FORM 2
TH E P A TENTS ACT, 1 9 7 0
(Act 39 of 1970)
COMPLETE SPECIFICATION
(See Section 10; Rule 13)
Title: “An improved process for the preparation of
Clindamycin of Formula (2)”.
Applicants: SUMAR BIOTECH LLP
Address: Plot No.: 112, 113, 114, G.I.D.C. Estate, Tal:
Gozaria, Dist: Mehsana-382825, Gujarat, India.
Nationality: An Indian Company
The following specification describes the nature of the invention:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Clindamycin of formula (2). More particularly, the present invention relates to two different processes for the preparation of Clindamycin of formula (2) from Lincomycin of formula (1).

B A CKG R OUND OF THE INV E NTION
Clindamycin of formula (2) is a compound selected from group of 7-halo-7-deoxylincomycins, Clindamycin is an antibiotic used to treat a wide variety of bacterial infections. The compound is also known as 7(S)-chloro-7-deoxylincomycin, methyl 7-chloro-6,7,8-trideoxy-6-(l-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-l- thio-L-threo- -D-galacto-octo-pyranoside or methyl 7-chloro-6,7,8-trideoxy-6-[[(l-methyl-4-propyl-2-pyrrolidinyl)carbonyl] amino] - 1 -thio- -threo-α-D-galacto-octo- pyranoside.
Processes for preparing 7-halo-7-deoxylincomycins are known. US Patents US3435025, US3496163 and US3509127 disclose a process in which the 7-hydroxyl group of lincomycin and analogous compounds are replaced with a halogen group by reacting said compounds with a Rydon reagent and heating the resulting product. The use of thionyl chloride to convert lincomycin and analogous

compounds to 7-chloro-7-deoxy compounds is described in US Patents US3496163, US3509127 and US3574186.
A process for preparing 7-halo-7-deoxylincomycin by the use of a sulfite-protected lincomycin and Rydon reagents is described in US 3714141.
The use of a Vilsmeier reagent to substitute a halo atom for a hydroxyl group has been described. Eilingsfeld et al, Angew. Chem. 72, 836 (1960) and Eilingsfeld et al, Chem. Ber. 96 2671 (1963). Evans et al, JOC 33, 1074 (1968) discloses on page 1075 that while a Vilsmeier reagent prepared from methanesulfonyl chloride and dimethylformamide was successfully used to replace a primary hydroxyl group, it was not in attempts to replace a secondary hydroxyl group.
The structure of the adduct formed between dimethylformamide and thionyl chloride from which sulfur dioxide has not been removed has been investigated by Ferre et al, Tet. Lett. 2161 (1969) and the conditions for converting the dimethylformamide thionyl chloride adduct to the corresponding amide chloride has been described; Kikagawa et al, Chem. Pharm, Bull. 19, 2629 (1971). Bosshard et al, Helv. Chim. Acta. 42, 1653 (1959) discloses the use of dimethyl formamide as a catalyst in the conversion of carboxylic acids to acid chlorides.
Hepburn et al, J. Chem. Soc. Perkin I, 754 (1976) and Hepburn et al, Chem. & Ind. 664 (1974) describes the use of amide chlorides obtained from Vilsmeier reagents to replace hydroxyl groups by chlorine or bromine groups. However, the hydroxyl containing compounds were relatively simple alcohols and did not approach the complexity of the lincomycin molecule.
While the prior art describes the use of both Vilsmeier reagents and amide chlorides obtained therefrom in reactions similar to that of the process of this instant invention, the prior art is confusing at best. This is particularly true with respect to whether or not it is preferred

to use the Vilsmeier reagent or to remove sulfur dioxide from it and use the resulting amide chloride.
CN103172683A of Zhejiang Hisoar Pharmaceutical Co Ltd filed on 10/04/2004 has disclosed a method for preparing clindamycin hydrochloride. The method for preparing clindamycin hydrochloride comprises the following steps that: (1) performing chlorination reaction of clindamycin hydrochloride and a Vilsmeiser reagent, so as to obtain a reaction liquid containing clindamycin hydrochloride crude product; (2) performing hydrolysis, extraction and concentration on the reaction liquid so as to obtain clindamycin free alkali and then insulating for 20-120 minutes at 90-1200C; (3) performing the salt forming reaction of clindamycin hydrochloride alcoholate in an ethanol water solution with the volume percentage concentration of 90-95 percent so as to obtain clindamycin hydrochloride alcoholate; and (4) dealcoholating the clindamycin hydrochloride alcoholate to obtain clindamycin hydrochloride.
There is a demand of providing a simple, easy to operate, industry & economically viable and single step environment friendly process for the preparation of Clindamycin of formula (2) from Lincomycin of formula (1). Applicant has found that the proposed processes for the preparation of Clindamycin of formula (2) provide increased yield of clindamycin of formula (2) with improved quality having lesser amounts of impurities in the final product.
OBJECTS OF THE INVENTION
Accordingly, the main object of the present invention is to overcome the problems faced by the prior art processes in the preparation of Clindamycin of formula (2).
There is an object of the present invention is to provide a simple, environment friendly, robust, easy to operate, industry & economically

viable and single step environment friendly process for the preparation of Clindamycin of formula (2) from Lincomycin of formula (1).
It is also an object to provide a process for the preparation of clindamycin of formula (2) from Lincomycin of formula (1) that provides increased yield of clindamycin of formula (2) with improved quality having lesser amount of impurities in the final product.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to two different processes for the preparation of Clindamycin of formula (2) from Lincomycin of formula (1).

The present invention provides a simple, environment friendly, robust, easy to operate, industry & economically viable and single step environment friendly process for the preparation of Clindamycin of formula (2) from Lincomycin of formula (1).
The present innovators have comprehensively and successfully investigated the possibility of developing a new process for the p r ep arat i o n o f Clin damy cin of formula (2).
Both proposed Route of synthesis along with the brief process for the preparati on of Clindamycin of formula (2) i s sh ow n as fol low s:


Scheme-1: Route of Synthesis for Preparation of Clindamycin of formula (2) using triflic anhydride and catalyst:
Brief Process: Lincomycin of formula (1) is reacted with triflic anhydride and quarternary ammonium chloride in presence of organic base in organic solvent at temperature between 00C to 800C to give Clindamycin of formula (2).
Now according to the first embodiment of the present invention, there is provided a one pot process for the preparation of clindamycin of formula (2) as per the scheme-1.
Accordingly, a process for the preparation of Clindamycin of formula (2) from lincomycin of formula (1) comprises, the stages of:
i. Dissolving hydrochloride salt of Lincomycin of formula (1) in a
mixture of organic solvents at a temperature between 20-500C by
adjusting pH at 9-10 using organic base; ii. Reacting stage-i with triflic anhydride and quaternary ammonium
compound for 2-4 hours at a temperature 0-500C; iii. Filtering the mass and adding water into the filtrate and carrying
out layer separation to get organic mass. iv. Distilling out the organic mass of stage-iii till the half volume of
mass removed; v. Stirred the reaction mass at 0-100C and filtered it to obtain
clindamycin of formula (2).
Lincomycin of formula (1) may be used in its salts form selected from hydrochloride (HCl) or any other known salts, preferably Lincomycin HCl is used in the process for the preparation of Clindamycin of formula (2).

In the process for the preparation of clindamycin of formula (2) as shown in the scheme-1, organic solvent is selected from but not limited to tetrahydrofuran (THF), dichloromethane (MDC), chloroform (CHCl3), acetonitrile (AcN), toluene.
Quaternary ammonium chloride is selected from from but not limited to triethylbenzyl ammonium chloride (TEBACl), alkyl dimethyl benzyl ammonium chloride, alkyl didecyl dimethyl ammonium chloride, and dialkyl dimethyl ammonium chloride. Alky means C1-C10 alkyl.
Organic base is selected from but not limited to di-isopropylethyl amine (DIPEA), triethyl amine (TEA), diethyl amine (DEA), pyridine, morpholine, lutidine.
Organic solvent quantity in the reaction mass is kept between 10-15 volume while the ratio of lincomycin HCl: Triflic anhydride: organic solvent is kept in the range: 1:1.5-1.8w/w: 10-15vol/w.
After completion of reaction, the reaction mass is taken for work up and purification as per the process requirement to obtain pure clindamycin of formula (2).
Scheme-2: Route of Synthesis for Preparation of Clindamycin of formula (2) using SO2Cl2:

Brief Process: Lincomycin of formula (1) is reacted with SO2Cl2 in presence of reagents selected from benzotriazole or imidazole in an organic solvent at a temperature between -400C0C to 800C to give Clindamycin of formula (2).

The process described herein one pot conversion of sterically and electronically hindered alcohol of lincomycin to their respective chloride via 1-sulphonate of benzotriazole and imidazole. Benzotriazole (BtH) and imidazole reagents are known for their cost effectiveness.
In one embodiment of the process for the preparation of clindamycin
of formula (2), benzotrizollium 1-sulphonate salt (BtZ) or imidazolium
1-sulphonate salt (ImZ) may be prepared separately and then reacted
it with lincomycin of formula (1) in presence of organic solvent to give
clindamycin of formula (2).
Benzotrizollium 1-sulphonate salt (BtZ) may be prepared between the
reaction of SO2Cl2 with with benzotriazole in an organic solvent.
Imidazolium 1-sulphonate salt (ImZ) may be prepared between the
reaction of SO2Cl2 with imidazole in an organic solvent.
It is also possible to generate benzotrizollium 1-sulphonate salt (BtZ)
or imidazolium 1-sulphonate salt (ImZ) in-situ in the process which
further converts Lincomycin of formula (2) to clindamycin of formula
(2).
In case if BtZ, the in situ generated BtZ possibly fragments into BtH
and SO3, may be due to the remote activation of carbon bearing -OH
group by the benzotriazolium salt (BtH+Cl_) during the reaction, which
leads to the displacement of nucleofuge (sulfonic ester). This has been
exemplified in the conversion of alcohol to their corresponding chloride
in excellent yield.
Organic solvent used in the process may be selected from but not limited to tetrahydrofuran (THF), dichloromethane (MDC), chloroform (CHCl3), acetonitrile (AcN), toluene, dimethylformamide (DMF), Dimethylsulfoxide (DMSO).
Reaction temperature during the reaction may be kept between -400C to 800C.

After completion of reaction, the reaction mass is taken for work up and purification as per the process requirement to obtain pure clindamycin of formula (2).
Clindamycin may also be converted into pharmaceutical acceptable salt for ex. Clindamycin HCl, Clindamycin phosphate, or other clindamycin pharmaceutically acceptable salts known in the art.
EXAMPLES
General Process for the preparation of Clindamycin of formula (2)
as per Scheme-1:
In a round bottom flask equipped with all reaction equipments including cooling and heating arrangements, HCl salt of Lincomycin of formula (1) is charged with one or more organic solvent(s) and organic base at 20-50°C at a pH between 9-10 and cooled the reaction mass at 0-15°C under stirring. Triflic anhydride and quarternary ammonium salt (phase transfer catalyst) is added to the reaction mass at 0 to 30°C and allowed the reaction mass to stir for 2 to 4 hrs at 20-500C to get reaction complies. Reaction mass is then cooled between 10 to 15°C, filtered the mass to remove quarternary ammonium salt from the mass. Water is added to the filtrate and organic layer is separated from the mass, the said organic layer is then distilled off till the half volume of organic solvent remains in the mass. Cooled the reaction mass to 0 to 10°C and stirred it till the product precipitated out. Filter the mass to get Clindamycin of formula (2).
Organic solvent quantity in the reaction mass is kept between 2-12
volume.
Ratio of lincomycin HCl: Triflic anhydride: organic solvent is kept in
the range: 1:1.5-1.8w/w: 10-15vol/w.
Yield of the final product: between 40-70%

Examples with different parameters are provided as follows:

Ex. No.
01 02
03 04 05
06 07
08 Ratio of
Formula
(1):triflic
anhy.:organic
solvent Organic solvent Organic base Quaternery
Ammo.
compounds Yield
(in
%w/w) & HPCL Purity

1:1.5:10 Toluene (10volumes) DIPEA TEBACl 40% & 50%

1:1.5:10 Toluene (10volumes) DIPEA Dialkyl dimethyl ammonium chloride 48% & 60%

1:1.7:10 Toluene:CHCl3 (5:5volumes) Lutidine TEBACl 58% & 85%

1:1.77:10 Toluene:ACN (8:2volumes) DIPEA TEBACl 56% & 62%

1:1.77:12 Toluene:ACN (6:6volumes) DIPEA Alkyl
dimethyl
benzyl
ammo.
chloride 62% & 95%

1:1.7:12 THF:MDC (6:6volumes) DIPEA TEBACl 45% & 40%

1:1.77:12 Toluene:ACN (6:6volumes) DIPEA Alkyl
dodecyl
dimethyl
ammo.
chloride 55% & 60%

1:1.77:12 Toluene:ACN (6:6volumes) DIPEA TEBACl 70% & 98%
ADVANTAGES:
1. The proposed process for the preparation of clindamycin of formula (2) is a one pot or single step process.
2. The proposed process is a simple, environment friendly, robust, easy to operate, industry & economically viable and environment friendly process.
3. The proposed process provides increased yield of clindamycin of formula (2) with improved quality having less amount of impurities in the final product.

We claim:
1. A process for the preparation of Clindamycin of formula (2) from
lincomycin of formula (1) comprises, the stages of: i. Dissolving hydrochloride salt of Lincomycin of formula (1) in a mixture of organic solvents at a temperature between 20-500C by adjusting pH at 9-10 using organic base; ii. Reacting stage-i with triflic anhydride and quaternary ammonium compound for 2-4 hours at a temperature 0-500C;
iii. Filtering the mass and adding water into the filtrate and carrying out layer separation to get organic mass.
iv. Distilling out the organic mass of stage-iii till the half volume of mass removed;
v. Stirred the reaction mass at 0-100C and filtered it to obtain clindamycin of formula (2).
2. The process for the preparation of Clindamycin of formula (2) as claimed in claim-1 wherein in stage-i, a mixture of organic solvent is a mixture of two or more organic solvents selected from tetrahydrofuran (THF), dichloromethane (MDC), chloroform (CHCl3), acetonitrile (AcN), toluene.
3. The process for the preparation of Clindamycin of formula (2) as claimed in claim-1 wherein in stage-i, organic base is selected from di-isopropylethyl amine (DIPEA), triethyl amine (TEA), diethyl amine (DEA), pyridine, morpholine, lutidine.
4. The process for the preparation of Clindamycin of formula (2) as claimed in claim-1 wherein in stage-ii, quaternary ammonium compound is selected from triethylbenzyl ammonium chloride (TEBACl), alkyl dimethyl benzyl ammonium chloride, alkyl didecyl dimethyl ammonium chloride, and dialkyl dimethyl ammonium chloride.
5. The process for the preparation of Clindamycin of formula (2) as claimed in claim-1 & 4 wherein in quarternary ammonium compound alky means C1-C10 alkyl.

6. The process for the preparation of Clindamycin of formula (2) as claimed in claim-1 wherein in stage-i and stage-ii, ratio of lincomycin HCl : organic solvent : triflic anhydride is 1w/w : 1.5-1.8w/w : 10-15volume.