion of the amide to form compound III.
  • a derivative and precursor of captopril were prepared as follows.
  • the S-protected 2-methyl-3-thiopropanoic acid corresponding to formula VII is formed where pyrrolidine, carbon disulfide and methacrylic acid are allowed to react — preferably in equimolar amounts — either with, or without a solvent present.
  • the reactants are dissolved in a solvent, for example, 2-propanol or ethyl acetate, in the amounts of about 5 to about 40 weight percent. This solution is then either refluxed for about 1 to about 10 hours or kept at room temperature for from about 1 to about 5 days.
  • the desired product either crystallizes spontaneously from solution or is induced to crystallize by the addition of a non-solvent.
  • the S- protected 2-methyl-3-thiopropanoic acid precursor is isolated by filtration or centrifugation, washed with a small amount of crystallization solvent and air dried or dried in an oven or vacuum oven. This material is pure enough to be used in the coupling reaction with L-proline or another nucleophile to form the S-protected 2-methyl-3- thiopropanoic acid.
  • the compound is dissolved in methylene chloride or another suitable solvent at a concentration of about 2 to about 15 weight percent and is treated with about 0.9 to about 1.1 equivalent of an inorganic acid chloride, typically thionyl chloride at about -5 ⁇ C to about 25 ⁇ c After about 10 minutes to about 1 hour L-proline or another nucleophile is added followed by the addition of about 2 to about 5 equivalents of an organic base, for example, pyridine at a temparature of from about -5 ⁇ C to about 25"C After about 0.5 to about 2 hours, the solution is washed with aqueous acid to remove the base.
  • an inorganic acid chloride typically thionyl chloride at about -5 ⁇ C to about 25 ⁇ c
  • L-proline or another nucleophile is added followed by the addition of about 2 to about 5 equivalents of an organic base, for example, pyridine at a temparature of from about -5 ⁇ C to about 25"C
  • the solution is washed with
  • the product is (i) crystallized directly from solution, (ii) induced to crystallize by addition of a non-solvent, (iii) collected by. evaporating the reaction solvent followed by dissolving the product in a solvent from which it can be recrystallized, or (iv) crystallized by a combination of the above.
  • Described herein are also methods that relate to the production of a useful precursor for combining with an amine whereby the resulting amide undergoes self-fractional _ , Q _
  • a method for preparing a precursor which is useful for preparing derivatives of captopril and its analogues pertains to a method for making a compound of the formula XXIII
  • the method comprises:
  • Another method for preparing a precursor which is useful for preparing derivatives of captopril and its analogues pertains to a method for making a compound of the formula XXV
  • the method comprises: a) reacting the compound of the formula XXVI (CH 2 ) n C a HR l COR 1Q (XXVI) ,
  • Another method for preparing a precursor which is useful for preparing derivatives of captopril and its analogues pertains to a method for making a compound of the formula XXVII
  • the method comprises: a) reacting the compound of the formula XXVI and a compound of the formula XVII to form the compound of the formula XXVII wherein the substituent groups in the compound are defined above; and b) isolating said compound of the formula XXVII.
  • the methods also relate to the preparation of compounds wherein the protecting group portion of the compound is variable as noted whereas the thioalkanoyl portion of the compound is limited to 2- methyl-3-thiopropanoyl.
  • the methods are useful in the situation wherein the protecting group is limited to pyrrolidinocarbonyl or pyrrolidinothioxomethyl, and the thioalkanoyl portion of the compound is limited as noted.
  • captopril and captopril analogues as the racemic mixture or chiral species is also described herein.
  • the desired racemic species is obtained by affecting the removal of the thiol protecting group.
  • the precursor can be separated as a pure diastereomer by its self-fractional crystallization, and subsequently treated to remove the thiol protecting group to obtain captopril or a captopril analogue.
  • Specific details regarding the preparation of captopril and its analogues are exemplified by the following procedures used in preparing captopril.
  • the preparation of a mixture of diastereomers is accomplished starting from non-optically active raw materials that condense to form a racemic mixture of S- protected 2-methyl-3-thiopropanoic acid. Such syntheses of S-protected captopril and its analogues are noted previously herein. This material is then coupled with L- proline to form S-protected captopril as a mixture of diastereomers.
  • This can be conducted by two general processes. One involves isolation of the racemic acid precursor from one set of solvents (e.g. isopropanol/water) and subsequent coupling to L-proline in another solvent (e.g. methylene chloride) . The other general approach conducts both reactions in one solvent (e.g., ethyl acetate) without precursor isolation.
  • solvents e.g. isopropanol/water
  • L-proline e.g. methylene chloride
  • the (S,S) diastereomer will crystallize from the solution while the remaining mother liquor contains predominately the other diastereomer.
  • the solid can be collected by filtration or centrifugation. After washing with said crystallizing solvent, the solid is further converted by de-protection to captopril while the filtrate is sent for proline recovery and recycling.
  • the solvent- wet crystals, isolated from the above fractional crystallization, represent 40 to 49% recovery of the (S,S) diastereomer of the protected captopril (or captopril analog) .
  • Captopril and captopril analogs can be produced from their S-protected derivatives by direct hydrolysis of the S-protected derivative.
  • the S-protected material is first dissolved in a concentrated aqueous solution of an alkali metal hydroxide (e.g. , potassium or sodium hydroxide) — preferably with the hydroxide at a concentration from about 5 wt % to about 25 wt % — to yield a solution containing about 5 wt % to about 25 wt % of the S-protected captopril derivative.
  • an alkali metal hydroxide e.g. , potassium or sodium hydroxide
  • a preferred hydroxide solution is aqueous potassium hydroxide.
  • This solution is then refluxed for from about 1 hour to about 24 hours, preferably under an inert gas (e.g., nitrogen) atmosphere.
  • an inert gas e.g., nitrogen
  • the solution is acidified to a pH of about 0 to about 3, and then it is extracted with an organic solvent.
  • Suitable organic solvents include methylene chloride, ethyl acetate, and chloroform.
  • the solvent is removed or concentrated, and the desired (S3, S) diastereomer of captopril or captopril analog is isolated by crystallization, chromatography, or yet another standard purification method.
  • the filtrate from the asymmetric crystallization step contains predominately the (R,S) diastereomer of the S-protected captopril.
  • the crystallizing solvent is evaporated and replaced with a solution of a strong acid (e.g. , hydrochloric acid) .
  • This mixture is heated to reflux for about 1 to about 10 hours to hydrolyze the amide bond.
  • the proline is then recovered by conventional means and recycled as the free amino acid or its hydrochloride salt.
  • the preferred embodiment of this invention which is useful in preparing captopril and its analogues pertains to a method for the production of a compound of the formula XXVIII
  • a further description of the compounds prepared by this method includes the compounds of the formula XXVII: 1. wherein R is hydroxy, R. is lower alkyl wherein said lower alkyl is methyl, R 3 is hydrogen, 4S-hydroxy or 4S-arylthio, n is 1, m is 3, C has an Si configuration and C. has an L configuration.
  • Another embodiment of this invention which is useful in preparing captopril and its analogues pertains to a method for the production of a compound of the formula
  • a further description of the compounds prepared by this method includes the compounds of the formula XXVII: wherein R- is selected from the group consisting of L-proline and substituted L-proline wherein the substituted L-proline is selected from the group consisting of 4S_-(phenylthio)-L-proline and 4S-hydroxy L-proline.
  • a further embodiment of this invention which is useful in preparing captopril and its analogues pertains to a method for the production of a compound of the formula XXX and basic salts thereof, wherein all of the substituent groups are defined above, comprising: a) preparing a mixture of diastereomers of a compound of formula V wherein the diastereomeric mixture contains two stereoisomers which have opposite configurations
  • a further description of the compounds prepared by this method includes the compounds of the formula XXVII: wherein R_ is selected from the group consisting of L-proline and substituted L-proline wherein the substituted L-proline is selected from the group consisting of 4S-(phenylthio)-L-proline and 4S-hydroxy L-proline.

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Abstract

Cette invention concerne de nouveaux procédés de conversion d'un mélange diastéréomère de dérivés protégés par S d'un inhibiteur oralement actif d'une enzyme de conversion d'angiotensine (ACE) et ses analogues en ces composants diastéréomères séparés résolus optiquement. Plus particulièrement, l'invention concerne des procédés de préparation de captopril optiquement purifiés et ses analogues à partir de précurseurs racémiques. Ce procédé de résolution est effectué par crystallisation fractionnaire de dérivés protégés par S de captopril et ses précurseurs, lesquels dérivés sont utiles car (1) ils sont facilement préparés à partir de nouveaux précurseurs, (2) ils sont réductibles en leurs espèces stéréoisomères optiquement purifiées et (3) ils sont convertibles en des espèces stéréoisomères non dérivées qui correspondent à l'inhibiteur pharamacologiquement actif et ses analogues. De nouveaux procédés de préparation des dérivés et de leurs précurseurs sont également décrits. De plus, les nouveaux dérivés et leurs précurseurs sont également décrits dans la présente invention.
EP19890910744 1988-09-13 1989-09-12 Methods for preparing captopril and its analogues Withdrawn EP0434743A4 (en)

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US24420388A 1988-09-13 1988-09-13
US244203 1988-09-13

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EP0434743A4 true EP0434743A4 (en) 1991-09-25

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JP (1) JPH04500673A (fr)
AU (1) AU4304789A (fr)
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Publication number Priority date Publication date Assignee Title
HU208954B (en) * 1990-09-21 1994-02-28 Egyt Gyogyszervegyeszeti Gyar Process for producing 1-(3-mercapto-(2s)-methyl-1-oxo-propyl)-l-prolyn
US5026873A (en) * 1989-11-06 1991-06-25 E. R. Squibb & Sons, Inc. Process for direct isolation of captopril

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4105776A (en) * 1976-06-21 1978-08-08 E. R. Squibb & Sons, Inc. Proline derivatives and related compounds
GB2066252A (en) * 1979-12-29 1981-07-08 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of 1-(3-mercapto-/2s/-methylpropionyl)-pyrrolidine-/2s/-carboxylic acid
GB2066243A (en) * 1979-07-30 1981-07-08 Squibb & Sons Inc Iminothioacyldihydropyrazole carboxylic acid derivatives iminothioacylproline derivatives and related compounds
EP0035336A2 (fr) * 1980-02-26 1981-09-09 JOHN WYETH & BROTHER LIMITED Procédé de préparation de dérivés de proline et composés analogues
US4297282A (en) * 1979-03-02 1981-10-27 Sumitomo Chemical Company, Limited Resolution of mercaptopropionic acids

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4046889A (en) * 1976-02-13 1977-09-06 E. R. Squibb & Sons, Inc. Azetidine-2-carboxylic acid derivatives
IT7851510A0 (it) * 1977-10-28 1978-10-16 Sandoz Ag Ammidi di amminoacidi ciclici loro preparazione e loro applicazione quali medicamenti
US4154934A (en) * 1978-08-11 1979-05-15 E. R. Squibb & Sons, Inc. Mercaptoacylamino derivatives of heterocyclic carboxylic acids

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4105776A (en) * 1976-06-21 1978-08-08 E. R. Squibb & Sons, Inc. Proline derivatives and related compounds
US4297282A (en) * 1979-03-02 1981-10-27 Sumitomo Chemical Company, Limited Resolution of mercaptopropionic acids
GB2066243A (en) * 1979-07-30 1981-07-08 Squibb & Sons Inc Iminothioacyldihydropyrazole carboxylic acid derivatives iminothioacylproline derivatives and related compounds
GB2066252A (en) * 1979-12-29 1981-07-08 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of 1-(3-mercapto-/2s/-methylpropionyl)-pyrrolidine-/2s/-carboxylic acid
EP0035336A2 (fr) * 1980-02-26 1981-09-09 JOHN WYETH & BROTHER LIMITED Procédé de préparation de dérivés de proline et composés analogues

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of WO9002732A1 *
Tetrahedron, Vol. 33, No. 38, 1977, pages 2725-2736; S.H. WILEN et al.: "Strategies in optical resolutions", whole article; especially chapter 4 (pages 2730-2732); figure 2. *

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IL91581A0 (en) 1990-04-29
IL91581A (en) 1993-07-08
AU4304789A (en) 1990-04-02
EP0434743A1 (fr) 1991-07-03
JPH04500673A (ja) 1992-02-06
WO1990002732A1 (fr) 1990-03-22

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