Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 3-CYCLOHEXYL ALANINE DERIVATIVE

Abstract

The present invention relates to an improved process for the preparation of 3-cyclohexyl alanine derivative of the formula (I), wherein R<SUP>1</SUP>,R<SUP>2</SUP>, R<SUP>3</SUP>, R<SUP>4</SUP>, R<SUP>5</SUP> may be same or different and independently represent hydrogen, (C<SUB>1</SUB>-C <SUB>5</SUB>) alkyl group or OX, where X is a hydrogen atom or removable hydroxy protecting group such as(C<SUB>1</SUB>-C <SUB>5</SUB>)alkyl, aryl, tetrahydropyran; P represents hydrogen atom and M represents a hydrogen atom or metal cation or (C<SUB>1</SUB>-C <SUB>5</SUB>) alkyl group or an aryl group or an organic base like dicyclohexyl amine, piperidine, triethylamine, their derivatives, their analogs, their stereoisomers, their polymorphs, their salts and their solvates which comprises : redoing L-phenyl alanine of formula (II) where all the symbols are as defined above in the presence of a catalyst, separating the catalyst from the reaction mixture, isolating and recovering the 3-cyclohexyl alanine of the formula (I), from the reaction mixture.

Full Text

Field of Invention The present invention relates to an improved process for the preparation of 3-cyclohexyl alanine and its derivatives. The present invention particularly relates to an improved process for the preparation of 3-cyclohexyl alanine of the formula (I), wherein R',R2,R3,R4,R5 may be same or different and independently represent hydrogen, (Cp C5) alkyl group or OX, where X is a hydrogen atom or a removable hydroxy protecting group such as (C1-C5) alkyl, aryl, tetrahydropyran ; P represents hydrogen atom or a removable amino protecting group such as benzyloxy carbonyl, tert-butyloxy carbonyl and M represents a hydrogen atom or metal cation or (Ci-Cs)alkyl group or an aryl group or an organic base like dicyclohexyl amine, piperidine, triethylamine, their derivatives, their analogs, their stereoisomers, their polymorphs, their salts and their solvates. 3-cyclohexyl alanine of the formula (I) forms part of several peptides of pharmaceutical importance. For example, its use as renin inhibitor for the treatment of hypertension is disclosed in European patent application Nos. 0 371 179; 0 468 641 and US patent application No. 5 229 518 etc. Its use as metallo proteinase inhibitor for cancer treatment is disclosed in International application No. WO 93/24475 and as analgesic is disclosed in US patent No.4,273,704. Its activity against immuno deficiency syndrome by activating effectively the phagocytic action of macrophages and polymorpho-nuclear leukocytes is disclosed in European patent application No. 0 454 302 and International applications No. WO 92/04370. The use of 3-cyclohexyl alanine as sweetening agent for pharmaceutical products and food stuffs is disclosed in German patent application Nos. 1,936,159 & 1,948,788. Background of the Invention Several reports describes the process for the preparation of 3-cyclohexyl alanine by hydrogenation of L-phenylalanine in acidic medium. The hydrogenated product was isolated by evaporation of the solvent and then derivatized to produce amino group protected 3-cyclohexyl alanine, since protected amino acids are most commonly used in peptide synthesis. Use of acetic acid for the reduction of amino acids may lead to racemisation of the product [Sakieki et al, J. Chem. Soc. Jpn., (1959), 80, 1035; Matsuo et al, Chem. Pharm. Bull. (1970), 18, 1788] and may corrode the reaction vessel. US patent No. 4,273,704 describes a process for the preparation of 3-cyclohexyl alanine reacting L-phenylalanine in 90% aq. acetic acid in the presence of RJ1-AI2O3 as catalyst for 24 hours at 37 °C. The catalyst is separated by filtration and filtrate is concentrated to dryness. The N-carbenoxy protection is then carried out in presence of NaOH solution. US patent Nos. 5,229,518 & 5,182,266 disclose a process for the preparation of the 2(S)-cyclohexyl alanine by hydrogenating L-Phenyl alanine over Pd/C in acetic acid. After completion of the reaction, the catalyst is filtered and solvent is concentrated to yield the desired compound. European patent application No. 0 454 302, describes a process for the preparation of D-cyclohexyl alanine by hydrogenating D-phenylalanine in aq. acetic acid (1:1) over Pt02 under 70 kg/cm2 pressure at room temperature. After 7 hrs, the catalyst is filtered off and the filtrate is concentrated. The recrystallised compound is suspended in a mixture of dioxane and 3N sodium hydi oxide solution under ice cooling and then di-tert-butyl-pyrocarbonate added to get N-tert-butoxy carbonyl-D-cyclohexyl alanine. International patent application No. WO 92/04370 describes a method for the preparation of L-cyclohexyl alanine which comprises hydrogenation of L-phenyl alanine over Pt02 under 47 psi of pressure for 2 days in 70 % of acetic acid. After completion of the reaction, the catalyst was filtered and the solvent concentrated under reduced pressure. The present invention is based upon our finding that alkaline solutions are conveniently used as solvents for the hydrogenation of phenyl alanine of formula (II) under mild pressure and ambient temperature conditions. Objective of the Invention The main objective of the present invention is to provide an improved process for the preparation of 3-cyclohexyl alanine of the formula (I), as defined above, their derivatives, their analogs, their stereoisomers, their polymorphs, their salts & their solvates. Another objective of the present invention is to provide a simple, commercially viable, cost effective process for the preparation of 3-cyclohexyl alanine of the formula (I), (a), by minimizing the number of plant operations, (b) using non-hazardous starting materials. Summary of the Invention Accordingly, the present invention provides an improved process for the preparation of 3-cyclohexyl alanine derivative of the formula (I), wherein R , R , R , R , R may be same or different and independently represent hydrogen, (Q-C5) alkyl group or OX, where X is a hydrogen atom or a removable hydroxy protecting group such as (Ci-C5) alkyl, aryl, tetrahydropyran ; P represents hydrogen atom and M represents a hydrogen atom or metal cation or (C1-C5) alkyl group or an aryl group or an organic base like dicyclohexyl amine, piperidine, triethylamine, their derivatives, their analogs, their stereoisomers, their polymorphs, their salts and their solvates, which comprises : i). reducing L-phenyl alanine of the formula (II) where all the symbols have the meanings defined above in a solution of alkaline or alkaline earth metal of the Group IA and IIA elements and in the presence of a catalyst at a temperature in the range of 10-70 °C, at a pressure ranging from atmospheric pressure to 300 psi, ii). separating the catalyst from the reaction mixture by conventional methods, iii). isolating the compound of formula (I) by conventional methods and if desired, iv). converting the compound of formula (I) obtained in step (iii) into its derivatives, analogues, stereoisomers, salts & solvates by reacting with a carbonate such as benzyloxy carbonyl chloride or di-t-butyl dicarbonate followed by treatment with bases such as NaOH, KOH or dicyclohexyl alanine. Detailed Description of the Invention The catalyst used in the above said process may be selected from platinum, palladium or rhodium and the like mounted on alumina or carbon. The alkaline solution used is selected from the hydroxides of Group IA and IIA elements preferably hydroxides of lithium, sodium, potassium and the like. The temperature for the reduction may range from 10 °C to 70 °C, preferably at room temperature. The reduction may be carried out at a pressure ranging from atmospheric pressure to 300 psi. The reaction time may range from 6-15 h, preferably from 8-12 h. The separation of the catalyst from the reaction mixture may be affected by centrifuging the reaction mixture or by filtration. The isolation of the compound of the formula (I) where P represents hydrogen atom and M represents metal cation such as Li, Na, K etc may be carried out by conventional methods such as evaporating the solvent at elevated temperature or freeze drying or spray drying the reaction mass. Compound of formula (I) where both P & M represents hydrogen may be isolated from reaction mass after separating the catalyst and adjusting the pH of reaction mass to isoelectric point. The said compound so precipitated out may be separated by fitration or centrifugation. The protection of compound of the formula (I) where P represents hydrogen atom may be carried after separating the catalyst from reaction mass, directly without isolating the compound of formula (I) where P represents hydrogen by reacting with a carbonate such as benzyloxycarbonyl chloride or di-t-butyl dicarbonate. Cyclohexyl alanine of the formula (I) where P represents a protective group may be recovered by acidification of the reaction mixture and the compound of formula (I) where P represents a protective group taken from carbonate family may be extracted into suitable organic solvent and then solvent evaporated. Conversion of compound of the formula (I) where P represents hydrogen atom or a protecting group and M represent hydrogen atom to its salt may be carried out by reacting the compound with an equimolar quantity of inorganic bases like NaOH, KOH or organic bases like dicyclohexyl alanine and the isolating required compound in salt form by conventional methods like evaporation of the solvent or filtration of the salt. The present invention is described in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1 : Preparation of (S)-3-cyclohexyl alanine A solution of L-phenyl alanine (20 g) in 2N NaOH (200 ml) was hydrogenated at 50-60 psi of pressure in presence of 5 % Rh-Al203 (2 g) at room temperature. After completion of the reaction (8-10 hrs), the catalyst was separated from reaction mixture by filtration. The pH of the filtrate was adjusted to iso-electric point. The (S) 3-cyclohexyl alanine product so precipitated out of the solution was filtered, washed thoroughly with water and dried to yield 19.2 g (95 %) of the product, m.p. :274-275 °C. Example-2 : Preparation of (S)-3-cyclohexyI alanine sodium salt To a solution of L-phenyl alanine (20 g) in IN NaOH (125 ml), 5 % Rh-Al203 (2 g) was added and hydrogenated at 50-60 psi pressure at room temperature. After completion of the reaction (8-10 h), catalyst was separated by the filtration and the reaction mixture could be spray dried or freez dried or simply evaporated under vacuum to yield white powder (22 g; 92 %) of (S)-3-cyclohexyl alanine sodium salt. m.p. 283-85 °C. Example - 3 : Preparation of N-benzyloxy carbonyl (S)-3-cyclohexyl alanine A sc ution of L-phenyl alanine (20 g) in 2N NaOH (100 ml) in presence of 5 % Rh-Al203 (2 g) was hydrogenated at 50 psi pressure, at room temperature. After completion of the reaction (8-10 h), the catalyst was separated by filtration. To the filtrate, benzyl chloroformate (24.8 ml) and 2N NaOH solution (12.5 ml) were added simultaneously at 0 °C while the reaction mixture was stirred vigorously. After completion of reaction, the reaction mixture was cooled to 0°C and acidified with dil. HC1. The product was extracted into organic solvent, washed with water, concentrated to yield 31.948 g (86.4 %) of colourless syrupy material. Example - 4 : Preparation of 2(S)-N-benzyIoxycarbonyl-3-cyclohexyl alanine sodium salt To a solution of 3-cyclohexyl alanine (10 g) obtained from Example - 1 in 2N NaOH solution (100 ml) was added benzyl chloroformate (24 ml of 50% in toluene) and 4N NaOH solution (25 ml) simultaneously at 0 °C in 30 min. while stirring the reaction mixture vigorously. After completion of the reaction, the reaction mixture was acidified with dil. HC1 to pH 3-4 at 0 °C. The product was then extracted into suitable organic solvent, organic layers washed with water brine and concentrated to get a thick syrup, a solution of NaOH (1.35 g) in MeOH (50 ml) was adde.l to the syrup and stored for lh at room temperature. Methanol was distilled off to get a white coloured solid which was dried in vacuum oven at 50 °C until it was free from solvent and moisture to yield 2-(S)-N-benzyloxy carbonyl-3-cyclohexyl alanine sodium salt.(15.65g, 81.6%). Example - 5 : Preparation of 2(S)-N-benzyloxycarbonyl-3-cyclohexyI alanine dicyclohexyl amine salt A solution of (S)-phenyl alanine (20 g) in 2N KOH (100 ml) was hydrogenated over 5 % Rh-A12C 5 (2 g) under 50-60 psi of hydrogen pressure at room temperature. After completion of the reaction (8-10 h), the catalyst was separated by filtration. To the filtrate at 0 °C, benzyl chloroformate (108 ml) and 2N KOH (25 ml) were added simultaneously in about 30 min. The reaction mixture was acidified to pH 3-4 at 0 °C. The compound was extracted into ethyl acetate. Organic layer was washed with water to neutral pH, then dicyclohexyl amine (22 g) was added drop wise at room temperature. The salt so separated out was filtered, dried to yield the title compound 49 g (86 %), m.p. 157 - 158 °C. Example - 6 : Preparation of (R)-3-cyclohexyl alanine A solution of D-phenyl alanine (5 g) in IN NaOH (150 ml) was hydrogenated over 5 % Rh-A1203 (1 g) at room temperature under 50-60 psi of pressure. After completion of the reaction (8-10 h), the catalyst was separated by filtration and the pH of filtrate was adjusted to its isolelectric point with dil. HCl. The compound precipitated out was filtered, washed thoroughly with water and dried to yield (R)-3-cyclohexyl alanine.(4.6 g : 88.77%) Example - 7 : Preparation of (S)-3-(2-methyl cyclohexyl) alanine : To a solution of O-methyl phenylalanine (5 g) in 2N NaOH (50 ml) at room temperature was added 5% Rh-Al203 (1 g) and hydrogenated under 60-70 psi of pressure for 10-12 h. The catalyst was filtered off and then the filtrate pH was adjusted to isoelectric point. The precipitated product was filtered and dried to yield (S)-3-(2-methyl cyclohexyl)alanine. Yield : 4.8 g (92.89%). Example - 8 : Preparation of 2(S)-N-tert-butyloxy carbonyl-3-cyclohexyl alanine dicyclohexyl amine salt Di-tert butyl dicarbonate (6.8 g) in dioxane (10 ml) and IN NaOH solution (25 ml) were added drop wise to a cold solution of 3-cyclohexyl alanine (4.5 g) obtained from Example - 1 in 2N NaOH (25 ml) while stirring the reaction mixture vigorously. After 18 h at room temperature, the reaction mixture was acidified to pH 4-5 with solid KHSO4. The product was extracted into ethyl acetate, washed with water and brine and then dicyclohexylalanine (4.8 g) was added at 00m temperature. The solid so precipitated out was filtered after 1 h, washed with ethyl acetate and dried to yield the product (10.26g; 86.3%) as fine free flowing white solid, m.p. 170-172 °C. Example - 9 : Preparation of 2(S)-N-tert-butyloxycarbonyl-3-cyclohexyl alanine sodium salt A solution of (S)-phenyl alanine (10 g) in IN NaOH was hydrogenated over 5% Pd/C (5 g) at 45-50 °C under 280-300 psi of pressure for 2 days. The catalyst was separated and the filtrate was neutralized with dil. HC1 to pH 6.0 at 0 °C. The organic compound was separated out and filtered. The compound (10 g) was then dissolved in 2N NaOH solution (50 ml). At 0 °C was adde.l di-t-butyloxy dicarbonate (13.3 g) in 25 ml dioxane along with IN NaOH (50 ml) and stirred at room temperature for 18 h. The solution was made acidic with KHSO4 until pH 2-4 and the compound was extracted into ethyl acetate, washed with water and concentrated. The residue was then added to NaOH (2.33 g) dissolved in methanol (100 ml). After 2 h of stirring at room temperature, the solvent was evaporated and the residue was titurated with toluene to yield (17 g) (95.7%) white free flowing product (hygroscopic in nature), m.p. : Did not melt upto 300 °C. Ad\ mintages of the Invention : 1. High solubility of the starting material viz., L-phenyl alanine of the formula (II) in alkaline solution, which facilitates the reaction. 2. The possibility of one pot reaction for the preparation of N-protected derivatives of 3-cyclohexyl alanines without isolating the intermediate product. 3. Use of alkaline solution for the reduction reaction does not corrode the reaction vessel. 1. A process for the preparation of a derivative of 3-cyclohexyl alanine derivative of the formula (I), wherein Rl, R2, R3, R4, R5 may be same or different and independently represent hydrogen, (Ci-C5) alkyl group or OX, where X is a hydrogen atom or removable hydroxy protecting group such as (C1-C5) alkyl, aryl, tetrahydropyran ; P represents hydrogen atom and M represents a hydrogen atom or metal cation or (C1-C5) alkyl group or an aryl group or an organic base like dicyclohexyl amine, piperidine, triethylamine, their derivatives, their analogs, their stereoisomers, their polymorphs, their salts and their solvates which comprises : i). reducing L-phenyl alanine of the formula (II) where all the symbols have the meanings defined above in a solution of alkaline or alkaline earth metal of the Group IA and IIA elements and in the presence of a known catalyst at a temperature in the range of 10-70 °C, at a pressure ranging from atmospheric pressure to 300 psi, ii). separating the catalyst from the reaction mixture by conventional methods, iii). isolating the compound of formula (I) by conventional methods and iv). converting the compound of formula (I) obtained in step (m) into its derivative by reacting with a carbonate such as benzyloxy carbonyl chloride or di-t-butyl dicarbonate followed by treatment with bases such as NaOH, KOH or dicyclohexyl alanine. 2. The process as claimed in Claim 1, wherein, the catalyst used is selected from palladium or rhodium mounted on alumina or carbon or PtC2 3. The process as claimed in claim 1 and 2, wherein the reaction is effected at room temperature. 4. A process for the preparation of a derivative of 3-cyclohexyl alanine of the formula (I), substantially as herein described with reference to the examples.

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