CZ20022250A3 - Process for preparing irinotecan - Google Patents

Abstract

Process for the preparation of irinotecan (7-ethyl-10- [4- (1-piperidino) -1piperidino] carbonyloxy-camptothicin) radical ethylation (10- (4- (1-piperidino) -1-piperidinolcarbonyloxyamptothecin) propanal.

Description

Technical field

The present invention relates to a process for the preparation of irinotecan (7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxy-camptothecin hydrochloride trihydrate) of the formula (I):

Irinotecan is used as a cytostatic (topoisomerase inhibitor) especially in the treatment of lung and rectal cancer.

BACKGROUND OF THE INVENTION

Irinotecan is prepared by condensation of 7-ethyl-10-hydroxycamptothecin of formula

with 1-chlorocarbonyl-4-piperidinopiperidine of the formula:

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9 · 99

9 i

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and.

(US Patent 4,604,463; ANN N.Y. Acad. Sci. 803.13 (1996); CHEM. Pharm. Bull. 39 (6) 1446 (1991)).

A disadvantage of this method of preparing irinotecan is that 7-ethyl-10-hydroxycamptothecin must be of relatively high purity, at least 95% (HPLC). In order to achieve this quality, the crude material must be purified by crystallization, with about 50% losses.

Another disadvantage of this process for the production of irinotecan is that a large amount of acetic acid (50 ml of acetic acid per gram of 7-ethyl-10-hydroxycamptothecin) is required to produce 7-ethyl-10-hydroxycamptothecin, which then contaminates the waste water.

SUMMARY OF THE INVENTION

The disadvantages of the prior art solutions are eliminated by the process for the preparation of irinotecan of formula (I) according to the invention, consisting in the ethylation of 10- [4- (1-piperidino) -1-piperidino] carbonyloxycarbamptothecin of formula (II):

a suitable ethylating agent, preferably propanal, in the presence of ferrous sulfate and hydrogen peroxide in dilute sulfuric acid. Sulfuric acid protonates the pyridine nitrogen in the molecule of (II). Thus, the entry of the ethyl radical to the para position in the pyridine ring is preferred. The sulfuric acid is used in an amount of 28 mol to 170 mol per 1 mol of (II), preferably 60 mol. Propanal is used in at least an equivalent amount. The hydrogen peroxide is used in an amount of 3 mol to 9 mol per 1 mol of (II), preferably 6.7 mol. The ferrous sulphate is used in an amount of 3 mol to 6 mol per 1 mol of compound (II), preferably 4.2 mol.

The temperature of the ethylation reaction is in the range of + 5 ° C to -15 ° C, preferably at -10 ° C. Table 1:

Temperature, “C Substance (H), relative. % HPLC Compound (I), relative. % HPLC +5 17 59 +1 1.3 73 -8 0.1 78 -10 0.4 79 -15 18.2 59

After the ethylation of (II) is complete, the sulfuric acid is removed with calcium chloride. The organic ballasts are removed by extraction with a chlorinated aliphatic hydrocarbon, preferably chloroform.

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4445 · 4

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After adjusting the pH to 6.5 to 7 with alkaline hydroxide, the base (I) is extracted from the aqueous phase into chloroform. After distilling off the chloroform, the distillation residue is dissolved in a non-polar non-chlorinated organic solvent, preferably ethyl acetate, and the compound (I) is precipitated by the action of hydrogen chloride. The active substance content is at least 90% relative. (HPLC).

The crude (I) was purified by preparative liquid chromatography.

The main advantage of the process for the preparation of the compound (I) according to the invention is that there is no loss of substance (I) in the treatment of the reaction mixture after the ethylation of the compound (II).

G (0.0179 mol) of 10- [4- (1-piperidino) -1-piperidino] carbonyloxy-camptothecin is dissolved in 200 ml of water. 21 g (0.0755 mol) of ferrous sulfate heptahydrate are added, cooled to 44 DEG C., concentrated sulfuric acid (44 ml, 0.8 mol) and propanal (5.4 ml, 0.074 mol) are added at the same temperature.

The reaction mixture was cooled to -10 ° C and 9.5 ml (0.1208 mol) of hydrogen peroxide (30%) was added at this temperature with vigorous stirring. After the addition of hydrogen peroxide, the reaction mixture was stirred at this temperature for about 30 minutes.

The reaction mixture was then added with vigorous stirring to a solution of 178g of calcium chloride in 1 liter of water. The resulting calcium sulfate was removed by filtration and the filter cake was washed with about 1 liter of water.

The filtrate was extracted twice with 500 ml of chloroform. To the aqueous phase was added 500 ml of chloroform and the pH of the aqueous phase was adjusted to 6.5-7 at a temperature of up to 10 ° C with a 20% aqueous solution of alkaline hydroxide. The chloroform phase is separated and the chloroform is distilled off using a rotary evaporator.

The distillation residue was dissolved in 150 ml of anhydrous ethyl acetate and 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxy-camptothecin hydrochloride precipitated with hydrogen chloride which was isolated by filtration.

Yield: 4.34 g of crude 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycarbamptothecin hydrochloride containing about 90% of the active compound (HPLC) which is about 35% of theory.

Claims (6)

Patent claims A process for the preparation of 7-ethyl-10- [4- (1-piperidino) -1-piperidino] -carbonyloxy-camptothecin hydrochloride trihydrate of formula (I), characterized in that 10- [4- (1-piperidino) -1- piperidino] carbonyloxy-camptothecin of formula (II) is ethylated with a suitable ethylating agent, preferably propanal. 2. Process according to claim 1, characterized in that the sulfuric acid is used in an amount of 28 to 170 mol per 1 mol of substance (II), preferably 60 mol. Method according to claims 1 and 2, characterized in that the propanal is used in a minimum equivalent amount. 4. Process according to claims 1, 2 and 3, characterized in that the hydrogen peroxide is used in an amount of 3 moles to 9 moles per 1 mol of the substance (II), preferably 6.7 moles. Process according to claims 1, 2, 3 and 4, characterized in that the ferrous sulfate is used in an amount of 3 moles to 6 moles per 1 mol of the substance (II), preferably 4.2 moles. 6. Process according to claims 1, 2, 3, 4 and 5, characterized in that the temperature of the ethylation reaction ranges from + 5 ° C to -15 ° C, preferably at -10 ° C.