FIELD OF THE INVENTION

The present invention provides a novel process for the preparation of tert-butyl 2-((27?, 4S)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate of formula (I). The present invention further relates to a process for the preparation of Rosuvastatin calcium by using the formula (I).

BACKGROUND OF THE INVENTION

HMG-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGCR) is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor as well as oxidized species of cholesterol. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. Drugs that inhibit HMG-CoA reductase are known collectively as HMG-CoA reductase inhibitors (or "statins"). Statins (or HMG-CoA reductase inhibitors) are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular disease and statins have been found to prevent cardiovascular disease in those

who are at high risk. A number of statins are on the market including: Simvastatin, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, and Rosuvastatin. Rosuvastatin is a synthetic lipid lowering agent for oral administration. Rosuvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase, having a mechanism of action similar to that of other statins. Rosuvastatin is approved for the treatment of high LDL cholesterol (dyslipidemia), total cholesterol (hypercholesterolemia), and/or triglycerides (hypertriglyceridemia). Chemically, Rosuvastatin calcium is bis[(£)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](37?, 5!S)-3,5-dihydroxyhept-6-enoic acid] calcium salt. The empirical formula is (C22H27FN306S)2 Ca. Its molecular weight is 1001.14, and its chemical structure is represented below: Rosuvastatin is marketed by AstraZeneca under the trade name, Crestor®. The primary use of Rosuvastatin is for the treatment of dyslipidemia.

US 5260440 first disclosed a process for preparing Rosuvastatin calcium which involved the use of intermediate, methyl (3£)-3-(ter/-butyldimethylsilyloxy)-5-oxo-6- triphenylphosphoranylidene hexanate of following structure. in - \j This intermediate is not stable at ambient temperature, not economical as it requires a number of purification steps to prepare Rosuvastatin and is difficult to use on industrial scale. WO 03087112 relates to process for preparation of a chiral compound, tert-buty\ (3R)-3-(hydroxy-protecting group)-6-alkylphosphinyl or sulfonyl group-5-oxohexanate, which is synthesized from 3-hydroxy diethyl glutarate via partial hydrolysis by a microorganism wherein X is P(=0)(Me)2 or S(0)(alky], alkoxy or aryl) and P is t-butyldimethylsilyl group and the use of the chiral compound in the process for the production of HMG-CoA reductase inhibitor, such as Rosuvastatin.

This process is not feasible on an industrial scale as it involves the use of an expensive microorganism and requires very low temperature such as -78°C, which is a hindrance in the scale-up operations. US 2009076292 relates to a process for preparing chiral intermediates of Rosuvastatin of the following formula These intermediates are used in the processes for the preparation of ?-butyl (3#)-(t-butyl dimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxohexanoate and (3^)-(t-butyl dimethylsilyloxy)-5-oxo-6-triphenyl-phosphoranylidene hexanoate, chirally pure Rosuvastatin intermediates used in the preparation of HMG-CoA reductase inhibitors. The chiral intermediates require a number of purification steps, require the use of dimethoxy borane reagent and hence are not industrially feasible. The inventors of the present invention have directed their attention towards a process for preparing chirally pure terf-butyl 2-((2R, 45)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate of formula (I), which are cost effective and are suitable for industrial scale production.

SUMMARY OF THE INVENTION

The present invention provides a novel process for the preparation of tert-butyl 2-((2R, 4S)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate of formula (I), comprising:

i) cleavage of the dioxane ring of tert-butyl 2-((4tf,5S)-6-(acetoxymethyl)-2,2-dimethyl- l,3-dioxan-4-yl)acetate, compound of formula (A) by using acid in presence of polar solvent to produce compound of formula (B)

ii) condensation of compound of formula (B) in a non polar solvent with cyclohexanone under acidic conditions to provide compound of formula (C)

iii) selective hydrolysis of compound of formula (C) in presence of base and polar solvent to provide compound of formula (D)

iv) oxidation of compound of formula (D) in presence of suitable oxidizing agent, nitroxyl radical as a catalyst, co-oxidant and polar solvent to provide compound of formula (I)

DETAILED DESCRIPTION OF THE INVENTION

An embodiment of the present invention provides a novel process for the preparation of iert-butyl 2-((2R, 4S)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate of formula (I), which comprises following steps:

i) cleavage of the dioxane ring of tert-h\xXy\ 2-((4^,55)-6-(acetoxy methyI)-2,2-dimelhyl- l,3-dioxan-4-yl) acetate, compound of formula (A) by using acid in presence of polar solvent to produce compound of formula (B) an acid is selected from the group comprising of hydrochloric acid, acetic acid, sulfuric acid and the like, preferably hydrochloric acid. The polar solvent selected from the group comprising of acetonitrile, water, dichloromethane, tetrahydrofuran and the mixtures thereof, preferably acetonitrile and water at ambient temperature, ii) condensation of compound of formula (B) in a non polar solvent with cyclohexanone under acidic conditions

The condensation reaction is carried out in presence of non polar solvent selected from the group comprising of toluene, hexane, preferably toluene and an acid is selected from the group comprising of inorganic acids such as hydrochloric acid, sulphuric acid, preferably concentrated sulphuric acid at a temperature range of 0-5 °C. iii) selective hydrolysis of compound of formula (C) in presence of base and polar solvent to produce the compound of formula D

The base used in the reaction is selected from the group comprising of inorganic base such as alkali metal bases like sodium carbonate, potassium carbonate, preferably potassium carbonate in presence of polar solvents such as alcoholic solvents like ethanol, methanol, isopropanol, preferably methanol at ambient temperature, iv) Anelli's oxidation of compound of formula (D) in presence of suitable oxidizing agent, nitroxyl radical as a catalyst, co-oxidant and polar solvent to produce the compound of formula I The suitable oxidizing agent is selected from the group comprising of sodium chlorate, sodium hypochlorite, preferably sodium hypochlorite and the nitroxyl radical is 2,2,6,6-tetramethylpiperidin-l-yl) oxy (TEMPO) in presence of co-oxidant such as potassium bromide and polar solvents such as dichloromethane and water. The reaction is carried at a temperature range of-10 to 15 °C, preferably 0°C.

A novel process for the preparation of tert-buty\ 2-((2R, 45>4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate of formula (I) which is used in the preparation of Rosuvastatin calcium, can be illustrated in the following scheme: The present invention gives a stable intermediate, wherein the use of cyclohexane protecting group, increases the selectivity for obtaining the desired trans isomer of the Rosuvastatin calcium in good yield. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

EXAMPLES

Example-1: Preparation of (3R, 5S)-tert-buty\ 6-acetoxy-3, 5-dihydroxyhexanoate (B) To tert-butyl 2-((4^,55)-6-(acetoxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (30.2 g, 0.1 mol) in acetonitrile (150ml), hydrochloric acid solution (2ml of concentrated HC1 in 50 ml water) was added drop-wise for 60 min at 20-25° C and the reaction mixture was stirred for 1-2 h at the same temperature. After completion of the reaction, the pH of the reaction mixture was adjusted to 6-7 with saturated sodium bicarbonate solution. Water (250 ml) and dichloromethane (200ml) were added and to the reaction mixture and stirred for 10 min. The layers were separated and the aqueous layer was extracted with dichloromethane (2 xlOO ml). The combined organic layer was washed with water (3x100ml), the organic layer was dried over sodium sulphate and distilled completely to give the titled compound. Weight: 21g (79.8%)

ExampIe-2: Preparation of tert-butyl 2-((2#, 4S)-4-(acetoxy methyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate(C) To (3R,5S)-tert-buty\ 6-acetoxy-3,5-dihydroxyhexanoate (26.3g,0.1mol) solution cyclohexanone (10 g,0.1 mol) in toluene (50 ml) and concentrated sulphuric acid (2ml) were added at 0-5° C and stirred for 1-2 h. After completion of the reaction, the layers were separated and the organic layer was dried over anhydrous potassium carbonate and distilled completely under reduced pressure at below 50° C to yield the titled compound. Weight: 27.2 g(81%).

Example-3: Preparation of fer/-butyl 2-((2/?,4S)-4-(hydroxymethyI)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate(D) To a clear solution of tert-butyl 2-((2V?,4S)-4-(acetoxymethyl)-l,5-dioxaspiro[5.5]widecan-2-yl) acetate 34.3g, O.lmol) in methanol (150ml), was added potassium carbonate (180 mg) at 25-35° C and stirred for 2 hours at the same temperature. Dichloromethane (150ml) and water (180 ml) were added to the reaction mixture and stirred for 10-15min. The layers were separated and the aqueous layer was extracted with dichloromethane (2x50ml). The combined organic layer was washed with water (3 x 50ml), distilled the solvent completely under reduced pressure to give titled compound. Weight: 26.4 g (86.5%)

Example-4: Preparation of tert-butyl 2-((2J£, 45)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (I) To a clear solution of tert-butyl 2-((2£,4S>4-(hydroxymethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (30.3 g, O.lmol) in dichloromethane(300ml), Potassium bromide(1.6 g) and TEMPO(100 mg) were added at 0° C, followed by addition of saturated sodium bicarbonate solution(84 ml) and sodium hypochlorite solution (71 ml, having assay=10.5%W/V) drop-wise in 30-40 min. 10% hypo solution( 100ml) was added to the reaction mixture and stirred for 10 min. The layers were separated and the aqueous layer was extracted with dichloromethane (100ml). The combined organic layer was washed with brine solution (2x100ml); the solvent was distilled off completely under reduced pressure at below 40° C to yield the titled product. Weight: 24.3g (81.6%)

1. A process for the preparation of tert-buty\ 2-((2R, 45)-4-formyl-l ,5 dioxaspiro[5.5]undecan-2-yl)acetate of formula (I), comprising the steps of:

i) cleavage of the dioxane ring of ter/-butyl 2-((4R,5S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate, compound of formula (A) by using an acid in presence of polar solvent to produce compound of formula (B)

ii) condensation of compound of formula (B) in a non polar solvent with cyclohexanone under acidic conditions to provide compound of formula (C)

iii) selective hydrolysis of compound of formula (C) in presence of base and polar 1 solvent to provide compound of formula (D)

iv) oxidation of compound of formula (D) in presence of suitable oxidizing agent, nitroxyl radical as a catalyst, co-oxidant and polar solvent to provide compound of formula (I)

2. The process according to claim 1, an acid is selected from the group comprising of hydrochloric acid, acetic acid, sulfuric acid and the like, preferably hydrochloric acid.

3. The process according to claim 1, the polar solvent selected from the group comprising of acetonitrile, water, dichloromethane, tetrahydrofuran and the mixtures thereof, preferably acetonitrile and water at ambient temperature.

4. The process according to claim 1, the non polar solvent is selected from the group of toluene, hexane, preferably toluene.

5. The process according to claim 1, the base used in the reaction is selected from the group comprising of inorganic base alkali metal bases selected from sodium carbonate, potassium carbonate, preferably potassium carbonate

6. The process according to claim 1, in step-iii, polar solvent is selected from the alcoholic solvents like ethanol, methanol, isopropanol, preferably methanol.

7. The process according to claim 1, the suitable oxidizing agents is selected from the group of sodium chlorate, sodium hypochlorite, preferably sodium hypochlorite.

8. The process according to claim 1, the nitroxyl radical is 2,2,6,6-tetramethylpiperidin-l-yl)oxy (TEMPO).

9. The process according to claim 1, co-oxidant is potassium bromide.