Title of Invention

NOVEL BORONATE ESTERS

Abstract

The present invention relates to optically active dihydroxy hexanoate derivatives, boronate esters of formula (IIa) which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin. Ar = unsubstituted or substituted aryl or heteroaryl; R3 = alkyl from 1 to 8 carbons, aryl or aralkyl; R4 = O, OH, CN or a halogen and a =single bond or a double bond.

Full Text

FITLE OF THE INVENTION Novel Boronate esters FIELD OF THE INVENTION The present invention relates to optically active dihydroxy hexanoate derivatives of formula IIa and more particularly to compounds of formula II which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin. BACKGROUND OF THE INVENTION where R1 and R2 are independently chosen alkyl of one to three carbons and R3 is alkyl of from 1 to 8 carbon atoms, alternatively wherein R1 and R2 are independently chosen from alkyl of one to three carbons, phenyl or R1 and R2 taken together as -(CH2)n- wherein n is 4 or 5 and R3 is alkyl of from 1 to 8 carbon atoms and also compounds of Formula lb defined above is a valuable structural element for synthesizing compounds, which are known as anti-hypercholesterolemic agents having an inhibitory effect on HMG-CoA reductase. EP 0 319 847 describes a process for the preparation of compounds of formula 1 starting from L-Malic acid. This process, however, suffers from the fact that the process is not industrially scalable and also possesses purification problems due to the non¬crystalline nature of the intermediates. US 5,399,722 describe a process starting from commercially available ethyl w-cloroacetoacetate or its benzyloxy derivative. The disadvantages of this process are that a stereo selective reduction using a costly ruthenium-BINAP catalyst in employed and the desired compound of formula 1 is obtained in six steps. US 5,481,009 describe a process starting from 4-phenyl-3-butenoic acid in about 5 steps. The process uses expensive materials like - N, 0-Dimethyl hydroxylamine and hazardous steps (ozonolysis) to obtain the desired product. US 5,998,633 describes a process for the preparation of protected esters of 3,4-dihydroxy butyric acid from a carbohydrate moiety which is transformed Into the desired 3,4-dihydroxy butanolc acid derivatives in about 4 steps. The 3.4-dihvdroxv hutanoir arid derivative is then functionalized into compounds of formula I involving a multiple number of steps. US 6,140,527 describes a process for producing butyric acid derivatives starting from a butene derivative followed by reaction with an addition reagent capable of adding across the double bond. However, this procedure does not afford chiral molecules and hence necessitates the need for a resolution step. EP 0 104 750 describes a process for the preparation of 5-hydroxy-3-oxo pentanoic acid derivatives by alkylation of 3-hydroxybutyrate derivatives. The derivatives mentioned in this patent are racemic molecules and thus necessitating a resolution step. The objective of the present is to provide a simple and industrially scalable process for the preparation of derivatives of formula I starting from commercially available and inexpensive malic acid. Summary of the invention To achieve the said object the present invention provides a product of formula Ila and more particularly a compound of formula II wherein Ar = unsubstituted or substituted aryl or heteroaryl R3 = alkyl from 1 to 8 carbons, aryl or aralkyl R4 = 0, OH, CN or a halogen and a = single bond or double bond The present invention also provides for a process for the manufacture of compounds of formula II Ar = unsubstituted or substituted aryl or heteroaryl R3 = alkyl from 1 to 8 carbons, aryl or aralkyi which comprises of: (a) reacting compound of formula III with the anion of tertiary butyl acetate to give a compound of formula IV, where G is tetrahydropyranyl, tert-butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, aryl or aralkyi, (b) subjecting compound of formula IV to reduction to give a compound of formula V, where G is tetrahydropyranyl, tert- butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, aryl or aralkyi. ( c) protecting the compound of formula V with ArB(0H)2 to give a compound of formula VI, where Ar is unsubstituted or substituted aryl or heteroaryl, G is tetrahydropyranyl, tert-butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, ( f) deprotection of the compound of formula VI using mild acid catalyst to give a compound of formula II. Said ArB(0H)2 is boronic acid. The compound of formula II is oxidized to a compound of formula VIII, where R3 is alkyl from 1 to 8 carbons, aryl or aralkyi and Ar is unsubstituted or substituted aryl or heteroaryl using pyridinium chioro chromate or DMSO/oxalyl chloride. The compound of formula II is further converted to a compound of formula IX, where R3 is alkyl from 1 to 8 carbons, aryl or aralkyi, Ar is unsubstituted or substituted aryl or heteroaryl and X is a halogen. The compound of formula IX is further converted to a compound of formula VII, where R3 Is alkyl from 1 to 8 carbons, aryl or aralkyi, Ar is unsubstituted or substituted aryl or heteroaryl. The product of formula Ila and more particularly of formula II are used in the synthesis of atorvastatin, cerivastatin, pitavastatin, fluvastatin or rosuvastatin. Detailed Description of the invention Compound of formula II serves as a good intermediate for the synthesis of important substrates, which are useful in the synthesis of statins. Compound of formula II can be converted into a facile leaving group by treating with tosyl chloride, methane sulfonyl chloride and the resulting intermediate can be displaced with cyanide to give compounds of formula VII. Compound of formula II can be converted to formula IX by reacting with aqueous HBr solution or by reaction with triphenyl phosphine and CBr4 which is then converted to compound of formula VII. Compound of formula II can be oxidized using standard procedures to give a compound of formula VIII. The present invention relates to optically active dihydroxy hexanoate derivatives of formula Ila which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fiuvastatin. The invention is further illustrated with examples below, which are not intended to be limiting. Example 1: Synthesis of methyl 4-triphenylmethyloxy-3-hydroxybutyrate (Formula III) To 25g of methyl 3,4-dihydroxybutanoate was added to 250mi of DCM and stirred to dissolve and 19.8g of pyridine was charged and cooled to 0°C. 41.4g of trityl chloride was dissolved in 50ml of DMC and was added at 0-5°C for 15 min. The temperature was allowed to rise to RT and was stirred at RT for 17h. Water was added and the layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was triturated with 25ml of cydohexane and the product was purified to give 15g of the pure product. NMR (CDCI3) : 4.25 (m, IH), 3.6 (s, 3H), 3.15 (d, 2H), 2.5 (m, 2H), 7.2-7.4 (m, 15H) Example 2: Synthesis of tert-butyl 6-triphenylmethyloxy-5-hydroxy-3-oxohexanoate (Formula IV) To 125ml of THF, 24g of diisopropylamine were charged and was cooled to -15°C. 168ml of 1.2N n-BuLi was added at -15 to -5°C and was stirred for 30min. 21.56g of tert-butyl acetate in 45ml of THF which was pre-cooled to -45°C was added maintaining the temperature between -45 to -25°C for 60min. Cool the reaction mixture to -45°C and 30g of example-1 in THF was added over a period of 20min and the stirring was continued at -25°C for 90min. Water was added and the layers were separated. The aqueous layer was extracted using EtOAc and the combined organic layers were washed with brine, water, dried and concentrated to give the title compound which was used as such for the next step. Example 3: Synthesis of tert-butyl 6-triphenylmethyioxy-3,5-dihydroxhexanaote (Formula V) To the crude material obtained in example-2,150ml of THF was added followed by 15ml of MeOH and was chilled to -60°C. 26ml of MDEB (50% solution in THF) was added over a period of 20min and stirring was continued for a further 30min. The reaction mixture was cooled to -80°C and 5g of sodium borohydride was added in portions and the after completion of addition the reaction mixture was stirred for 5h at -78°C. Acetic acid was added to adjust the pH to 7 and water was added. The aqueous layer was extracted using EtOAc, washed with brine, dried and concentrated to give the title compound which was used as such for the next step. Example 4: Synthesis of tert-Butyl 6-triphenylmethyloxy-3,5-phenylboranatohexanoate (Formula VI) The crude product from example-3 was dissolved in 100ml of toluene and 5.6g of phenyl boronic acid was added. Water was removed by azeotropic distillation over a period of 3h. The reaction mixture was cooled to RT and toluene was removed under reduced pressure. 30ml of methanol was added and the precipitated solid was filtered to give 10g of the title product. Example 5: Synthesis of tert-butyl 6-hydroxy-3,5-(phenylboranato)hexanoate (Formula II) To 5g of the product from example-4 20ml of DCM was added and was chilled to 0°C. 5ml of TFA was added and was stirred at 20°C for 6h. Water was separated and the organic layer was washed with bicarbonate, brine, dried and concentrated to give the title product, which was purified by column chromatography. NMR (CDCI3) : 7.7-7.8 (m, 2H), 7.4-7.5 (m, IH), 7.3-7.4 (m, 2H), 4.5 (m, IH), 4.2 (m, IH), 3.6 (m, IH), 3.5 (m, IH), 2.55 (m, IH), 2.45 (m, IH), 2.0 (m, IH), 1.7 (m, IH) 1.5 (s, 9H) Example 6: Synthesis of tert-butyl 6-cyano-3,5-(phenylboranato)hexanoate (Formula VII) 5g of the product obtained from example 5 was taken in dichloromethane (50mL) and pyridine (lOmL) was added. The contents were cooled to -10°C and methanesulfonyl chloride (1 eq) was added drop wise. After 5-6 hours of stirring at 0°C, the contents were washed with bicarbonate, water and brine. The solvent was removed under reduced pressure to afford the 0-methanesuifonyl derivative, which was used as such for the next step. The crude mesylate was taken in DMSO (5 vols.) and 1.5 equivalents of potassium cyanide was added. The contents were maintained at reflux for a period of 18-22h. DMSO was removed under reduced pressure and the contents were extracted using ethyl acetate and was washed with bisulfite, brine and solvent was removed under reduced pressure to afford the desired product. Example 7: Synthesis of t-butyl 6-oxo-3,5-phenylboranatohexanoate (Formula VIII) 4.3g of dimethylsulfoxide was added drop wise to a solution of 2.4ml of oxalyl chloride in 100ml of dichloromethane maintained at -78°C. The mixture was stirred at that temperature for a period of 15min and 5g of the compound from example 5 dissolved in dichloromethane was added drop wise. After stirring for 15min, 17ml of triethyl amine was added and the reaction mixture was allowed to warm to ambient temperature in 2h period. Reaction mixture was concentrated and the residue was dissolved in water and extracted using diethyl ether. Removal of solvent affords the title compound. Example 8: Synthesis of tert-butyl 6-triphenylmethyloxy-3,5-(l-napththalenyl)boranatohexanoate (Formula Via) The crude product from example-3 was dissolved in 100 ml of toluene and 7.1 g of 1-napthalene boronic acid was added. Water was removed by azetropic distillation over a period 3h. The reaction mixture was cooled to RT and toluene was removed under reduced pressure.30ml of methanol was added and the precipitated solid was filtered to give 14g of the title product. Example 9: Synthesis of tert-butyi 6-triphenylmethyloxy-3,5-(2-methylphenyl)boranatohexanoate (Formula VIb) The crude production from example-3 was dissolved in 100ml of toluene and 6.1g of 2-methylphenyl boronic acid was added. Water was removed by azetropic distillation over a period of 3h. The reaction mixture was cooled to RT and toluene was removed under reduced pressure. 30ml of methanol was added and the precipitated solid was filtered to give 12g of the title product. Example 10: Synthesis of tert-butyl 6-triphenylmethyloxy-3,5-(4-methoxyphenyl)boranatohexanoate (Formula Vic) The crude product from example-3 was dissolved in 100ml of toluene and 6.3 g of 4-methoxyphenyl boronic acid was added. Water was removed by azetropic distillation over a period of 3h. The reaction mixture was cooled to RT and toluene was removed under reduced pressure. 30ml of methanol was added and the precipitated solid was filtered to give 12g of the title product. Example 11: Synthesis of tert-butyl 6-triphenylmethyloxy-3,5-(8-quinolinyl)boranatohexanoate (Formula Vlf) The crude product from example-3 was dissolved in 100ml of toluene and 6.1g of quinoline-8-boronic acid was added. Water was removed by azetropic distillation over a period of 3h. The reaction mixture was cooled to RT and toluene was removed under reduced pressure. 30ml of methanol was added and the precipitated solid was filtered to give Ug of the title product. Example 12: Synthesis of tert-butyl 6-triphenylmethyloxy-3,5-(3-nitrophenyl)boranatohexanoate (Formula VId) The crude product from example-3 was dissolved in 100ml of toluene and 6.1 g of 3-nitrophenyl boronic acid was added. Water was removed by azetropic distillation over a period of 3h. The reaction mixture was cooled to RT and toluene was removed under reduced pressure. 30ml of methanol was added and the precipitated solid was filtered to give 10g of the title product. Example 13: Synthesis of tert-butyi 6-triphenylmethyloxy-3,5-(2,6-difluorophenyl)boranatohexanoate (Formula Vie) The crude product from example-3 was dissolved in 100ml of toluene and 6.3 g of 2,6-difluorophenyl boronic acid was added. Water was removed by azetropic distillation over a period of 3h. The reaction mixture was cooled to RT and toluene was removed under reduced pressure. 30ml of methanol was added and the precipitated solid was filtered to give 12g of the title product. S We claim: 1. The product of formula Ila wherein Ar = unsubstituted or substituted aryl or heteroaryl R3 = alkyl from 1 to 8 carbons, aryl or aralkyl R4 = 0, OH, CN or a halogen and a = single bond or double bond 2. The product as claimed in claim 1 wherein said product is a compound of formula II wherein Ar = unsubstituted or substituted aryl or heteroaryl R3 = alkyl from 1 to 8 carbons, aryl or aralkyl 3. A process for the manufacture of compounds of formula II Ar = unsubstituted or substituted aryl or heteroaryl R3 = alkyl from 1 to 8 carbons, aryl or aralkyl which comprises of: (a) reacting compound of formula III with the anion of tertiary butyl acetate to give a compound of formula IV, where G is tetrahydropyranyl, tert-butyldimethyl silyl or trityl and R3 Is alkyl from 1 to 8 carbons, aryl or aralkyi. Formula III Formula IV (b) subjecting compound of formula IV to reduction to give a compound of formula V, where G Is tetrahydropyranyl, tert- butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, aryl or aralkyi, (c) protecting the compound of formula V with ArB(0H)2 to give a compound of formula VI, where Ar Is unsubstituted or substituted aryl or heteroaryl, G is tetrahydropyranyl, tert-butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, aryl or aralkyl, and (f) deprotection of the compound of formula VI using mild acid catalyst to give a compound of formula II. 4. A process as claimed in claim 3 wherein ArB(0H)2 Is Phenyl boronic acid. 5. A process as claimed in claim 3 wherein the prepared compound of formula II is further oxidized to a compound of formula VIII, where R3 is alkyl from 1 to 8 carbons, aryl or aralkyl and Ar is unsubstituted or substituted aryl or heteroaryl using pyridinlum chloro chromate or DMSO/oxalyl chloride. 6. A process as claimed in claim 3 wherein the prepared compound of formula II Is further converted to a compound of formula IX, where R3 is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar is unsubstituted or substituted aryl or heteroaryl and X Is a halogen. 7. A process as claimed in claim 6 wherein compound of formula II is converted to compound of formula IX by reacting compound of formula II with aqueous HBr solution or by reaction with triphenyl phosphine and CBr4. 8. The product as claimed in claim 1, is used in the synthesis of atorvastatin, cerivastatin, pitavastatin, fluvastatin or rosuvastatln.

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