U.S. Pat. No. 4,337,201 (Petrillo, Jr. et. al.) describes certain esters of phosphinylalkanoyl prolines or phosphinylalkanoyl substituted prolines as inhibitors of angiotensin converting enzyme (ACE). These enzymes convert angiotensin I into angiotensin II, the latter being a powerful vasoconstrictor causing hypertension. Inhibition of ACE results in reduction of blood pressure, thereby improving the quality of life of the patient susceptible to or suffering from hypertension.
Among the phosphinylalkanoyl esters described in U.S. Pat. No. 4,337,201 is the compound generically known as fosinopril sodium, marketed under the brand name Monopril®. Fosinopril sodium is administrated orally either alone or in combination with diuretics for treatment of hypertension. It is also used as an adjunct in the treatment of congestive heart failure.
Fosinopril is an optically active compound having total four centres of asymmetry, three on carbon and one on phosphorous atom. Out of the sixteen isomers possible for this compound, only one of the isomers is a therapeutic i.e. a pharmaceutical. The desired isomer possessing therapeutic value is [1[S*(R*)], 2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-L-proline, mono-sodium salt and accordingly fosinopril sodium is represented by formula (I).

The prior art methods for synthesis of fosinopril, essentially consists of the following:    (i) Petrillo, Jr. et. al. in U.S. Pat. No. 4,337,201 discloses a process for preparation of phosphinyl alkanoyl proline esters of general formula (3) comprising of reacting a phosphinyl acetic acid of formula (1) with a proline derivative of formula (2), the coupling reaction being accomplished using known amide forming procedures.

Alternatively, compound of formula (3) is prepared by alkylation of the hydroxy compound of formula (4) with a halo compound of formula (5), followed by basic hydrolysis.

In compounds of formula (1) to (5) mentioned hereinbefore synthesis of fosinopril is achieved and completed when R1 is phenylbutyl; R2 is isobutylpropionate; R3 is hydrogen; R4a is alkyl or arylalkyl, preferably benzyl; R4 is hydrogen; R5 is 4-cyclohexyl proline, n is zero and X is halogen.
However, this patent does not:    (a) even remotely suggest any method for synthesising to specifically obtain the desired isomer of fosinopril sodium (I), thus making it clear that the product obtained by the methods described in the patent is a mixture of either all possible sixteen isomers or is a mixture of some of the possible isomers,    (b) suggest, teach or disclose any method for separating the desired isomer of fosinopril from the mixture of isomers and    (c) suggest, teach or disclose any synthesis of esters of phosphinyl alkanoyl prolines with the cycloalkyl group at the 4-position of the proline ring having a (trans) configuration. All examples described in the patent relate to synthesis of such esters with the said cycloalkyl group having a (cis) configuration. The (trans) configuration of the cyclohexyl ring is required in fosinopril sodium.    (ii) Petrillo, Jr. et. al. in U.S. Pat. No. 4,873,356 describe a method for synthesis of the desired isomer of fosinopril sodium (I), which is an improvement over the general method described in U.S. Pat. No. 4,337,201.It addresses the shortcomings associated with the said U.S. Pat. No. 4,337,201.
The method disclosed in this patent comprises of alkylating a phosphinyl acetic acid derivative of formula (6) with a haloester of formula (7) in the presence of an organic base selected from triethylamine, pyridine, tripropylamine and DBU to give the corresponding ester of formula (8) as a mixture of two diastereomers. The carboxylic acid ester protective group is removed by hydrogenolysis to give the phosphinyl acetic acid compound of formula (9), which is obtained as mixture of a pair of racemic forms i.e. a mixture of two diastereomers, namely a mixture of compounds of formula (9 A) and its mirror image (9 B); (9 C) and its mirror image (9 D).
The racemic mixture of compounds (9 A) and its mirror image (9 B) is separated from the other pair (9 C) and its mirror image (9 D) by recrystallisation from suitable solvents such as isobutyl acetate or methyl isobutyl ketone, which is further resolved by treatment with optically active amines such as L-cinchonidine or other conventional resolving agents to give the resolved salt of enantiomer (9 B). Treatment with a strong acid gives the pure phosphinyl acetic acid isomer (9 B), the desired addendum for further elaboration to fosinopril sodium.
Thus, the pure single isomer (9 B) when reacted with trans)-4-cyclohexyl-L-proline gives fosinopril, which is converted to the sodium salt of formula (I) by conventional methods.
The chemistry practised in U.S. Pat. No. 4,873,356 is schematically summarised in Scheme-1.

U.S. Pat. No. 4,873,356 further claims that compound (8) including all stereomers thereof, compound (9), including all stereomers thereof i.e. compound (9 A) and its mirror image (9 B); compound (9 C) and its mirror image (9 D) and the intermediate salt of compound (9 B) with the resolving agent are all novel compounds.
This further substantiates the earlier observation that separation of such racemic mixtures or diastereomeric mixtures formed in the reaction was never meant to be a part of the spirit and scope of the process(es) disclosed in U.S. Pat. No. 4,337,201.    (i) U.S. Pat. No. 5,008,399 (Sedergran et. al.) describes a process which is an improvement over that disclosed in U.S. Pat. No. 4,873,356. The improvement effected comprises carrying out the reaction of compound (6) and compound (7) in the presence of organic bases such as 4-methylmorpholine, diazabicyclooctane, quinuclidine, 1-methylpyrolidine or cinchonidine to give compound (8) as a mixture of four isomers, which on hydrogenolysis gives compound (9) as a mixture of two diastereomeric pairs i.e. a mixture of compounds (9 A) and its mirror image (9 B); (9 C) and its mirror image (9 D). The diastereomeric pair is separated and resolved as described in U.S. Pat. No. 4,873,356 to give the pure isomer (9 B).
U.S. Pat. No. 5,008,399 claims that by utilising the organic bases mentioned therein an increase in diastereoselectivity is achieved affording the racemic mixture of compounds (9 A) and its mirror image (9 B) in a ratio of 1.5 over the other racemic mixture i.e. (9 C) and its mirror image (9 D). This is an improvement over a ratio of 1.2 achieved by employing a base such as triethylamine as disclosed in U.S. Pat. No. 4,873,356. An overall increase in efficiency of preparing fosinopril sodium (I) is thus achieved.
The processes described in U.S. Pat. Nos. 4,873,356 and 5,008,399, while leading to the synthesis of fosinopril sodium having the desired optical purity, are associated with the following disadvantages. In particular, the processes of this patent:                involves separation of isomers that are mirror images of each other i.e. enantiomers or a racemic mixture (9 A) and its mirror image (9 B) from (9 C) and its mirror image (9 D)        requires optical resolution for further separation of the enantiomers (9 A).        requires optical resolution for further separation of the enantiomers (9 A) and its mirror image (9 B),        involves considerable wastage of the desired isomer (9 B) and utilisation of expensive resolving agents (one to two molar equivalents) and organic bases (about two molar equivalents), in the separation of enantiomers followed by optical resolution thereby resulting in an overall decrease in efficiency and increase in the cost of manufacture of the end product i.e. fosinopril sodium and        do not teach or disclose any method for recycling of the unwanted isomers (9 A), (9 C) and (9 D) back to the desired isomer (9 B).            (i) Besides the aforementioned process patents, various methods are reported for preparation of key intermediates required for synthesis of fosinopril. For instance, U.S. Pat. No. 4,168,267 (Petrillo, Jr., et. al.), U.S. Pat. No. 4,384,123 (Petrillo. Jr., et. al.), U.S. Pat. No. 4,448,772 (Karanewsky et. al.), U.S. Pat. No. 4,594,199 (Thottathil et. al.) and U.S. Pat. No. 4,602,092 (Thottathil et. al.) disclose processes for synthesis of the phosphinyl acetic acid fragment of fosinopril. U.S. Pat. No. 4,316,905 (Krapcho et. al.), U.S. Pat. No. 4,501,901 (Thottathil et. al.), U.S. Pat. No. 4,588,819 (Thottathil et. al.), U.S. Pat. No. 4,734,508 (Thottathil et. al.), U.S. Pat. No. 4,912,230 (Anderson et. al.), U.S. Pat. No. 4,912,231 (Kronenthal et. al.) and U.S. Pat. No. 4,937,355 (Kloss et. al.) describe processes for synthesis of the optically active (cis/trans)-4-cyclohexyl-L-proline fragment.    (ii) In addition, it is known that the sodium salt of fosinopril can exist in two polymorphic forms, designated as Form-A and Form-B. The polymorphic forms differ in their respective solid state IR, 13C NMR and 31P NMR spectra as well as X-ray (powder) diffraction patterns. Of the two forms, Form-A, which is the therapeutic is believed to be thermodynamically more stable. No other polymorphic form for fosninopril sodium has been reported so far.    (iii) U.S. Pat. No. 5,162,543 (Grosso et. al.) discloses a selective process for preparation of any one of the two polymorphs of fosinopril sodium as well as a process for inter conversion of one form into the other. Polymorphic Form-A is obtained by crystallisation of fosinopril sodium in a keto or hydroxylic solvent or a mixture thereof in presence of water, the requirement being water should constitute ≧2% or more of the total solvent(s). When the crystallisation is carried out in a keto or hydroxylic solvent or a mixture thereof, wherein the water content is ≦0.2% Form-B is obtained. Rapid evaporation of a methanolic solution of Form-A containing ≦0.2% of water converts it to the other form i.e. Form-B.    (iv) The inference one draws from the methods described in U.S. Pat. No. 5,162,543 is that the formation of the respective polymorphs is not only dependent on the solvent employed but also on the amount of water present in the solvents(s).
H. G. Brittain et. al. [Journal of Pharmaceutical & Biomedical Analysis, 1993, Vol 11 (No. 11/12), pp 1063–1069] describe methods for preparation of the two polymorphic forms. For instance, Form-A is obtained by crystallisation of fosinopril sodium from various organic solvents such as acetone, acetonitrile, alcohols and the like containing water. The authors claim that formation of this polymorphic form is independent of the solvent used as long as the crystallisation is slow. There is no mention on the amount of water that is necessary for formation of this form.
Form-B, on the other hand, is obtained by rapid/flash evaporation of the solvent from a solution of fosinopril sodium in that solvent.
There are no reports available on the existence of polymorphic forms for other salts of fosinopril, such as alkali metal salts with lithium, potassium, rubidium and cesium or alkaline earth metal salts with beryllium, magnesium, calcium, strontium and barium or salts of fosinopril with heavy metals.
Thus, to summarise the prior art:    a) the general methods described in U.S. Pat. No. 4,337,201 lead to a mixture of all possible sixteen isomers or mixture of some of the possible isomers of fosinopril. No method for separation and isolation of the pure desired isomer is mentioned,    b) the specific methods disclosed in U.S. Pat. Nos. 4,873,356 and 5,008,399, lead to formation of only four isomers of fosinopril. However, enantiomers, which are mirror images of each other are separated from the mixture,    c) separation of the pure desired isomer from the racemic mixture calls for optical resolution,    d) optical resolution leads to considerable wastage of the desired isomer leading to low efficiency and increase in cost of manufacture,    e) no method is described for recycling of the unwanted isomers back to the desired one, and    f) formation of polymorphic Form-A of fosinopril sodium is dependent on the solvent(s) employed and the amount of water present in the solvent(s).
A need, therefore, exists for a method for the synthesis of fosinopril sodium, which in addition to eliminating/minimising the disadvantages, specially optical resolution associated with the prior art methods, provides a cost-effective and convenient method for synthesis of the objective compound.