Field of Invention:

The present invention relates to an improved process for the preparation of compounds of formula-I and II, which are key intermediates for the preparation of Rosuvastatin and its pharmaceutically acceptable salts.

Background of the Invention:

Rosuvastatin, described chemically as [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] is a synthetic lipid-lowering agent. It is used commercially in the form of its calcium salt for the pharmaceutical products sold as CRESTORfTM).

U.S. Pat. No. 4,970,313 describes a process for preparation of key intermediates of rosuvastatin and its related compounds. A process for the preparation of the Intermediate of Formula I involves oxidation of its corresponding hydroxy compound by using oxalylchloride. The process involves the hazardous and expensive chemicals like oxalylchloride, which is not feasible for scale up. This process is conducted at cryogenic temperatures like -78[deg.] C which is industrially, economically not feasible and unsafe to handle.

All the prior known process for the preparation of compound of formula-I and II uses oxalylchloride, tetrapropylammonium perruthenate and [gamma]-manganese dioxide, which are hazardous and expensive chemicals and not suitable for the commercial scale process.

These foregoing problems are avoided by the present invention, which is a convenient and cost-effective process for the preparation of compounds of Formulas-I and II. The compounds of Formulas-I and II are known for being particularly useful as intermediates for preparing pharmaceutically active substances, which are used as HMG CoA reductase inhibitors and antihypercholesterolemic agents, one among them is rosuvastatin.

Advantageous of the present Invention:

> Avoids the usage of hazardous and expensive chemicals like oxalylchloride, tetrapropylammonium perruthenate and y-manganese dioxide for the conversion of hydroxyl compounds to its corresponding aldehydes.

> Uses low cost reagents which are suitable for large scale process

Eco-friendly and easy to scale up process.

Brief Description of the Invention:

The present invention relates to an improved process for the preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I and n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-II which are key intermediates for the synthesis of rosuvastatin and its pharmaceutically acceptable salts.

The first aspect of the present invention is to provide an improved process for the preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I, comprising of oxidizing the tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-Ill using l,3,5-trichloro-2,4,6-triazinetrione (trichloroisocyanuric acid) in presence of 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) in a suitable solvent to provide tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I.

The second aspect of the present invention is to provide an improved process for the preparation of n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-II, comprising of oxidizing the n-butyl-2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-IV using l,3,5-trichloro-2,4,6-triazinetrione (trichloroisocyanuric acid) in presence of 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) in a suitable solvent to provide n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-1,3 -dioxan-4-yl)acetamide compound of formula-II.

Detailed Description of Invention:

As used herein the present invention the term "suitable solvents" refers to solvents selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, n-pentane, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like dichloromethane, chloroform and ethylene dichloride; "nitrile solvents" like acetonitrile and propionitrile; polar solvents like water; and mixtures thereof.

As used herein the present invention, the term "anti-solvent" refers to a solvent which is used to precipitate the solid from a solution and the suitable anti-solvent used herein the present invention is hydrocarbon solvent.

As used herein the present invention, the oxidizing agent is l,3,5-trichloro-2,4,6-triazinetrione (trichloroisocyanuric acid).

As used herein the present invention, the catalyst is 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO).

The first aspect of the present invention is to provide an improved process for the preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I, comprising of oxidizing the tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-Ill using l,3,5-trichloro-2,4,6-triazinetrione (trichloroisocyanuric acid) in presence of 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) in a suitable solvent to provide tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I.

In a preferred embodiment of the present invention is to provide an improved process for the preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I, comprising of oxidizing the tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-Ill using l,3,5-trichloro-2,4,6-triazinetrione (trichloroisocyanuric acid) in presence of 2,2,6,6- tetramethyl-1-piperidinyloxy free radical (TEMPO) in dichloromethane to provide tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I.

The trichloro isocyanuric acid used for oxidizing the compound of formula-Ill of the present invention is in the mole proportions of between 0.8 and 2.0 moles, preferably 1.0 to 1.5 moles per mole of compound of formula-Ill.

The oxidation of compound of formula-Ill is conducted at a temperature ranging from -10 °C to 20°C, preferably -5 °C to 5 °C.

The second aspect of the present invention is to provide an improved process for the preparation of n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-II, comprising of oxidizing the n-butyl-2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-IV using l,3,5-trichloro-2,4,6-triazinetrione (trichloroisocyanuric acid) in presence of 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) in a suitable solvent to provide n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-1,3 -dioxan-4-yl)acetamide compound of formula-II.

In a preferred embodiment of the present invention is to provide an improved process for the preparation of n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-II, comprising of oxidizing the n-butyl-2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-IV using l,3,5-trichloro-2,4,6-triazinetrione (trichloroisocyanuric acid) in presence of 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) in dichloromethane to provide n-butyl-2-((4R,6S)-6-formyl-2,2 -dimethyl-1,3-dioxan-4-yl)acetamide compound of formula-II.

The trichloro isocyanuric acid used for oxidizing the compound of formula-IV of the present invention is in the mole proportions of between 0.8 and 2.0 moles, preferably 1.0 to 1.5 moles per mole of compound of formula-IV.

The oxidation of compound of formula-IV is conducted at a temperature ranging from -10 °C to 20°C, preferably -5 °C to 5 °C.

The present invention is schematically represented in scheme-I as follows: Scheme: 1

The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not construed as limitation of the scope of invention.

Examples:

Example-1: Preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate (Formula-I)

To a solution of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-Ill (10 g), dichloromethane (80 ml) and TEMPO (0.1 g), added a pre-cooled solution of trichloroisocyanuric acid (9.82 g) in dichloromethane (20 ml) at 0-5°C and then stirred for 2 hours at 0-5°C. After completion of the reaction, the reaction mixture was filtered and the bed was washed with dichloromethane and the obtained filtrate was washed with sodium bicarbonate solution, followed by water and then with sodium chloride solution. The dichloromethane layer was dried with sodium sulfate and then distilled off the solvent completely under reduced pressure to get title compound. Yield: 8.5 g.

Example-2: Preparation of n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide (Formula-II)

To a solution of n-butyl-2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-IV (10 g), dichloromethane (80 ml) and TEMPO (0.1 g), added a pre-cooled solution of trichloroisocyanuric acid (9.86 g) in dichloromethane (20 ml) at 0-5°C and then stirred for 2 hours at 0-5°C. After completion of the reaction, the reaction mixture was filtered and the bed was washed with dichloromethane and the obtained filtrate was washed with sodium bicarbonate solution, followed by water and then with sodium chloride solution. The dichloromethane layer was dried with sodium sulfate and then distilled off the solvent completely under reduced pressure to get title compound. Yield: 9.0 g.

We Claim:

1. An improved process for the preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I, comprising of oxidizing the tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate compound of formula-Ill using l,3,5-trichloro-2,4,6-triazinetrione (trichloro isocyanuric acid) in presence of 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO) as a catalyst in a suitable solvent.

2. An improved process for the preparation of n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-II, comprising of oxidizing the n-butyl-2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetamide compound of formula-IV using l,3,5-trichloro-2,4,6-triazinetrione (trichloro isocyanuric acid) in presence of 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO) as a catalyst in a suitable solvent.

3. The process according to claim-1 or 2, the oxidation is conducted at a temperature ranging from -10 °C to 20°C.

4. The process according to claim-1 or 2, the oxidation is conducted at a temperature ranging from -5 °C to 5°C.

5. The process of claim 1 or 2, wherein the oxidation occurs in a solvent selected from dichloromethane, tetrahydrofuran, toluene, dimethylsulfoxide, N,N-dimethyl formaide, or N,N-dimethylacetamide.

6. The process of claim 1 or 2, wherein the oxidation occurs in dichloromethane.

7. An improved process for the preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I, comprising of oxidizing the tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate compound of formula-Ill using l,3,5-trichloro-2,4,6-triazinetrione (trichloro isocyanuric acid) in presence of 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO) in dichloromethane to provide tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I.

8. An improved process for the preparation of n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-II, comprising of oxidizing the n-butyl-2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetamide compound of formula-IV using l,3,5-trichloro-2,4,6-triazinetrione (trichloro isocyanuric acid) in presence of 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO) in dichloromethane to provide n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-II.

9. The process according to claim 1 or 7, the use of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-I as an intermediate in the synthesis of rosuvastatin and its pharmaceutically acceptable salts.

10. The process according to claim 2 or 8, the use of n-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-II as an intermediate in the synthesis of rosuvastatin and its pharmaceutically acceptable salts.