The way to obtain 8-methyl-8-azabicyclo[3,2,1]oct-3-silt ester of indole-3-carboxylic acid

 

(57) Abstract:

The invention relates to an improved process for the preparation of 8-methyl-8-azabicyclo[3,2,1]Oct-3-silt ester of indole-3-carboxylic acid hydrochloride which is a substance tropisetrona and is used as an antiemetic, effective for vomiting caused by chemotherapy drugs. Describes how to obtain 8-methyl-8-azabicyclo[3,2,1] Oct-3-silt ester of indole-3-carboxylic acid by reacting N-methyl-8-azabicyclo[3,2,1]Octan-3-ol with a derivative of indole, as a derivative of indole use 3-trichloroacetamido, the reaction mixture is boiled in an environment of oxygen-containing solvents in the presence of traces of caustic alkalis and target product emit a known manner. The technical result - the proposed method eliminates the use of inflammable, utility, does not require time-consuming purification of the final product and used the original connection is available.

The invention relates to the field of organic chemistry and synthesis of medical drugs specifically to a method for producing 8-methyl-8-azabicyclo [3,2,1] Oct-3-silt ester of indole-3-carboxylic acid formulate, effective for vomiting caused by anticancer chemotherapy drugs (Mashkovsky M. D. drugs. - M.: Medicine, 1993.-T. I.-s.)

A method of obtaining 8-methyl-8-azabicyclo [3,2,1] Oct-3-silt ester of indole-3-carboxylic acid by the interaction of a solution of acid chloride of indole-3-carboxylic acid in tetrahydrofuran (THF) with lithium alcoholate N-methyl-8-azabicyclo [3,2,1] Octan-3-ol, prepared from N-methyl-8-azabicyclo [3,2,1] Octan-3-ol (tropine), utility in hexane in an environment of absolute THF at 20oC. After decomposition of the reaction mixture with a solution of soda, the reaction product is extracted with dichloromethane. The crude product is purified column chromatography and crystallized from a mixture of dichloromethane-ethyl acetate. The output is not shown. The melting point of 201-202oC (the melting point of the hydrochloride of 8-methyl-8-azabicyclo [3,2,1] Oct-3-silt ester of indole-3-carboxylic acid 283-285oC (decomposition)). (Patent 4789673 USA, MCI4A 61 K 31/46. Heterocyclic corboxylic acid amides and esters. / Peter Donatsch (Switzerland). Gunter Engel (Germany), Bruno Hugl (Switzerland). - N 119360; Statements. 10.11.1987, Publ. 6.12.1988; NCI 546/112.-10s.)

The disadvantages of this method are:

a) inflammable utility;

b) application dorg on 6,35 g and 4.8 g of the original N-methyl-8-azabicyclo [3,2,1] Octan-3-ol (tropine) and the acid chloride of indole-3-carboxylic acid, respectively).

The present invention is to provide a method for obtaining 8-methyl-8-azabicyclo [3,2,1] Oct-3-silt ester of indole-3-carboxylic acid, devoid of the above disadvantages.

The task can be solved using the proposed new method of obtaining 8-methyl-8-azabicyclo [3,2,1] Oct-3-silt ester of indole-3-carboxylic acid.

How is that 8-methyl-8-azabicyclo [3,2,1] Oct-3-silt ether indole-3-carboxylic acid is produced by interaction of N-methyl-8-azabicyclo [3,2,1] Octan-3-ol (tropine) F. III and 3-trichloroacetimidate F. II in the presence of traces of caustic alkalis.

The reaction is carried out by heating the raw materials in the environment oxygenated solvents (THF, dioxane, dimethyl ether of diethylene glycol, dimethyl ether of ethylene glycol and other cyclic and acyclic ethers).

The process is carried out according to the following scheme:

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The reaction mechanism is californina decomposition of 3-trichloroacetimidate when interacting with the alcoholate N-methyl-8-azabicyclo [3,2,1] Octan-3-ol. This reaction is well flows in the synthesis of esters of indole-3-carboxylic acid and various primary alcohols (Kelarev Century. And. and other Synthesis functional the conditions, when this reaction was progressing with secondary alcohols, representative of which is N-methyl-8-azabicyclo [3,2,1] Octan-3-ol (according to).

Example 1. In 250 ml of 1,4-dioxane is dissolved to 26.6 g (0.1 mole) 3-trichloroacetimidate and 21.1 grams (0.15 mole) of anhydrous N-methyl-8-azabicyclo [3,2,1] Octan-3-ol, then add 2 drops of concentrated solution of sodium hydroxide and heated the reaction mixture to a boil. Within 1 hours drive away 25-35 ml of solvent, and then continue to heat to boiling for 24 hours (control over the progress and termination of the reaction is determined by thin-layer chromatography on plates Silyfol, eluent-chloroform). The solvent is distilled under reduced pressure (25-30 mm RT. Art.). To the cooled residue is poured 50 ml of sulphuric ether, stirred, filtered N-methyl-8-azabicyclo [3,2,1] Octan-3-silt ether indole-3-carboxylic acid. Get to 19.9 g (70%) of the desired product (I). Melting point 203oC (from acetone).

Similar results were obtained when using as solvent dimethyl ether of diethylene glycol and derivatives of 1,3-dioxane.

Example 2. 2.8 g (0,01 mol) of 8-methyl-8-azabicyclo [3,2,1] Oct-3-silt ester of indole-3-carboxylic acid was dissolved in 20 ml of acetone ml of sulphuric ether, mix. After 1 hour, the residue is filtered off, washed with 20 ml of sulphuric ether. Get 2,88 g (90%) of the hydrochloride of 8-methyl-8-azabicyclo [3,2,1] Oct-3-silt ester of indole-3-carboxylic acid with a melting point 282-284oC (with decomposition).

The claimed method of obtaining 8-methyl-8-azabicyclo [3,2,1] Oct-3-silt ester of indole-3-carboxylic acid has the following advantages over known:

a) does not require the use inflammable, utility;

b) does not require time-consuming purification of the final product;

in) source 3-trichloroacetamido is available chemical compound obtained in one stage of the indole and the acid chloride of trichloroacetic acid with a yield of 71% ( Bergmann I. The Reaction of N-Acylpyridinium Salts with Indole. - J. Heterosycl. Chem. - 1970. - Vol. 7, N 5. - P. 1071-1076).

The way to obtain 8-methyl-8-azabicyclo[3,2,1]Oct-3-silt ester of indole-3-carboxylic acid by reacting N-methyl-8-azabicyclo[3,2,1]Octan-3-ol with a derivative of indole, characterized in that as a derivative of indole use 3-trichloroacetamido, the reaction mixture is boiled in an environment of oxygen-containing solvents in the presence of traces of caustic alkalis and target product emit a known manner.

 

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in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

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in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

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in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

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in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

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in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

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in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

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in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

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in radical

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