CN102584815A

CN102584815A - Method for preparing tropisetron hydrochloride on large scale

Info

Publication number: CN102584815A
Application number: CN2011100074533A
Authority: CN
Inventors: 杨俊�; 吴锋; 向红琳; 张静; 陈敏; 朱敏; 甘丽红; 陈锋
Original assignee: HUNAN KANGPU MEDICAL RESEARCH INSTITUTE
Current assignee: HUNAN KANGPU MEDICAL RESEARCH INSTITUTE
Priority date: 2011-01-14
Filing date: 2011-01-14
Publication date: 2012-07-18

Abstract

The invention relates to a method for preparing tropisetron hydrochloride on large scale, which comprises the steps that: indole-3-formic acid reacts with thionyl chloride in 1,2-dichloroethane, so indole formyl chloride is obtained, 1,2-dichloroethane and thionyl chloride are removed by reduced pressure distillation, and tetrahydrofuran solution is added; under the condition that tetrahydrofuran exists, alpha-tropine reacts with sodium hydroxide to obtain alpha-tropine sodium salt; the tetrahydrofuran solution of the indole formyl chloride reacts with the tetrahydrofuran solution of the alpha-tropine sodium salt, so tropisetron is obtained; and finally, the tropisetron reacts with hydrochloric acid, and the high-purity tropisetron hydrochloride is prepared after purification.

Description

A kind of method of scale preparation Tropisetron hydrochloride

Technical field

The invention belongs to the fine chemical product production field, particularly a kind of preparation technology of Tropisetron hydrochloride, purposes produce the antiemetic medicine.

Background technology

In the chemistry of Tropisetron hydrochloride (Tropisetron hydrochloride) is by name-1H-Indole-3-Carboxylic Acid-8-methyl-assorted nitrogen dicyclo [3.2.1] oct-3-yl ester hydrochloride; It is high selectivity 5-HT3 receptor antagonist; Be applicable to the nausea and vomiting that causes after prevention and treatment children and adult cancer chemotherapy, radiotherapy and the operation, Fig. 1 seen in its chemical structural formula.

As existing preparation method, at USP (US3980668, US4789673; US4797406 has introduced in US4803199) with indole-3-carboxylic acid and oxalyl chloride reaction, obtaining 3-indoles formyl chloride with methylene dichloride and normal hexane processing; The tropine lithium alkoxide reaction that under the n-Butyl Lithium activation, generates with tropanol then obtains tropisetron through aftertreatment, and last and hydrochloric acid salify makes Tropisetron hydrochloride; Its reaction principle is seen Fig. 2, and this process is very complicated, complex steps; Actual consumption is many, and reaction yield is merely 20%.

As the improvement of aforesaid method, document [Tropisetron hydrochloride synthetic, Shandong medicine industry; 2002,21 (1): 5] replace oxalyl chloride with THIONYL CHLORIDE 97 cheap and easy to get in, one step of condensation has been removed inflammable and explosive n-Butyl Lithium; Created condition for the industriallization safety in production, acidylate, condensation two-step reaction are merged into a step, do not separate midbody; Simplified operational condition, but its yield is merely 25%.

In document [the synthetic improvement of Tropisetron hydrochloride, Huaihai Institute of Technology journal, 2003; 12 (4): 41 ~ 43; Synthesis of Tropisetron Hydrochloride is improved, Hunan Normal University's journal (medicine), 2006; 3 (4): 29 ~ 30] obtain Tropisetron hydrochloride with 50%, 52.8% yield respectively in, but still used the acvator of expensive n-Butyl Lithium as condensation reaction.

Summary of the invention

The present invention is intended to overcome the weak point of existing Tropisetron hydrochloride synthesis technique; The preparation method of a kind of high yield, acquisition high-purity hydrochloric acid tropisetron safe, pollution-free, with low cost, easy and simple to handle is provided; Be fit to large-scale production, can satisfy the requirement of field of medicaments.

The concrete preparation process of the present invention is following:

(1) indole-3-carboxylic acid and sulfur oxychloride (SOCl2) react in 2-ethylene dichloride, toluene or the benzene 1, and preferred 1,2 ethylene dichloride obtains indoles-3-formyl chloride; Indole-3-carboxylic acid, sulfur oxychloride carry out the mol ratio of acyl chloride reaction can select 1:1 ~ 2, is preferably 1:1.5; Temperature of reaction is 30-40 ℃, preferred 35 ℃; Reaction times 18-30 hour, preferred 24 hours.

(2) α-tropanol and sodium hydroxide (NaOH) react in THF (THF), obtain α-tropine sodium alkoxide; The mol ratio that α-tropanol and NaOH react can be selected 1:1 ~ 1.5, preferred 1:1.2; Temperature of reaction is 25-45 ℃, preferred 35 ℃; Reaction times 18-30 hour, preferred 24 hours.

(3) in the presence of THF, indoles-3-formyl chloride and α-tropine sodium alkoxide reaction obtains tropisetron; Indoles-3-formyl chloride, tropine sodium alkoxide carry out the mol ratio of esterification can select 1:0.8 ~ 1.5, preferred 1:1.1; Temperature of reaction is 30-50 ℃, preferred 40 ℃; Reaction times 24-36 hour, preferred 30 hours.

(4) tropanol sodium salt and indoles-3-formyl chloride is in THF stirring reaction 18-24 hour, tropisetron solution.

(5) tropisetron solution in absolute ethyl alcohol, Virahol, acetone, chloroform or ETHYLE ACETATE with hydrochloric acid reaction, preferred absolute ethyl alcohol or acetone are after after the cooling, filtration, carrying out washing treatment, separate out the high-purity hydrochloric acid tropisetron.

The present invention and Tropisetron hydrochloride synthesis technique ratio in the past, innovative point is following:

(1) high (> 82.3% of the synthesis technique yield that is adopted);

(2) high (> 99.5% of resulting Tropisetron hydrochloride purity);

(3) avoided adopting inflammable and explosive n-Butyl Lithium, increased security;

(4) cancel expensive n-Butyl Lithium as acvator, practiced thrift cost;

(5) in the whole process of preparation,, easy and simple to handle without separation of intermediates.

Description of drawings

Fig. 1 is the structural formula of Tropisetron hydrochloride of the present invention;

Fig. 2 is the structural formula of 3-indoles formyl chloride of the present invention;

Fig. 3 is the structural formula of α of the present invention-tropine sodium alkoxide;

Fig. 4 is a process flow sheet of the present invention;

Fig. 5 is the reaction principle figure of preparation Tropisetron hydrochloride in the prior art.

Embodiment

(1) preparation of indoles-2-formyl chloride:

In the 500mL there-necked flask, add 20.0g indole-3-carboxylic acid, 300mL 1,2-ethylene dichloride and 3 mL DMF stir and slowly drip 20 mL sulfur oxychlorides down; 45 ℃ of reaction 8h; Steam and remove unnecessary sulfur oxychloride and 1, the 2-ethylene dichloride adds 100 mL THFs and dissolves subsequent use.

(2) preparation of α-tropine sodium alkoxide:

In 500 mL there-necked flasks, add 19.0g α-tropanol, 100mL THF and 5.4g NaOH solid, stirring reaction 4h is subsequent use under the room temperature.

(3) preparation of Tropisetron hydrochloride:

THF solution with indoles-3-formyl chloride under the room temperature slowly drops in the THF solution of tropine sodium alkoxide, and 35 ℃ of stirring reactions spend the night, and THF is reclaimed in underpressure distillation; Use 95% ethyl alcohol recrystallization, get faint yellow solid, add the 70mL absolute ethyl alcohol; Heating for dissolving, the cooling back feeds HCl gas, stirring at room reaction 30min; Suction filtration gets the Tropisetron hydrochloride bullion.The absolute ethyl alcohol recrystallization gets white crystalline product 21.2g (liquid chromatogram measuring purity is 99.91%), and total recovery is 53.29%, and fusing point is 283 ~ 285, and the spectrum of product is consistent with bibliographical information.

Claims

1. the preparation method of a Tropisetron hydrochloride (Tropisetron hydrochloride) is characterized in that may further comprise the steps:

(1) (Thionyl chloride SOCl2) 1, reacts in 2-21 monochloroethane, obtains indoles-3-formyl chloride for indole-3-carboxylic acid and sulfur oxychloride;

(2) α-tropanol and sodium hydroxide (NaOH) THF (Tetrahydrofuran, THF) in the reaction, obtain α-tropine sodium alkoxide;

(3) in the presence of THF, indoles-3-formyl chloride and α-tropine sodium alkoxide reaction gets tropisetron;

(4) tropisetron and hydrochloric acid reaction get Tropisetron hydrochloride.

2. according to the method for claim 1, it is characterized in that the reaction solvent of indoles-3-formyl chloride compound is 1, a kind of or its mixture in 2-ethylene dichloride, methylene dichloride, toluene, the benzene; Preferred 1; 2 ethylene dichloride, temperature are 30 ~ 40 ℃, reaction times 18-30 hour.

3. according to the method for claim 1, the reaction solvent that it is characterized in that α-tropanol sodium compound be THF (Tetrahydrofuran, THF), hexanaphthene, preferred THF, temperature is 25 ~ 45 ℃, 18 ~ 30 hours reaction times.

4. according to the method for claim 1, the reaction solvent that it is characterized in that the Tropisetron hydrochloride compound be THF (Tetrahydrofuran, THF), hexanaphthene, preferred THF, temperature is 30 ~ 50 ℃, 24 ~ 36 hours reaction times.

5. method according to claim 1 is characterized in that final product is a Tropisetron hydrochloride.

6. method according to claim 1 is characterized in that the solvent that tropisetron with gained converts tropisetron salt to is a kind of or its mixture in absolute ethyl alcohol, Virahol, acetone, chloroform, the ETHYLE ACETATE, preferred absolute ethyl alcohol or acetone.