PROCESS FOR PREPARING IRINOTECAN

Abstract

The present invention relates to a process for the preparation of pure irinotecan or salts thereof, and a process for the preparation of intermediate compound 7-ethyl-10-hydroxycamptothecin.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction pattern of irinotecan hydrochloride trihydrate prepared according to Example 11.

FIG. 2 is a differential scanning calorimetry curve of irinotecan hydrochloride trihydrate prepared according to Example 11.

FIG. 3 is an infrared absorption spectrum of irinotecan hydrochloride trihydrate prepared according to Example 11.

FIG. 4 is a thermogravimetric analysis curve of irinotecan hydrochloride trihydrate prepared according to Example 11.

Claims

1. A process for preparing irinotecan or a salt thereof, comprising purifying 7-ethyl-10-hydroxycamptothecin by: i) slurrying 7-ethyl-10-hydroxycamptothecin in an alcohol; thenii) dissolving 7-ethyl-10-hydroxycamptothecin in acetic acid, removing acetic acid to form a concentrated solution, and combining with an alcohol to form a precipitate; theniii) recrystallizing 7-ethyl-10-hydroxycamptothecin.

2. The process of claim 1, wherein an alcohol for i) is a C1-C6 alkyl alcohol.

3. The process of claim 1, wherein an alcohol for ii) is a C1-C6 alkyl alcohol.

4. The process of claim 1, wherein an alcohol for i) comprises methanol.

5. The process of claim 1, wherein an alcohol for i) comprises methanol.

6. The process of claim 1, wherein recrystallization in iii) is from a solution comprising N,N-dimethylformamide, dimethylsulfoxide, or N,N-dimethylacetamide.

7. The process of claim 1, wherein recrystallization in iii) is from a solution comprising N,N-dimethylformamide.

8. The process of claim 1, further comprising reacting crystallized 7-ethyl-10-hydroxycamptothecin with 4-piperidinopiperidinecarbamoyl chloride to form irinotecan.

9. A process for purifying irinotecan, comprising adding a solution comprising irinotecan to a column of silica gel, eluting using dichloromethane, then eluting using an eluent comprising a mixture of methanol and dichloromethane.

10. The process of claim 6, wherein a mixture of methanol and dichloromethane comprises about 5 percent by volume methanol.

11. A process for the preparation of irinotecan hydrochloride trihydrate comprising reacting irinotecan with hydrochloric acid in water.

12. Irinotecan hydrochloride trihydrate prepared by the process of claim 1 and containing: less than about 0.15% by weight of (S)-4-ethyl-4-hydroxy-1H-pyrano[3′, 4′:6,7]indolizino(1,2-b)quinoline-3,14(4H,12H)-dione;less than about 0.15% by weight of (S)-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino(1,2-b)quinoline-3,14(4H,12H)-dione;less than about 0.15% by weight of (S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino(1,2-b)quinoline-3,14(4H,12H)-dione;less than about 0.15% by weight of (S)-4,11-diethyl-4-hydroxy-1H-pyrano[3′,4′:6,7]indolizino(1,2-b)quinoline-3,14(4H,12H)-dione;less than about 0.15% by weight of (S)-4,8,11-triethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino(1,2-b)quinoline-3,14(4H,12H)-dione;less than about 0.15% by weight of (S)-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino(1,2-b)quinoline-3,14(4H,12H)-dione-9-(1,4-bipiperidine)-1′-carboxylate; andless than about 0.15% by weight of (S)-4,8,11-triethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino(1,2-b)quinoline-3,14(4H,12H)-dione-9-(1,4′-bipiperidine)-1′-carboxylate.

13. Irinotecan hydrochloride trihydrate of claim 9, containing less than about 0.005% by weight of (S)-4,8,11-triethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino(1,2-b)quinoline-3,14(4H,12H)-dione-9-(1,4′-bipiperidine)-1′-carboxylate.