NZ625522B2 - Novel process for the preparation of intermediates of hmg-coa reductase inhibitors - Google Patents

Abstract

Provided is a process for the preparation of chiral pentanoic acid derivative intermediates of the general formula II, which are useful in the preparation of HMG-CoA reductase inhibitors such as rosuvastatin or pitavastatin. The initial step of the process involves the use of the enzyme Candida antarctica lipase B. Further provided are intermediate compounds and their preparation. rctica lipase B. Further provided are intermediate compounds and their preparation.

Description

NOVEL PROCESS FOR THE PREPARATION OF INTERMEDIATES OF HMG-COA REDUCTASE TORS AH26(10927034_1):LNB WO 80219 H3C.N o=$=o CH3 Formula-A Rosuvastatin calcium is marketed under the etary name CRESTOR for treatment of mammals such as human and administrated as daily dosage form of 5 mg, 10 mg, 20 mg and 40 mg.

Rosuvastatin and its pharmaceutically able salts were first disclosed in European patent publication EP 0521471. It also discloses process for the preparation of Rosuvastatin calcium.

Bis{(3R, SS, 6E)[2-cyclopropyl(4-fluorophenyl)—3-quinolyl]-3,5-dihydroxy- 6-heptenoate} menocalcium of Formula-B (Pitavastatin .Calcium) is an HMG-CoA reductase inhibitor, developed by Nissan Chemical Industries for the ent of hyperlipidemia. l 5 a-B Pitavastatin and its pharmaceutically acceptable salts were first disclosed in European patent publication EP 0304063. It also discloses process for the preparation of Pitavastatin sodium.

United States Patent No. 5,260,440 and PCT publication No. WO 03/097614, disclose the synthesis of Rosuvastatin from the intermediate 3(R)-3(tert—butyldimethylsilyloxy) oxotriphenyl-phosphoranylidene hexanoate.

PCT publication No. W0 112 discloses the synthesis of Rosuvastatin from intermediate, -(t-butyldimethylsilyloxy)dimethoxyphosphinylox0-hexanoate.

US 5,117,039 discloses the process for the ation of (3R)[(tert- butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester by the ring opening of 3-[(tert-Butyldimethylsilyl)oxy] pentanedioic anhydride using benzyl D- mandelate which gives less yields along with impurities.

US 20090076292 discloses process for the preparation of Rosuvastatin by using the intermediates 3(R)-3(tert-butyldimethylsilyloxy)oxotriphenyl-phosphoranylidene ate and (3R)(t-butyldimethylsilyloxy)dimethoxyphosphinyl-S-oxo- hexanoate. These intermediates are prepared by a novel intermediate i.e. chiral base salt of hydroxy protected diethyl glutarate.

US 2005/0070605 A1 discloses the oselective opening of 3-hydroxy protected ic anhydride by phenylethylamine to form an amide bond, and further conversion to obtain the HMG-CoA ase inhibitor.

The compound 3(R)—3(tert-butyldimethylsilyloxy)oxotriphenyl-phosphoranylidene hexanoate can be prepared from the pentanoic acid derivatives of the following Formula- II. 0 OX 0 Formula-II wherein X is hydrogen or hydroxy protecting group and R1 is carboxyl protecting group.

In prior art nd of Formula-II is prepared by the resolution of the racemate or asymmetric synthesis. These routes have disadvantages in the industrial scale preparation.

The present invention provides an industrially scalable process for the pentanoic acid derivatives of Formula—II and further conversion to HMG-CoA reductase inhibitors.

OBJECT AND SUMMARY OF THE INVENTION: The principle object of the present invention is to provide novel process for the preparation of pentanoic acid derivatives of Formula-11‘ and further conversion into HMG-CoA ase inhibitors. 0 ox o HOWOR, ‘ I Formula-II wherein X is hydrogen or hydroxy protecting group and R1 is carboxyl ting group.

One aspect of the present invention provides, s for the preparation of compound of Formula-II comprising the steps of: a) enzymatic enantioselective amidation of nd of a-III in presence of suitable enzyme to get amide compound of Formula-IV 0 OH 0 0 OH O MOWOR R2O NH 2 2 Formula—III Formula-IV n R2 is C1-C5 alkyl or aryl or arylalkyl group; b) transesterification of compound of Formula-IV into compound of Formula-V O OH O RSOWNHZ Formula-V wherein Ryis C1-C5 alkyl or aryl or arylalkyl group with proviso that R3 is ent than the R2 of Formula-IV; c) protecting the hydroxy group with suitable hydroxy protecting group to get compound of Formula-VI 0 OX 0 RsOWNHZ Formula-VI wherein X is suitable protecting group; d) converting the compound of a-VI into compOund of Formula-VII; and 0 OX 0 HOWNH2 Formula-VII e) converting compound of Formula-VII into compound of Formula-II. 0 OX 0 HOW0R1 Formula-II wherein R1 is carboxyl protecting group and X is defined above.

DETAILED DESCRIPTION OF THE INVENTION: The present invention s to novel process for the preparation of pentanoic acid derivatives of compound of Formula-II, used as intermediates of HMG—CoA reductase inhibitors and further conversion to HMG-CoA reductase inhibitors.

The compound of Formula-II is used in the ation of heptenoate side chain intermediates ofHMG-CoA reductase tors.

One aspect of the present invention provides process for the ation of compound of Formula-II comprising the steps of: a) tic enantioselective amidation of compound of Formula-III in ce of suitable enzyme to get amide compound of Formula-IV 0 OH O ‘ R20 0R2 R20 NHZ Fonnula—III Formula-IV wherein R2 is C1-C5 alkyl or aryl or arylalkyl group; b) transesterification of compound of Formula-IV into compound of Formula-V O OH O 1.on Formula-V n R3 is, C1-C5 alkyl or aryl or arylalkyl group with o that R3 is different than R2 of Formula-IV; c) protecting the hydroxy group with suitable hydroxy protecting group to get compound of Formula-VI 0 OX 0 R3OWNHZ Formula-VI wherein X is a le ting group; d) converting the compound of Formula-VI into compound of a-VII; and o ox o Formula-VII e) converting compound of Formula-VII into compound of Formula-II 0 OX 0 HOWORI Formula-II wherein R1 is carboxyl protecting group and X is defined above.

R1 of the present invention is selected from carboxyl protecting group and X is hydroxy protecting group. Suitable protecting groups are available in the literature and well familiar to the person skilled in the art. Examples of le protecting groups can be found in standard works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M.

Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 in "Methoden der organischen Chemie", Houben-Weyl, 4th n, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H.

Jescheit, "Aminosauren, e, Proteine", Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and or in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate", Georg Thieme Verlag, Stuttgart 1974. Preferable carboxyl protecting groups are C1-C5 alkyl, aryl, arylalkyl, more preferably C1—C5 alkyl.

Suitable hydroxy protecting groups are alkyl, aryl, arylalkyl, trialkylsilyl and diarylalkylslyl. Preferably trialkylsilyl or diarylalkylslyl. The protecting groups are trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or diphenyl(tert—butyl)silyl group.

As per the present invention, in step-a, compound of formula III is selectively amidified by using enzyme. The enzyme used in this reaction is selected from hydrolytic enzymes, e.g. lipases, esterases, proteases. The preferred enzymes are microbial lipases that show amidation activity of esters with ammonia or amines in c media. Exceptional performance is ed by using lipases from the Candida genus, especially the Candida antartica lipase. The isoenzyme B is most red. To obtain acceptable activity for hydrolases in organic media, immobilization of the enzyme on a porous solid t is advantageous. The suitable enzyme used is an immobilized version of Candida antartica lipase B using anhydrous ammonia in an organic solvent. The organic solvent used in this step is an alcohol solvent or ethereal solvent. The alcohol t is ed from ethanol, methanol, isopropanol, tert-butanol or 2—methylbutan-2—ol (tert—Pentanol), 2- methyl-Z-butanol, preferably tert-Pentanol. The ethereal solvent is selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether ,2-methyltetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane, dimethoxyethane, diethyleneglycol diemthyl ether, preferably 1,4-dioxane. The obtained monoamide ester intermediate compound of Formula-IV is tallized to highly enantiomeric compound of Formula-IV.

The step-b of this ion involves transesterification of compound of Formula-IV. The transesterification of the nd of Formula-IV is d out in presence of catalyst.

The suitable catalyst is selected from sts, which shows high sterification ty under essentially neutral ions, as the compounds of formula IV and a V show limited optical stability under the usual strongly basic transesterification conditions. Catalysts that are active under essentially neutral conditions are dialkyltindialkoxide (e.g. dibutyltin dimethoxide) and tetraalkyl esters of titanium, e.g. tetramethyl orthotitanate, tetraethyl orthotitanate, tetrapropyl itanate, tetraisopropyl orthotitanate, tetrabutyl orthotitanate and tetrabenzyl itanate. Most preferred is the cially available tetraisopropyl orthotitanate. In a l embodiment the tetraisopropyl orthotitanate can be first mixed with excess benzyl alcohol under vacuum to produce a on of tetrabenzyl itanate in benzyl alcohol. In this reaction very less amount of catalyst is used. The compound of Formula-IV is reacted with respective alcohol compound to yield required ester. In this reaction preferably araylalkyl ester, more preferably benzyl ester is ed by reacting compound of Formula-IV with benzyl alcohol. The preferable catalyst used in this reaction is titanium catalyst and the titanium catalyst needs to be removed from the product. In most procedures this involves on of some water to form insoluble hydrated TiOz, but this generates a precipitate with unfavorable filtration propertiesuAn alternative workup process has been ped, in which the reaction mixture is added to an aqueous solution of (DL/meso) tartaric acid: The tartaric acid forms a water soluble and stable titanium x, while releasing the benzyl amidoester to the organic phase.

The step-c of this invention involves protection of the compound of Formula-V. The compound of Formula-V is protected by suitable protecting group such as alkyl, aryl, arylalkyl, trialkylsilyl and diarylalkylslyl in presence of base and organic solvent. The suitable protecting group used in this reaction is tert-Butyldimethylsilyl group. The base is selected from tertiary aliphatic amines or secondary aromatic or tertiary aromatic amines such as triethyl amine, diisopropylethylamine, N-methyl morpholine, pyridine, 4- dimethylaminopyridine, DBU, DBN, imidazole and N—methylimidazole, preferably imidazole. The organic solvent used in this reaction is a polar aprotic solvent, such as dichloromethane, chloroform, 1,2—dichloroethane, trifluoromethylbenzene, dimethylformamide, ylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, acetonitrile, benzonitrile, preferably dimethylformamide.

The step-d of this invention involves conversion of compound of Formula-VI to compound of Formula-VII. This sion can be carried out by hydrolysis or catalytic hydrogenation of compound Vof Formula-VI. The catalytic hydrogenation of compound of Formula-VI is takes place in the presence of catalyst selected from transition metals that show hydrogenolysis of benzyl ester, preferably palladium on d support like Pd/C or Pd/A1203, preferably Pd catalyst in presence of hydrogen in an ester, l, ether or ic solvents, ably ester t. The preferable ester solvent is ethyl acetate.

The step-e of this invention involves the conversion of compound of Formula-VII into nd of Formula-II by the conversion of the amide to 'an ester. The reaction involves usage of ylformamide dimethylacetal under mild basic conditions. Under mild basic conditions this reagent converts the amide to a reactive acylformamidine, which then reacts with alcohols to form the corresponding ester, while it suppresses the esterification of the free carboxylic acid group. The base used in this, reactionis selected from alkalimetal alkoxides like sodium methoxide or ium methoxide, preferably sodium methoxide. The solvent used in this reaction is methanol.

Advantages of the present invention The current reaction scheme avoids the use of chiral auxiliaries, cryogenic reaction conditions and yields an overall higher yield of desired optically pure monoester of formula II. The low amount of enzyme used in the first step can be recycled and reused many times, thus ing the tion cost of the desired product. Many of the intermediates are crystalline solids that can be upgraded in chemical and optical purity by crystallization.

The compound of Formula-III is prepared by the prior art process as disclosed in Tetrahedron;43(1);45-58;1987, Canadian journal of chemistry;66(6);1422-4;1988 and Journal of the American chemical society;68;721 ; 1946.

The compound of Formula-II is further converted into HMG-CoA reductase inhibitors of Formula-I by the conventional methods as disclosed in US RE 37,314, US 440, WO 2003087112, US 2007037979 and CN 100506796.

For example the compound of a-II is further ted into Rosuvastatin m by the following procedure as depicted in the below scheme. 0 OX 0 Th C ox o HOWORII ————> Ph—P/\ Ph I Formula-II N \ \o H3CNAN’I CH3 o=s=o CH3 Deprotection <———- Reduction 0H 0 0‘R Hydrolysis NI . . ____.__> Rosuvastatin m H3C.N/I\N’ CH3 Salt formation O=§=O CH3 For example the compound of Formula-II is further converted into Pitavastatin calcium by the following procedure as depicted in the below scheme. 0 OX o If“ 0 OX 0 ' W Ph_P\ HO 0Rl / 0R1 Formula-II Deprotection ‘—-——- Reduction Hydrolysis ORl ———> Pitavastatin Calcium‘ Salt formation All s, patent ations, and non-patent publications cited herein by reference should be considered in their entirety. The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. 2012/000770 Experimental procedure: Example —- 1: Process for the Preparation of compound of Formula-IV (where R2=Me) Tert—Pentanol (1.1 L). was saturated with gaseous a until about 1 mo] (17 g) has been evaporated from the ammonia cylinder. To this Compound of Formula-Ill (R2=Me) (125 g; 0.7lmol) was added, followed by the addition of immobilized CAL-B - T 1-350; 12.5 g). The reactor was closed and mechanically stirred at ambient temperature.

After completion of the reaction enzyme was removed by filtration over a 100 um sieve and washed with methanol. The filtrate evaporated under reduced pressure at a temperature below 50 °C_ to yield an oily residue. This residue was purified by crystallization from pyl acetate to yield (S)-Methyl 3-hydroxyglutaramate.

Example — 2: Process for the Preparation of compound of Formula-V (where R3=Benzyl) ‘ (S)—Methyl 3-hydroxyglutaramate ed from e-1 (16.1 g; 0.1mol) was mixed with benzyl alcohol (25 g). The e was heated under vacuum (< 15 mbar) at 55 °C to remove traces of moisture. Neat tetraisopropyl orthotitanate (3 ml; 10mol %) was added and the mixture heated under full vacuum for 3h at 55-57 °C. The mixture was cooled and diluted with 1 volume of Tetrahydrofuran. The organic mixture was slowly added in 10m to a vigorously stirred e of aqueous tartaric acid (1 M, 100 ml) and ethyl acetate. The organic phase was d and the aqueous phase extracted with ethyl acetate. The combined organic extracts were washed with dilute sodium bicarbonate solution. The organic phase was evaporated under reduced pressure and MTBE was added and the mixture cooled with stirring. The obtained thick suspension was filtered and washed with cold MTBE and pentane to yield (S)—Benzyl 3-hydroxyglutaramate. — 3: . Example Process for the ation of compound of Formula-VI (where zyl and X= Tert-butyldimethylsilyl) '30 A mixture of (S)-Benzyl 3-hydroxyglutaramate (66 g; 0.28 mol; 97 % e.e.) and imidazole (23 g; 0.34 mol; 1.2 eq.) was mixed with dimethylformamide‘ (70 ml). To this mixture a solution of tert-Butyldimethylsilyl de (45 g; 0.3 mol) in dimethylformamide (150 ml) was added under cooling (+5 °C). The mixture was warmed to 25 °C and stirred for lhour. The mixture was quenched with water. The mixture was diluted further with water and extracted with isopropylacetate. The organic extract was washed with water and diluted with sodium onate and brine. ‘ After evaporation (S)-Benzyl 3-[tert- butyldimethylsilyloxy]glutaramate as an oil was obtained.

Example — 4: s for the Preparation of compound of Formula-VII (where X= Tert-butyldimethylsilyl) (S)-Benzyl 3-[tert-butyldimethylsilyloxy]glutaramate from example-3 (48.5 g) was dissolved in ethyl acetate (350 ml) and placed in a 500 ml glass pressure reactor with magnetic stirring. Palladium on charcoal catalyst (5 %, 0.48 g) was added to this and the mixture was enated under 2.7 atmosphere of hydrogen for 4 hours. The pressure was released and the e was d. The catalyst was washed with 25' ml ethyl acetate and kept for reuse. The” filtrate was mixed with'water. The pH of the mixture was adjusted to 8.5 using 2.5 M aqueous ammonia under stirring. The aqueous phase was extracted once with MTBE. The clear aqueous phase was cooled to + 5 °C and slowly acidified to pH 4.4 using conc HCl. A thick itate was formed at pH 4.8-5. The mixture was filtered and the solid was washed once with Water and dried under reduced pressure to yield (S)[tert-butyldimethylsilyloxy]glutaric acid monoamide.

Example — 5: Process for the Preparation of compound of Formula-II (where X= Tert-butyldimethylsilyl and R1=Me) (S)[tert-Butyldimethylsilyloxy]glutaric acid monoamide (4.6 g) was dissolved under argon atmosphere in anhydrous methanol (30 ml). The pH of the reaction mixture was adjusted to 11.4 by the addition of sodium methoxide solution (3.6 ml 30 %). The on was mixed under argon with 5.0 g of dimethylformamide dimethylacetal (42 mmol). The mixture was stirred under inert atmosphere for 20h at 30 °C. The obtained mixture was slowly added to a stirred e of dichloromethane and dilutes phosphoric acid. The organic phase was washed with water and evaporated to give (R)-Methyl 3- [tert-butyldimethylsilyloxy]glutarate.

WO 80219 2012/000770 Example — 6: Process for the Preparation of (S)-methylhydroxyglutaramate Tert-pentanol (800 ml) was saturated With ammOnia gas to about 1.0-1.5'mole. To this dimethy1hydroxy glutarate (100 g) was added followed by the addition of 3 g immobilized CAL-B(CAL B-Tl-AMDZ). The flask was closed and stirred at 20-25°C.

After completiOn of reaction enzyme was removed by filtration and washed the enzyme with tert-pentanol (100 ml). The filtrate was evaporated under reduced pressure 'at a ature below 50°C to yield a residue. This e was purified by crystallization from tertrpentanol/tert-butyl methyl ether mixture to give (S)—methy1 hydroxyglutaramate.

Example — 7: Process for the Preparation of (S)-Benzylhydroxyglutaramate Mixture of Benzyl alcohol (131.0 g), (S)-methy1—3-hydroxyglutaramate (100 g) and Tetraisopropyl orthotitanate (17.5 g) are mixed in a flask. The mixture was stirred under vacuum at 50-60°C for about 5 hrs. The reaction mixture was cooled and diluted with isopropyl e (500 ml). The on mixture was added to a stirred on of Tartaric acid (37 g in 370 ml DM water) and 500 ml isopropyl acetate mixture. The on mixture was stirred and pH was adjusted to 0 by Aq ammonia solution.

Layers were separated. The organic phase was removed and the aqueous phase was ted with isopropyl acetate. Combined organic layer was Washed with Aq ammonia and tartaric acid solution followed by brine wash. The organic phase Was dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield oil. To this oil utyl methyl ether (800 ml) was added, stirred, cooled, filtered and dried to give (S)- Benzylhydroxyglutaramate.

Example — 8: Process for the Preparation of (S)-Benzylhydroxyglutaramate Mixture of Benzyl alcohol (131.0 g), (S)-methy1hydroxyglutaramate .(100 g) and Tetraisopropyl orthotitanate (17.5 g) are mixed in a flask. The mixture was stirred under vacuum at C for about 5 hrs. The reaction mixture was cooled and diluted with dichloromethane (500 ml). The reaction mixture was added to a stirred solution of Tartaric acid (37 g in 370 ml DM water) and 500 ml dichloromethane mixture. The reaction mixture was stirred and pH was adjusted to 7.0-8.0 by Aq ammonia solution.

Layers were separated. The organic phase was removed and the aqueous phase was extracted with dichloromethane. Combined organic layer was washed with Aq a and tartaric acid solution followed by brine wash. The organic phase was dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield oil. To this oil tert-butyl methyl ether (800 ml) was added, stirred, cooled, filtered and dried to give (S)- ‘ Benzylhydroxyglutaramate.

Example — 9: Process for the Preparation of (S)-benzyl(tert-butyl ylsilyloxy) amate (S)-Benzylhydroxyglutaramate (100 g) was dissolved in dimethyl formamide. To this Imidazole (35 g) was added and the solution was cooled to 5°C. To this a solution of tert- butyldimethylsilylchloride (68.5 g) dissolved in yl formamide (250 ml) was added under cooling. The e was warmed to 20-25°C and stirred. The reaction mixture was cooled and ed with water. To the reaction mixture ethyl acetate and water was added and stirred. The layers were separated and the organic phase was washed thrice with water. The organic phase was evaporated under reduced re to yield (S)- benzyl(tert-butyl dimethylsilyloxy) glutaramate as oil.

Example — 10: s for the Preparation of (S)(tert-butyl dimethylsilyloxy) glutaric acid monoamide (S)-Benzyl(tert-butyl dimethylsilyloxy) amate (100 g) was dissolved in ethyl acetate and placed in pressure flask. To this Palladium on charcoal (5 %, 1 g) was added and stirred under hydrogen atmosphere (~ 2.8 Kg). Palladium was removed by filtration.

‘ The filtrate was mixed with water and adjusted pH to ~ 9.0 by using Aq ammonia solution. The reaction mass was stirred and layers were separated. The aqueous phase was washed with romethane and dichloromethane was added to aqueous phase.

The reaction mass was cooled to 5°C and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution heptane was added, stirred, d and dried to yield (tert-butyl dimethylsilyloxy) glutaric acid monoamide.

Example -— 11: Process for the ation of ($)(tert—butyl dimethylsilyloxy) glutaric acid monoamide (S)-Benzyl-3—(tert-butyl dimethylsilyloxy) glutaramate (100 g) was dissolved in ethyl acetate and placed in pressure flask. To this ium on charcoal (5 %, 1 g) was added and d under hydrogen atmosphere (~ 2.8 Kg). ium was removed by filtration.

The filtrate was mixed with water and adjusted pH to ~ 9.0 by using Aq ammonia solution. The reaction mass was stirred and layers were separated. The aqueous phase was washed with dichloromethane and romethane was added to aqueous phase.

The reactiOn mass was cooled to 5°C and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution pentane was added, stirred, filtered and dried to yield (S)(tert-butyl dimethylsilyloxy) glutaric acid monoamide.

Example — 12: Process for the Preparation of (S)(tert-butyl dimethylsilyloxy) glutaric acid monoamide (S)-Benzyl—3-(tert-butyl dimethylsilyloxy) glutaramate (100 g) was dissolved in ethyl acetate and placed in pressure flask. To this Palladium on charcoal (5 %, l g) was added and d under hydrogen atmosphere (~ 2.8 Kg). ium was removed by filtration.

The filtrate was mixed with water and adjusted pH to ~ 9.0 by using Aq ammonia on. The reaction mass was stirred and layers were separated. The aqueous phase was washed with dichloromethane and dichloromethane was added to aqueous phase.

The reaction mass was cooled to 5°C and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution hexane was added, stirred, filtered and dried to yield (S)(tert-butyl dimethylsilyloxy) ic acid monoamide.

Example - 13: s for the Preparation of (R)—Methy1—3-(tert- butyldimethylsilyloxy)glutarate (S)—3-(tert-butyl dimethylsilyloxy) glutaric acid monoamide (100 g) was dissolved in methanol (650 ml) under nitrogen here. The reaction mass was ~ 25 % Sodium methoxide solution (82.9 g) was added under cooling. Then reaction mass was heated to ~ 25°C and to this dimethyl formamide dimethylacetal (100 g) was slowly added. The '10 e was stirred for ~ 20 hrs at 25°C. The reaction mass was slowly added to a stirred ' mixture of dichloromethane and diluted phosphoric acid solution. Layers were separated.

The organic phase was washed thrice with water, dried over sodium sulphate and evaporated under d pressure to yield (R) —Methyl(tert-butyldimethylsilyloxy) glutarate.

Example — 14: Process for the Preparation of (S)-Benzyl-3—hydroxyglutaramate Tert-pentanol (800 ml) was saturated with ammonia gas to about 1.0-1.5 mole. To this dimethyl—3-hydroxy glutarate (100 g) was added followed by the addition of 3 g immobilized CAL-B (CAL B-Tl-AMDZ). The flask was closed and stirred at 20-25°C.

Afier completion of reaction enzyme was removed by filtration and washed the enzyme with tert-pentanol (100 ml). The filtrate was evaporated under reduced re at a temperature below 50°C to yield a residue. To this residue mixture of Benzyl alcohol (131.0 g), (S)-methyl—3-hydroxyglutaramate (100 g) and Tetraisopropyl orthotitanate (17.5 g) are mixed in a flask. The mixture was stirred under vacuum at 50-60°C for about 5 hrs. The reaction mixture was cooled and diluted with isopropyl acetate (500 ml). The reaction mixture was added to a stirred solution of Tartaric acid (37 g in 370 ml DM water) and 500 ml isopropyl acetate mixture. The reaction mixture was stirred and pH was adjusted to 7.0-8.0 by Aq ammonia solution. Layers were separated. The organic phase was removed and the aqueous phase was extracted with pyl acetate.

Combined organic layer was washed with Aq ammonia and tartaric acid solution ed by brine wash. The organic phase was dried over ous sodium sulphate and evaporated under reduced re to yield oil. To this oil tert-butyl methyl ether (800 ml) was added, stirred, cooled, filtered and dried to give (S)-Benzyl—3- hydroxyglutaramate.

Example —- 15: Process for the Preparation of (S)(tert-butyl dimethylsilyloxy) glutaric acid ide (S)-Benzylhydroxyglutaramate (100 g) was dissolved in dimethyl formamide. To this ole (35 g) was added and the solution was cooled to 5°C. To this a solution of tert- butyldimethylsilylchloride (68.5 g) dissolved in yl formamide (250 ml) was added under cooling. The mixture was warmed to 20-25°C and stirred. The reaction mixture was cooled and quenched with water. To the reaction mixture ethyl acetate and water was added and stirred. The layers were separated and the organic phase was washed thrice with water. Tothe c phase Palladium on al (5 %, 1 g) was added and stirred under hydrogen atmosphere (~ 2.8 Kg). Palladium was removed by filtration. The filtrate was mixed with water and adjusted pH to ~ 9.0 by using Aq a solution. The reaction mass was stirred and layers were separated. The aqueous phase was washed with dichloromethane and dichloromethane was added to aqueous phase. The reaction mass was cooled to 5°C and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution heptane was added, stirred, filtered and dried to yield (S)(tert-butyl dimethylsilyloxy) glutaric acid monoamide.

Example — 16: Process for the Preparation of (S)-methylhydroxyglutaramate Tert-pentanol (200 ml) was saturated with anhydrous ammonia at ambient pressure. This was cooled to ambient temperature and to this CaLB-Tl-AIVfl) enzyme (1.25 g) and yl 3-hydroxyglutarate (25.3 g) were added. The resulting mixture was gently stirred with a magnetic stirrer at ambient temperature (20-21 °C) for 18h. The enzyme was removed by filtration and washed with tert—pentanol (25 ml). The clear e (200 g) was concentrated under reduced re at a maximum temperature of + 50 °C to light brown oil. The oil was again dissolved in tert-pentanol (90 ml) and placed in a ically stirred 500 ml vessel. To this MTBE (Methyl tert-butyl ether) was slowly added under seeding with methyl (S)hydroxyglutaramate (10 mg). The crystal suspension was cooled in an ice—bath to +5 °C. The reaction mass was filtered, washed with MTBE and dried to yield (S)§methylhydroxyglutaramate.

Example — 17: Process for the Preparation of (S)-Benzylhydroxyglutaramate (S)-Methyl-3—hydroxyglutaramate (41.2 g) and benzyl alcohol (54 g) were placed in a 250 ml flask. This mixture 'was heated under vacuum to 55 °C to get clear solution. To this neat soprOpyl orthotitanate (7.5 ml) was added. The mixture was d at 55- 58 °C under vacuum. The reaction mixture was diluted with isopropyl acetate and added to a solution of tartaric acid (7.5 g in 50 ml water) and isopropyl acetate (200 ml). The organic phase was removed and washed with water, NaHC03-solution and brine. The organic phase was dried over sodium sulfate and evaporated to blue oil. The aqueous phases were additionally extracted with ethyl acetate to yield colorless oil. The combined oily al was mechanically stirred with MTBE and seeded with (S)—Benzyl hydroxyglutaramate. The thick suspension was cooled in an ice-bath to 5 °C and aged for 15m, ed by filtration. The solid was washed with MTBE and pentane (50 ml). The resulting was dried to yield (S)-Benzylhydroxyglutaramate.

Example —— 18: Process for the Preparation of (S)-benzyl(tert-butyl ylsilyloxy) glutaramate (S)-Benzylhydroxyglutaramate (49.5 g) was dissolved in anhydrous dimethylformamide (50 ml) and added to a 500 ml flask containing solid imidazole (17.1 g). To this a solution of tert—butyldimethylsilyl chloride (34 g) in dimethylformamide (120 ml) was added and reaction flask was cooled in an th. The reaction was quenched by addition of saturated ethyl acetate. The mixture was stirred at ambient temperature. To this water was added and the biphasic mixture was stirred for 1 hour.

The mixture wasthen washed with water. The organic phases were mixed and washed with water to remove traces of dimethylformamide. The c phase was ated under reduced pressure to yield (S)—benzyl(tert-butyl dimethylsilyloxy) glutaramate.

Example — 19: Process for the Preparation of (S)—3-(tert-butyl dimethylsilyloxy) glutaric acid monoamide (S)-benzyl—3-(tert-butyl dimethylsilyloxy) glutaramate (70 g) was dissolved in ethyl acetate (350 ml) and placed in a 500 ml glass pressure vessel. To this dry 5% Pd/C (1.4 g) was added under vacuum and pressurized with hydrogen gas at 2.7 bar overpressure. The mixture was stirred magnetically while remaining connected to the en source. The catalyst was removed by filtration and washed with a small volume of ethyl acetate (25 ml). The clear filtrate was mixed with water and dilute ammonia. The aqueous phase was isolated and the organic phase extracted with water. The ed aqueous phase was washed with MTBE and degassed under vacuum to remove traces of organic solvent. The mixture was placed in an ice-bath. The cooled aqueous on was acidified using dilute phosphoric acid to obtain thick suspension. This was filtered, washed with cold water and dried to yield (S)—3-(tert-butyl dimethylsilyloxy) glutaric acid monoamide.

Example — 20: Process for the Preparation of (R)—Methyl(tertbutyldimethylsilyloxy rate (S)(tert-butyl dimethylsilyloxy) glutaric acid monoamide (10 g) was ved in anhydrous methanol (90ml) and placed under Argon. To this mixture sodium methoxide solution (8.6 g) was added. To this neat dimethylformamide dimethyl acetal (10 g) was added and the resulting mixture stirred under Argon at 30 °C for 16 hours. The mixture was cooled and added to a pre cooled mixture of ethyl acetate (150 m1) and aqueous citric acid (19 g in 100 ml water). To the ing homogeneous mixture MTBE and brine was added. The organic phase was washed twice with water and dried using a brine wash and sodium sulfate. The dried on was carefully evaporated to yield (R)—Methyl(tert- butyldimethylsilyloxy)glutarate.

WE

Claims (24)

CLAIM :

1. A process for the preparation of nd of Formula-II comprising the steps of: a) enzymatic enantioselective amidation of compound of Formula-III in presence of suitable enzyme to get amide compound of Formula-IV wherein R2 is C1-C5 alkyl or aryl or arylalkyl group; b) transesterification of compound of Formula-IV into compound of Formula-V wherein R3 is C1-C5 alkyl or aryl or arylalkyl group with proviso that R3 is different than R2 of Formula-IV; c) protecting the hydroxy group with suitable hydroxy ting group to get compound of Formula-VI n X is a suitable protecting group; d) converting the compound of Formula-VI into compound of Formula-VII; and e) converting compound of Formula-VII into compound of a-II AH26(11490917_1):RTK wherein R1 is carboxyl protecting group and X is defined above.

2. The process according to claim 1, wherein the enzyme is a hydrolase.

3. The process according to claim 2, wherein the hydrolase is lipase, esterase or protease.

4. The process according to claim 3, n lipase is Candida Antartica lipase.

5. The process according to claim 4, wherein lipase is Candida Antartica lipase B.

6. The process according to any one of the preceding claims, wherein R3 is arylalkyl group in compound of a-V.

7. The s according to any one of the preceding claims, wherein transesterification of the compound of Formula-IV is carried out in presence of st.

8. The process according to claim 7, wherein catalyst is ed from tetramethyl orthotitanate, tetraethyl itanate, tetrapropyl orthotitanate, tetraisopropyl itanate, tetrabutyl orthotitanate or tetrabenzyl orthotitanate.

9. The process according to any one of the preceding claims, wherein compound of Formula- VI is converted into compound of Formula-VII by catalytic enation.

10. The process according to any one of the preceding claims, wherein R1 is C1-C5 alkyl group in compound of Formula-II.

11. A s for the preparation of amide compound of Formula-IV comprising: enzymatic enantioselective amidation of compound of Formula-III in presence of suitable enzyme and an alcohol solvent wherein R2 is C1-C5 alkyl or aryl or arylalkyl group. AH26(11490917_1):RTK

12. A process for the preparation of a compound of Formula-II, Formula-IV, Formula-V, Formula-VI or Formula-VII, said process being substantially as hereinbefore described with nce to any of the examples.

13. The process according to any one of claims 1 to 10 or 12, wherein nd of Formula- II, Formula-IV, Formula-V, Formula-VI or Formula-VII is further converted into a HMG-CoA ase inhibitor.

14. The process according to claim 11, wherein compound of Formula-IV is further converted into a HMG-CoA reductase inhibitor.

15. The s according to claim 13 or claim 14, wherein the HMG-CoA reductase inhibitor is Rosuvastatin or Pitavastatin.

16. A compound of Formula-II, Formula-V, Formula-VI or Formula-VII, when prepared by a s according to any one of claims 1 to 10 or 12.

17. A compound of Formula IV, when prepared by a process according to claim 11 or claim

18. A compound of Formula-V wherein R3 is an arylalkyl group.

19. A compound of Formula-VI wherein X is a y protecting group, and R3 is an arylalkyl group.

20. A compound of Formula-VI AH26(11490917_1):RTK wherein X is a y protecting group selected from an alkyl, aryl, arylalkyl, trialkylsilyl or diarylalkylsilyl group, and R3 is a C1-C5 alkyl or aryl or arylalkyl group.

21. A compound of Formula-VII wherein X is a hydroxy protecting group.

22. A process for the preparation of a HMG-CoA reductase inhibitor, the process comprising the conversion of a compound of any one of claims 16 to 21 into a HMG-CoA reductase inhibitor.

23. The process according to claim 22, wherein the HMG-CoA reductase inhibitor is Rosuvastatin or Pitavastatin.

24. A HMG-CoA reductase inhibitor, when prepared by a s according to any one of claims 13 to 15 or 22 to 23. Mylan Laboratories Ltd By the Attorneys for the ant SPRUSON & ON Per: AH26(11490917_1):RTK