THE GAZETTE OF INDIA: EXTRAORDINARY (PART H—Sec. 3(ii)l
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule13)

3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

4. DESCRIPTION (Description shall start from next page.)
5. CLAIMS (not applicable for provisional specification. Claims should start with the preamble — "l/we claim" on separate page)
6. DATE AND SIGNATURE (to be given at the end of last page of specification)
7. ABSTRACT OF THE INVENTION (to be given along with complete specification on separate page)
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Title of the invention: Preparation of Irinotecan by the use of a carbonylation agent and an alkaline solvent.
Inventors: Kannan Vishwanath, Vikas Sadvilkar, Kashi Vishwanath Vishwanath
Inventor Company: Benzochem Lifesciences, Mumbai.
Preparation of Irinotecan by the use of a carbonylation agent and an
alkaline solvent.
Abstract:
The invention relates to an improved process for the preparation of Irinotecan of enhanced yield, purity by contacting 4-piperidinopiperidine with 7-ethyl-10 hydroxy-camptothecin to obtain crude Irinotecan which is subsequently purified by solvent treatment and obtaining purified Irinotecan.

BACKGROUND
U.S. Pat. No. 4,604,463 describes the preparation of 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin by condensation of 7-ethyl-10-hydroxycamptothecin with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride in pyridine at room temperature. According to WO200519223 this method leads to coloured impurities in the product. In order to avoid these, 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin was prepared by condensation of 7-ethyl-10-hydroxycamptothecin with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride in a polar aprotic solvent such as acetonitrile and in the presence of 4-dimethyl-
1
aminopyridine. The condensation proceeds in suspension, where the polar aprotic solvent dissolves only 4-dimethylaminopyridine whereas 7-ethyl-10-hydroxycamptothecin and 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride in this polar aprotic solvent remain undissolved. The amount of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride employed in the condensation reaction is preferably 1.3 to 3 mol, more preferably 1.6 to 1.9 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin. The amount of 4-dimethylaminopyridine used in the condensation ranges preferably between 1.5 and 4 mol, more preferably between 1.8 and 2.2 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin. The amount of the polar aprotic solvent used in the condensation is preferably 400 to 600 mol, more preferably 430 to 460 mol, per mol of 7-ethyl-10-hydroxycamptothecin. The condensation is performed preferably at a temperature from 70 to 80.degree. C, more preferably at 73 to 77.degree. C.
SUMMARY:
According to the present invention a method for preparing 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-camptothecin is disclosed comprising:
A reacting a mixture of 4-piperidinopiperidine and 7-ethyl-10-hydroxycamptothecin with a base as a solvent for the reaction.
DETAILED DESCRIPTION:
The amount of base is preferably calculated to be the 1.1 times to 30 times the amount of 4-
piperidino piperidine present during the reaction.
The amount of dimethyl carbonate can be from 1.0 to about 1.5 equivalents of 7-ethyl-10-hydroxy camptothecin. However, the more dimethyl carbonate is added, the more impurities will arise. Therefore 1.0 to 1.3 equivalents of dimethyl carbonate are preferred.
An advantage of the above-described process is that the reaction temperature can be brought down to 35-40.degree. C, as compared to 70-80.degree. C. in the process of WO2005019223A1.
All major solvents are avoided except for pyridine or triethylamine.
The following examples describes a preferred embodiment of the invention.
EXAMPLE 1
A mixture of 0.2 mol 7-ethyl-10-hydroxycamptothecin and 0.2 mol of 4-piperidinopiperidine, is
treated with 1.5 litres of triethylamine at 35 to 40.degree. C. After 36 h the organic layer is treated
with water and the distillables are distilled under high vacuum. 800 ml methanol are added within
30 min at reflux. The mixture is cooled to 2-5.degree. C. and stirred for at least 1 h at 2-5degree.
C. The suspension is further cooled to 0 degree. C, stirred for at least 1 additional hour and
subsequently filtered off and dried in vacuo.
The crude product (Irinotecan free base) is crystallized from 2-methoxyethanol.
Yield: 82%
Appearance: yellow, crystalline powder
EXAMPLE 2
mixture of 0.2 mol 7-ethyl-10-hydroxycamptothecin and 0.2 mol of 4-piperidinopiperidine, is
treated with 1.5 litres of pyridine at 35 to 40.degree. C. After 36 h the organic layer is treated with
water and the distillables are distilled under high vacuum. 800 ml methanol are added within 30
min at reflux. The mixture is cooled to 2-5.degree. C. and stirred for at least 1 h at 2-5degree. C.
The suspension is further cooled to 0 degree. C, stirred for at least 1 additional hour and
subsequently filtered off and dried in vacuo.
2-

The crude product (Irinotecan free base) is crystallized from 2-methoxyethanol.
Yield: 88%
Appearance: yellow, crystalline

powder

Claims:
We claim the

Following :
Avoidance of the use of Class ! solvents such as benzene, toluene, etc The single -pot synthesis using all the three reactants simultaneously.
The easy removal of the product from the reactants.

3 .