CS209618B1 - Method of making-1-methyl-1,2,3,4-tetrahydro-9h-pyrido/3,4-b/indole -1-karboxylate - Google Patents

Abstract

Methyl 1-methyl-1,2,3,4-tetrahydro-9H- -pyrido (3,4-b) indole-1-carboxylate of formula I, (AND) an important intermediate in the synthesis of some drugs, arises by transesterification of tricyclic of the amino ester of formula II (II) wherein R is allyl is 2 to 4 sodium methoxide methanol. carbon atoms

Description

The present invention relates to a process for the preparation of methyl 1-methyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-1-carboxylate of formula X

(AND)

The compound of formula (I) is known and is an important intermediate in drug synthesis.

According to the literature (Kuehne ΜE. et al., J. Org. Chem. 44. '2477 (1979), this ester is produced by condensing tryptamine hydrochloride with methyl pyruvate at elevated temperature, or by an alternative process ( Hahn, G. et al., Lieb. Ann. Chem., 520, 107 (1935)) acidifies the acid with methanol, and we have now found that the methyl ester I can also be conveniently prepared by trans-esterification from other esters of the corresponding parent acid.

The principle of the invention is that the tricyclic amino ester of formula II

wherein R is C 2 -C 4 alkyl is heated with sodium methoxide in methanol.

According to the invention, a solution of the amino ester of formula XI in methanol is added with a solution of sodium methoxide and the mixture is heated to boiling.

According to a preferred embodiment, less than a stoichiometric, preferably catalytic amount of sodium methoxide is used.

Alternatively, the transesterification can also be carried out by heating the compound of formula II with methanol in the presence of a mineral acid. However, this procedure yields the ester of formula I in a lower yield.

Examples

Example 1

To a solution of 3.0 g (11.61 mmol) of ethyl 1-methyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-1-carboxylate (III, R = Hg. CH 2) in 20 ml of anhydrous methanol is added a solution of 0.023 g (1.0 mmol) of sodium in 10 ml of anhydrous methanol and the mixture is heated to boiling for 45 minutes when the reaction is complete by thin layer chromatography. After cooling and addition of 1.5 ml of 30% ammonium chloride solution, the reaction mixture is evaporated to dryness on a rotary evaporator. The residue was partitioned between 2 x 35 mL methylene chloride and 30 mL water. The combined organic phases were washed with 10 ml of water and, after drying over sodium sulfate, evaporated in vacuo. The residue was crystallized from benzene / petroleum ether (5: 1). 2.35 g (82.9%) of methyl 1-methyl-1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole-1-carboxylate (I) are obtained. Melting point: 135.5-139 ° C.

Example2

A mixture of 28.64 g (100 mmol) of butyl 1-methyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-1-carboxylate (II, R = CH2.CH2.CH2) CH 3) and a solution of sodium methoxide, prepared by dissolving 0.115 g (5.0 mmol) of sodium in 200 ml of absolute methanol, is heated to boiling for 1.5 hours. After addition of 5 ml of 30% ammonium chloride solution, the reaction mixture is evaporated water pump. The residue was partitioned between 2 x 100 mL chloroform and 100 mL water. The combined organic phases were washed with 30 ml of water and 2 x 50 ml of brine and evaporated on a rotary evaporator. The residue is recrystallized from benzene. 18.13 g of methyl 1-methyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-1-carboxylate (I) are obtained, m.p. 135-138.5 ° C. . Yield 74.2%.

Claims (1)

A process for the preparation of methyl 1-methyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-1-carboxylate of formula I (I), characterized in that the tricyclic amino ester of the general formula II, a coon (IX) in which R is an alkyl of 2 to 4 carbon atoms, is heated in methanol to boiling with a catalytic amount of sodium methoxide.