FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of 3,4-0-anisylidene-7(S)-chloro-7-deoxy-lincomcin hydrochloride, a key intermediate in the synthesis of Clindamycin Palmitate hydrochloride which in turn is converted to Clindamycin Paimitate hydrochloride by condensation with palmitoyi chloride in the presence of a base followed by hydrolysis.
BACKGROUND OF THE INVENTION:
Clindamycin Palmitate hydrochloride (CLEOCIN) is a semi synthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin. Clindamycin Palmitate hydrochloride is chemically known as 7(S)-Chloro-7-deoxy-lincomycin-2-palmitate hydrochloride and is represented by the following structural formula-l:

Clindamycin Palmitate hydrochloride was described in US 3580904.The said patent disclosed three step process for the preparation of Clindamycin Paimitate hydrochloride. In step one 7(S)-chloro-7-deoxy-lincomycin hydrochloride was reacted with anisaldehyde to give 3,4-0-anisyiidene-7-(S)-chloro-7-deoxy-lincomycin hydrochloride. The second step involves dissolution of 3,4-0-anisylidene-7-(S)-chloro-7-deoxy-lincomycin hydrochloride in chloroform followed by condensation with palmitoyi chloride in the presence of pyridine. The third step involves dissolution of 3,4-0-anisylidene-7-(S)-chloro-7-deoxy-lincomycin -2-palmitate hydrochloride in acetic acid and heated to 90° C followed by removal of solvent under vacuum thus isolating crude Clindamycin Palmitate hydrochloride. The crude Clindamycin Palmitate hydrochloride was purified by using mixture of solvents.
Still there is a need to develop an improved process for the preparation of Clindamycin Palmitate hydrochloride which involves fewer steps and easy purification methods feasible industrially. The present process provides Clindamycin Palmitate hydrochloride with a high purity and yield.
-2-

OBJECT OF THE INVENTION
The present invention relates to an improved process for the preparation of 3,4-0-anisylidene-7(S)-chloro-7-deoxy-lincomcin hydrochloride, a key intermediate in the synthesis of Clindamycin Palmitate hydrochloride which in turn is converted to Clindamycin Palmitate hydrochloride by condensation with palmitoyi chloride in the presence of a base followed by hydrolysis.
SUMMARY OF THE INVENTION
The main aspect of the present invention relates to an improved process for the preparation of 3, 4-0-anisylidene-7(S)-chloro-7-deoxy-lincomcin hydrochloride, a key intermediate in the synthesis of Clindamycin Palmitate hydrochloride.
Another aspect of the present invention relates to an improved process for the preparation of 3, 4-0-anisylidene-7(S)-chloro-7-deoxy-lincomcin hydrochloride wherein, Clindamycin hydrochloride is reacting with p-anisaldehydedimethylacetal in the presence of an acid catalyst and suitable solvent.
Yet another aspect of the present invention relates to an improved process for the preparation of 3, 4-0-anisylidene-7(S)-chloro-7-deoxy-lincomcin hydrochloride wherein. Clindamycin hydrochloride is reacted with p-anisaldehyde in the presence of an acid catalyst and sulfolane in a solvent.
Yet another aspect of the present invention relates to an improved process for the preparation of Clindamycin Palmitate hydrochloride by reacting 3, 4-0-anisylidene-7(S)-chloro-7-deoxy-lincomcin hydrochloride with palmitoyi chloride in the presence of base followed by hydrolysis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of 3,4-0-anisylidene-7(S)-chloro-7-deoxy-lincomcin hydrochloride, a key intermediate in the synthesis of Clindamycin Palmitate hydrochloride.
One embodiment of the present invention relates to an improved process for the preparing 3, 4-0-anisylidene-7(S)-chloro-7-deoxy-lincomycin hydrochloride of the formula-ll

which is hydrolysis to afford the compound of formula I in presence of an acid.
According to the present invention, the preparation process involves the steps of suspending 3, 4-0-anisylidene-7(S)-chloro-7-deoxy-lincomycin hydrochloride in a chlorinated solvent selected from dichloromethane, chloroform, preferably dichloromethane, adding an organic base such as pyridine followed by addition of palmitoyi chloride at reflux temperature and maintaining for about 4 hours, cooling the reaction mass up to room temperature, adding an alcoholic solvent preferably methanol, removing the solvent completely and degas the residue at a temperature of about 40-42°C, adding chlorinated solvents preferably dichloromethane, adding conc.hydrochloric acid, removing the solvent and adding ketone solvents preferably acetone to the residue, removing the ketone solvent and finally isolating from solvent selected from acetone, acetonitrile and tetrahydrofuran or mixter thereof.

-6-

EXAMPLES:
1) Preparation of 3, 4-0-anisylidene-7(s)-chloro-7-deoxy-lincomycin hydrochloride.
Clindamycin hydrochloride (20 gm) was dissolved in acetonitrile (100 ml) and p-anisaldehyde dimethylacetal (24 gm), p-toluenesulfonic acid (0.9 gm) was added to the solution and heated to reflux for about 18 hr.The resulting reaction mass was cooled to 25-30 °C, stirred the reaction mass for Ihr and filter the mass, washed the wet cake with acetonitrile and isolated 18 gm of desired compound.
2) Preparation of 3, 4-0-anisylidene-7(s)-chloro-7-deoxy-lincomycin hydrochloride.
Clindamycin hydrochloride (20 gm) was suspended in cyclohexane (100 ml) and sulfolane (40 ml), p-anisaldehyde (44 gm), p-toluenesulfonic acid (0.4 gm) was added to the solution, stirred for lOmin and heated to reflux for about 24 hr.The resulting reaction mixture was cooled to 25-30 °C, stirred the reaction mass for Ihr and filter the mass, washed the wet cake with acetone and isolated 23 gm of desired compound.
3) Preparation of Clindamycin Palmitate hydrochloride
Pyridine (6.8 gm) was added to the stirred solution of 3, 4-0-anisylidene-7(s)-chloro-7-deoxy-lincomycin hydrochloride (20 gm) in dichloromethane (120 ml) and the resulting mixture was heated to reflux (40-45°C). PalmitoyI chloride (16.Og in 20 ml dichloromethane) was added slowly at reflux temperature and maintained the reflux for 4hrs. Cooled the reaction mass temperature to room temperature, added methanol (100 ml) and distilled out solvent completely under vacuum at 40°C. To this residue dichloromethane was added and degas the residue at 40-42°C and organic layer was washed with water (50ml), to this solution aqueous hydrochloric acid (3.0g) was added at 25-30°C. After completion of the reaction, organic layer was washed with water (20 ml) and distilled out solvent completely under vacuum at 40-45°C. Added acetone (120 ml), stirred for 1 hr and distilled out completely, further the residue was suspended in acetone and added acetonitrile (1200 ml), stirred the reaction mass for Ihr and filter the mass, washed the wet cake with acetonitrile (1200 ml) and isolated 14 gm of desired compound.

We Claim:
1. An improved process for the preparation of 3, 4-0-anisylidene-7(S)-chloro-7-deoxy-
with p-anisaldehyde in the presence of a solvent, sulfolane and an acid catalyst.
5. The process according to claim 4, wherein the solvent is cyclohexane.
6. The process according to claim 4, wherein the acid catalyst is p-toluene sulfonic acid