CN103965160A

CN103965160A - Synthesis method of hydrogen sulfate clopidogrel intermediate derivative

Info

Publication number: CN103965160A
Application number: CN201410213438.8A
Authority: CN
Inventors: 许刘华; 刘明明; 刘加根
Original assignee: NANTONG CHENGXIN AMINO ACID CO Ltd
Current assignee: NANTONG CHENGXIN AMINO ACID CO Ltd
Priority date: 2014-05-16
Filing date: 2014-05-16
Publication date: 2014-08-06

Abstract

The invention relates to a synthesis method of a hydrogen sulfate clopidogrel intermediate derivative. The synthesis method comprises the following steps: (1) preparation of 2-bromothiophene: adding a hydrobromic acid aqueous solution and thiophene to a reaction container, controlling temperature at 4-6 DEG C, slowly adding hydrogen peroxide, after ending addition, continuously carrying out heat preservation for 1-3 hours, and standing still for layering, and carrying out reduced pressure distillation on an organic layer so as to obtain the 2-bromothiophene, wherein the preferable mass ratio of the hydrobromic acid to the thiophene to the hydrogen peroxide is 475: 200: 325; and (2) preparation of thiopheneethanol: adding a mixed solution of magnesium metal, methylbenzene and tetrahydrofuran to the reaction container.

Description

A kind of synthetic method of bisulfate clopidogrel midbody derivant

Technical field

The present invention relates to the synthetic field of chemical industry.

Background technology

2-thiophene ethanol is the raw material of synthesizing clopidogrel hydrogen sulfate intermediate, its derivative 2 thiophene ethyl amine can be used for the synthetic of multi-medicament, the critical medication intermediate of the new drug of the preparation multiple cardiovascular disease relevant with thrombocyte and thrombus and anti-inflammatory analgesic, for example, for the synthesis of important drugs hydrochloric acid thiophene chloropyridine, bisulfate clopidogrel and the hydrochloric acid prasugrel of cardiovascular and cerebrovascular diseases.Along with continually developing of its derived product, the prospect of 2-thiophene ethanol and derivative will be more wide.

Synthesising process research report about 2-thiophene ethanol is more, and the technique of report mainly contains butyllithium technique, sodium reagent technique, ester reducing process, palladium Catalytic processes and grignard reagent technique at present.Current domestic main employing grignard reagent Process.Concrete synthesis technique is as follows:

1 butyllithium technique

US Patent No. 4127580 has been reported and take thiophene as starting material, with butyllithium, thiophene is replaced through 2 positioning metalizations, then carries out condensation reaction with oxyethane and obtains 2-thiophene ethanol lithium, is finally hydrolyzed to obtain target product [2].Reaction equation is as follows:

2 sodium reagent techniques

Japanese Patent JP512368 has reported take thiophene as starting material, under electron transfer agents condition, with sodium Metal 99.5, to 2 metallization reaction of thiophene, then with reacting ethylene oxide, is finally hydrolyzed to obtain target product.Reaction equation is as follows:

3. ester reducing process

At J.Am.Chem.Soc., 1991,113 (13): 5093-5095 has reported that take 2-thiophene acetic acid ester is starting material, with quaternary ammonium salt, cooks phase-transfer catalyst, with sodium borohydride reduction, obtains target product.Reaction equation is as follows:

4 palladium Catalytic processes

Chinese patent CN102964334A has reported that take 2-bromothiophene and vinyl alcohol p-toluenesulfonic esters is starting raw material, first by palladium catalysis Heck reaction, prepare 2-thiofuran ethylene alcohol p-toluenesulfonic esters, then it is reacted and is converted into 2-thiophene ethanol by selective reduction, and reaction equation is as follows:

5 grignard reagent techniques

Japanese Patent JP242657 and JP242658 have reported take thiophene as starting material, through bromine bromination, at tetrahydrofuran (THF) (THF), reacts production form reagent with MAGNESIUM METAL (Mg), grignard reagent and oxyethane effect, is hydrolyzed to obtain target product.Reaction equation is as follows:

From above-mentioned each processing condition, butyllithium technique, sodium reagent technique and Grignard reagent technique all need to be reacted at anhydrous condition, while wherein using butyllithium technique, and butyllithium expensive, severe reaction conditions, preparation difficulty, synthetic yield is 79% left and right.In sodium reagent technique, before thiophene metal sodium, sodium Metal 99.5 need be divided into fragment, then in toluene, make sodium Metal 99.5 and disperse reagent, then react with thiophene, this reaction is comparatively loaded down with trivial details, not easy to operate, is difficult to suitability for industrialized production.In ester reducing process; the process of preparing thiophene acetic acid ester need be through operations such as thiophene acetylize, Willgerodt rearrangement, hydrolysis, esterifications, and step is many, and each yield is low; atom utilization is low, and environmental pollution is the expensive suitability for industrialized production that is unsuitable for of sodium borohydride reduction agent in addition seriously.In palladium Catalytic processes, palladium is expensive, severe reaction conditions, preparation difficulty, and in product, heavy metal remnants are difficult to remove, and in Grignard reagent technique at present, exist bromine volatile, to shortcomings such as equipment corrosion are serious.

Summary of the invention

Goal of the invention: in order to overcome above-mentioned defect, the invention provides the synthetic method of more simple, the workable bisulfate clopidogrel midbody derivant of a kind of method.

The technical solution used in the present invention: a kind of synthetic method of bisulfate clopidogrel midbody derivant, its step is as follows:

The preparation of step 1:2-bromothiophene

In reaction vessel, add commercially available hydrobromic acid aqueous solution and thiophene, control temperature 4～6C, slowly drip hydrogen peroxide, finish and continue insulation 1-3 hour, stratification; Organic layer underpressure distillation obtains 2-bromothiophene; Described Hydrogen bromide, thiophene, with the mass ratio of hydrogen peroxide be 450～500: 200: 300～350; In the synthetic method technical scheme of above-described 2-bromothiophene: the mass ratio of described Hydrogen bromide, thiophene, hydrogen peroxide is preferably 475: 200: 325

The synthetic route of the synthetic method of 2-bromothiophene of the present invention is as follows:

The preparation of step 2:2-thiophene ethanol

In reaction vessel, add commercially available MAGNESIUM METAL, toluene and tetrahydrofuran (THF) mixing solutions, disposablely add a little 2-bromothiophene initiation reaction, after reaction causes, slowly drip 2-bromothiophene, control 25～40 ℃ of temperature, finish and continue insulation 1 hour, to the oxyethane that passes into metering in reaction vessel, control 5～20 ℃ of temperature, finish, reaction continues insulation 3～24 hours at 5～80 ℃, with 15% aqueous sulfuric acid, stir at low temperatures and extract the reaction of going out, stratification; Organic layer underpressure distillation obtains 2-thiophene ethanol; The mass ratio of described magnesium, toluene, tetrahydrofuran (THF) and 2-bromothiophene is 30: 200～250: 80～100: 160～200, in the synthetic method technical scheme of above-described 2-bromothiophene: the mass ratio of described magnesium, toluene, tetrahydrofuran (THF) and 2-bromothiophene is preferably 30: 200: 80: 160;

In the present invention, the synthetic route of the synthetic method of 2-thiophene ethanol is as follows:

Useful effect: compared with prior art, the bromine volatilization in current form technique that overcomes of the inventive method, to an equipment corrosion difficult problem, improves reaction yield simultaneously, simplify operation, there is better operability, more low-cost, technique is simple, is conducive to suitability for industrialized production.

Embodiment

Below in conjunction with embodiment, the invention will be further described, but protection scope of the present invention is not limited to the following examples.

Embodiment 1: a kind of synthetic method of bisulfate clopidogrel midbody derivant, comprises the steps:

1), 2-bromothiophene preparation: add commercially available 48% hydrobromic acid aqueous solution in the there-necked flask of 1L, add 200 grams, thiophene (2.38mol), control 4 ℃ of temperature, slowly drip 325 grams, hydrogen peroxide, finish and continue insulation 2 hours, stratification, organic layer underpressure distillation obtains 350 grams of 2-bromothiophenes (2.14mol), content 99.8%, yield 90%.

2), 2-thiophene ethanol preparation: add the commercially available MAGNESIUM METAL of 30g in dry reaction container, 200g toluene and 80g tetrahydrofuran (THF) mixing solutions, disposablely add a little 2-bromothiophene initiation reaction, after reaction causes, slowly drip 2-bromothiophene 160g (1mol) altogether, control 25 ℃ of temperature, finish and continue insulation 1 hour, to the oxyethane that passes into metering in reaction vessel, control 5 ℃ of temperature, finish, reaction continues insulation 24 hours at 5 ℃, with 15% aqueous sulfuric acid, stir at low temperatures and extract the reaction of going out, stratification; Organic layer underpressure distillation obtains 120 grams of 2-thiophene ethanols (0.937mol), content 99.5%, yield 93.7%.

Embodiment 2: a kind of synthetic method of bisulfate clopidogrel midbody derivant, comprises the steps:

1), 2-bromothiophene preparation: add commercially available 48% hydrobromic acid aqueous solution in the there-necked flask of 1L, add 200 grams, thiophene (2.38mol), control 5 ℃ of temperature, slowly drip 325 grams, hydrogen peroxide, finish and continue insulation 3 hours, stratification, organic layer underpressure distillation obtains 350 grams of 2-bromothiophenes (2.14mol), content 99.8%, yield 90%.

2), 2-thiophene ethanol preparation: add the commercially available MAGNESIUM METAL of 30g in dry reaction container, 250g toluene and 100g tetrahydrofuran (THF) mixing solutions, disposablely add a little 2-bromothiophene initiation reaction, after reaction causes, slowly drip 2-bromothiophene 163g (1mol) altogether, control 40 ℃ of temperature, finish and continue insulation 1 hour, to the oxyethane that passes into metering in reaction vessel, control 25 ℃ of temperature, finish, reaction continues insulation 3 hours at 80 ℃, with 15% aqueous sulfuric acid, stir at low temperatures and extract the reaction of going out, stratification; Organic layer underpressure distillation obtains 110 grams of 2-thiophene ethanols (0.859mol), content 99.5%, yield 85.9%.

Embodiment 3: a kind of synthetic method of bisulfate clopidogrel midbody derivant, comprises the steps:

1), 2-bromothiophene preparation: add commercially available 48% hydrobromic acid aqueous solution in the there-necked flask of 1L, add 200 grams, thiophene (2.38mol), control 6 ℃ of temperature, slowly drip 325 grams, hydrogen peroxide, finish and continue insulation 2 hours, stratification, organic layer underpressure distillation obtains 350 grams of 2-bromothiophenes (2.14mol), content 99.8%, yield 90%.

2), 2-thiophene ethanol preparation: add the commercially available MAGNESIUM METAL of 30g in dry reaction container, 225g toluene and 90g tetrahydrofuran (THF) mixing solutions, disposablely add a little 2-bromothiophene initiation reaction, after reaction causes, slowly drip 2-bromothiophene 163g (1mol) altogether, control 30 ℃ of temperature, finish and continue insulation 1 hour, to the oxyethane that passes into metering in reaction vessel, control 15 ℃ of temperature, finish, reaction continues insulation 12 hours at 45 ℃, with 15% aqueous sulfuric acid, stir at low temperatures and extract the reaction of going out, stratification; Organic layer underpressure distillation obtains 115 grams of 2-thiophene ethanols (0.898mol), content 99.5%, yield 89.8%.

Claims

1. a synthetic method for bisulfate clopidogrel midbody derivant, is characterized in that, its step is as follows:

1) 2-bromothiophene preparation: add hydrobromic acid aqueous solution, thiophene in reaction vessel, control 4～6 ℃ of temperature, slowly drip hydrogen peroxide, finish and continue insulation 1～3 hour, stratification; Organic layer underpressure distillation obtains 2-bromothiophene; The mass ratio of described Hydrogen bromide, thiophene, hydrogen peroxide is 475: 200: 325.

2) 2-thiophene ethanol preparation: add MAGNESIUM METAL, toluene and tetrahydrofuran (THF) mixing solutions in reaction vessel, disposablely add a little 2-bromothiophene initiation reaction, reaction slowly drips 2-bromothiophene after causing, control 25～40 ℃ of temperature, finish and continue insulation 1 hour, in reaction vessel, pass into oxyethane, control 5～20 ℃ of temperature, finish, continue insulation 3～24 hours, with 15% aqueous sulfuric acid, stir at low temperatures and extract the reaction of going out, stratification; Organic layer underpressure distillation obtains 2-thiophene ethanol; The mass ratio of described magnesium, toluene, tetrahydrofuran (THF) and 2-bromothiophene is 30: 200～250: 80～100: 160～200.

2. the synthetic method of bisulfate clopidogrel midbody derivant according to claim 1, is characterized in that: the mass ratio of described magnesium, toluene, tetrahydrofuran (THF) and 2-bromothiophene is preferably 30: 200: 80: 160.