EP0432204A1 - Derives et precurseurs de captopril et ses analogues - Google Patents

Derives et precurseurs de captopril et ses analogues

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Publication number
EP0432204A1
EP0432204A1 EP89910020A EP89910020A EP0432204A1 EP 0432204 A1 EP0432204 A1 EP 0432204A1 EP 89910020 A EP89910020 A EP 89910020A EP 89910020 A EP89910020 A EP 89910020A EP 0432204 A1 EP0432204 A1 EP 0432204A1
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EP
European Patent Office
Prior art keywords
compound
proline
group
lower alkyl
formula
Prior art date
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Ceased
Application number
EP89910020A
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German (de)
English (en)
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EP0432204A4 (en
Inventor
Charles M. Zepp
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Sunovion Pharmaceuticals Inc
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Sepracor Inc
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Publication of EP0432204A1 publication Critical patent/EP0432204A1/fr
Publication of EP0432204A4 publication Critical patent/EP0432204A4/en
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    • 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
    • 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
    • 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 S-protected derivatives of an orally active inhibitor of an angiotensin-converting enzyme (ACE) and its analogues, which derivatives are useful for the reasons 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. Consequently, this invention also relates to the novel precursors. Novel methods for preparing the derivatives and their precursors are also noted herein. In addition, methods for converting the derivatives to the resolved de- derivatized stereoisomeric species of the ACE inhibitor and its analogues are described.
  • ACE angiotensin-converting enzyme
  • 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 d 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 levorotator .
  • 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 . 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 2___'3S-tartaric acid are diastereomers whereas 2R,3R- tartaric acid and 2 ⁇ 3,3 ⁇ -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.
  • a mixture of 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 (+)-S_-2-(6-methoxy-2- naphthyl)propanoic 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 S_(+) 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 he odynamic 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.
  • 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. Such diastereomeric mixtures are created by addition of a chiral and optically purified
  • ,_ diasteromers have different physical properties (e.g. , lb solubility) and are hence readily separable from one another.
  • Yoshioka et al. [U.S. Patent No. 3,879,451] treated a mixture of (4 -cis- and ( ⁇ J-trans- chrysanthemic acids with an optically active aromatic amine and recovered the resulting diastereomeric amine salts of
  • Halmos [U.S. Patent No. 4,151,198] treated a mixture of N-acyl-D ⁇ Lt ⁇ J-phenylalanine isomers with D(- )-2-(2,5-dime h lbenzylamino)-1-butanol to obtain a crystalline salt, from which N-acyl-L(+)-phenylalanine
  • 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
  • Cinchonidine, D-(-)-2- aminobutanol or a derivative thereof were used as fractional crystallization reagents.
  • 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.
  • optically active amines such as l-( ⁇ -naphthyl)-ethylamine and ⁇ ,j ⁇ -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 (C.J. Sih, PCT No. WO87/05328 p. 2) .
  • 2-methylpropanamide precursor used in a captopril synthesis Following the isolation of that resolved N-[3- halo-2-methylpropanoyl]proline, the amide can be converted . . . to the corresponding diastereomeric S-protected derivatives of 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,
  • Y 2 -COS-(CH 2 ) ⁇ -C IH 1 -C0 2 H wherein Y is an alkyl group, preferably C- g alkyl group, an aralkyl group, preferably C ? aralkyl group or an aryl group, preferably g _ 26 aryl group; Y is an alkyl group, preferably ⁇ ⁇ 1 _ 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 J is an alkyl group, preferably C1.—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 compounds which are thiol protected derivatives of pharmaceutically active inhibitors of Angiotensin-converting enzyme (ACE) .
  • ACE Angiotensin-converting enzyme
  • the novel compounds are useful in that, as diastereomeric mixtures resulting from non-stereospecific synthesis, they readily undergo a fractional crystallization process referred to herein as "self fractional crystallization,” which allows the isolation of a single optically pure derivative of the desired biologically active compound.
  • This derivative is readily converted to the pure pharmaceutically active stereoisomer of the ACE inhibitor by removal of a thiol protecting group.
  • ACE inhibitor derivatives are also novel compounds which are included in the subject matter of this invention.
  • 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 wherein the compositions of matter are amide compounds having an S-protected thiol moiety. Also included are intermediates useful in the preparation of these novel S-functionalized amide compounds.
  • 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".
  • S-protected drug precursor requires no further stereochemical purification. This self-fractional crystallization behavior is attributed to the physical properties resulting from the novel thiol protecting group.
  • racemic S-functionalized c carboxylic acid compounds are covered by this invention, as are the S-functionalized amide compounds which result from their reactions with alpha-amino acids or alpha-amino 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 isomer of the desired compound.
  • reaction of the claimed racemic S-functionalized carboxylic acid compound (after conversion to a suitable acylating
  • Embodiments of this invention pertain to compositions of matter which are capable of 0 . . . undergoing self-fractional crystallization and which, by further chemical processing, are readily converted to the stereochemically enriched form of biologically active compounds. Methods of making such novel compounds and methods of converting them to biologically active agents 5
  • captopril e.g. captopril and its analogues
  • R- 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 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, phenoxy, hydroxy, thiol, alkylthio, arylthio, halide, phenyl and substituted phenyl, and 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 hydroxyl and R is hydrogen) and - ⁇ substituted L-proline selected from the group consisting of
  • R_ and R groups are each represented as such to note that they can substitute for any methylene (-CH -) 2 hydrogen(s) of the ring.
  • the 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) .
  • the preferred embodiment of this invention comprises novel compositions of matter pertaining to a compound of the formula III
  • R is selected from the group consisting of hydroxy, amino and lower alkoxy; is selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halide, phenyl and substituted phenyl; R is selected from the
  • 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 S or R configuration; C. has a D or L configuration; n is 1, 2 or 3; and basic salts
  • inventions also encompass the compound of formula III wherein said cyclic secondary amino has the formula I as described above; said R_ is an
  • ,15_ imino which has the formula NRo, wherein Ro, 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
  • R is hydroxy
  • R is lower alkyl wherein said lower alkyl is methyl
  • R trash is S .
  • R trash 25 2 ' 3 is hydrogen, 4S_-hydroxy or 4£3-phenylthio, n is
  • R. is a cyclic secondary amino of the formula I above wherein R_ is hydrogen and p is
  • lower alkoxy is methoxy or t-butoxy
  • R is lower alkyl wherein said lower alkyl is methyl
  • S , R- is hydrogen, 4S_-hydroxy or 4S-phenylthio ,
  • 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; and 3) wherein R is lower alkoxy wherein said lower alkoxy is methoxy, R. is lower alkyl wherein said lower alkyl is methyl, R is 0, R 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- is hydrogen and p is 3, and C. has an L configuration.
  • Another embodiment of this invention comprises novel compositions of matter pertaining to a compound of the formula IV
  • R_ is S, R. is a cyclic secondary amino of formula I above wherein R ⁇ is hydrogen and p is 3, and R_ is a) L-proline or b) substituted L-(proline) wherein the substituted L-proline is
  • Another preferred embodiment of this invention comprises novel compositions of matter pertaining to a compound of the formula V r
  • R Thallium is selected from the group consisting of 0 and S; R q is pyrrolidino; and basic salts thereof wherein all the other substituents are defined as above.
  • FIG. 1 For embodiments of this invention, embodiments of this invention include a compound: 1) wherein Rg is S, and R 7 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 i is part.
  • R 1 Q is selected from the group consisting of lower alkoxy and hydroxy, and basic salts thereof wherein the other substituents are defined as above.
  • R. is lower alkyl wherein said lower alkyl is methyl
  • E. 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 1Q is hydroxy.
  • captopril and its analogues which undergo self-fractional crystallization whereby the diastereomeric species are convertable to captopril and its analogues is also described.
  • the derivatives are useful since they are incorporated with the S-protecting groups which make them susceptible to self-fractional crystallization.
  • Such derivatives can be de-protected to form desirable diastereomeric amides, or hydrolyzed to form diastereomeric amines (Fig. 1) .
  • 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
  • R 11 is imino, and the other substituents are defined above, comprises:
  • step b) converting said compound of the formula XVIII 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
  • step d) reacting said formed acylating agent of step c) with a compound of the formula II to form said compound of the formula IX; and e) isolating said compound of the formula IX.
  • 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.
  • 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
  • the desired product either crystallizes spontaneously from solution or is induced to crystallize by the addition of a non-solvent. After chilling to about
  • 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 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 C to about 25°C. After about 10 minutes to about
  • 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.
  • an organic base for example, pyridine
  • the solution is washed with aqueous acid to remove the base.
  • 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 crystallization.
  • the reaction of the precursor with carboxyl-substituted heterocyclic amine compounds of the formula II and more specifically proline or substituted proline, whereby the protected thiol derivatives of captopril and its analogues are easily prepared, is of particular interest.
  • the precursor is useful since it is incorporated with the S-functionalized substituent which facilitates the previously noted derivative's susceptibility to self-fractional crystallization upon its formation from that precursor.
  • 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
  • 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:
  • 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. 5.2.3 PREPARATIONS OF CAPTOPRIL AND ITS ANALOGUES FROM THEIR THIOL-PROTECTED DERIVATIVES
  • captopril and captopril analogues as the racemic mixture or chiral species is also known.
  • the preparation of captopril and captopril analogues as the racemic mixture or chiral species is also known.
  • 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 0 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) 5 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.
  • 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 alkaline metal 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.
  • 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. After cooling, 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 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.
  • One method which is useful in preparing captopril and its analogues pertains to a method for the production of a compound of the formula XXVIII
  • Another method which is useful in preparing captopril and its analogues pertains to a method for the production of a compound of the formula XXX
  • Another method 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, comprises: a) preparing a mixture of diastereomers of a compound of formula V wherein the diastereomeric mixture contains two stereoisomers which have opposite configurations at Ca; and basic salts thereof; b) preparing a solution of said mixture of said diastereomers in a solvent; c) allowing predominantly one diastereomer of said mixture to crystallize from the resulting solution, said solution becoming enriched in the other diastereomer; d) separating said crystallized and resolved diastereomer from said resulting solution containing said other resolved diastereomer; e) removing the thiol protecting substituent of the formula XXXI
  • a solution of the compound of formula XXXII (750 g, 3.21 m) was prepared in 4.0 1 of dichloromethane and was chilled in an ice bath to 15°C.
  • Thionyl chloride (382 g, 234.5 ml, 3.21 m) was run into this stirred solution over the course of 15 minutes.
  • the slurry thus formed was stirred on ice for 1/2 hour, after which L-proline (370 g, 3.21 m) was added.
  • the pyridine (763 g) was dripped in over a 45 minute period, the temperature being kept at less than 25°C by use of an ice bath. Upon complete addition of the pyridine, the solution was stirred at room temperature for 1 hour.
  • captopril as an oil.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

Cette invention concerne de nouveaux dérivés protégés par S d'un inhibiteur actif par voie orale d'une enzyme de conversion d'angiotensine (ACE) et ses analogues, lesquels dérivés sont utiles pour les raisons suivantes: (1) ils sont facilement préparés à partir de nouveaux précurseurs, (2) ils sont réductibles en leurs espéces stéréoisomères optiquement purifiées et (3), ils sont convertibles en des espèces stéréoisomères non dérivées qui correspondent à l'inhibiteur pharmacologiquement actif et ses analogues. En conséquence, cette invention concerne également les nouveaux précurseurs. De nouveaux procédés de préparation des dérivés et de leurs précurseurs sont également décrits. De plus, des procédés de conversion des dérivés en ces espèces stéréoisomères réduites et dé-dérivées de l'inhibiteur ACE et ses analogues sont décrits.
EP19890910020 1988-08-26 1989-08-25 Derivatives and precursors of captopril and its analogues Ceased EP0432204A4 (en)

Applications Claiming Priority (2)

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US23760588A 1988-08-26 1988-08-26
US237605 1988-08-26

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EP0432204A1 true EP0432204A1 (fr) 1991-06-19
EP0432204A4 EP0432204A4 (en) 1992-08-12

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EP19890910020 Ceased EP0432204A4 (en) 1988-08-26 1989-08-25 Derivatives and precursors of captopril and its analogues

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EP (1) EP0432204A4 (fr)
JP (1) JPH04503662A (fr)
AU (1) AU4200489A (fr)
IL (1) IL91444A (fr)
IN (1) IN170190B (fr)
WO (1) WO1990002118A1 (fr)

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KR100418901B1 (ko) * 2001-09-04 2004-02-14 엘지전자 주식회사 건조세탁기의 오버플로우장치
US7169805B2 (en) 2003-05-28 2007-01-30 Nicox S.A. Captopril derivatives

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GB2066243A (en) * 1979-07-30 1981-07-08 Squibb & Sons Inc Iminothioacyldihydropyrazole carboxylic acid derivatives iminothioacylproline derivatives and related compounds
DD235929A1 (de) * 1979-11-28 1986-05-21 Wolfen Filmfab Veb Verfahren zur chemischen sensibilisierung fotografischer silberhalogenidemulsionen
GB2170806A (en) * 1985-02-11 1986-08-13 Boryung Pharm N-(b-mercapto-iso-butyryl)proline, derivatives and a process for their preparation

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US4372960A (en) * 1980-12-12 1983-02-08 Warner-Lambert Company Quaternary derivatives of N-(substituted-aminoalkyl)-2-oxo-1-pyrrolidine-acetamides as cognition activators
IT1224168B (it) * 1986-08-01 1990-09-26 Finanziaria R F Spa Ora Finanz Derivati del pirrolidin-2-one ad attivita' nootropa

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Publication number Priority date Publication date Assignee Title
GB2066243A (en) * 1979-07-30 1981-07-08 Squibb & Sons Inc Iminothioacyldihydropyrazole carboxylic acid derivatives iminothioacylproline derivatives and related compounds
DD235929A1 (de) * 1979-11-28 1986-05-21 Wolfen Filmfab Veb Verfahren zur chemischen sensibilisierung fotografischer silberhalogenidemulsionen
GB2170806A (en) * 1985-02-11 1986-08-13 Boryung Pharm N-(b-mercapto-iso-butyryl)proline, derivatives and a process for their preparation

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CHEMICAL ABSTRACTS, vol. 106, 1987, Columbus, Ohio, US; abstract no. 58866K, SCHROETER D.; DIETZSCH, W.; HOYER E.; STEINECKE G.: 'Chemical sensitization of silver halide photographic emulsions. & DD-A-235 929 (VEB Filmfabrik Wolfen) 21 May 1986' page 590 *
CHEMICAL ABSTRACTS, vol. 87, 1977, Columbus, Ohio, US; abstract no. 52725F, MUSTAFAEV N.P. ET. AL.: 'Synthesis and study of some dithiocarbamic acid esters & Zh. Org. Khim. 1977, 13(5),985-90 ' *
CHEMICAL ABSTRACTS, vol. 97, 1982, Columbus, Ohio, US; abstract no. 5495C, KLEINPETER E.; BEHRENDT S.; BEYER L.; DIETZSCH W.; BORSDORF R.: 'Dynamic NMR studies of the restricted rotation at the NC(X) bonding fragment, & J. Prakt. Chem. 1982, 324(1), 29-45.' page 537 *
See also references of WO9002118A1 *

Also Published As

Publication number Publication date
JPH04503662A (ja) 1992-07-02
IL91444A (en) 1994-12-29
AU4200489A (en) 1990-03-23
WO1990002118A1 (fr) 1990-03-08
EP0432204A4 (en) 1992-08-12
IN170190B (fr) 1992-02-22
IL91444A0 (en) 1990-04-29

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