Source: {"pile_set_name": "USPTO Backgrounds"}

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