CS211143B1 - Process for the preparation of esters of 20-desethyl-20-allyclinkadifformin - Google Patents

Abstract

The invention relates to a process for the production of 20-desethyl-20-allylvincadifformic acid esters of the general formula I, COOR in which R denotes alkyl with 1 to 3 carbon atoms, by reacting 1-methyltetrahydropyrido(3,4-b)indole-1-carboxylic acid ester of the general formula II, in which R has the same meaning as above, with 2-allyl-5-chloropentanal, in an inert solvent, at the boiling point of the reaction mixture, with the optional addition of an organic tertiary base. The new compounds of the general formula I are important intermediates in the production of pharmaceuticals.

Description

The present invention relates to a process for the preparation of the 20-tert-ethyl-20-allylvincadifforminic acid esters of the general formula (I).

COOH (I) wherein R is alkyl; having from 1 to 3 carbon atoms, all of the novel compounds serving as important intermediates in the manufacture of pharmaceuticals.

According to the invention, the general formula (I) is prepared by the preparation of 1-methyltetrahydropyrido (3,4-b) indole-1-carboxylic acid esters of general formula (II),

in which R has the same meaning as above, condenses with a stoichiometric amount, but preferably with a 25 to 100% excess of the 2-ellyl-5-chloropentanal of formula III

CH = O

C ₁ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH = CHg (III) in an inert organic solvent, for example a C 6 -C 8 aromatic hydrocarbon, preferably toluene, or a chlorinated aromatic hydrocarbon, with preferably chlorobenzene, at the boiling point of the reaction mixture. A tertiary organic base such as diazabicyclononene or diazabicycloundecene may be added to the reaction mixture before the reaction is complete.

Alternatively, the reaction may be carried out in a mixture of any of the above hydrocarbons with a polar solvent such as methanol or ethanol.

The following examples illustrate but do not limit the generality of the process of the invention.

Example!

A mixture of 53.0 g (0.217 mol) of ethyl 1-methyl-1,2,3,4-tetrahydropyrido (3,4-b) indole-1-carboxylate (compound of formula II, R is methyl), 36.95 g (0.23 mol) of 2-allyl-5-chloropentanal (compound of formula III), 0.15 g of p-toluenesulfonic acid and 4000 ml of toluene are heated to boiling under a water separator for 120 h. After 49 and 65 h, 9.0 g (0.056 mol) of 2-allyl-5-chloropentanal are added in each case, and after 04 hours 63.95 g (0.42 mol) of diazabicyclotomecene are added.

The progress of the reaction was monitored by thin layer chromatography on silica gel. The toluene layer is separated while hot and concentrated to a volume of about 700 ml and the precipitated solid is filtered off with suction, the filtrate is evaporated in a rotary evaporator and the residue is dissolved in a mixture of 200 ml of ether and 600 ml of petroleum ether.

The solution obtained is repeatedly shaken with a 7% hydrochloric acid solution (800 ml and 2.times.250 ml). The oily substance precipitates and is taken up in 500 ml of chloroform and the solution is added to the aqueous phase. The biphasic mixture thus obtained was made alkaline with concentrated aqueous ammonia solution to pH 12 while cooling with water. The organic phase was separated and the aqueous phase was extracted twice with 150 ml of water and 150 ml of brine each time and evaporated in a water pump vacuum. The residue was dissolved in a minimum amount of benzene and loaded onto a 150 g silica gel column. The core fraction was eluted with a 1: 1 mixture of benzene and chloroform and concentrated to a volume of about 70 ml.

Cil 43

a. apply 350 g of silica gel to the column. The column was eluted with benzene and a 10: 1 mixture of benzene and chloroform. Evaporation of the eluate gave 51.85 g of glassy 20-decyl-20-allyl-vincadifformin (compound of formula I, R being methyl). Yield 68.2% of theory.

Example 2

To a solution of 13.6 g (0.05 mol) of propyl 1-methyl-1,2,3,4-tetrahydropyrido (3,4-b) indole-1-carboxylate (compound of formula II, R is propyl) in 750 16.05 g (0.1 mol) of 2-allyl-5-chloropentanal (compound of formula III) and 25 ml of p-toluenesulfonic acid are added to ml of chlorobenzene. The mixture was heated to boiling under a water separator for 130 hours, after which the diazabicyclononene (12.45 g, 0.1 mol) was added after 115 hours. The chlorobenzene solution was separated hot and evaporated on a rotary evaporator. The residue is dissolved in a mixture of 50 ml of ether and 300 ml of petroleum ether and treated as in Example 1. 10.4 g (55.1% of theory) of glassy propyl 20-decyl-20-allylvincadifforminate (compound of formula I) are obtained. R is propyl).

Claims (2)

A process for the preparation of 20-Desyl-20-allylvincadifforminic acid esters of the general formula I, COOR in which H represents an alkyl of 1 to 3 carbon atoms, characterized in that the esters of 1-methyltetrahydropyrido (3,4-b) indole-1-carboxylic acid of the general formula II, II (II) NH COOR H / H ₃ C in which R has the same meaning as above, condenses with a stoichiometric amount, but preferably with a 25 to 100% excess of 2-allyl-5-chloropentanal of formula III CH ϊ O AND C1-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH = CH ₂ (m) in an inert organic solvent such as an aromatic hydrocarbon having 6 to 8 carbon atoms, preferably toluene, or a chlorinated aromatic hydrocarbon, preferably chlorobenzene, at the boiling point of the reaction mixture. 2. Process according to claim 1, characterized in that a tertiary organic base, for example diazabicyclononene or diazabicycloundecene, is added to the reaction mixture before the reaction is completed.