Which comprises, (i) Protecting the N6-position of L-Lysine with trifluoro acetyl group and acid moiety with benzyl group, (ii) Coupling the resultant N6-trifluoro acetyl-L-Lysine benzyl ester with ethyl trans-p-benzoyl acrylate, to yield the novel compound of the formula II, N2-[1(S)-ethoxy carbonyl-3-oxo-3-phenyl propyl]-N6-trifluoro acetyl-L-Lysine benzyl ester, (iii) Reducing and de-benzylation N2-1-[1(S) ethoxy carbonyl-3-oxo-3-phenyi propyl]-N6-trifluoro acetyl-L-Lysine benzyl ester hydrochloride by hydrogenation to yield N2-1-[1(S) ethoxy carbonyl-3-phenyl propyl]-N6-trifluoro acetyl-L-Lysine. (iv) Coupling the N2-1-[1(S) ethoxy carbonyl-3-phenyl propyl]-N6-trifluoro acetyl-L-Lysine obtained in step (iii) with L-proline benzyl ester hydrochloride in the presence of 1-hydroxy benzotriazole and dicyclohexylcarbodiimide. (v) Debenzylating the N2-1-[1(S) ethoxy carbonyl-3-phenyl propyl]-N6-trifluoro acetyl-L-Lysyl-L-proline benzyl ester by hydrogenation. (vi) Hydrolyzing the N2-1-[1(S) ethoxy carbonyl-3-phenyl propyl]-N6-trifluoro acetyl-L-Lysyl-L-proline to get Lisinopril dihydrate and. (vii) Purifying the Lisinopril dihydrate using Ion exchange resin lndion-225H to give pure Lisinopril dihydrate of the formula I.
This application also discloses a novel intermediate N2-[1(S)-ethoxy carbonyl-3-oxo-3-phenyl propyl]-N6-trifluoro acetyl-L-Lysine benzyl ester and a process for its preparation.

This invention relates to an improved process for the preparation of Lisinopril. Lisinopril is chemically (S)-1-[N2-1(1-carboxy-3-phenyl propyl)-L-Lysyl]-L-proline. This invention particularly relates to an improved process for the preparation of (S)-1-[N2-1(1-carboxy-3-phenylpropyl)-L-Lysyl-L-prolJne dihydrate of the formula I (hereinafter also referred to as Lisinopril dihydrate).
This invention also relates to novel intermediate or tne Tormuia ii. N^-f1-(SV ethoxy carbonyl-3-oxo-3-phenyl propyl]-N2-trifluoro acetyl-L-Lysine benzyl ester, which is useful for the preparation of Lisinopril dihydrate and a process for its preparation.

Lisinopril dihydrate of the formula I is a Pharmaceutical compound useful as angiotensin -converting enzyme inhibitor and is therefore, useful for hypertension and for the prevention of heart failure.
Prior art :-
Lisinopril was first disclosed in EP No. 12401, corresponding to US patent No. 4,374,829 by Merck & Co. This patent describes the synthesis of Lisinopril by condensation of 2-oxo-4-phenyl butyhc acid with N-t-butoxy carbonyl-L-Lysyl-L-proline in the presence of sodium cyanoborohydride. The product is absorbed on

strong acid Ion exchange resin, and eluted with 2% pyridine in water, product rich cuts are stripped to a glass and treated with 4N hydrochloric acid in ethyl acetate to remove the N-t-butoxy carbonyl protecting group. The resulting hydrochloride salt is converted to the free base by absorbing on strong acid Ion exchange resin and eluting with 2% pyridine in water. Freeze drying of product rich cuts affords N-a-(1 -carboxy-3-phenyl propyl)-L-Lysyl-L-proline.
Process for preparation of LisinophI by using phenyl propanaldehyde is reported in EP No 79521. In this process phenyl propanaldehyde is used instead of 2-oxo-4-phenyl butyric acid reacting with N-t-butoxy carbonyl-L-Lysyl-L-proline in the presence of potassium cyanide to synthesize Lisinopril. Another patent JP 08,283,289 discloses the synthesis of N2-[(S)-1-ethoxycarbonyl-3-phenyl propyl]-N2-trifluoro acetyl-L-Lysyl-L-proline an intermediate for Lisinopril. The process involves amination of Ethyl-4-phenyl butyrate denvatives with N2-trifluoro acetyl-L-Lysyl-L-proline tert. butyl ester.
Process for the preparation of Lisinopril has also reported in various patents using different protecting groups. For example in US patent No 4,808,741, acid moiety of Lysine was protected by silyl ester and amine at N2 is protected by benzyloxy carbonyl group. The protected lysine was condensed with methyl-2-bromo-4-phenyl butanoate and then de-protected alkyl silyl group with treatment of water The resultant N2-(1S-methoxy carbonyl-3-phenyl-propyl)-N2-benzyloxy carbonyl- L-Lysine was further condensed with L-proline methyl ester hydrochloride in the presence of dicyclohexyl carbodiimide (DCC) and triethyl amine. De-blocking of N2-benzyloxy carbonyl group was done with 10% Palladium-Carbon catalyst and ester hydrolysis was effected using sodium hydroxide.
ES Patent No. 2,018,906 discloses a process for the preparation of Lisinopril by making mixed anhydride of N- (1-carboethoxy phenyl propyl)-t-butoxy carbonyl-L-Lysine with 1,8-diazabicyclo [5.4.0] undec-7-ene, (DBU). COCI2. The mixed anhydhde was treated with L-proline trimethyl silyl ester in methylene chloride.

The preparation of mixed anhydride of L-Lysine is also reported in EP No. 943,621 by protecting both the amino groups with benzyl chloro formate and treating with N,N-dimethyl formamide and thionyl chlohde. The mixed anhydride was treated with proline to get peptide derivative [1-N-[ben2yloxy carbonyl]-L-Lysyl]-L-proline .
Veda,yasuyoshi. et.al. in WO 97 43,246 (1996) have described the process for the preparation of intermediate N2-[1-(S) alkoxy carbonyl-3-phenyl propyl]-N2-trifluoro acetyl-L-Lysine from N2-Trifluoro acetyl-L-Lysine . N®-Trifluoro acetyl-L-Lysine condensed with ethyl trans p-benzoyi acrylate with lithium hydroxide (LiOH) solution and then reduced with Palladium-carbon catalyst. Yamada et.al. in EP No. 239,062 and US patent no 4,925,969 have also reported the same process as Veda,yasuyoshi. et.al. WO 97 43.246 (1996), to get the intermediate N2-(1-(S) ethoxy carbonyl-3-oxo-3-phenyl propyl)-N2-trifluoro acetyl-L-Lysine.
Richter Gedeen et.al. in JP no 08,253,497 reported a process for the preparation of Lisinopril by the condensation of N2 -(1-(S) ethoxy carbonyl-3-oxo-3-phenyl propyl) -N24rifluoro acetyl-L-Lysine with L-proline benzyl ester hydrochloride in the presence of dicyclohexyl carbodiimide, N-Methyl morpholine in methylene chloride for effecting the peptide linkage.
Kalvod, Ladislau in CZ patent No. 280,793 has reported stereo specific synthesis of Lisinopril. In this process N2-phthaloyl protected-L-Lysine benzyl ester p-toluene sulphonic acid salt condensed with t-butyl-S-benzoyI acrylate in the presence of potassium carbonate (K2C03).This compound under went hydrolysis of benzyl ester and cycio condensation with phosgene to give the carboxy anhydride, which is condensed with silylated L-proline followed by benzylic hydrogenation, desilylation and hydrazinalysis of the phthalimide.
Sun, Ammin et.al in CN patent No. 1,140,708 have reported a process for the preparation of Lisinopril starting form N2-trifluoro acetyl-L-Lysine. N2-trifluoro

acetyl-L-Lysine condensed with 2-oxo-4-phenyl butyric acid in ethanol in the presence of SA*' zeolites and the resulting compound was reduced with Raney Ni and Hydrogen, which gave 45% N2-{1-ethoxy carbonyl-3-phenyl propyl)-N2-trifluoro acetyl-L-Lysine, which was then treated with tetramethyl ammonium hydroxide (Me4N0H) salt of L-proline in N,N-dimethyl formamide in the presence of N-Hydroxy succinamide and dicyclohexyl carbodiimide and thereafter hydrolysed with sodium hydroxide to give Lisinopril.
Disadvantage of prior art processes: -
In the process described and exemplified in the US patent No. 4,374,829 and US patent No. 4,472,380 Harris et.al a diamine acid for example L-Lysyl-L-proline, with t-butoxy-carbonyl protection of the acid function thereof, is condensed with 2-oxo-4-phenyl butyric acid, in the presence of sodium cyanoborohydride.
In EP patent No. 79521 phenyl propanaldehyde is used instead of 2-oxo-4-phenyl butync acid in the presence of potassium cyanide.
The cyanides are not only hazardous but also the process is very tedious, making it commercially not viable.
As per Jan oudenes US patent No. 4,808,741 for the siiyi protection of L-Lysine acid moiety with hexamethyl disilazane gives some disilylated by product such as along with acid silylation, N-silylation also takes place. To eliminate disilylated by-product there should be some proper control, which make the process costly and tedious.
Veda yasuyoshi. et.al. in their process condensed N2-trifluoro acetyl-L-Lysine directly with ethyl trans-p-benzoyi acrylate in the presence of aqueous lithium hydroxide solution in ethanol, as per this process, the Michael addition is carried out in basic aqueous alcoholic solutions, and the amino acid used is without any protection of its acid moiety. The resultant 1-alkoxy carbonyl-3-oxo-3- phenyl

propyl derivative is further catalytically reduced to 1-alkoxy carbonyl-3-phenyl propyl derivative, the reduction being carried out in an alcohol or a solvents containing the alcohol in the presence of a strong acid having a concentration of 0.4 to 5 N, the amount of the strong acid being carried out with in the range of 3-15 equivalents based on 1 mole of the 1-alkoxy carbonyl-3-oxo-3-phenyl propyl derivative.
This process may give the by-products like hydrolyzed by-product as 1-carboxy-3-phenyl propyl derivative and over reduced by-product as 1-alkoxy carbonyl-3-cyclohexyl propyl dehvative.
Sun, Ammin et.al in their process condensed N2-trifluoro acetyl-L-Lysine with 2-oxo-4-phenyl butyric acid in the presence of 5 A° zeolites. This process can also produce undesired by-products In stereo specific synthesis of Lisinopril reported by Kolvod, Ladislau the steps of silylation and dephthalylation with hydrazine are tedious and peptide linkage through mixed anhydnde of L-Lysine which was prepared with phosgene. Some other reports of mixed anhydride of L-Lysine condensed with L-proline also with Phosgene.
Use of phosgene itself very hazardous and therefore, this process is not commercially useful.
Objectives of the Present Inventioh: -
Therefore the main objective of the present invention is to provide an improved process for the preparation of Lisinopril dihydrate of the formula I, which is an antihypertensive compound overcoming the disadvantages of the prior art processes.

Another objective of the present invention is to provide an improved process for the preparation of Lisinopril dihydrate of the formula I, using a reagent HOBt (1-Hydroxy benzotriazole) with DCC (dicyclohexyl carbodiimide) for peptide synthesis of L-proline benzyl ester with N2-(1-(S) ethoxy carbonyl-3-phenyl propyl)-N2-trifluoro acetyl-L-Lysine as additive to increase the yield and decrease racemization.
Still another objective of the present invention is to provide a novel intermediate compound of the formula-ll useful for the preparation of Lisinopril dihydrate of the formula I.
Accordingly the present invention provides an improved process for the preparation of Lisinopril dihydrate [(S)-1-[N2-1(1-carboxy-3-phenyl propyl)-L-Lysyl ]-L-proline dihydrate] of the formula I.

Which comprises
(I) Protecting the N2-position of L-Lysine with trifluoro acetyl group and acid moiety with benzyl group.
(II) Coupling the resultant N2-trifluoro acetyl-L-Lysine benzyl ester with ethyl trans-p-benzoyi acrylate, to yield the novel compound N2-[1(S)-ethoxy carbonyl-3-oxo-3-phenyl propyl]-N2-trifluoro acetyl-L-Lysine benzyrester*of the formula II.
(iii) Reducing and debenzylating the novel N2-1-[1(S) ethoxy carbonyl-3-oxo-3-phenyl propyl]-N2-trifluoro acetyl-L-Lysine benzyl ester by hydrogenation by conventional methods to yield N2-1-[1(S) ethoxy carbonyl-3-phenyl propyl]-N2-trifluoro acetyl-L-Lysine.

(iv) Coupling the N2-1-[1(S) ethoxy carbonyl-3-phenyl propyl]-N2-trifluoro acetyl-L-Lysine obtained in step (iii) with L-proline benzyl ester hydrochloride in the presence of 1-hydroxy benzotriazole and dicyclohexylcarbodiimide.
(v) Debenzylating by hydrogenation using conventional methods the resulting N2-1-[1(S) ethoxy carbonyl-3-phenyl propyl]-N®-trifluoro acetyl-L-Lysyt-L-proline benzyl ester.
(vi) Hydrolyzing the N2-1-[1(S) ethoxy carbonyl-3-phenyl propyl]-N®-trifluoro acetyl-L-Lysyl-L-proline to get Lisinopril dihydrate and
(vii) Purifying the resulting Lisinopnl dihydrate using an acidic Ion exchange resin to give pure Lisinopnl dihydrate of the formula -1.
According to another feature of the present invention there is provided a novel N2-1 -[1 (S) ethoxy carbonyl-3-oxo-3-phenyl propyl]-N2-trifluoro acetyl-L-Lysine benzyl ester of the formula II, which is an intermediate useful for the preparation of Lisinopril dihydrate of the formula - I, which comprises,

(i) Protecting the N2-position of L-Lysine with trifluoro acetyl group and acid moiety with benzyl group and .
(ii) Coupling the resultant N2-trifluoro acetyl-L-Lysine benzyl ester with ethyl-trans-p-benzoyl acrylate to yield the novel compound of the formula - II, N2"1-[1(S) ethoxy carbonyl-3-oxo-3-phenyl propyl]-N®-trifluoro acetyl-L-Lysine benzyl ester.
Detailed description of the invention: -
.■•■■" "■*■■ ""
In the process for the preparation of Lisinopril dihydrate, according to the present invention, the benzyl ester of N2-trifluoro acetyl-L-Lysine is prepared from the L-Lysine in two simple high yield chemical process steps. The protection of N® position of L-Lysine is effected with trifluoro acetyl group by condensation of L-Lysine with ethyl trifluoro acetate in the presence of 50% sodium hydroxide solution. The ethyl trifluoroacetate used is prepared by esterification of trifluoroacetic acid with ethyl alcohol in the presence of sulphuric acid. The acid moiety of N2-trifluoro acetyl-L-Lysine protected with benzyl group as ester through acid chloride with phosphorous pentachloride followed by esterification with benzyl alcohol in acidic conditions. N®-trifluoro acetyl-L-Lysine benzyl ester hydrochloride so prepared is converted to free base by washing with inorganic aqueous base solution in hydrocarbon solvents such as toluene and further Michael addition reaction is carried out with ethyl trans-p-benzoyi acrylate at a temperature in the range of 0-15°C. to give the novel intermediate N2(1-ethoxy carbonyl-3-oxo-3-phenyl propyl)-N2-trifluoro acetyl-L-lysine benzyl ester of the formula (II).
Before the Michael addition, the inorganic base to be used for converting the hydrochloride salt to free base of N2-trifluoro-L-Lysine benzyl ester hydrochloride is not particulariy restricted but includes, among others, hydroxides and carbonates of alkali metals or alkaline earth metals. As specific examples of

such base, which can be used, there may be mentioned, among others, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate and alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide. Other inorganic bases may also be used. Among them, basic sodium or potassium compounds are preferred. From the operability viewpoint, these bases are preferably used in the form of aqueous solutions. It is generally advantageous to use them in the form of aqueous solution having a concentration of 5 to 40% by weight, preferably 5 to 10% by weight. These bases may be used singly or two or more of them may be used in combination. But while releasing the hydrochloride salt the aqueous layer should be basic, generally pH 8.00 to 11.00, preferably 10.0 to 10.5.
As regards the operation temperature in the Michael addition step, an especially high temperature or very low temperature is not required. Practically, the reaction can be carried out generally at 0-15°C, preferably at 5 -7°C.

hydrocarbon solvent without any basic or aqueous solution at 0*10°C. The acid moiety of amino acid protected with benzyl group in Michael addition reaction. The de-protection of benzyl group after Michael addition reaction need not go for another step it takes place while the reduction of carbonyl group with palladium on carbon catalyst under hydrogen pressure in the presence of acetic acid as solvent at 20-50''C, preferably at 40-45 "C. In general the hydrogen pressure of debenzvlation and carbonvl reduction in the ranae of 3.0 to 5.0 Ka/Cm^ preferably 4.0 to 4.2 Kg/Cm^. If more than 5.0 Kg/Cm2. by-product formation that is over reduction takes place.
Then the compound N2(1-(S) ethoxy carbonyl-3-phenyl propyl)-N2 - trifluoro acetyl-L-Lysine of the formula (III) may be reacted with appropriately chosen amino acid, to prepare the dipeptide denvative of Pharmaceutical activity, when it is desired to prepare LisinopnI. the amino acid is proline. Preferable, the proline is protected at its acid function by an ester group such as a benzyl ester to minimfse side reactions.
L-Proline treated with benzyl alcohol in the presence of thionylchloride to give L-proline benzvl ester hvdrochloride. The oeotide couolina of the N2M-(S) ethoxv carbonyl-3-phenyl propyl)-N2-trifluoro acetyl-L-Lysine with L-proline benzyl ester hydrochloride in the presence of 1-Hydroxy benzotriazole (HOBt) and dicyclohexyl carbodiimide (DCC).
The use of 1-Hydroxy benzotriazole reagent along with dicyclohexyl carbodiimide in the place of N-methyl morpholine or N-Hydroxy succinamide, provide significant advantage regarding recemization. The 1-hydroxy benzo triazole'is very common and well-known additive in the dicyclohexyl carbodiimide method for peptide synthesis. This reagent is particularly for increase the yield and as well as supress the recemization in peptide synthesis. 1-Hydroxy benzotriazole and dicyclohexyl carbodiimide can be used 1.0 to 1.5 molar equal. Practically the reaction can be earned out generally not more than

1.5 molar equal, preferably not higher than 1.2 molar equal, more preferably 1.1 molar equal.
Then de-protection of benzyl protecting group is effected by hydrogenation preferably , over palladium-carbon catalyst. Finally hydrolysis to de-protect the N2-position and carboethoxy to give Lisinopril dihydrate (I) technical product.
Lisinopril dihydrate technical product produced can be purified by passing through acidic ion exchange resin, preferably lndion-225H. Before loading the product, the Ion exchange resin should be regenerated by passing 5-10% inorganic acid solution followed by DM water. Inorganic acid solution is preferably hydrochlonc acid, more preferably 5% hydrochloric acid solution. Wash the resin with distilled water till the solution is free from chlondes (Silver nitrate test). Then the alkaline solution of Lisinopril can be absorbed by passing through the acidic ion exchange resin lndion-225H over a period 2-10 hrs. preferably 3-4 hrs.
Regarding preparation of alkaline solution of Lisinopril, 10 to 50% of alkali metal hydroxide solutions can be used, preferably 25 to 30% solutions of either sodium hydroxide or potassium hydroxide at a temperature in the range of 5 - 30°C. After complete absorption of the product into the resin, the resin is to be washed with distilled water, till the eluent is free from chlorides (Silver nitrate test). Then the product is eluted with dilute aqueous ammonia solution, preferably 3 - 4% aqueous ammonia solution. The product fractions are collected as per TLC. The fractions are mixed and degassed with Nitrogen followed by vacuum distillation to removed excess ammonia, adjusted pH to 5.2 - 5.3 with cone. Hydrochloric acid. The resultant product is given carbon treatment twice at 40 - 45'*C and water distilled off under reduced pressure below 60°C. untill 2 volumes remained in the flask. The product is seeded out and isolated by stirring at 40 - 45X for 24 hrs. then cooled to 20 - 25*0 slowly over a period of 2 - 3 hrs. and stirred at 20 - 25X for 24 hrs. to get pure Lisinopril dihydrate.

The foregoing description is only illustrative the present invention and it is not intended to limit its scope Many other specific embodiments of the present invention which will be obvious and apparent to one skilled in the art from the foregoing disclosure are also fall within the scope of the present invention . More details of carrying out the process of the present invention are given in the examples given below which are provided for the sole purpose of illustrating the invention and therefore should not be construed to limit the scope of the invention.
Example -I
Step (1) Preparation of Ethyl trifluoro acetate :
Absolute ethyl alcohol (1200 ml) (M,C.< 0.1%) is treated drop wise with trifluoro acetic acid (1000 g) over a penod of Ihr. at 20-25''C. then the resulting mixture treated drop wise with cone. Sulphuric acid (265 ml) during Ihr.at 15-25''C. Heat the reaction mass to reflux and maintain at reflux for 3hrs. then distill off ethyl trifluoro acetate atmosphencally. Wash the distillate with 5% sodium carbonate solution (500 ml) followed by 5% sodium chloride solution (500 ml) to give 1089 g. ethyl trifluoro acetate. Yield : 87.4%,
Step (2) Preparation of N2-Trifluoro acetyl-L-Lysine:
L-Lysine HCI 500 g (2.7374 mole) is dissolved in 500 ml water. The solution is cooled to 20-25X, adjusted the pH to 10.7-10.8 using 50% NaOH solution (400 ml). Then the solution is diluted with Isopropyi alcohol (2 L). The solution is cooled to 0-5''C and ethyl trifluoro acetate 450 g (3.06 mole) is added drop wise during 1 hr. at O-5'C, and maintained for 4 hrs. at 0-5''C. Filtered and washed the product, with 500 ml of chilled Isopropyi alcohol and dry the product at 70-75X to give 455 g N2-trifluoro acetyl-L-Lysine, yield : 69%

step (3) Preparation of N2-Trifluoro acetyl -L-Lysine benzyl ester hydrochloride :
Dissolved N2-trifluoro acetyl-L-Lysine 250 g (1.037 mole) obtained as above in 2.5 L methylene chloride. Passed dry HCI gas untill pH of reaction mass is acidic at 0-5''C. Phosphorous pentachloride 250 g (1.220 moles) is added in 5-6 lots during 1 hr. at 0-5°C, Stirred for 4 hrs. and benzyl alcohol 670 g (6.20 moles) is added during Ihr. period. Maintained the reaction mass for 1 hr. at 0-5''C, then 1 hr at 10-15X, I hr at 15-20^ 1 hr. at 20-25X. Finally allowed to 25-30X and stirred for 12 hrs. Cooled to 10X, added chilled water 2.8 L at 10-15X, stir for 30 min and adjusted the pH to 10.5 using 50% aqueous sodium hydroxide solution (450 ml). Separated the layers and extracted the aqueous layer with 500 ml of Methylene chloride, and combine both organic layers. Passed dry HCI gas to the methylene chlonde layer untill pH acidic at 0-5''C. then stirred for 1 hrat 0-5''C and filtered to give 189 g of N2-trifluoro acetyl-L-Lysine benzyl ester hydro chlonde yieJd 49.58%.
Step(4)Preparation of N2-[1-(S)-Ethoxycarbonyl"3-oxo-3-phenyl propyl ]-N2-trifluoroacetyl-L-Lysinebenzyl ester Hydrochloride :
N2-trifluoro acetyl-L-Lvsine benzvl ester hvdrochlohde 600 a (1.6326 molest obtained as described above is stirred with toluene 3.6 L and 10% NaOH solution (660 ml) at 20-25X. pH of aqueous layer to be 10-10.5. Adjusted the pH if necessary. Separated the aqueous layer and dried the toluene layer over anhydrous sodium sulphate. Ethyl trans-p-benzoyi acrylate 720 g (3.51 moles) was added drop wise to the Toluene layer during 2 hrs. at 5-7''C. after addition, stirred for 16 hrs. Passed dry HCI gas untill pH get acidic at 5-10''C and stirred for another 1 hr, filtered and washed the product with 600 ml. toluene. Hexane 4.2 L was added to the product, stirred for 1 hr. at reflux temperature then 1 hr. at 25-30X filtered and dried to aet Dure N2-rifS)-ethoxv carbonvl-3-oxo-3-

phenyl propyl]-N2-tnfluoroacetyl-L-Lysine benzyl ester hydrochloride. 568 g (60.87%).
Step (5) Preparation of N2-[1 (S)-Ethoxy carbonyl-3-phenyl propyl]N2-trifluoro acetyl-L-Lysine:
N2-[1 (S)-ethoxycarbonyl-3-oxo-3-phenyl propyl]N2-trifluoroacetyl-L-Lysine benzyl ester hydrochloride 75 g (0.1312 moles) prepared as described above was dissolved in acetic add (750 ml) in a hydrogenation vessel 5% palladium carbon catalyst 15 g was added and passed H2T gas with 4.0-4.5 Kg/cm^ pressure for 12 hrs. at 40-45''C. Filtered the palladium carbon catalyst and concentrated under reduced pressure below 65''C get residue. Dissolved the residue in 375 ml of 50% aqueous industrial metylated spint (IMS), then adjusted the pH to 4.2 with aqueous ammonium hydroxide solution,(15 ml), stirred for 2 hr. at 25-30°C and stirred for another 2 hrs at 5-10c, filtered and washed with 50 ml 50% aqueous IMS to get N2-[1(S)-ethoxy carbonyl-3-phenyl propyljN2-trifluoro acetyl-L-Lysine. The technical product is leached with 50% aqueous IMS at 20-25°C, to give 33 g, yield: 58.34%.
Step (6) Preparation of (S)-1-[N2-1(1-carboxy-3-phenyl propyl)-L-Lysyll-L-proline dihydrate (LisinoprtI dihydrate) Technical :
Charged thionyl chloride 220 g (1.8487 moles) to the stirred solution of benzyl alcohol 1320 ml at -6''C to -4°C (reaction is highly exothermic). Then maintained for 1 hr. at -6°C to -4°C. Then added L-proline 100 g (0.8695 moles) at Oc. stirred for 48 hrs. at 25-30c. Distilled off the excess HCI under reduced pressure and poured in Diisopropyl ether 4.25 L stirred for 2 hrs. and filtered the product. Again, slurried the product in 1 L Diisopropyl ether to give 225 g of L-proline benzyl ester hydrochloride.

Charged the resultant L-proline benzyl ester Hydrochloride 28.5 g (0.1183 moles) in methylene chloride (750 ml) and triethylamine (34 ml). Then added 1-hydroxy benzotnazole 19.5 g (0.1276 mole) and N2-[1(S)-ethoxy carbonyl-3~phenyl propyl]-N2-trifluoro acetyl-L-Lysine 50 g (0.1160 moles). Cooled to 10°C. dicyclohexyl carbodiimide 26.3 g (0.1276 moles) at 10-15X is added, stirred for 15 hrs at 25-30°C. filtered the salts and washed with methylene chloride 50 ml. washed the methylene chloride layer with 500 ml of 5% NaHCOs solution and concentrated the methylene chloride layer below 45'*C. dissolved the residue in 250 ml of acetone and undissolved salts are removed by filtration, washed the salts with 50 ml acetone. Concentrated the acetone layer to get 75 g of residue.
Dissolved the above residue (75 g) in industrial methylated spirit (IMS) (750 ml) in autoclave, added 5% Palladium Carbon (7.5 g) and passed hydrogen gas with 4.0 -4.2 Kg/cm" pressure for 12 hrs at 35-40''. After ensuhng the reaction is completed, filtered the catalyst and concentrated the reaction mass under reduced pressure below 50''C to give 66 g of residue. Dissolved the residue in NaOH solution (17.5 g in 196 ml of DM water) and stirred for 16 hrs. at 25-30X.
After ensuring the formation of Lisinopril, filtered the undissolved salts adjust the^
pH to 5.2 - 5.3 with cone. HCI (34 ml). Distilled off water completely under reduced pressure below 50°C. added methanol (250 ml) and stirred at 25-30''C. for 30 min. Filtered and washed the salts with 50 ml methanol and concentrated. Repeated the process again to remove all salts. Finally, residue dissolved in Isopropyl alcohol 28 ml, ethyl acetate 28 ml, and water 14 ml mixture, after seeding, stirred for 36 hrs. at 25-30*'C. Filtered and washed the product with above mixture of solvents (50 ml), dried the product at 50-55*'C to give 34.5 g of Lisinopril dihydrate (Technical).
Step (7) Purification of Lisinopril dihydrate :
Acidic Ion exchange resin (Indion - 225H) (600 ml) is charged i column. The resin is washed with DM water (600 ml), and with 5%
acid (600 ml). Thereafter with DM water till pH is neutral. Then washed the resin with distilled water (1200 ml) till the solution is free from chlorides (Silver nitrate test). The alkaline solution of Lisinopril dihydrate (Tech) is passed through resin drop wise during 3-4 hrs. For making the alkaline solution of Lisinopnl dihydrate, Technical product (40 g) obtained above is dissolved in DM water by adjusting pH to 10.45 - 10.50 with 10% sodium hydroxide solution while stirring at a temperature in the range of 15-20''C. Then the resin is washed with distilled water until free from chlorides (Silver nitrate test). Then eluted with 4% aqueous ammonia (1.25 L). Collect the fractions which is monitored by TLC, mix the fractions, degas the solution with Nitrogen followed by vacuum distillation to remove excess ammonia, pH is adjusted to 5.2 - 5.3 with cone. Hydrochloric acid. Carbon treatment was given twice (4.0 g each) at 40 - 45°C. distilled off water under reduced pressure below SO'C until 80 ml solution remained in the flask Seed and stirred for 24 hrs at 40 - 45°C. then cooled to 20 - 25c slowly dunng 2 hr. stirred at 20 - 25°C for 24 hrs. and filtered the product, washed with chilled, distilled water 20 ml. Dried the product at 45 - 50*'C under vacuum to yield Lisinopril dihydrate (Pharma grade) 24 g, yield: 60%, HPLC purity > 99.5%, sulphated ash : 0.05%.
• Advantages of the invention
• The de-protection of benzyl group of formula II after Michael addition reaction need not go for another step, it takes place while the reduction of carbonyl group with palladium on carbon catalyst while hydrogenation. This is added advantage of selecting benzyl ester of formula II. Where as other protecting group needs additional step for de-protection.
• The process of the invention is simple and safe and can be employed for commercial production.