WO2005010028A1 - Alpha-amino acid benzothiazolylthio ester as intermediates for manufacture of ace inhibitors and process for preparation thereof - Google Patents

Alpha-amino acid benzothiazolylthio ester as intermediates for manufacture of ace inhibitors and process for preparation thereof Download PDF

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Publication number
WO2005010028A1
WO2005010028A1 PCT/IN2003/000257 IN0300257W WO2005010028A1 WO 2005010028 A1 WO2005010028 A1 WO 2005010028A1 IN 0300257 W IN0300257 W IN 0300257W WO 2005010028 A1 WO2005010028 A1 WO 2005010028A1
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formula
lower alkyl
group
tri
carbon atoms
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PCT/IN2003/000257
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English (en)
French (fr)
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Girij Pal Singh
Himanshu Madhav Godbole
Pravin Raghunath Mahajan
Sagar Purushottam Nehate
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Lupin Limited
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Priority to AU2003272077A priority Critical patent/AU2003272077A1/en
Priority to PCT/IN2003/000257 priority patent/WO2005010028A1/en
Publication of WO2005010028A1 publication Critical patent/WO2005010028A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms

Definitions

  • the present invention relates to novel compounds of formula (I), being intermediates for the manufacture of ACE inhibitors of formula (II)
  • R is a lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 is hydrogen or lower alkyl of 1-4 carbon atoms
  • R 2 is lower alkyl of 1-4 carbon atoms or lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group
  • Z is an amino acid or its derivative thereof .
  • This invention further provides novel method for preparation of compounds of formula 20 1 and formula II as well as the preparation of lisinopril in high diastereomeric selectivity.
  • Hypertension is currently treated in one of the five ways, viz. with (a) Diuretics, which increase the elimination of sodium;
  • ACE Angiotensin Converting Enzyme
  • ACE Angiotensin Converting Enzyme
  • ACE inhibitors of formula (II) could be manufactured in high diastereomeric selectivity through a novel activated ester of the carboxylic acid fragment (III), viz 2'- benzothiazolylthio ester, which is simple and cost-effective in comparison to the known methods for synthesis of such ACE inhibitors
  • novel 2'- benzothiazolylthio esters in turn can be prepared from the respective carboxylic acid fragment (III) in a simple manner, utilizing cheap and readily available raw materials SUMMARY OF THE INVENTION
  • R is a lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 is hydrogen or lower alkyl of 1-4 carbon atoms
  • R 2 is lower alkyl of 1-4 carbon atoms or lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group.
  • R is a lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 is hydrogen or lower alkyl of 1-4 carbon atoms
  • R 2 is lower alkyl of 1-4 carbon atoms or lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group comprising either,
  • Y is a hydroxy group (-OH)
  • R is a lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 is lower alkyl of 1-4 carbon atoms
  • R 2 is lower alkyl of 1-4 carbon atoms or lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group with 2,2'-dithio bis[benzthiazol] of formula (V)
  • Y is halogen
  • R is a lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 is lower alkyl of 1-4 carbon atoms
  • R 2 is lower alkyl of 1-4 carbon atoms or lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group with 2-mercaptobenzothiazole of formula (VI)
  • R is a lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 is hydrogen or lower alkyl of 1-4 carbon atoms
  • R 2 is lower alkyl of 1-4 carbon atoms or lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group
  • Z is an amino acid selected from those given in Chart-I
  • R is a lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 is hydrogen or lower alkyl of 1-4 carbon atoms
  • R 2 is lower alkyl of 1-4 carbon atoms or lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group
  • R 3 is hydrogen or an easily removable carboxyl protective group in the presence of an inert, non-hydroxy- containing organic solvent and optionally in the presence of a base at a temperature ranging from -20° C to -5° C, with the proviso that when R 3 is hydrogen compounds of formula (II) and their pharmaceutically acceptable salts thereof are obtained directly and when R 3 is a carboxyl protective group, removal of the said protective group give compounds of formula (II) and their pharmaceutically acceptable salts thereof.
  • R 3 Hydrogen or Protective Group Scheme-in : Novel Method For Synthesis of ACE Inhibitors of Formula (II) As Per The Present Invention
  • R 4 and R 5 are either hydrogen or a amino and carboxyl protective group respectively; with a compound of formula (IN ),
  • R 6 is hydrogen or lower alkyl of 1-4 carbon atoms; the asterik (*) on the carbon bearing the (-COOR 6 ) group is either racemic having the (R/S) configuration or has the (Reconfiguration; and L is a leaving group, in the presence of a base and in the presence of an inert solvent at a temperature of between -80° C to +80° C to give a novel compound of formula (IN 5 ), wherein R 4 and R 5 are a amino and carboxyl protective group respectively and R 6 is hydrogen or lower alkyl of 1-4 carbon atoms and the asterik (*) on the carbon bearing the (-COOR 6 ) group is either racemic having the (R/S) configuration or has the (S)-conf ⁇ guration; and optionally removal of the protective group R 5 to give compound of formula (IN ),
  • R 4 is an amino protective group and R 5 is hydrogen, or through reductive amination of an ⁇ -keto compound of formula (IV s ),
  • R 6 is as defined hereinearlier, with the L-lysine derivative of formula (IN ), in aqueous solution in the presence of sodium cyanoborohydride or reduction of the intermediate Schiff s base in an inert organic solvent and in the presence of a hydrogenation catalyst and a hydrogenation agent to give a novel compound of formula (IN 5 ), wherein R 4 and R 5 are a amino and carboxyl protective group respectively and R 6 is hydrogen or lower alkyl of 1-4 carbon atoms and the asterik (*) on the carbon bearing the (-COOR 6 ) group is either racemic having the (R/S) configuration or has the (S)-configuration; and optionally removal of the protective group R to give compound of formula (IN 5 ), wherein R 4 is an amino protective group and R is hydrogen, and
  • R 4 is an amino protective group and R 5 is hydrogen; R is hydrogen or lower alkyl of 1-4 carbon atoms and the asterik (*) on the carbon bearing the (- COOR 6 ) group is either racemic having the (R/S) configuration or has the (S)- configuration with
  • R 4 is an amino protective group and R 6 is hydrogen or lower alkyl of 1-4 carbon atoms and the asterik (*) on the carbon bearing the (-COOR 6 ) group is either racemic having the (R/S) configuration or has the (S)-configuration or reaction of compound of formula (IN 9 ),
  • R 4 is an amino protective group and R 5 is halogen ;
  • R 6 is hydrogen or lower alkyl of 1-4 carbon atoms and the asterik (*) on the carbon bearing the (- COOR 6 ) group is either racemic having the (R/S) configuration or has the (S)- configuration and X is a halogen atom, with
  • R 4 is an amino protective group and R is hydrogen or lower alkyl of 1-4 carbon atoms and the asterik (*) on the carbon bearing the (-COOR 6 ) group is either racemic having the (R/S) configuration or has the (S)-configuration, with a L-proline derivative of formula (VII 1 ),
  • R 4 is an amino protective group and R 6 is hydrogen or lower alkyl of 1-4 carbon atoms and the asterik (*) on the carbon bearing the (-COOR 6 ) group is either racemic having the (R/S) configuration or has the (S)-configuration, and iv) removal of protective groups from compound of formula (II 3 ), and optionally separating the diastereomers to give lisinopril of formula (II 2 ).
  • Y is hydroxyl
  • R is lower alkyl of 1-4 carbon atoms or is phenyl
  • R 1 is hydrogen or lower alkyl of 1-4 carbon atoms
  • R 2 is lower alkyl of 1-4 carbon atoms with 2,2'-dithio bis[benzthiazol] of formula (N),
  • the reaction is suitably effected in the presence of a tri-(lower alkyl)- or tri-(aryl)- phosphine or phosphite and in the presence of an inert, non-hydroxy-containing organic solvent and optionally in the presence of a base at a temperature ranging between -30° C to +50° C to give compounds of formula (I), wherein R 1 is lower alkyl of 1-4 carbon atoms and optionally removal of the lower alkyl ester group to give compounds of formula (I), wherein R 1 is hydrogen,
  • Suitable tri-(lower alkyl) phosphines include trimethyl phosphine, triethylphosphine, tri-n-propyl phosphine, triisopropyl phosphine, tri-n-butyl phosphine, tri-isobutyl phosphine, tri-t-butyl phosphine and the like.
  • Suitable tri-(lower alkyl) phosphites include trimethyl phosphite, triethylphosphite, tri- n-propyl phosphite, triisopropyl phosphite, tri-n-butyl phosphite and the like.
  • Suitable tri-(aryl) phosphines include triphenyl phosphine, tri (p-methoxyphenyl) phosphine, tri (o-chlorophenyl) phosphine, tri (p-chlorophenyl) phosphine, tri (m-tolyl) phosphine, tri (o-tolyl) phosphine, tri (p-tolyl) phosphine, tri (m-bromophenyl) phosphine, tri (p-bromophenyl) phosphine, tri (p-iodophenyl) phosphine, tri (p-n- propylphenyl) phosphine, tri (p-tert-butylphenyl) phosphine, tri (p-isopropoxyphenyl) phosphine and the like
  • Suitable tri-(aryl) phosphites include triphenyl phosphite, tri (p-methoxyphenyl) phosphite, tri (o-chlorophenyl) phosphite, tri (p-chlorophenyl) phosphite, tri (m-tolyl) phosphite, tri (o-tolyl) phosphite, tri (p-tolyl) phosphite, tri (m-bromophenyl) phosphite, tri (p-bromophenyl) phosphite, tri (p-iodophenyl) phosphite, tri (p-n-propylphenyl) phosphite, t ⁇ (p-tert-butylphenyl) phosphite, tri (p-isopropoxyphenyl) phosphite and the like
  • Tri-(lower alkyl) phosphines and tri (aryl) phosphines are preferred over the tri-(lower alkyl) phosphites and tri (aryl) phosphates Among the tri (lower alkyl) phosphines and the tri (aryl) phosphines, the tri (aryl) phosphines are preferred Among the tri (aryl) phosphines, the more preferred is triphenyl phosphine, primarily because of commercial availability
  • the tri (lower alkyl) phosphines or phosphites and the tri (aryl) phosphines or phosphites are employed in molar proportions of 1 0 to 2 0 moles per mole of compound of formula (IN 1 ), in particular 1 0 to 1 50 moles per mole of compound of formula (IN 1 ), preferably 1 0 to 1 30 moles per mole of compound of formula (IN 1 )
  • the reaction can be carried out in the presence of or absence of an organic base There is no material difference in both sets of reactions and both give compounds of formula (I) possessing substantially identical purity in substantially identical yield
  • the organic bases that can be used are selected from triethylamine, pyridine, 2,3- diaminopyridine, 2,4-diaminopyridine, ⁇ -methyl morpholine and the like Triethylamine is preferred, primarily because of its low cost and commercial availability.
  • the base is employed in molar proportions of 1.0 to 5.0 moles per mole of compound of formula (IN 1 ), preferably in molar proportions of 1.0 to 3.0 moles per mole of compound of formula (IN 1 ).
  • the reaction is suitably effected in an inert, non-hydroxy-containing organic solvent.
  • a non-hydroxy-containing organic solvent is meant to include and cover organic solvents, which do not contain a hydroxyl (-OH) group. Such non-hydroxy- containing organic solvents are further inert.
  • inert organic solvent is meant an organic solvent which, under the reaction conditions does not enter into any appreciable reaction with either the reactants or the products.
  • the inert, non-hydroxy-containing organic solvents that can be used for the reaction include hydrocarbons, both aliphatic and aromatic, including pentane, hexane, heptane, octane, cyclopentane, cyclohexane and cycloheptane, toluene, m-, o- or p- xylene, benzene, mesitylene and the like; ethers, cyclic and acyclic such as diethyl ether, butyl ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2- dimethoxyethane and the like; carboxylic acid esters such as ethyl acetate, methyl formate, methyl acetate, amyl acetate, n-butyl acetate, sec-butyl acetate, tert-butyl acetate, methyl propy
  • the particular inert, non-hydroxy-containing organic solvent employed as a medium for the preparation of compounds of formula (I) or as a medium for their use in preparation of ACE inhibitors of formula (II) is not critical, however, such solvent properties like polarity, melting or boiling point, and ease of isolation of compounds of formula (I) may be considered in selecting a most suitable solvent.
  • Preferred solvents for the preparation of compounds of formula (I) as per the present process described hereinbelow are hydrocarbons, especially aromatic hydrocarbons; carboxylic acid esters, especially ethyl acetate; ether, especially tetrahydrofuran; and halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the most preferred solvents are halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the reaction temperature may for example be from -30° C to +50° C, in particular -10° C to +30° C, preferably -5° C to + 20° C.
  • 2,2'-dithio bis[benzthiazol] of formula (V) which is commercially available is employed in molar proportions of 1.0 to 2.0 moles per mole of compound of formula (IV 1 ), in particular 1.0 to 1.50 moles per mole of compound of formula (IN 1 ), preferably 1.0 to 1.30 moles per mole of compound of formula (IN 1 ).
  • the tri (lower alkyl) phosphine/phosphite or the tri (aryl) phosphine/phosphite is dissolved in the inert, non-hydroxy-containing organic solvent, to which is added 2,2'-dithio bis[benzthiazol] of formula (N).
  • the reaction mixture is agitated for 45 to 60 mns at a temperature of 20° C to 30° C. Thereafter, the reaction mixture is cooled to -10° C to + 10° C to which is added the carboxylic acid compound of formula (IN 1 ), wherein R 1 is hydrogen or lower alkyl of 1-4 carbon atoms; R 2 is lower alkyl of 1-4 carbon atoms, followed by addition of the base.
  • reaction mixture is agitated at the same temperature for 45 to 60 mns and thereafter gradually increased to 20° C to 30° C and agitated at the same temperature for about 2 to 5 hrs.
  • Evaporation of the solvent gives compound of formula (I), wherein R 1 is lower alkyl of 1-4 carbon atoms; R is lower alkyl of 1-4 carbon atoms, which can be used as such for use in preparation of ACE inhibitors of formula (II) or can be purified by conventional methods prior to use.
  • compound of formula (I) can be prepared as per the abovementioned method, but in the absence of a base.
  • Compounds of formula (I), wherein R 1 is hydrogen; R 2 is lower alkyl of 1-4 carbon atoms can be prepared by removal of the lower alkyl ester groups of compounds of formula (I), wherein R 1 is lower alkyl of 1-4 carbon atoms; R 2 is lower alkyl of 1-4 carbon atoms.
  • the present invention provides 2'-benzthiazolyl thioester of N-[1(S)- ethoxycarbonyl butyl]-(S)-alanine of formula [I 1 , corresponding to compound of formula (I), wherein R is methyl, R 1 is ethyl; R 2 is methyl] and a method of preparation thereof and 2'-benzthiazolyl thioester of N-[l(S)-ethoxycarbonyl-3-phenylpropyl]-(S)- alanine of formula [I , corresponding to compound of formula (I), wherein R is phenyl, R 1 is ethyl; R 2 is methyl] and a method of preparation thereof.
  • Compound (I 1 ), corresponding to compound of formula (I), wherein R is methyl, R 1 is ethyl and R 2 is methyl is useful as an intermediate for preparation of the ACE inhibitor, Perindopril; whereas compound (I 2 ), corresponding to compound of formula (I), wherein R is phenyl, R 1 is ethyl and R 2 is methyl is useful as an intermediate for preparation of the ACE inhibitors such as Delapril, Enalapril, Imidapril., Moexipril, Quinapril, Ramipril, Spirapril, and Trandolapril.
  • 2'-benzthiazolyl thioester of N-[l(S)-ethoxycarbonyl butyl]- (S)-alanine of formula (I 1 ), corresponding to compound of formula (I), wherein R is methyl, R 1 is ethyl; R 2 is methyl can be prepared by dissolving triphenyl phosphine in an inert, non-hydroxy-containing organic solvent. To the solution is added 2,2'-dithio bis[benzthiazol] of formula (V). The reaction mixture is agitated for 45 to 60 mns at a temperature of 20° C to 30° C.
  • reaction mixture is cooled to -10° C to + 10° C to which is added N-[l(S)-ethoxycarbonyl butyl]-(S)-alanine (IN 1 ), corresponding to compound of formula (IN), wherein R is methyl, R 1 is ethyl; R 2 is methyl followed by addition of the base.
  • the reaction mixture is agitated at the same temperature for 45 to 60 mns and thereafter gradually increased to 20° C to 30° C and agitated at the same temperature for about 2 to 5 hrs. Evaporation of the solvent gives compound of formula (I 1 ) as an oil.
  • the oil can be chromatographed over silica gel using a mixture of chloroform and petroleum ether (40-60° C) in a ratio of 3:7 as eluent to give a pure product, which exhibits the following spectral characteristics.
  • 2 '-benzothiazolylthio ester of N-[l(S)-ethoxycarbonyl- 3-phenylpropyl]-(S)-alanine of formula [I 2 , corresponding to compound of formula (I), wherein R is phenyl, R 1 is ethyl; R 2 is methyl] can be prepared by dissolving triphenyl phosphine in an inert, non-hydroxy-containing organic solvent. To the solution is added 2,2'-dithio bis[benzthiazol] of formula (V). The reaction mixture is agitated for 45 to 60 mns at a temperature of 20° C to 30° C.
  • reaction mixture is cooled to - 10° C to + 10° C to which is added N-[l(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanine (IV 1 ), corresponding to compound of formula (IN), wherein R is phenyl, R 1 is ethyl; R 2 is methyl, followed by addition of the base.
  • the reaction mixture is agitated at the same temperature for 45 to 60 mns and thereafter gradually increased to 20° C to 30° C and agitated at the same temperature for about 2 to 5 hrs. Evaporation of the solvent gives compound of formula (I 2 ) as an oil.
  • the oil can be chromatographed over silica gel using a mixture of chloroform and petroleum ether (40-60° C) in a ratio of 3:7 as eluent to give a pure product, which exhibits the following spectral characteristics.
  • carboxylic acid compounds of formula (IN 1 ) used for preparation of compounds of formula (I) are known and are commercially available or can be prepared by methods known in the art.
  • R is lower alkyl of 1-4 carbon atoms or is phenyl; R 1 is hydrogen or lower alkyl of 1-4 carbon atoms; and R 2 is lower alkyl of 1-4 carbon atoms,
  • the reaction is suitably effected in the presence of an inert, non-hydroxy-containing organic solvent and in the presence of a base.
  • halogen refers to an halogen atom selected from chlorine, bromine or iodine.
  • the organic bases that can be used are selected from triethylamine, pyridine, 2,3- diaminopyridine, 2,4-diaminopyridine, ⁇ -methyl morpholine and the like. Triethylamine is preferred, primarily because of its low cost and commercial availability.
  • the base is employed in molar proportions of 1.0 to 5.0 moles per mole of compound of formula (IN 2 ), preferably in molar proportions of 1.0 to 3.0 moles per mole of compound of formula (IN 2 ).
  • the reaction is suitably effected in an inert, non-hydroxy-containing organic solvent
  • a non-hydroxy-containing organic solvent has been defined hereinearlier in Section 1(a) and the same "inert, non-hydroxy-containing organic solvents" referred to hereinbefore in Section 1(a) can also be used herein for preparation of compounds of formula (I) by reaction of the acid halide of formula (IN 2 ) with 2- mercaptobenzothiazole of formula (NI)
  • inert, non-hydroxy-containing organic solvent employed as a medium for the preparation of compounds of formula (I) or as a medium for their use in preparation of ACE inhibitors of formula (II) is not critical, however, such solvent properties like polarity, melting or boiling point, and ease of isolation of compounds of formula (I) may be considered in selecting a most suitable solvent
  • Preferred solvents for the preparation of compounds of formula (I) as per the present process described hereinbelow are hydrocarbons, especially aromatic hydrocarbons, carboxylic acid esters, especially ethyl acetate, ether, especially tetrahydrofuran, and halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane
  • the most preferred solvents are halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane
  • the reaction temperature may for example be from -30° C to +50° C, in particular -10° C to +30° C, preferably -5° C to + 20° C
  • 2-mercaptobenzothiazole of formula (VI), which is commercially available is employed in molar proportions of 1 0 to 2 0 moles per mole of compound of formula (IN 2 ), in particular 1 0 to 1 50 moles per mole of compound of formula (IN 2 ), preferably 1 0 to 1 30 moles per mole of compound of formula (IN 2 )
  • 2'-benzthiazolyl thioester of N-[l(S)-ethoxycarbonyl butyl] - (S)-alanine of formula (I 1 ), corresponding to compound of formula (I), wherein R is methyl, R 1 is ethyl; R 2 is methyl can be prepared by dissolving 2- mercaptobenzothiazole of formula (VI) in a inert, non-hydroxy-containing organic solvent and the base. The reaction mixture is agitated for 45 to 60 mns at a temperature of 20° C to 30° C.
  • reaction mixture is cooled to -10° C to + 10° C to which is added N-[l(S)-ethoxycarbonyl butyl] -(S)-alanine carboxylic acid halide [IV 2 , corresponding to compound of formula (IN), wherein R is phenyl, R 1 is ethyl; R 2 is methyl].
  • the reaction mixture is agitated at the same temperature for 45 to 60 mns and thereafter gradually increased to 20° C to 30° C and agitated at the same temperature for about 2 to 5 hrs. Evaporation of the solvent gives compound of formula (I 1 ) as an oil.
  • the oil can be chromatographed over silica gel using a mixture of chloroform and petroleum ether (40-60° C) in a ratio of 3:7 as eluent to give a pure product, which exhibits the spectral characteristics given hereinbefore in Section 1(a).
  • 2'-benzthiazolyl thioester of N-[l(S)-ethoxycarbonyl- 3-phenylpropyl]-(S)-alanine of formula (I 2 ), corresponding to compound of formula (I), wherein R is phenyl, R 1 is ethyl; R 2 is methyl can be prepared by dissolving 2- mercaptobenzothiazole of formula (VI) in a inert, non-hydroxy-containing organic solvent and the base. The reaction mixture is agitated for 45 to 60 mns at a temperature of 20° C to 30° C.
  • reaction mixture is cooled to -10° C to + 10° C to which is added N-[l(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanine carboxylic acid halide [IV 2 , corresponding to compound of formula (IV), wherein R is phenyl, R 1 is ethyl; R 2 is methyl].
  • the reaction mixture is agitated at the same temperature for 45 to 60 mns and thereafter gradually increased to 20° C to 30° C and agitated at the same temperature for about 2 to 5 hrs. Evaporation of the solvent gives compound of formula (I 2 ) as an oil.
  • the oil can be chromatographed over silica gel using a mixture of chloroform and petroleum ether (40-60° C) in a ratio of 3:7 as eluent to give a pure product, which exhibits the spectral characteristics given hereinbefore in Section 1(a).
  • the starting carboxylic acid halide compounds of formula (IN 2 ) used for preparation of compounds of formula (I) can be prepared by methods known in the art, particularly by the method disclosed in GB Patent No. 2,095,252 as well as by our pending PCT Application No. PCT/IN03/00042, dated February 28, 2003.
  • R 4 and R 5 are either hydrogen or a amino and carboxyl protective group respectively;
  • R 6 is hydrogen or lower alkyl of 1-4 carbon atoms; and the asterik (*) on the carbon bearing the (-COOR 6 ) group is either racemic having the
  • Compound of formula (IN 5 ) is an useful intermediate for preparation of the novel compounds of formula (I), and thereby, in turn provides a novel method for preparation of the ACE inhibitor, lisinopril of formula (II 2 ).
  • the amino protective group corresponding to group R that can be employed are those protective groups routinely practiced in the art, specially those routinely used in peptide synthesis.
  • Suitable protective groups include but are not limited to a substituted benzyloxycarbonyl group such as a tertiary butoxycarbonyl group, benzyloxycarbonyl group, p-nitrobenzyloxy carbonyl group etc.; a urethane type protective group such as isobornyloxycarbonyl group etc.; an acyl type protective group such as trifluoroacetyl group, a formyl group, a phthaloyl group etc. Of these, in particular, trifluoroacetyl group is preferred, since it can be removed easily with alkali.
  • carboxyl protective group corresponding to group R are easily removable carboxyl protective groups routinely utilized in organic chemistry. These include inter alia, those forming an alkyl ester e.g. methyl, ethyl, tert-butyl esters; halo-lower alkyl esters e.g. 2-chloroethyl, 2,2,2,-trichloroethyl esters; lower acyl-lower alkyl esters e.g.
  • lower alkanoylmethyl 2-acetyl ethyl, phenacyl, p- bromophenacyl, ⁇ -benzoylbenzyl esters; lower alkoxy-lower alkyl esters e.g. methoxymethyl ester; lower acyloxy-lower alkyl esters e.g. acetoxymethyl, pivaloyloxymethyl, N,N- dimethylglycyloxymethyl, benzoyloxymethyl esters; lower lJ-dicarbo-lower alkoxyalkyl esters e.g. dicarbomethoxymethyl, dicarbethoxymethyl esters; lower aryl esters e.g.
  • phenyl, pyridyl esters optionally substituted by an inert group e.g. nitro, methoxy, or lower alkyl; aralkyl esters e.g. benzyl, benzhydryl, naphthylmethyl and pyridylmethyl esters optionally substituted by an inert group e.g. nitro, methoxy or lower alkyl; a trialkylsilyl group e.g. a tri (C ⁇ - )alkyl silyl, e.g. trimethylsilyl; and other groups known to those skilled in the art.
  • an inert group e.g. nitro, methoxy, or lower alkyl
  • aralkyl esters e.g. benzyl, benzhydryl, naphthylmethyl and pyridylmethyl esters optionally substituted by an inert group e.g. nitro, methoxy or lower alkyl
  • Preferred carboxyl protective groups are trialkylsilyl, specially trimethylsilyl and aralkyl, specially benzyl esters.
  • the asterik (*) on the carbon bearing the (-COOR 6 ) group is either racemic having the (R/S) configuration or has the preferred (S)-configuration, both of which falls within the scope of this invention.
  • Compound of formula (IN 5 ) can be prepared by any of the following methods, viz.
  • R 6 is hydrogen or lower alkyl of 1-4 carbon atoms; the asterik (*) on the carbon bearing the (-COOR 6 ) group is either racemic having the (R/S) configuration or has the (Reconfiguration; and L is a leaving group, in the presence of a base and in the presence of an inert solvent at a temperature between -80° C to +80° C to give compound of formula (IN 5 ), followed by optionally removal of the amino and carboxyl protective groups R 4 and R 5 to give compound of formula (IN 5 ), in which R 4 and R 5 are hydrogen.
  • compound of formula (IN 5 ) can be obtained in which the center of chirality (*) produced in the S ⁇ reaction is in the (S) or (R/S) configuration, depending on whether the center of chirality (*) in the starting material compound (IN 7 ) is in the (Reconfiguration or is racemic i. e. (R/S)-configuration.
  • the center of chirality (*) in the starting material compound (IN 7 ) is racemic i. e. in the (R/S)-configuration
  • the center of chirality (*) in the product obtained (IN 5 ) is also racemic i. e. giving the product as a diastereomeric mixture of (R)- and (S)- isomers.
  • the diastereomers can be separated by methods known in the art to give the desired product (IN 5 ), as the diastereomerically pure (S)-isomer.
  • the leaving group L in compound of formula (IN 7 ) are those groups amenable to easy nucleophilic displacement.
  • Such leaving groups include a tosyloxy or , mesyloxy group disclosed in US Patent No. 4 350 704; a trifluoromethanesulfonyloxy group as disclosed in US Patent No. 4 525 301; or a phenyl sulfonyloxy group or a phenyl sulfonyloxy group, wherein the phenyl is substituted by halogen, or nitro group, as disclosed in US Patent No. 5 066 801.
  • the trifluoromethanesulfonyloxy group and the phenyl sulfonyloxy group or a phenyl sulfonyloxy group, wherein the phenyl is substituted by halogen, or nitro group are the most preferred, since unlike the tosyloxy or mesyloxy leaving groups, they give the product, with little racemisation.
  • Compound of formula (IN 7 ) is typically employed in equimolar or in slight excess of the equimolar quantity with respect to the lysine derivative of formula (IN 6 ) used. Typically it is employed in a molar proportions of 1.0 to 1.20 moles per moles of compound of formula (IN 6 ).
  • Suitable bases that can be used in the reaction include inorganic salts, such as carbonates like sodium carbonate, potassium carbonate, lithium carbonate and cesium carbonate and organic bases, such as, for example, triethylamine, pyridine, 2,3- diaminopyridine, 2,4-diaminopyridine, ⁇ -methyl morpholine and the like.
  • the base can be used in the stoichiometric amount or in excess.
  • the base is employed in molar proportions of 1.0 to 5.0 moles per mole of compound of formula (IN 6 ), preferably in molar proportions of 1.0 to 3.0 moles per mole of compound of formula (IN 6 ).
  • Suitable inert solvents are those which cannot react with the leaving group L and can be selected from halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride etc.; hydrocarbons such as hexane, toluene etc.; alcohols such as methanol, ethanol, isopropanol etc.; nitriles such as acetonitrile, propionitrile etc.; ethers such as diethyl ether, dioxane, tetrahydrofuran etc.; and amides such as dimethylformamide, hexamethylphosphoramide etc.
  • the reaction in dichloromethane, chloroform or carbon tetrachloride is particularly preferred.
  • R 6 has the same meaning as defined hereinearlier with a L-lysine derivative of formula (IN 6 ),
  • R 4 and R 5 are either hydrogen or a amino and carboxyl protective group respectively, in aqueous solution in the presence of sodium cyanoborohydride or by reduction of the intermediate Schiff s base in an inert organic solvent and in the presence of a hydrogenation catalyst and a hydrogenation agent or gives compound of formula (IN 5 ).
  • the ⁇ -keto compound of formula (IN 8 ) is reacted with the L-lysine derivative of formula (IN 6 ) in aqueous solution or in a suitable inert organic solvent in the presence of sodium cyanoborohydride to give compound of formula (IN 5 ), in which the center of chirality (*) is racemic i. e. giving the product as a diastereomeric mixture of (R)- and (S)-isomers.
  • the diastereomers can be separated by methods known in the art to give the desired product (IN 5 ), as the diastereomerically pure (S)-isomer.
  • compound of formula (IN 5 ) may be catalytically reduced, for example, by hydrogenation in the presence of 10% palladium on carbon or Raney Nickel to yield compound of formula (IN 5 ), in which the center of chirality (*) is racemic i. e. giving the product as a diastereomeric mixture of (R)- and (S)-isomers.
  • the diastereomers can be separated by methods known in the art to give the desired product (IN 5 ), as the diastereomerically pure (S)-isomer.
  • Suitable inert solvents are those selected from halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride etc.; hydrocarbons such as hexane, toluene etc.; alcohols such as methanol, ethanol, isopropanol etc.; nitriles such as acetonitrile, propionitrile etc.; ethers such as diethyl ether, dioxane, tetrahydrofuran etc.; and amides such as dimethylformamide, hexamethylphosphoramide etc.
  • the reaction in dichloromethane, chloroform or carbon tetrachloride is particularly preferred.
  • ⁇ -[l(S)-l-ethoxycarbonyl-3-phenylpropyl]- ⁇ - trifluoroacetyl- L-lysine of formula (IN ) [corresponding to compound of formula (IN 5 ), wherein R 4 is trifluoroacetyl, R 5 is hydrogen and R 6 is ethyl] and ⁇ -[1(S)-1- ethoxycarbonyl-3-phenylpropyl]- L-lysine of formula (IN 5 ) [corresponding to compound of formula (IN 5 ), wherein R 4 is hydrogen, R 5 is hydrogen and R 6 is ethyl] can be prepared by anyone of the methods enumerated hereinabove.
  • compounds of formula (IN 5 ) and (IN 5" ) can be prepared the following way.
  • reaction mixture preferably in the same inert organic solvent and the reaction mixture agitated at 25-30° C for 18-20 hrs, till completion of reaction.
  • the reaction mixture is quenched with water and after separation of the organic layer and evaporation of the solvent the ⁇ - [l(S)-ethoxycarbonyl-3-phenylpropyl]- ⁇ 6 -trifluoroacetyl-L-lysine of the following formula (IN 10 ) is obtained as an oil.
  • the oil can be purified by chromatography over silica gel using a mixture of ethyl acetate and hexane as eluent to give a pure product having the following spectral and physical characteristics.
  • the benzyl protective group is removed under catalytic hydrogenation conditions known in the art in the presence of Group NIII transition metal catalysts.
  • the catalysts are selected from palladium on carbon, palladium on alumina, palladium on barium carbonate, palladium on barium sulfate, palladium on calcium carbonate, palladium on kieselguhr (diatomaceous earth), palladium on silica-alumina, palladium on silica-gel, palladium on strontium carbonate, palladium on tin oxide, palladium on titania, palladium hydroxide on carbon, platinum on carbon, platinum dioxide, platinum on alumina, platinum on barium carbonate, platinum on barium sulfate, platinum on calcium carbonate, platinum on kieselguhr (diatomaceous earth), platinum on silica- alumina, platinum on silica-gel, platinum on strontium carbonate, platinum on tin oxide, platinum on titania, iridium on carbon, iridium on alumina powder, rhodium on carbon, rhodium hydroxide on carbon, rhodium
  • the ⁇ -trifiuoroacetyl protective group can be removed by suitable methods to give the free amino compound (IN 5 " ),
  • the starting N 6 -trifluoroacetyl-S-lysine benzyl ester is prepared by benzylation of N 6 - trifluoroacetyl-S-lysine as per the conventional methods.
  • the N 6 -trifluoroacetyl-S- lysine can in turn be prepared by reaction of L-lysine hydrochloride and an alkyl trifluoroacetate as per the method described by T. J. Blacklock et. al, in /. Org. Chem., 1988, 53, 836-44.
  • novel compounds of formula (I) can be prepared by reacting a peptide derivative of formula (IN),
  • R is a lower alkyl of 1-4 carbon atoms or phenyl;
  • R 1 is hydrogen or lower alkyl of 1-4 carbon atoms;
  • R 2 is lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group;
  • Y is a hydroxy group (-OH)
  • novel compounds of formula (I) can be prepared by reacting the peptide derivative of formula (IN),
  • R is a lower alkyl of 1-4 carbon atoms or phenyl;
  • R 1 is lower alkyl of 1-4 carbon atoms;
  • R 2 is lower alkyl of 1-4 carbon atoms or lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group;
  • Y is halogen
  • the reaction is suitably effected in the presence of a tri-(lower alkyl)- or tri-(aryl)- phosphine or phosphite and in the presence of an inert, non-hydroxy-containing organic solvent and optionally in the presence of a base at a temperature ranging between -30° C to +50° C to give compounds of formula (I), wherein R 1 is lower alkyl of 1-4 carbon atoms and optionally removal of the lower alkyl ester group to give compounds of formula (I), wherein R 1 is hydrogen,
  • Suitable tri-(lower alkyl) phosphines include trimethyl phosphine, triethylphosphine, tri-n-propyl phosphine, triisopropyl phosphine, tri-n-butyl phosphine, tri-isobutyl phosphine, tri-t-butyl phosphine and the like.
  • Suitable tri-(lower alkyl) phosphites include trimethyl phosphite, triethylphosphite, tri- n-propyl phosphite, triisopropyl phosphite, tri-n-butyl phosphite and the like.
  • Suitable tri-(aryl) phosphines include triphenyl phosphine, tri (p-methoxyphenyl) phosphine, tri (o-chlorophenyl) phosphine, tri (p-chlorophenyl) phosphine, tri (m-tolyl) phosphine, tri (o-tolyl) phosphine, tri (p-tolyl) phosphine, tri (m-bromophenyl) phosphine, tri (p-bromophenyl) phosphine, tri (p-iodophenyl) phosphine, tri (p-n- propylphenyl) phosphine, tri (p-tert-butylphenyl) phosphine, tri (p-isopropoxyphenyl) phosphine and the like.
  • Suitable tri-(aryl) phosphites include triphenyl phosphite, tri (p-methoxyphenyl) phosphite, tri (o-chlorophenyl) phosphite, tri (p-chlorophenyl) phosphite, tri (m-tolyl) phosphite, tri (o-tolyl) phosphite, tri (p-tolyl) phosphite, tri (m-bromophenyl) phosphite, tri (p-bromophenyl) phosphite, tri (p-iodophenyl) phosphite, tri (p-n-propylphenyl) phosphite, tri (p-tert-butylphenyl) phosphite, tri (p-isopropoxyphenyl) phosphite and the like.
  • Tri-(lower alkyl) phosphines and tri (aryl) phosphines are preferred over the tri-(lower alkyl) phosphites and tri (aryl) phosphates.
  • the tri (aryl) phosphines are preferred.
  • the tri (aryl) phosphines the more preferred is triphenyl phosphine, primarily because of commercial availability.
  • the tri (lower alkyl) phosphines or phosphites and the tri (aryl) phosphines or phosphites are employed in molar proportions of 1.0 to 2.0 moles per mole of compound of formula (IV 3 ), in particular 1.0 to 1.50 moles per mole of compound of formula (IV 3 ), preferably 1.0 to 1.30 moles per mole of compound of formula (IN 3 ).
  • the reaction can be carried out in the presence of or absence of an organic base. There is no material difference in both sets of reactions and both give compounds of formula (I) possessing substantially identical purity in substantially identical yield.
  • the organic bases that can be used are selected from triethylamine, pyridine, 2,3- diaminopyridine, 2,4-diaminopyridine, ⁇ -methyl morpholine and the like. Triethylamine is preferred, primarily because of its low cost and commercial availability.
  • the base is employed in molar proportions of 1.0 to 5.0 moles per mole of compound of formula (IN 3 ), preferably in molar proportions of 1.0 to 3.0 moles per mole of compound of formula (IN 3 ).
  • the reaction is suitably effected in an inert, non-hydroxy-containing organic solvent.
  • a non-hydroxy-containing organic solvent has been defined hereinearlier in Section 1(a) and 1(b) and the same "inert, non-hydroxy-containing organic solvents" referred to hereinbefore in Section 1(a) can also be used herein for preparation of compounds of formula (I) by reaction of the acid halide of formula (IN ) with 2- mercaptobenzothiazole of formula (NI).
  • the particular inert, non-hydroxy-containing organic solvent employed as a medium for the preparation of compounds of formula (I) or as a medium for their use in preparation of ACE inhibitors of formula (II) is not critical, however, such solvent properties like polarity, melting or boiling point, and ease of isolation of compounds of formula (I) may be considered in selecting a most suitable solvent.
  • Preferred solvents for the preparation of compounds of formula (I) as per the present process described hereinbelow are hydrocarbons, especially aromatic hydrocarbons; carboxylic acid esters, especially ethyl acetate; ether, especially tetrahydrofuran; and halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the most preferred solvents are halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the reaction temperature may for example be from -30° C to +50° C, in particular -10° C to +30° C, preferably -5° C to + 20° C.
  • 2,2'-dithio bis[benzthiazol] of formula (N) which is commercially available is employed in molar proportions of 1.0 to 2.0 moles per rhole of compound of formula (IN 3 ), in particular 1.0 to 1.50 moles per mole of compound of formula (IN 3 ), preferably 1.0 to 1.30 moles per mole of compound of formula (IN 3 ).
  • the tri (lower alkyl) phosphine/phosphite or the tri (aryl) phosphine/phosphite is dissolved in the inert, non-hydroxy-containing organic solvent, to which is added 2,2'-dithio bis[benzthiazol] of formula (N).
  • the reaction mixture is agitated for 45 to 60 mns at a temperature of 20° C to 30° C.
  • reaction mixture is cooled to -10° C to + 10° C to which is added the carboxylic acid compound of formula (IN 3 ), wherein R 1 is hydrogen or lower alkyl of 1-4 carbon atoms; R 2 is lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group, followed by addition of the base.
  • the reaction mixture is agitated at the same temperature for 45 to 60 mns and thereafter gradually increased to 20° C to 30° C and agitated at the same temperature for about 2 to 5 hrs.
  • compound of formula (I) can be prepared as per the abovementioned method, but in the absence of a base.
  • the compound of formula (IN 3 ), which has the free amino function of group R 2 can be used as such for reaction with 2,2'-dithio bis[benzthiazol] of formula (N), however, it is preferable to protect the amino function of the group R 2 to give compound of formula (IN 3 ), in which the amino function is protected prior to reaction with compound of formula (N). Removal of the amino protective groups by suitable methods would then give compounds of formula (I), in which the amino function is free.
  • Suitable amino protective groups that can be employed are those routinely practiced in the art, specially those routinely used in peptide synthesis.
  • Suitable protective groups include but are not limited to a substituted benzyloxycarbonyl group such as a tertiary butoxy carbonyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group etc.; a urethane type protective group such as isobornyloxycarbonyl group etc.; an acyl type protective group such as trifluoroacetyl group, a formyl group, a phthaloyl group etc. Of these, in particular, trifluoroacetyl group is preferred, since it can be removed easily with alkali.
  • R is lower alkyl of 1-4 carbon atoms or is phenyl
  • R 1 is hydrogen or lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group
  • R 2 is lower alkyl of 1-4 carbon atoms
  • reaction is suitably effected in the presence of an inert, non-hydroxy-containing organic solvent and in the presence of a base
  • halogen refers to an halogen atom selected from chlorine, bromine or iodine
  • the organic bases that can be used are selected from triethylamine, pyridine, 2,3- diaminopyridine, 2,4-diaminopyridine, ⁇ -methyl morpholine and the like Triethylamine is preferred, primarily because of its low cost and commercial availability
  • the base is employed in molar proportions of 1 0 to 5 0 moles per mole of compound of formula (IV 4 ), preferably in molar proportions of 1 0 to 3 0 moles per mole of compound of formula (IN 4 )
  • reaction is suitably effected in an inert, non-hydroxy-containing organic solvent
  • a non-hydroxy-containing organic solvent has been defined hereinearlier in Section 1(a) and the same "inert, non-hydroxy-containing organic solvents" referred to hereinbefore in Section 1(a) and 1 (b) can also be used herein for preparation of compounds of formula (I) by reaction of the acid halide of formula (IN 4 ) with 2- mercaptobenzothiazole of formula (NI)
  • the particular inert, non-hydroxy-containing organic solvent employed as a medium for the preparation of compounds of formula (I) or as a medium for their use in preparation of ACE inhibitors of formula (II) is not critical, however, such solvent properties like polarity, melting or boiling point, and ease of isolation of compounds of formula (I) may be considered in selecting a most suitable solvent
  • the most preferred solvents are halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the reaction temperature may for example be from -30° C to +50° C, in particular -10° C to +30° C, preferably -5° C to + 20° C.
  • 2-mercaptobenzothiazole of formula (VI), which is commercially available is employed in molar proportions of 1.0 to 2.0 moles per mole of compound of formula (IV 4 ), in particular 1.0 to 1.50 moles per mole of compound of formula (IV 4 ), preferably 1.0 to 1J0 moles per mole of compound of formula (IV 4 ).
  • reaction mixture is agitated at the same temperature for 45 to 60 mns and thereafter gradually increased to 20° C to 30° C and agitated at the same temperature for about 2 to 5 hrs.
  • Evaporation of the solvent gives compound of formula (I), wherein R 1 is lower alkyl of 1-4 carbon atoms; R 2 is lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group , which can be used as such for use in preparation of ACE inhibitors of formula (II) or can be purified by conventional methods prior to use.
  • the compound of formula (IV 4 ), which has the free amino function of group R 2 can be used as such for reaction with 2,2'-dithio bis[benzthiazol] of formula (V)., however, it is preferable to protect the amino function of the group R 2 to give compound of formula (IV 4 ), in which the amino function is protected prior to reaction with compound of formula (V). Removal of the amino protective groups by suitable methods would then give compounds of formula ((I), in which the amino function is free.
  • Suitable amino protective groups that can be employed are those routinely practiced in the art, specially those routinely used in peptide synthesis.
  • Suitable protective groups include but are not limited to a substituted benzyloxycarbonyl group such as a tertiary butoxycarbonyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group etc.; a urethane type protective group such as isobornyloxycarbonyl group etc.; an acyl type protective group such as trifluoroacetyl group, a formyl group, a phthaloyl group etc. Of these, in particular, trifluoroacetyl group is preferred, since it can be removed easily with alkali.
  • the present invention provides 2'-benzthiazolyl thioester of N-[l(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -trifluoroacetyl-L-Lysine of formula [I 3 , corresponding to compound of formula (I), wherein R is phenyl, R 1 is ethyl; R 2 is N 6 - trifluoroacetyl-L-Lysine] and a method of preparation thereof and 2'-benzthiazolyl thioester of N-[l(S)-ethoxycarbonyl-3-phenylpropyl]-L-Lysine of formula [I 4 , corresponding to compound of formula (I), wherein R is phenyl, R 1 is ethyl; R 2 is lysine] and a method of preparation thereof. (I 3 ) (I 4 )
  • Compound (I 3 ), and compound (I 4 ) are useful as intermediates for preparation of the ACE inhibitor, lisinopril.
  • 2 '-benzothiazolylthio ester of N-[l(S)-ethoxycarbonyl-3- phenylpropyl]-N 6 -trifluoroacetyl-L-lysine of formula [I 3 , corresponding to compound of formula (I), wherein R is phenyl, R 1 is ethyl; R 2 is N 6 -trifluoroacetyl-L-lysine] can be prepared by dissolving triphenyl phosphine in an inert, non-hydroxy-containing organic solvent. To the solution is added 2,2'-dithio bis[benzthiazol] of formula (V).
  • reaction mixture is agitated for 45 to 60 mns at a temperature of 20° C to 30° C. Thereafter, the reaction mixture is cooled to -10° C to + 10° C to which is added N- [l(S)-ethoxycarbonyl-3-phenylpropyl]- N 6 -trifluoroacetyl-L-lysine [IV 5 , corresponding to compound of formula (IV 5 ), wherein R 4 is N 6 -trifluoroacetyl, R 5 is hydrogen, and R 4 is ethyl], followed by addition of the base.
  • reaction mixture is agitated at the same temperature for 45 to 60 mns and thereafter gradually increased to 20° C to 30° C and agitated at the same temperature for about 2 to 5 hrs. Evaporation of the solvent gives compound of formula (I 3 ) as an oil.
  • the oil can be chromatographed over silica gel using a mixture of ethyl acetate and hexane as eluent 'to give a pure product, which exhibits the following spectral characteristics.
  • 2'-benzthiazolyl thioester of N-[l(S)-ethoxycarbonyl- 3-phenylpropyl]-N 6 -trifluoroacetyl-L-lysine of formula [I 3 , corresponding to compound of formula (I), wherein R is phenyl, R is ethyl; R is N -trifluoroacetyl-L-lysine] can be prepared by dissolving 2-mercaptobenzothiazole of formula (VI) in a inert, non- hydroxy-containing organic solvent and the base. The reaction mixture is agitated for 45 to 60 mns at a temperature of 20° C to 30° C.
  • reaction mixture is cooled to -10° C to + 10° C to which is added N-[l(S)-ethoxycarbonyl-3-phenylpropyl]- N 6 -trifluoroacetyl-L-lysine [IV 5 , corresponding to compound of formula (IV 5 ), wherein R 4 is N 6 -Trifluoroacetyl, R 5 is hydrogen, and R 4 is ethyl].
  • the reaction mixture is agitated at the same temperature for 45 to 60 mns and thereafter gradually increased to 20° C to 30° C and agitated at the same temperature for about 2 to 5 hrs. Evaporation of the solvent gives compound of formula (I 3 ) as an oil.
  • the oil can be chromatographed over silica gel using a mixture of ethyl acetate and hexane as eluent to give a pure product, which exhibits the following spectral characteristics.
  • Advantases of compounds of formula (I) i) The compounds of formula (I), in particular 2'-benzothiazolyl thioester of N- [l(S)-ethoxycarbonyl butyl]-(S)-alanine of formula (I 1 ), corresponding to compound of formula (I), wherein R is methyl, R 1 is ethyl, R 2 is methyl; 2'- benzothiazolyl thioester of N-[l(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanine of formula (I 2 ), corresponding to compound of formula (I), wherein R is phenyl, R 1 is ethyl, R 2 is methyl; 2'-benzthiazolyl thioester of N-[1(S)- ethoxycarbonyl-3-phenylpropyl]-N 6 -trifluoroacetyl-L-Lysine of formula (I 3 ),
  • novel compounds of formula (I) are therefore, useful as intermediates for preparation of ACE inhibitors of formula (II).
  • R is a lower alkyl of 1-4 carbon atoms or phenyl
  • R 2 is lower alkyl of 1-4 carbon atoms or lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group
  • Z is an amino acid derivative selected from those given in Chart-I COOH
  • compounds of formula (I) are useful and provide a novel method for manufacture of commercially valuable ACE inhibitors and their pharmaceutically acceptable salts thereof, hereingiven below.
  • Delapril as disclosed in US Patent No. 4,385,051
  • Enalapril and Enalaprilat as disclosed in US Patent No. 4,374,829
  • iii. Imidapril and Imidaprilat as disclosed in US Patent No. 4,508,727
  • Lisinopril as disclosed in US Patent No. 4,374,829
  • v. Moexipril and Moexiprilat as disclosed in US Patent No. 4,344,949
  • Perindopril and Perindoprilat as disclosed in US Patent No. 4,508,729; vii. Quinapril and Quinaprilat, as disclosed in US Patent ISto. 4,344,949; viii. Ramipril, as disclosed in US Patent No. 4,587,258; ix. Spirapril and Spiraprilat, as disclosed in US Patent No. 4,470,972; and x. Trandolapril and Trandolaprilat, as disclosed in US Patent No. 4,933,361.
  • the method of manufacture of compounds of formula (II), comprises reaction of compounds of formula (I) with an amino acid derivative of formula (VII), z R (VII)
  • R 3 is hydrogen or an easily removable carboxyl protective group in the presence of an inert, non-hydroxy- containing organic solvent and in the presence of a base, with the proviso that when R 3 is hydrogen compounds of formula (II) and their pharmaceutically acceptable salts thereof are obtained directly and when R 3 is a carboxyl protective group, removal of the said protective group give compounds of formula (II) and their pharmaceutically acceptable salts thereof.
  • Suitable easily removable carboxyl protective groups of the amino acid fragment Z which fall under the scope of the group R 3 are those protective groups routinely utilized in organic chemistry. These include inter alia, those forming an alkyl ester e.g. methyl, ethyl, tert-butyl esters; halo-lower alkyl esters e.g. 2-chloroethyl, 2,2,2,-trichloroethyl esters; lower acyl-lower alkyl esters e.g.
  • phenyl, pyridyl esters optionally substituted by an inert group e.g. nitro, methoxy, or lower alkyl; aralkyl esters e.g. benzyl, benzhydryl, naphthylmethyl and pyridylmethyl esters optionally substituted by an inert group e.g. nitro, methoxy or lower alkyl; a trialkylsilyl group e.g. a tri (C 1- )alkyl silyl, e.g. trimethylsilyl; and other groups known to those skilled in the art.
  • an inert group e.g. nitro, methoxy, or lower alkyl
  • aralkyl esters e.g. benzyl, benzhydryl, naphthylmethyl and pyridylmethyl esters optionally substituted by an inert group e.g. nitro, methoxy or lower alkyl
  • Preferred carboxyl protective groups are trialkylsilyl, specially trimethylsilyl and aralkyl, specially benzyl esters.
  • R Lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 Hydrogen or lower alkyl of 1-4 carbon atoms
  • R 2 Lower alkyl of 1-4 carbon atoms
  • Z Amino acid given in Chart-I
  • the bases that can be employed are preferably organic bases and are selected from diethylamine, pyridine, 2J-diaminopyridine, 2,4-diaminopyridme, N-methyl morpholine and the like. Triethylamine is preferred, primarily because of its low cost and commercial availability.
  • the base is employed in molar proportions of 1.0 to 5.0 moles per mole of compound of formula (VII), preferably in molar proportions of 1.0 to 3.0 moles per mole of compound of formula (VII).
  • the reaction is suitably effected in an inert, non-hydroxy-containing organic solvent.
  • a non-hydroxy-containing organic solvent has been defined hereinearlier in Section 1(a) and the same "inert, non-hydroxy-containing organic solvents" referred to hereinbefore in Section 1(a)- 1(c) can also be used herein for preparation of compounds of formula (I) by reaction of the acid halide of formula (IV 2 ) with 2- mercaptobenzothiazole of formula (VI).
  • the particular inert, non-hydroxy-containing organic solvent employed as a medium for the preparation of compounds of formula (I) or as a medium for their use in preparation of ACE inhibitors of formula (II) is not critical, however, such solvent properties like polarity, melting or boiling point, and ease of isolation of compounds of formula (I) may be considered in selecting a most suitable solvent.
  • Preferred solvents for the preparation of compounds of formula (II) as per the present process described hereinbelow are hydrocarbons, especially aromatic hydrocarbons; carboxylic acid esters, especially ethyl acetate; ether, especially tetrahydrofuran; and halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the most preferred solvents are halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the reaction temperature may for example be from -20° C to -5° C, preferably -5° C to - 10° C.
  • the compounds of formula (II) may further be purified by methods known in the art for obtaining the said compounds of high purity.
  • the ACE inhibitor, Perindopril obtained as an oily residue after evaporation of the organic solvent is dissolved in a mixture of water and diisopropyl ether and the solution cooled to 0-5° C.
  • the pH of the solution is adjusted to between 8.0 and 9.0 using a 10% aqueous solution of sodium hydroxide.
  • the aqueous layer is separated from the organic phase and the pH of the solution made acidic in the range of 2.0 to 2.5 by addition of 6N hydrochloric acid.
  • the aqueous layer is extracted with diisopropyl ether and the layers separated.
  • the pH of the aqueous layer is adjusted to 3.5 to 4.0 using a 10% aqueous solution of sodium hydroxide and the product extracted into dichloromethane.
  • Perindopril of high purity can be isolated by evaporation of dichloromethane or by precipitation by addition of an anti-solvent.
  • Other ACE inhibitors for e.g. Quinapril, Ramipril, Trandolapril and the like can be purified by methods suitable to the product.
  • R Lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 Hydrogen or lower alkyl of 1-4 carbon atoms
  • R 2 Lower alkyl of 1-4 carbon atoms
  • Z Amino acid given in Chart-I
  • the bases that can be employed are preferably organic bases and are selected from triethylamine, pyridine, 2,3-diaminopyridine, 2,4-diaminopyridine, N-methyl morpholine and the like. Triethylamine is preferred, primarily because of its low cost and commercial availability.
  • the base is employed in molar proportions of 1.0 to 5.0 moles per mole of compound of formula (VII), preferably in molar proportions of 1.0 to 3.0 moles per mole of compound of formula (VII).
  • the reaction is suitably effected in an inert, non-hydroxy-containing organic solvent.
  • a non-hydroxy-containing organic solvent has been defined hereinearlier in Section 1(a) and the same "inert, non-hydroxy-containing organic solvents" referred to hereinbefore in Section 1(a) can also be used herein for preparation of compounds of formula (I) by reaction of the acid halide of formula (IV 2 ) with 2- mercaptobenzothiazole of formula (VI).
  • the particular inert, non-hydroxy-containing organic solvent employed as a medium for the preparation of compounds of formula (I) or as a medium for their use in preparation of ACE inhibitors of formula (II) is not critical, however, such solvent properties like polarity, melting or boiling point, and ease of isolation of compounds of formula (I) may be considered in selecting a most suitable solvent.
  • Preferred solvents for the preparation of compounds of formula (II) as per the present process described hereinbelow are hydrocarbons, especially aromatic hydrocarbons; carboxylic acid esters, especially ethyl acetate; ether, especially tetrahydrofuran; and halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the most preferred solvents are halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the reaction temperature may for example be from -20° C to +30° C, in particular between 0° C to +30° C , preferably +20° C to + 25° C.
  • bases their molar proportions and the inert, non-hydroxy-containing organic solvent that can be employed are as defined hereinbefore.
  • silylating reagents that can be employed in the method for preparing compounds of formula (VII), wherein R 3 is a trialkylsilyl group and Z is the amino acid derivative given in Chart-I include, but are not restricted to hexamethyl disilazane,, bis silyl acetamide and trimethyl chlorosilane.
  • the silylating reagent is normally employed in molar proportions of 1.0 to 2.0 moles per mole of compounds of formula (VII), wherein R 3 is hydrogen and Z is the amino acid derivative given in Chart-I, preferably in molar proportions of 1.0 to 1.5 moles.
  • the compounds of formula (II) may further be purified by methods known in the art for obtaining the said compounds of high purity.
  • reaction temperature is raised to 25 -30° C and agitated at this temperature for 12-24 hours till completion of reaction.
  • Evaporation of the organic solvent gives the benzyl ester of the ACE inhibitor compounds of formula (II). Further removal of the benzyl protective group gives the ACE inhibitor compounds of formula (II).
  • R Lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 Hydrogen or lower alkyl of 1-4 carbon atoms
  • R 2 Lower alkyl of 1-4 carbon atoms
  • Z Amino acid given in Chart-I
  • the bases that can be employed are preferably organic bases and are selected from triethylamine, pyridine, 2,3-diaminopyridine, 2,4-diaminopyridine, N-methyl morpholine and the like. Triethylamine is preferred, primarily because of its low cost and commercial availability.
  • the base is employed in molar proportions of 1.0 to 5.0 moles per mole of .compound of formula (VII), preferably in molar proportions of 1.0 to 3.0 moles per mole of compound of formula (VII).
  • the reaction is suitably effected in an inert, non-hydroxy-containing organic solvent.
  • a non-hydroxy-containing organic solvent has been defined hereinearlier in Section 1(a) and the same "inert, non-hydroxy-containing organic solvents" referred to hereinbefore in Section 1(a) can also be used herein for preparation of compounds of formula (I) by reaction of the acid halide of formula (IV 2 ) with 2- mercaptobenzothiazole of formula (VI).
  • the particular inert, non-hydroxy-containing organic solvent employed as a medium for the preparation of compounds of formula (I) or as a medium for their use in preparation of ACE inhibitors of formula (II) is not critical, however, such solvent properties like polarity, melting or boiling point, and ease of isolation of compounds of formula (I) may be considered in selecting a most suitable solvent.
  • Preferred solvents for the preparation of compounds of formula (II) as per the present process described hereinbelow are hydrocarbons, especially aromatic hydrocarbons; carboxylic acid esters, especially ethyl acetate; ether, especially tetrahydrofuran; and halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the most preferred solvents are halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the reaction temperature may for example be from -20° C to -5° C, preferably -15° C to - -5° C.
  • the compounds of formula (II) may further be purified by methods known in the art for obtaining the said compounds of high purity.
  • the ACE inhibitor compounds of formula (II), wherein R 2 is lower alkyl of 1- 4 carbon atoms to which is attached an amino or substituted amino group can also be prepared by the methods enumerated hereinearlier in sub-sections 2(a) to 2(c) comprising reaction of compound of formula (I), wherein R 2 is lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group and compound of formula (VII), wherein R 3 is hydrogen or a carboxyl protective group and Z is the amino acid derivative given in Chart-I.
  • R Lower alkyl of 1-4 carbon atoms or phenyl
  • R 1 Hydrogen or lower alkyl of 1-4 carbon atoms
  • R 2 Lower alkyl of 1-4 carbon atoms to which is attached an amino or substituted amino group
  • Z Amino acid given in Chart-I
  • Suitable amino protective groups that can be employed are those routinely practiced in the art, specially those routinely used in peptide synthesis.
  • Suitable protective groups include but are not limited to a substituted benzyloxycarbonyl group such as a tertiary butoxycarbonyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group etc.; a urethane type protective group such as isobornyloxycarbonyl group etc.; an acyl type protective group such as trifluoroacetyl group, a formyl group, a phthaloyl group etc. Of these, in particular, trifluoroacetyl group is preferred, since it can be removed easily with- alkali.
  • the bases that can be employed are preferably organic bases and are selected from triethylamine, pyridine, 2,3-diaminopyridine, 2,4-diaminopyridine, N-methyl morpholine and the like. Triethylamine is preferred, primarily because of its low cost and commercial availability.
  • the base is employed in molar proportions of 1.0 to 5.0 moles per mole of compound of formula (VII), preferably in molar proportions of 1.0 to 3.0 moles per mole of compound of formula (VII).
  • the reaction is suitably effected in an inert, non-hydroxy-containing organic solvent
  • a non-hydroxy-containing organic solvent has been defined hereinearlier in Section 1(a) and the same "inert, non-hydroxy-containing organic solvents" referred to hereinbefore in Section 1(a) can also be used herein for preparation of compounds of formula (I) by reaction of the acid halide of formula (IV 2 ) with 2- mercaptobenzothiazole of formula (VI).
  • the particular inert, non-hydroxy-containing organic solvent employed as a medium for the preparation of compounds of formula (I) or as a medium for their use in preparation of ACE inhibitors of formula (II) is not critical, however, such solvent properties like polarity, melting or boiling point, and ease of isolation of compounds of formula (I) may be considered in selecting a most suitable solvent.
  • Preferred solvents for the preparation of compounds of formula (II) as per the present process described hereinbelow are hydrocarbons, especially aromatic hydrocarbons; carboxylic acid esters, especially ethyl acetate; ether, especially tetrahydrofuran; and halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the most preferred solvents are halogenated hydrocarbons, especially dichloromethane and 1,2-dichloroethane.
  • the reaction temperature may for example be from -20° C to -5° C, preferably -15° C to - -5° C.
  • Removal of the amino protective group of R 2 and the carboxyl protective group of R 3 can be carried out be conventional methods known in the art.
  • R 4 is an amino protective group and R 6 is hydrogen or lower alkyl of 1-4 carbon atoms and the asterik (*) on the carbon bearing the (-COOR 6 ) group is either racemic having the (R/S) configuration or has the (S)-conf ⁇ guration, and removal of protective groups from compound of formula (II 3 ), and optionally separating the diastereomers to give lisinopril of formula (II 2 ).
  • Suitable carboxyl protective groups E are selected from those easily removable carboxyl protective groups of the amino acid fragment Z, which fall under the scope of the group R 3 are those protective groups routinely utilized in organic chemistry. These include inter alia, those forming an alkyl ester e.g. methyl, ethyl, tert-butyl esters; halo-lower alkyl esters e.g. 2-chloroethyl, 2,2,2,-trichloroethyl esters; lower acyl-lower alkyl esters e.g.
  • an alkyl ester e.g. methyl, ethyl, tert-butyl esters
  • halo-lower alkyl esters e.g. 2-chloroethyl, 2,2,2,-trichloroethyl esters
  • lower acyl-lower alkyl esters e.g.
  • lower alkanoylmethyl 2-acetyl ethyl, phenacyl, p- bromophenacyl, ⁇ -benzoylbenzyl esters; lower alkoxy-lower alkyl esters e.g. methoxymethyl ester; lower acyloxy-lower alkyl esters e.g. acetoxymethyl, pivaloyloxymethyl, N,N- dimethylglycyloxymethyl, benzoyloxymethyl esters; lower 1,1-dicarbo-lower alkoxyalkyl esters e.g. dicarbomethoxymethyl, dicarbethoxymethyl esters; lower aryl esters e.g.
  • phenyl, pyridyl esters optionally substituted by an inert group e.g. nitro, methoxy, or lower alkyl; aralkyl esters e.g. benzyl, benzhydryl, naphthylmethyl and pyridylmethyl esters optionally substituted by an inert group e.g. nitro, methoxy or lower alkyl; a trialkylsilyl group e.g. a tri (C ⁇ -4 )alkyl silyl, e.g. trimethylsilyl; and other groups known to those skilled in the art.
  • an inert group e.g. nitro, methoxy, or lower alkyl
  • aralkyl esters e.g. benzyl, benzhydryl, naphthylmethyl and pyridylmethyl esters optionally substituted by an inert group e.g. nitro, methoxy or lower alkyl
  • Preferred carboxyl protective groups are lower alkyl, trialkylsilyl, specially trimethylsilyl and aralkyl, specially benzyl esters.
  • the lower alkyl esters, in particular ethyl ester is more preferred since this carboxyl protective group can be removed in simultaneously in one-pot along with the N 6 -trifluoroacetyl group and the ethoxycarbonyl group attached to the carbon bearing the lysine fragment, which is an added advantage of the process, thereby rendering it commercially attractive.
  • Triphenyl phosphine (2.8 g, 0.011 moles) was dissolved in dichloromethane (30 ml) at a temperature of 25-30° C.
  • 2,2'-Dithiobis(benzothiazole) (V, 3.5 g, 0.011 moles) was added to the solution under stirring at the same temperature.
  • the reaction mixture was stirred for 45 min. to 1 hr and then cooled to 0-5° C.
  • N-[1(S)- ethoxycarbonyl butyl]-(S)-alanine (1.92 g, 0.0088 moles) at the same temperature and the reaction mixture was stirred for 5-10 min.
  • Triethyl amine (1.4 ml) was then added and the reaction mixture stirred for 30-45 min. The temperature was raised to 25-30° C and stirring was continued for 2-2.5 hrs. The reaction mixture was then concentrated at 35-40° C under reduced pressure to give an oily mass. The oil was chromatographed over silica gel using a mixture of chloroform and petroleum ether (40-60° C) as eluent (3:7) to give the pure title compound as an oil.
  • Triphenyl phosphine (2.8 g, 0.011 moles) was dissolved in dichloromethane (30 ml) at a temperature of 25-30° C.
  • 2,2'-Dithiobis(benzothiazole) (V, 3.5 g, 0.011 moles) was added to the solution under stirring at the same temperature.
  • the reaction mixture was stirred for 45 min. to 1 hr and then cooled to 0-5° C.
  • N-[1(S)- ethoxycarbonyl butyl]-(S)-alanine (1.92 g, 0.0088 moles) at the same temperature and the reaction mixture was stirred for 30-45 min The temperature was raised to 25-30° C and stirring was continued for 2-2.5 hrs.
  • Triphenyl phosphine (6.25 g, 0.023 moles) was dissolved in dichloromethane (60 ml) at a temperature of 25-30° C.
  • 2,2'-Dithiobis(benzothiazole) (V, 7.9 g, 0.023 moles) was added to the solution under stirring at the same temperature.
  • the reaction mixture was stirred for 45 min. to 1 hr and then cooled to 0-5° C.
  • N-[1(S)- ethoxycarbonyl-3-phenylpropyl]-(S)-alanine (5.54 g, 0.0198 moles) at the same temperature and the reaction mixture was stirred for 5-10 min.
  • Triethylamine (3 ml) was then added and the reaction mixture stirred for 30-45 min. The temperature was raised to 25-30° C and stirring was continued for 2-2.5 hrs. The reaction mixture was then concentrated at 35-40° C under reduced pressure to give an oily mass. The oil was chromatographed over silica gel using a mixture of chloroform and petroleum ether (40-60° C) as eluent (3:7) to give the pure title compound as an oil.
  • the oil was dissolved in a mixture of water (15 ml) and diisopropyl ether (50 ml). The solution was cooled to 0-5° C and pH of the solution adjusted to 8J-8.6 using 10% aqueous sodium hydroxide solution. The reaction mixture was stirred at this pH for 15- 20 mins, filtered and the organic layer was separated. The aqueous layer was again cooled to 0-5° C and the pH adjusted to 2.2-2.5 using 6N hydrochloric acid. The aqueous solution was extracted with diisopropyl ether (25 ml X 2).
  • Triethylamine (1.4 ml) was added to the cooled reaction mixture and stirred for 5-10 min and the mixture further cooled to -10 to -20° C.
  • N-[l(S)-ethoxycarbonyl butyl] -(S)-alanine-2'- benzothiazolylthiol ester (3.5 g, 0.0106 moles, obtained from Examples 1 and 2), slowly over a period of 1 hr. After the addition was over the temperature was raised to 25-30° C and the mixture stirred at this temperature for 15-16 hrs. The reaction mixture was then concentrated under reduced pressure at 30-35° C to give an oily residue.
  • the oil was dissolved in a mixture of water (15 ml) and diisopropyl ether (50 ml). The solution was cooled to 0-5° C and pH of the solution adjusted to 8.3-8.6 using 10% aqueous sodium hydroxide solution. The reaction mixture was stirred at this pH for 15- 20 mins, filtered and the organic layer was separated. The aqueous layer was again cooled to 0-5° C and the pH adjusted to 2.2-2.5 using 6N hydrochloric acid. The aqueous solution was extracted with diisopropyl ether (25 ml X 2).
  • Step-1 Preparation of Perindopril benzyl ester
  • the Perindopril benzyl ester (2.9 g, 6J3 mmoles), obtained in Step-1 was dissolved in ethyl alcohol (15 ml) hydrogenated using 10% Palladium on carbon (0.29 g), under 45- 50 psi hydrogen pressure for 2.5-3 hrs. The reaction was performed at 25-30°C. After completion of the reaction, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to afford Perindopril as a viscous oil.
  • Step-1 Preparation of Quinapril benzyl ester
  • reaction mixture was stirred at 25-30° C for 2 hrs.
  • the reaction mixture was quenched by addition of water (25 ml).
  • the pH of the reaction mixture was adjusted to 8.5-9.0 using 2% aqueous sodium hydroxide solution.
  • the organic layer was separated and washed twice with water (25 ml) and concentrated under reduced pressure to give 8 g (75%) of Quinapril benzyl ester.
  • Triethylamine (2.8 ml) was added to the cooled reaction mixture and stirred for 5-10 min and the mixture further cooled to -10 to -20° C.
  • N-[l(S)-ethoxycarbonyl butyl]-(S)-alanine-2'- benzothiazolylthiol ester (8.5 g, 0.0216 moles, obtained from Examples 1 and 2), slowly over a period of 1 hr. After the addition was over the temperature was raised to 25-30° C and the mixture stirred at this temperature for 15-16 hrs. The reaction mixture was then concentrated under reduced pressure at 30-35° C, to give an oily residue.
  • the oil was dissolved in a mixture of water (25 ml) and diisopropyl ether (50 ml). The solution was cooled to 0-5° C and pH of the solution adjusted to 8J-8.6 using 10% aqueous sodium hydroxide solution. The reaction mixture was stirred at this pH for 15- 20 mins, filtered and the organic layer was separated. The aqueous layer was again cooled to 0-5° C and the pH adjusted to 2.2-2.5 using 6N hydrochloric acid. The aqueous solution was extracted with diisopropyl ether (25 ml X 2).
  • Triethylamine (2.75 ml) was added to the cooled reaction mixture and stirred for 5-10 min and the mixture further cooled to -10 to -20° C.
  • N-[l(S)-ethoxycarbonyl butyl]-(S)-alanine-2'- benzothiazolylthiol ester 5J9 g, 0.0136 moles, obtained from Examples 1 and 2), slowly over a period of 1 hr. After the addition was over the temperature was raised to 25-30° C and the mixture stirred at this temperature for 15-16 hrs. The reaction mixture was then concentrated under reduced pressure at 30-35° C, to give an oily residue.
  • the oil was dissolved in a mixture of water (25 ml) and diisopropyl ether (50 ml). The solution was cooled to 0-5° C and pH of the solution adjusted to 8J-8.6 using 10% aqueous sodium hydroxide solution. The reaction mixture was stirred at this pH for 15- 20 mins, filtered and the organic layer was separated. The aqueous layer was again cooled to 0-5° C and the pH adjusted to 2.2-2.5 using 6N hydrochloric acid. The aqueous solution was extracted with diisopropyl ether (25 ml X 2).
  • Step-1 Preparation of if-trifluoroacetyl-S-lysine O
  • Step-2 Preparation ofl ⁇ -trifluoroacetyl-S-lysine-benzylester 0
  • reaction mixture was then added into diisopropyl ether at 25-30° C, under vigorous stirring, wherein a solid separated out.
  • the solid N 6 -trifluoroacetyl-S-lysine-benzylester hydrochloride was collected by filtration.
  • the solid hydrochloride salt was dissolved in a mixture of dichloromethane (150 ml) and water (50 ml). The pH of the solution was adjusted to 8.80 using a solution of aqueous ammonia. The layers are separated and the organic layer is evaporated under reduced pressure to give 16 g (58%) of the title compound as an oil.
  • Step-3 Preparation ofN-[l(S)-ethoxycarbonyl-3-phenylpropylJ-N 6 -trifluoroacetyl-(S)- lysine benzyl ester
  • N 6 -trifluoroacetyl-S-lysine-benzylester (10 g, 0.0301 moles, as obtained in Step-2) in chloroform was added N-methyl morpholine (9J4 g, 0.0903 moles) at 25° C.
  • N-methyl morpholine 9J4 g, 0.0903 moles
  • the reaction mixture was cooled to 0-5° C and a solution of (R)-[2- trifluoromethanesulfonyloxy]-4-phenylbutyric acid ethyl ester (12J g, 0.0361 moles) in chloroform (25 ml) was added to it drop wise, maintaining the temperature in the range of 0-5° C.
  • reaction mixture was then allowed to come to 25-30° C and stirred for 18 hrs, till the completion of reaction is indicated by TLC.
  • the reaction mixture was quenched with water (25 ml).
  • the organic layer was separated and concentrated to afford the title compound as a thick oil.
  • the oil was passed through a column of silica gel using a mixture of ethyl acetate and hexane (1 :4) as the eluent to give 13 g (82.6%) of the title compound as an oil.
  • Step-4 Preparation ofN-[l(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -trifluoroacetyl-(S)- lysine
  • Step-6 Preparation of (S) — l-[ ⁇ 6 ti'ifluoroacetyl-(l-Carboxy-3-phenylpropyl)-L-lysyl]- L-proline ethyl ester (Protected Lisinopril)
  • the reaction mixture was quenched with water (10 ml).
  • the organic layer was separated and stirred with a solution of aqueous potassium hydroxide (10%>, 25 ml), till TLC indicated complete removal of the 2- mercaptobenzothiazole.
  • the organic layer was separated and concentrated under reduced pressure to afford 1.75 g (89.8 %) of the title compound as an oil.
  • Step-7 Preparation of (S) — l-[N 2 -(l-Carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate (Lisinopril dihydrate)
  • the column was eluted with 2%> aqueous ammonia. After complete elution, the eluent was concentrated at 40° C under reduced pressure to 25%> of the original volume. The pH of the concentrated mass was adjusted to 5.2 with concentrated HCI and the aqueous solution thus obtained was then further concentrated at 40°C under 50-80 mm Hg pressure till the water content of the residual mass is ⁇ 55%. Then 2- propanol (15 ml) was charged into the mass and the mixture was stirred for 10 min. at 25° C. The precipitated solid was collected by filtration and recrystallized from ethyl alcohol to give 0.40 g (50.5%>) of lisinopril dihydrate.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006131828A1 (en) * 2005-06-08 2006-12-14 Aurobindo Pharma Limited A process for the preparation of perindopril
CN106349185A (zh) * 2016-08-26 2017-01-25 河北科技大学 一种氨基保护的3‑羟基金刚烷甘氨酸苯并噻唑‑2‑硫醇活性酯、其制备方法及应用
CN106699592A (zh) * 2016-11-17 2017-05-24 浙江华海药业股份有限公司 一种制备赖诺普利中间体的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4847384A (en) * 1987-03-12 1989-07-11 Sandoz Pharm. Corp. Process for the preparation of certain nitrogen-containing mono- and bicyclic ace inhibitors, and novel intermediates useful therefor
AT394726B (de) * 1988-07-13 1992-06-10 Krka Tovarna Zdravil Verfahren zur herstellung von l-alanyl-l-prolin-derivaten

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4847384A (en) * 1987-03-12 1989-07-11 Sandoz Pharm. Corp. Process for the preparation of certain nitrogen-containing mono- and bicyclic ace inhibitors, and novel intermediates useful therefor
AT394726B (de) * 1988-07-13 1992-06-10 Krka Tovarna Zdravil Verfahren zur herstellung von l-alanyl-l-prolin-derivaten

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006131828A1 (en) * 2005-06-08 2006-12-14 Aurobindo Pharma Limited A process for the preparation of perindopril
CN106349185A (zh) * 2016-08-26 2017-01-25 河北科技大学 一种氨基保护的3‑羟基金刚烷甘氨酸苯并噻唑‑2‑硫醇活性酯、其制备方法及应用
CN106699592A (zh) * 2016-11-17 2017-05-24 浙江华海药业股份有限公司 一种制备赖诺普利中间体的方法
WO2018090963A1 (zh) 2016-11-17 2018-05-24 浙江华海药业股份有限公司 一种制备赖诺普利中间体的方法
US10633329B2 (en) 2016-11-17 2020-04-28 Zhejiang Huahai Pharmaceutical Co., Ltd. Method for preparing lisinopril intermediate
EP3543225A4 (en) * 2016-11-17 2020-07-08 Zhejiang Huahai Pharmaceutical Co., Ltd PROCESS FOR PREPARING INTERMEDIATE LISINOPRIL
CN106699592B (zh) * 2016-11-17 2020-12-08 浙江华海药业股份有限公司 一种制备赖诺普利中间体的方法

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