PREPARATION OF ATORVASTATIN INTERMEDIATES

INTRODUCTION

The disclosure relates to atorvastatin intermediates and processes for the preparation of atorvastatin intermediates including (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate.
Atorvastatin calcium has a chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-p,6-5-dlhydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate (hereinafter referred to by its adopted name "atorvastatin calcium"), and can be represented by structural Formula I.

Atorvastatin calcium is a synthetic lipid-lowering agent and is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. It is commercially available in products having the trademark LIPITOR, in the form of tablets containing the equivalent of 10, 20, 40, or 80 mg of atorvastatin.

U.S. Patent No. 5,273,995 discloses atorvastatin and its related compounds, along with their pharmaceutically acceptable salts. It also describes pharmaceutical compositions comprising atorvastatin calcium, and their use in the treatment of hypercholesterolemia.

International Application Publication No. WO 02/096915 describes a process for preparing y-hydroxy-p-ketoester using Meldrum's acid.
International Application Publication No. WO 2005/026107 describes a process for preparing ^butyl-6-cyano-5-hydroxy-3-oxohexanoate that involves t-butyldiphenylsilyl protection of the 3-hydroxy group.

The present process uses commercially available reagents and is a cost-effective process that can be used at a commercial quantity scale.
SUMMARY This application includes processes for the preparation of a compound of Formula II,
which process comprises of reacting an intermediate of Formula III with a compound of Formula IV in the presence of hexamethyldisilazane lithium salt (HMDS-Li),
wherein R is CN, OH, CI, Br, or I; Ri is a Ci-e alkyl group; R2 is a C1.6 alkyl group; and R3 is H or a hydroxyl protecting group.

This application includes trimethylsilyl {TMS)-protected intermediates of Formula VI or Formula VII and processes for their preparation, an embodiment of a process comprising:

(a) reacting (R)-ethyl 4-cyano-3-hydroxybutanoate of Formula V with
trimethylsilyl chloride to obtain a TMS-protected intermediate of Formula VI;

(b) reacting a TMS-protected intermediate of Fomiula VI with /-butyl acetate in
the presence of a base to obtain a TMS-protected intermediate of Formula VII; and

(c) hydrolyzing a TMS-protected intermediate of Formula VII to obtain (R)-t-butyl 6-cyano-5-hydroxy-3-oxohexanoate.

In an aspect, the present application provides processes for the preparation of atorvastatin or a salt thereof, comprising converting the intermediate compounds obtained by the processes of the present application into atorvastatin

DETAILED DESCRIPTION

All percentages and ratios used herein are expressed by weight of the total composition, and all measurements made are at about 25°C and about normal atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified othenwise. As used herein, "comprising" includes the elements recited, or their equivalent in structure or function, plus any other element or elements that are not recited. The terms "having" and "including" are also to be construed as open-ended. All ranges recited herein include the endpoints, including those that recite a range "between" two values. The tenns "about," "generally." "substantially,", and the like, are to be construed as modifying another term or value such that it is not an absolute, as defined by the circumstances and context as understood by those of skill in the art. This includes, at the very least, the degree of expected experimental error, technique error, and instmment error for a given technique used to measure a value. Whether so indicated or not, all values recited herein are approximate. Even though reactions are described for a specific isomer, it may be carried out using the other isomer or mixture of isomers in any ratio.
This disclosure includes processes for the preparation of a compound of Formula II,
wherein an embodiment of a process comprises reacting an intemriediate of Formula IV with a compound of Formula V in the presence of hexamethyldisilazane lithium salt (HMDS-Li),
wherein R is CN, OH, CI, Br, or I; Ri is a Ci-e a!kyl group; R2 is a Ci-e alkyl group; and R3 is H or a liydroxyl-protecting group.

Suitable hydroxyl-protecting groups that may be used include, but are not limited to, trimethyisilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl, or R and R3 combine to form a 3-5 member ring.

The compound of Formula IV is prepared using methods that are known in the art, or the processes of this application.

The compounds of Formula V that may be used in the processes of the present application include alkyl acetates, such as, for example, ethyl acetate, isopropyl aceatate, t-butyl acetate, and the like.

Suitable solvents that may be used in the reaction include, but are not limited to, tetrahydrofuran (THF), hydrocarbons such as, for example, xylene, toluene, and the like, ether solvents such as, for example, diethyl ether, diisopropyl ether, and the like, and mixtures thereof.

Suitable temperatures for conducting the reaction range from about -SS-C to about -65-C, or from about -SCC to about -70X.

Suitably, the HMDS-Li is used as a 20% to 30% w/v solution in an organic solvent such as THF.
The molar ratios of HMDS-Li to the compound of Formula IV may range from about 1 to about 6, or about 1 to about 4.

After completion of the reaction, the mixture may be quenched with an aqueous acid, such as hydrochloric acid, solution and the product may be extracted into a water-immiscible organic solvent.

The 3-hydroxyi protecting group may removed by the addition of an acid, such as hydrochloric acid, or any other suitable methods.
Suitable solvents that may be used for extraction include, but are not limited to, halogenated hydrocarbons such as, for example: dichloromethane, 1,2-dichloroethane, chloroform, and the like; ester solvents such as, for example, ethyl acetate, n-propyl acetate, and the like; hydrocarbons, such as, for example toluene, xylene, and the like; and mixtures thereof.

The organic layer may be distilled completely and the residue may be purified by slurrying in an ether solvent such as diethyl ether, diisopropyl ether and the like or a hydrocarbon mixture such as petroleum ether.

HMDS-Li that is used in the present application is a relatively safe and inexpensive reagent, making the process economical and suitable for commercial manufacturing.

This application includes TMS-protected intermediates of Formula VI and Formula VII and processes for their preparation, an embodiment of a process comprising:

(a) reacting (R)-ethyl 4-cyano-3-hydroxybutanoate of Formula V with
trimethylsilyl (TMS) chloride to obtain a TMS-protected intermediate of Formula VI;

(b) reacting a TMS-protected intermediate of Formula VI with f-butyl acetate in the presence of a base to obtain a TMS-protected intermediate of Formula VII; and

(c) hydrolyzing a TMS-protected intermediate of Formula VII to obtain (R)-t-butyl 6-cyano-5-hydroxy-3-oxohexanoate.

Step (a) involves reacting (R)-ethyl 4-cyano-3-hydroxybutanoate of Formula V with trimethylsilyl (TMS) chloride to obtain a TMS-protected intermediate of Formula VI.

The reaction of (a) may be carried out in the presence of a base. Suitable bases that may be used in the reaction include, but are not limited to, imidazole, alkyl amines such as, for example, triethylamine, diisopropylamine, diisopropylethylamine, and the like.

The reaction may be carried out in the presence of a catalyst such as, for example, dimethylaminopyridine (DMAP), pyridine, a 2,6-dialkylpyridine, and the like.

Suitable solvents that may be used In the reaction include, but are not limited to: chlorinated hydrocarbons such as, for example, dichloromethane, dichloroethane, chloroform and the like; hydrocarbons such as, for example, xylene, toluene and the like; and mixtures thereof.

Suitable temperatures for conducting the reaction range from about -15°C to about 20X, or about -S'C to about lOX.

After completion, the reaction mixture may be quenched with water and the organic layer containing the product may be used directly in the next reaction step, or the solvent may be distilled completely to obtain a residue.
Step (b) involves reacting a TMS-protected intermediate of Formula VI with t-butyl acetate in the presence of a base, to obtain a TMS-protected intermediate of Formula VII.
Suitable solvents that may be used in the reaction include, but are not limited to, tetrahydrofuran (THF), hydrocarbons, such as, for example xylene, toluene and the like, ether solvents such as, for example diethyl ether, diisopropyl ether, and the like, and mixtures thereof.

Suitable temperatures for conducting the reaction range from about -SS^C to about -eS^C, or from about -SOX to about -70''C.
Suitable bases that may be used include lithium disiopropylamide (LDA), n-butyllithium, HMDS-Li, and the like.

Suitably, the HMDS-Li is used as a 20% to 30% w/v solution in an organic solvent such as THF.
The molar ratio of HMDS-Li to a compound of Fomriula VI range from about 1:3, or 1:2.
Step (c) involves hydrolysis of a TMS-protected intermediate of Formula VII to obtain (R)-t-butyl6-cyano-5-hydroxy-3-oxohexanoate.

After reaction completion, the mixture may be quenched with an aqueous acid solution, such as a hydrochloric acid solution, and the product may be extracted into a water-immiscible organic solvent.

Suitable solvents that may be used for extraction include, but are not limited to; halogenated hydrocarbons, such as, for example dichloromethane, 1,2-dichloroethane, chloroform, and the like; ester solvents, such as, for example ethyl acetate, n-propyl acetate, and the like; hydrocarbons, such as, for example toluene, xylene, and the like; and mixtures thereof.

The organic layer may be distilled completely and the residue may be purified by slurrying in an ether solvent such as diethyl ether, diisopropyl ether and the like or a hydrocarbon mixture such as petroleum ether.

Trimethylsilyl chloride that is used in the processes of the present application is commercially available, relatively inexpensive, and results in higher yield of the product.
The processes include a very effective 2-carbon homologation of a 5-carbon subunit of Formula VI that uses lower molar equivalents of base and results in higher yield of the product, which makes the process economical and commercially attractive.

In an aspect, the present application provides processes for the preparation of atorvastatin or a salt thereof, comprising converting the intermediate compounds obtained by the processes of present application into atorvastatin.

The intermediate compounds obtained by the process of present application may be converted into any other suitable statin compound or a salt thereof, suitable processes being known in the art.

The following examples are provided to more fully illustrate certain specific aspects and embodiments, and are not intended to be limiting in any manner.

EXAMPLES EXAMPLE 1: Preparation of a TMS-protected intennediate of Formula VI.

30 g of ethyl-4-cyano-3-hydroxy butyrate and 75 mL of dichloromethane were charged into a round bottomed flask. The mixture was cooled to about 0° to 5'*C and stirred for 10 minutes. 21.72 g of trimethylsilyl chloride was added at about 0** to S^C over a period of about 60 minutes. 15.6 g of imidazole and 0.24 g of dimethylaminopyridine (DMAP) were charged and then the mixture was stirred at about 0" to SX for about 2 hours. The mixture was allowed to reach 25" to 30°C and stirred for 3 hours. After completion of the reaction, 90 mL of water was charged to the mixture and stirred for 10 minutes. The organic layer was separated and washed with 90 mL of water. The final organic layer was dried over sodium suphate and distilled completely under vacuum to afford 39.6 g of the title compound.

EXAMPLE 2: Preparation of (R)-t-butyl 6-cyano-5-hydroxy-3-oxohexanoate.

250 mL of THF was charged under a nitrogen atmosphere into a round bottomed flask equipped with a mechanical stirrer and was cooled to -80 to -70 "C. 43.6 g of hexamethyldisilazane lithium salt (20% w/v solution in THF) was charged into the flask. 30.3 g of t-butyl acetate was added to the mixture at -80 to -TCC, over about 30 minutes. The mixture was stirred for 30 minutes at -80 to -TOX. A solution of TMS-protected intermediate prepared as in Example 1 (50 g) In THF (50 mL) was added at -80 to -TOX over a period of about 60 minutes. The mixture was stirred for about 4 hours at -80 to -JO^C and then quenched by adding a mixture of cold water (1 L) and concentrated HCI (255 mL) at -80 to lOX. The organic layer was separated and the aqueous layer was extracted with 200 mL of ethyl acetate. Total organic layers were combined and washed with 150 mL of 10% sodium bicarbonate solution. The organic layer was dried over sodium sulphate and distilled completely under vacuum to obtain a residue.

110 mL of petroleum ether was charged to the residue and cooled to -5" to -lO^C under stirring for 20 minutes. The lower layer In the form of residue containing the product was separated and the process repeated with another lot of petroleum ether (110 mL). Petroleum ether traces were distilled from the final residue under vacuum to obtain 44 g of the title compound.

EXAMPLE 3: Preparation of (3R,5R)-t-butyl 6-cyano-3,5-dihydroxyhexanoate.

420 mL of THF and 42 g of (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate were charged into a round bottom flask under a nitrogen atmosphere. The mixture was cooled to -80° to -70*0 and 70 mL of methanol was added. 63 mL of diethyl methoxyborane was added. 12.6 g of sodium borohydride was added in 10 equal lots, with 10 minutes elapsing between two consecutive lots, under a nitrogen atmosphere. The mixture was stirred at -80" to -70°C for 2 hours, followed by quenching by adding a mixture of 50% aq. H2O2 solution (75.6 mL) and water (350 mL) at -70" to 0"C. The mixture was extracted with dichloromethane (630 mL; followed by 210 mL) and the total organic layer was washed with 10% aq. sodium bicarbonate solution (2x168 mL). The organic layer was further washed with 10% aqueous sodium chloride solution and finally dried over sodium sulphate. The organic layer was distilled completely under vacuum to obtain 38.2 g of the title compound.

EXAMPLE 4: Preparation of 1,1-dimethylethyl (4R-c/s)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate.

36 g of (3R,5RH-butyl 6-cyano-3,5-dihydroxyhexanoate, 216 mL of acetone and 144 mL of dimethoxypropane were placed into a round bottom flask under a nitrogen atmosphere. The mixture was cooled to 20-25''C and stirred for 15 minutes, 0.54 mL of methanesulphonic acid was charged to the reaction mixture at 20-25''C and then stirred for about 45 minutes. After completion of the reaction, it was quenched by adding sodium bicarbonate solution (18 g dissolved in 60.3 mL of water) and stirred for about 15 minutes. The mixture was extracted with petroleum ether (3x200 mL). 3.6 g of activated charcoal was added to the separated organic layer and stirred for about 15 minutes at 25-35*'C. Charcoal was removed by passing through a Hyflow (flux-calcined diatomaceous earth) bed and the bed was washed with 86.4 mL of hot (40-45''C) petroleum ether. The filtrate was washed with water and then the separated organic layer was distilled completely under vacuum below SOX. The obtained residue was kept under vacuum at 40-45''C for about 2 hours to remove traces of petroleum ether. 54 mL of petroleum ether was added to the residue and cooled to O-S^C. The mixture was stirred at 0-5''C for about 45 minutes. The mixture was filtered and the solid washed with chilled petroleum ether. The solid was dried below 40''C to obtain 20 g of the title compound. Purity by gas chromatography: 97.48 % w/w.

EXAMPLE 5: Preparation of (R)-t-butyl 6-cyano-5-hydroxy-3-oxohexanoate.

250 mL of THF was charged under a nitrogen atmosphere into a round bottom flask equipped with a mechanical stirrer and was cooled to -80° to -70 "C. 186.2 g of hexamethyldisilazane lithium salt (20% w/v solution in THF) was charged to the flask. 148 g of t-butyl acetate was added to the mixture at -80" to -70'*C, over a period of about 30 minutes. The mixture was stirred for 30 minutes at -80*' to -70''C. A solution of ethyl-4-cyano-3-hydroxybutyrate (50 g) in THF (50 mL) was added to the mixture at -80** to -70''C, over a period of about 60 minutes. The mixture was stirred for about 2 hours at -75*' to -70°C and then quenched by adding a mixture of cold water (1 L) and concentrated HCI (255 mL) at -SO** to lO^C. The organic layer was separated and the aqueous layer was extracted with 200 mL of ethyl acetate. Total organic layers were combined and washed with 150 mL of 10% sodium bicarbonate solution. The organic layer was dried over sodium sulphate and distilled completely under vacuum to obtain a residue.

55 mL of petroleum ether was added to the residue and cooled to -5" to -10X with stirring for 20 minutes. The lower layer in the form of residue containing the product was separated and the process repeated with another lot of petroleum ether (55 mL). Petroleum ether traces distilled from the final residue under vacuum to obtain 70.5 g of the title compound.

We claim;

1. A processes for the preparation of a compound of Formula II comprises of

reacting an intermediate of Formula III with a compound of Formula IV in the presence of hexamethyldisilazane lithium salt (HMDS-Lj),

wherein R is CN, OH, CI, Br, or I; Ri is a C1.6 alkyl group; R2 is a C1.6 atkyi group; and R3 is H or a hydroxyl protecting group.

2. The process of claim 1, wherein R is CN, Ri is tertiary butyl. R2 is ethyl and R3 is hydroxyl protecting group.

3. The process of claim 1 or claim 2, wherein R3 is a hydroxyl protecting group selected from trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, t-butyldjphenylsjlyl.

4. The process of claim 1, wherein molar ratios of HMDS-Li is from about 1 to about 4 per mole of the compound of Formula IV.

5. The process of claim 1, wherein the reaction is conducted at a temperature of about -85X to about -65°C.

6. A process for the preparation of (R)-t-butyl 6-cyano-5-hydroxy-3-oxohexanoate comprising:

(a) reacting (R)-ethyl 4-cyano-3-hydroxybutanoate of Formula V with trimethylsilyl chloride to obtain a TMS-protected intermediate of Formula VI;

(b) reacting a TMS-protected intermediate of Formula VI with t-butyl acetate in
the presence of a base to obtain a TMS-protected intermediate of Formula VII; and

(c) hydrotyzing a TMS-protected intermediate of Formula VII to obtain (R)-t-
butyl 6-cyano-5-hydroxy-3-oxohexanoate.

7. The process of claim 6, wherein the process of step (a) is conducted in the presence of a base selected from imidazole, triethylamine, diisopropylamine, diisopropylethylamine.

8. The process of claim 6, wherein the base used in step (b) is lithium disiopropylamide (LDA), n-butyllithium, HMDS-Li.

9. The process of claim 6, wherein the process of step (c) is conducted in an aqueous hydrochloric acid solution.

10. A process for the preparation of atorvastatin or a salt thereof, comprising
converting the intermediate compounds obtained by the processes of the present application into atorvastatin or a salt thereof.