FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of (trans)-4-cyclohexyl-L-proline of Formula I
Formula I which is an intermediate useful in the preparation of Fosinopril sodium of Formula II
Formula II
BACKGROUND OF THE INVENTION
Fosinopril is an effective and long lasting ACE (Angiotensin Converting Enzyme) inhibitor used in the treatment of hypertension and acute or chronic congestive heart failure. Fosinopril inhibits the enzyme which converts Angiotensin I into Angiotensin II.
US 4,337,201 and 4,384,123 disclose various phosphinylalkanoyl substituted prolines having Angiotensin Converting Enzyme inhibition activity including Fosinopril.
Specifically, the sodium salt of Fosinopril is described in Fed. Proc, Fed. Am. Soc. Exp. Biol., 1984, 43, 733 and its preparation is described in US 4,873,356. Fosinopril contains (trans)-4-cyclohexyl-L-proline as a key structural moiety.

US 4,912,230 discloses a process for the preparation of (cis)-4-hydroxy-L-proline sulfonate as shown below:

This patent discusses about only the inversion of hydroxy function of a (cis)-4-hydroxy-L-proline sulfonate by a modified Mitsunobu reaction. However, the process shown in the above patent does not describe further conversion to the synthesis of (trans)-4-cyclohexyl-L-proline.
US 4,912,231 describes the synthesis of (trans)-4-phenyl-L-proline as shown below:

This patent also does not describe the preparation of (trans)-4-cyclohexyl-L-proline from the corresponding phenyl compound.

The inventors have now developed a new improved reduction process for the preparation of (trans)-4-cyclohexyl-L-proline intermediate employing ruthenium on carbon as a catalyst.
OBJECTIVES OF INVENTION
The objective of the present invention is to develop an improved process for the preparation of Fosinopril intermediate (trans)-4-cyclohexyl-L-proline of Formula I and its further conversion to Fosinopril sodium of Formula II
SUMMARY OF INVENTION
Accordingly, the present invention relates to an improved process for the preparation of compound Formula I

with ruthenium on carbon in water or lower alcohol or mixtures thereof to obtain a compound of Formula I, followed by conversion to Fosinopril sodium of Formula II.
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes an improved process for the preparation of Fosinopril intermediate (trans)-4-cyclohexyl-L-proline of Formula I from Formula III and its further conversion to Fosinopril sodium of Formula II.

The aim of the present invention is hydrogenation of (trans)-4-phenyl-L-proline to (trans)-4-cyclohexyl-L-proline by using ruthenium on carbon as a catalyst in water or lower alcohols.
Normally the reduction of the compound of Formula III to Formula I is achieved by metal catalysts like Platinum, palladium and rhodium. However, the improved process consists of carrying out reduction with ruthenium on carbon in water or lower alcohols or mixtures thereof.
To the surprise of inventors, the reduction with palladium did not proceed at low pressures (< 30 kg/Cm2). The reduction with platinum on carbon or Pt02 proceeded well, but gave very low yields.
The inventors used ruthenium on carbon instead to carry out the reduction of compound of Formula III to Formula I that yielded good quality product with simple crystallization. Also the reduction was carried out in water or lower alcohols or mixtures thereof.
The use of ruthenium on carbon has the advantage of being cheap and commercially available catalyst. Hence, it is ideally suited to carry out the reduction for large quantities.
(Trans)-4-Phenyl-L-proline in water was heated in an autoclave at 70-75 °C and then 5% ruthenium on carbon powder was added and hydrogenated at 30-35 Kg/Cm for 10 hrs at 80-90 °C. After, completion of the reaction, the reaction mass was filtered and pH of the filtrate was adjusted to 5.4-5.6. The resulting reaction mass was concentrated to yield solid wet product which was further purified by dissolving in lower alcohol selected from methanol, ethanol, Isopropyl alcohol, and crystallizing by the addition of water. The product obtained was filtered and washed with water and ethyl acetate to yield pure (trans)- 4-cylohexyl-L-proline.
The conversion of compound Formula I to Fosinopril sodium of Formula II is achieved by previously known methods which include coupling the [R-[(R*,S*)]-[[2-methyl-l-(l-

oxopropoxy)]propoxy](4-phenylbutyl)-phosphinyl]acetic acid with (trans)-4-cyclohexyI-L-proline of Formula I followed by sodium ion treatment to give Fosinopril sodium.
The compound of Formula II is also prepared by known methods in literature.
The preparation of the compound of Formula I involving the key catalytic hydrogenation step resulting in (trans)-4-cyclohexyl-L-proline was achieved avoiding high pressure conditions and using an alternative metal catalyst like ruthenium on carbon which was subsequently used for large-scale throughput.
The present invention is exemplified by the following examples which are provided for illustration purposes and do not limit the scope of invention.
Example 1
Preparation of (trans)-4-cyclohexyl-l-proline
Water (900 ml) and (trans)-4-phenyl-L-proline hydrochloride (100 g, 0.22 mole) were added to an autoclave and heated the mixture to 70-75°C. To the mixture, 5% ruthenium on carbon powder (20 g) was added and hydrogenated at 30-35 Kg / Cm for 10 h at 80-90°C. After completion of reaction, the catalyst was filtered and pH of the filtrate was adjusted to 5.4-5.6 with 15% w/w aqueous sodium hydroxide solution at 20-30°C and concentrated to yield wet solid mass.
The above solid mass was dissolved in methanol (300 ml), treated with activated carbon and filtered. The filtrate was concentrated and treated with water (100 ml) to crystallize the product. The product was filtered, washed with water followed by ethyl acetate and dried to yield pure (trans)-4-cyclohexyl-L-proline.

Example 2

A mixture of [R-(R* ,S*)] - [ [2-methyl-1 -(1 -oxopropoxy)propoxy] (4-phenylbutyl)-phosphinyl] acetic acid cinchonidine salt (20 g, 0.0295 mole), methylene dichloride (200 ml) and water (200 ml) was acidified to pH 1.5-2.0 with dilute hydrochloric acid and separated the organic layer. The organic layer was washed with water and concentrated to yield [R-(R*,iS'*)]-[[2-Methyl-l-(l-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl] acetic acid as a viscous mass.
The above viscous mass was dissolved in methylene dichloride (80 ml), cooled to -5 to 5°C and treated with 1-hydroxybenzotriazole (4.39 g, 0.0325 mole) followed by a solution of 1,3-dicyclohexylcarbodiimide (6.39 g, 0.031 mole) in methylene chloride (200 ml). The resulting reaction mixture was stirred for 4 h and reacted with (trans)-4-cyclohexyl-L-proline (6.13 g, 0.031 mole) in the presence of triethylamine (4.48 g). The reaction mass was filtered and the filtrate was washed successively with cold dilute hydrochloric acid and cold water and concentration of the reaction mass under reduced pressure yielded Fosinopril acid.
The Fosinopril acid obtained as above was dissolved in ethyl acetate (100 ml, water 0.7% w/w) and cooled to 0-5°C. The insolubles were filtered and the filtrate was treated with the solution of sodium 2-ethylhexanoate (5.42 g) in ethyl acetate (40 ml, water 0.7% w/w) at 0-5°C. The reaction mixture was allowed to attain 20-30°C and stirred for 6 h, filtered the product and washed with acetone. The wet product was slurried in isopropyl alcohol (80 ml) for 1 h, filtered and dried to yield Fosinopril sodium (13.2 g).

WE CLAIM
1) An improved process for the preparation of (trans)-4-cyclohexyl-L-proline of
Formula I
Formula I
which comprises catalytic hydrogenation of the compound of Formula III
Formula III
with ruthenium on carbon in water or lower alcohols or mixtures thereof to obtain a compound of Formula I, followed by conversion to Fosinopril sodium of Formula II.
2) The process according to claim 1, wherein the compound of Formula I is further purified by treating with lower alcohol and water.
3) The process according to claim 2, wherein the lower alcohol is methanol.
4) The process according to claim 2, comprising the step of dissolving the compound of Formula I in methanol and crystallizing it by the addition of water.
5) The process according to claim 1, wherein the compound of Formula I is further converted to Fosinopril sodium of Formula II.