Preparation of vincadifformine and related derivatives

A process for the preparation of .+-.vincadifformine and related compounds of the formula:

• ##STR18## wherein each of R.sub.1 and R.sub.2 individually is hydrogen, hydroxy, acyloxy, carbamate, lower alkoxy of 1 to 7 carbon atoms, lower alkyl of 1 to 7 carbon atoms, or halo;
• R.sub.3 and R.sub.4 are the same or different and are hydrogen or alkyl of 1 to 7 carbon atoms;
• A represents an alkyl chain or unsaturated aliphatic hydrocarbon chain of 2 to 7 carbon atoms and which may be substituted by one or more alkyl, hydroxy or hydroxy-alkyl groups of 1 to 7 carbon atoms, which comprises the steps of:
• (a) reacting a tetrahydro-.beta.-carboline of the formula:
• ##STR19## with benzoyl chloride to form a compound of the formula:
• ##STR20## wherein .phi. represents a phenyl radical (b) reducing the compound of formula III by means of a reducing agent to form a compound of the formula:
• ##STR21## (c) chlorinating the compound of formula IV with t-butyl hypochlorite in the presence of triethylamine to form a compound of the formula:
• ##STR22## (d) reacting the compound of formula V with a dialkyl malonate salt of sodium or thallium wherein each alkyl group has 1 to 7 carbon atoms at reflux to form a compound of the formula:
• ##STR23## (e) hydrogenating the compound of formula VI into a compound of the formula:
• ##STR24## (f) decarboalkoxylating partly the compound of formula VI' to form a compound of the formula:
• ##STR25## (g) reacting the compound of formula VIII with an aldehyde selected from the group of haloaldehyde, alkylsulfoxyaldehyde, arylsulfoxyaldehyde, epoxyaldehyde or mixture thereof wherein said aldehyde has 3-14 carbon atoms in the presence of triethylamine to yield the desired vincadifformine or related compound of formula I.

A process for preparing .+-.vincadifformine or related compound of the formula:

• ##STR29## wherein each of R.sub.1 and R.sub.2 individually is hydrogen, hydroxy, acyloxy, carbamate, lower alkoxy of 1 to 7 carbon atoms, lower alkyl of 1 to 7 carbon atoms, or halo;
• R.sub.3 and R.sub.4 are the same or different and are hydrogen or alkyl of 1 to 7 carbon atoms;
• A represents an alkyl chain or unsaturated aliphatic hydrocarbon chain having from 2 to 7 carbon atoms and which may be substituted by one or more alkyl, hydroxy, or hydroxy-alkyl groups of 1 to 7 carbon atoms, which comprises reacting methyl 1,2,3,4,5,6-hexahydroazepino-[4,5b]-indole-5-carboxylate of the formula:
• ##STR30## with an aldehyde selected from the group of haloaldehyde, alkylsulfoxyaldehyde, arylsulfoxyaldehyde, epoxyaldehyde or mixture thereof wherein said aldehyde has 3-14 carbon atoms, in a dry methanol under a nitrogen atmosphere in the presence of dry triethylamine at room temperature to yield the desired compound of formula I.

A process for preparing .+-.vincadifformine or related compound of the formula:

• ##STR31## wherein each of R.sub.1 and R.sub.2 is hydrogen, hydroxy, acyloxy, carbamate, lower alkoxy of 1 to 7 carbon atoms, lower alkyl of 1 to 7 carbon atoms, or halo;
• R.sub.3 and R.sub.4 are the same or different and are hydrogen or an alkyl of 1 to 7 carbon atoms;
• A represents an alkyl chain or unsaturated aliphatic hydrocarbon chain of 2 to 7 carbon atoms and which may be substituted by one or more alkyl, hydroxy or hydroxy-alkyl groups, having from 1 to 7 carbon atoms, which comprises reacting an alkyl 1,2,3,4,5,6-hexahydroazepino-[4,5b]-indole-5-carboxylate of the formula:
• ##STR32## with an aldehyde selected from the group of haloaldehyde, alkylsulfoxyaldehyde, arylsulfoxyaldehyde, epoxyaldehyde or mixture thereof wherein said aldehyde has 3-14 carbon atoms in dry benzene under heating to yield the desired compound (I).