阅读说明：本技术 一种阿考替胺盐酸盐杂质的制备方法 (Preparation method of acotiamide hydrochloride impurity ) 是由 杨卫民 孙玉琴 于 2020-05-27 设计创作，主要内容包括：本发明公开了一种阿考替胺盐酸盐杂质的制备方法,将原料2,4,5-三甲氧基苯甲酸经酰氯化制得2,4,5-三甲氧基苯甲酰氯,再与2-氨基-4-乙氧基羰基-1,3-噻唑经酰胺化反应制得2-氨基-4-乙氧基羰基-1,3-噻唑(中间体1)；中间体1经氢氧化钠水解得2-[N-(2,4,5-三甲氧基苯甲酰基)氨基]-4-羧基-1,3-噻唑(中间体2)；中间体2先进行酰氯化反应得到酰氯基,然后再与N,N-二异丙基乙二胺酰胺化反应得到N-[2-(双异丙基氨基)乙基]-2-[(2,4,5-三甲氧基苯甲酰)氨基]-4-噻唑甲酰胺(阿考替胺),阿考替胺经成盐反应得盐酸阿考替胺。本发明采用上述一种阿考替胺盐酸盐杂质的制备方法,反应条件温和、操作简单、成本低、收率高、适合工业化生产。(The invention discloses a preparation method of acotiamide hydrochloride impurities, which comprises the steps of carrying out acyl chlorination on 2,4, 5-trimethoxybenzoic acid serving as a raw material to prepare 2,4, 5-trimethoxybenzoyl chloride, and carrying out amidation reaction on the 2,4, 5-trimethoxybenzoyl chloride and 2-amino-4-ethoxycarbonyl-1, 3-thiazole to prepare 2-amino-4-ethoxycarbonyl-1, 3-thiazole (an intermediate 1); the intermediate 1 is hydrolyzed by sodium hydroxide to obtain 2- [ N- (2,4, 5-trimethoxybenzoyl) amino ] -4-carboxyl-1, 3-thiazole (intermediate 2); and (3) carrying out acyl chlorination reaction on the intermediate 2 to obtain acyl chloride, carrying out amidation reaction on the acyl chloride and N, N-diisopropyl ethylenediamine to obtain N- [2- (di-isopropylamino) ethyl ] -2- [ (2,4, 5-trimethoxybenzoyl) amino ] -4-thiazole formamide (acotiamide), and carrying out salt forming reaction on the acotiamide to obtain the acotiamide hydrochloride. The preparation method of the acotiamide hydrochloride impurity is mild in reaction condition, simple to operate, low in cost, high in yield and suitable for industrial production.)

1. A preparation method of acotiamide hydrochloride impurity is characterized by comprising the following steps:

(1) performing acyl chlorination on 2,4, 5-trimethoxybenzoic acid serving as a raw material to prepare 2,4, 5-trimethoxybenzoyl chloride, and performing amidation reaction on the 2-amino-4-ethoxycarbonyl-1, 3-thiazole to prepare 2-amino-4-ethoxycarbonyl-1, 3-thiazole (an intermediate 1);

(2) the intermediate 1 is hydrolyzed by sodium hydroxide to obtain 2- [ N- (2,4, 5-trimethoxybenzoyl) amino ] -4-carboxyl-1, 3-thiazole (intermediate 2);

(3) the intermediate 2 is firstly subjected to acyl chlorination reaction to obtain acyl chloride, and then subjected to amidation reaction with N, N-diisopropylethylenediamine to obtain N- [2- (di-isopropylamino) ethyl ] -2- [ (2,4, 5-trimethoxybenzoyl) amino ] -4-thiazolecarboxamide (acotiamide), and the acotiamide is subjected to salt forming reaction to obtain acotiamide hydrochloride;

the reaction route is as follows:

2. a process for the preparation of acotiamide hydrochloride impurity according to claim 1, characterized in that: the chlorination reagent of the acyl chlorination reaction in the step (1) is thionyl chloride, the catalyst is N, N-dimethylformamide, the solvent of the acyl chlorination reaction is anhydrous toluene, the reaction temperature is 80 ℃, the reaction is carried out for 1.5 hours under the condition of stirring, and then the temperature is reduced to 40-50 ℃ and the solvent is evaporated out under reduced pressure.

3. A process for the preparation of acotiamide hydrochloride impurity according to claim 2, characterized in that: carrying out amidation reaction in a 1, 2-dichloroethane solvent in the step (1), heating the amidation reaction under stirring, carrying out reflux reaction at the reaction temperature for 6 hours, carrying out stirring crystallization after the reaction is finished, wherein the crystallization temperature is 15-25 ℃, washing and drying the crystals by using 1, 2-dichloroethane, washing the obtained dried solids by using deionized water under an alkaline condition, and then carrying out vacuum drying.

4. A process for the preparation of acotiamide hydrochloride impurity according to claim 1, characterized in that: and (2) carrying out the reaction in a methanol solvent, dropwise adding sodium hydroxide when the temperature is controlled to be 0-5 ℃, heating to room temperature after dropwise adding, reacting for 4-5 hours, dropwise adding hydrochloric acid when the reaction temperature is-10 to-5 ℃, adjusting the pH to be about 4 when the temperature is controlled to be 0-5 ℃, stirring for crystallization, washing the obtained solid with water and ethanol, and drying under reduced pressure for more than 12 hours at the temperature of 35-45 ℃.

5. A process for the preparation of acotiamide hydrochloride impurity according to claim 1, characterized in that: and (3) in the step (3), the acyl chlorinating agent for acyl chlorination is thionyl chloride, the acylation reaction is carried out in an organic solvent dichloroethane solution, the reaction temperature is reflux reaction, after the reaction is finished, dichloroethane is evaporated to dryness under reduced pressure, and then acetonitrile is used for pressurizing and drying.

6. A process according to claim 5 for the preparation of acotiamide hydrochloride impurity characterized in that: and (3) carrying out amidation reaction in an acetonitrile solvent, dropwise adding N, N-diisopropylethylenediamine at the temperature of 0 ℃, washing a reaction product by using dichloromethane and saturated salt solution, washing an organic phase after liquid separation by using anhydrous sodium sulfate, wherein the reaction temperature is room temperature, the amidation reaction time is 5-6 hours.

7. The process according to claim 6 for the preparation of acotiamide hydrochloride impurity, characterized in that: and (3) dissolving the obtained acotiamide into acetonitrile, dropwise adding hydrochloric acid for reaction, controlling the reaction temperature to be 10-20 ℃, dropwise adding hydrochloric acid until the pH value is 1-2 to finish dropwise adding, reacting for 4-5 hours, crystallizing by using isopropyl ether, and drying under reduced pressure for 12 hours at the temperature of 40-50 ℃.

Technical Field

The invention relates to the technical field of compound preparation, in particular to a preparation method of acotiamide hydrochloride impurity.

Background

Acotiamide hydrochloride, chemical name: n- [2- (diisopropylamino) ethyl ] -2- [ (2-hydroxy-4, 5-dimethoxybenzoyl) amino ] -1, 3-thiazole-4-carboxamide hydrochloride. The structural formula is as follows:

acotiamide is the first approved therapeutic agent for functional dyspepsia in the world, and dyspepsia symptoms are common and significantly reduce the quality of life of patients, wherein most patients have Functional Dyspepsia (FD). Recent data show that the dyspepsia symptoms of the general population in western countries are close to 40%, and the quality of life is remarkably reduced. A small part of people are caused by gastric ulcer and can be treated by radically treating helicobacter pylori, about 20 percent of symptomatic people belong to gastroesophageal reflux diseases and can be effectively treated by a proton pump inhibitor, but most of dyspepsia people belong to FD, and the treatment of FD is still challenging at present. The acotiamide hydrochloride oral tablet mainly acts through a mechanism of inhibiting acetylcholinesterase in the digestive tract, and can promote gastric motility, improve gastric accommodation disorder and enhance gastric fundus dilatation. Originally developed by Zeria new drug industry post corporation of japan, and later introduced by astella pharmaceuticals together with Zeria pharmaceuticals in japan.

The current preparation method of acotiamide hydrochloride and similar methods can be summarized as the following routes:

scheme 1,2, 4, 5-trimethoxybenzoic acid is used as a raw material to react with Lewis acid ester-based or amide-based solvents to obtain 2-hydroxy-4, 5-dimethoxybenzoic acid. Then toluene is used as a solvent, concentrated sulfuric acid is used as a catalyst, and reflux reaction is carried out to obtain an intermediate 2-hydroxy-4, 5-dimethoxyphenyl benzoate. And then the intermediate and 2-amino 4 ethoxycarbonyl-1, 3-thiazole are heated to react in the presence of triphenyl borate by using toluene as a solvent to generate 2- [ N- (4, 5-dimethoxy-2-hydroxybenzoyl) amino ]4 (ethoxycarbonyl) -1, 3-thiazole, and finally the intermediate and N, N diisopropyl ethylenediamine are heated in toluene to generate aminolysis of the ester to generate 2- [ N- (4, 5-dimethoxy-2-hydroxybenzoyl) amino ] -4- [ (2-diisopropyl aminoethyl) aminocarbonyl ] -1, 3-thiazole, and the target compound is obtained by hydrochloride formation operation. The method is troublesome to operate, triphenyl borate needs to be added as a reaction auxiliary agent, and the reagent is expensive and not beneficial to industrial production.

Scheme 2, 2-hydroxy-4, 5-dimethoxybenzoic acid is used as a raw material to react with phosgene, diphosgene or triphosgene in a non-polar solvent to generate a cyclic anhydride intermediate. The intermediate can directly react with 2-amino 4-ethoxycarbonyl-1, 3-thiazole without separation to obtain 2- [ N- (4, 5-dimethoxy-2-hydroxybenzoyl) amino ]4 (ethoxycarbonyl) -1, 3-thiazole. Then reacting with N, N-diisopropyl ethylenediamine in 1, 4-dioxane, and reacting with HCI to form hydrochloride to obtain the target product acotiamide hydrochloride. The phosgene and diphosgene adopted in the step 1 of the method are extremely toxic, so that the method has high danger in industrial use, and the low temperature control is strict during reaction, thereby being not beneficial to industrial production.

Disclosure of Invention

The invention aims to provide a preparation method of acotiamide hydrochloride impurities, which has the advantages of mild reaction conditions, simple operation, low cost, high yield and suitability for industrial production.

In order to achieve the aim, the invention provides a preparation method of acotiamide hydrochloride impurity, which comprises the following steps:

(1) performing acyl chlorination on 2,4, 5-trimethoxybenzoic acid serving as a raw material to prepare 2,4, 5-trimethoxybenzoyl chloride, and performing amidation reaction on the 2-amino-4-ethoxycarbonyl-1, 3-thiazole to prepare 2-amino-4-ethoxycarbonyl-1, 3-thiazole (an intermediate 1);

(2) the intermediate 1 is hydrolyzed by sodium hydroxide to obtain 2- [ N- (2,4, 5-trimethoxybenzoyl) amino ] -4-carboxyl-1, 3-thiazole (intermediate 2);

(3) the intermediate 2 is firstly subjected to acyl chlorination reaction to obtain acyl chloride, and then subjected to amidation reaction with N, N-diisopropylethylenediamine to obtain N- [2- (di-isopropylamino) ethyl ] -2- [ (2,4, 5-trimethoxybenzoyl) amino ] -4-thiazolecarboxamide (acotiamide), and the acotiamide is subjected to salt forming reaction to obtain acotiamide hydrochloride;

the reaction route is as follows:

preferably, the chlorination reagent of the acyl chlorination reaction in the step (1) is thionyl chloride, the catalyst is N, N-dimethylformamide, the solvent is anhydrous toluene, the reaction temperature is 80 ℃, the reaction is carried out for 1.5 hours under the condition of stirring, and then the temperature is reduced to 40-50 ℃ to evaporate the solvent under reduced pressure; the amidation reaction is carried out in a 1, 2-dichloroethane solvent, the temperature of the amidation reaction is increased under the stirring condition, the reflux reaction is carried out at the amidation reaction temperature, the reaction time is 6 hours, the reaction is completed, the reaction is stirred and crystallized, the crystallization temperature is 15-25 ℃, crystals are washed by the 1, 2-dichloroethane and then dried, and the obtained dried solid is washed by deionized water under the alkaline condition and then dried in vacuum.

Preferably, the reaction in the step (2) is carried out in a methanol solvent, sodium hydroxide is dropwise added when the temperature is controlled to be 0-5 ℃, the temperature is raised to room temperature after the dropwise addition, the reaction time is 4-5 hours, hydrochloric acid is dropwise added when the reaction temperature is-10-5 ℃, the pH is adjusted to be about 4 when the temperature is controlled to be 0-5 ℃, the mixture is stirred and crystallized, the obtained solid is washed by water and ethanol, and the reduced pressure drying is carried out for more than 12 hours at the temperature of 35-45 ℃.

Preferably, the acyl chlorination agent of the acyl chlorination reaction in the step (3) is thionyl chloride, the acylation reaction is carried out in an organic solvent dichloroethane solution, the temperature of the acyl chlorination reaction is reflux reaction, after the reaction is finished, dichloroethane is evaporated to dryness under reduced pressure, and then acetonitrile is used for pressurizing and drying; carrying out amidation reaction in an acetonitrile solvent, dropwise adding N, N-diisopropylethylenediamine at the temperature of 0 ℃, wherein the reaction temperature is room temperature, the amidation reaction time is 5-6 hours, washing a reaction product by using dichloromethane and saturated salt water, and drying an organic phase after liquid separation by using anhydrous sodium sulfate; and the salifying reaction is to dissolve the obtained acotiamide into acetonitrile, dropwise add hydrochloric acid for reaction, control the reaction temperature to be 10-20 ℃, dropwise add hydrochloric acid until the pH value is 1-2, so that the dropwise adding is completed, the reaction time is 4-5 hours, crystallize by using isopropyl ether, and dry under reduced pressure at the temperature of 40-50 ℃ for 12 hours.

Therefore, the preparation method of the acotiamide hydrochloride impurity has the advantages of mild reaction conditions, simplicity in operation, low cost, high yield and suitability for industrial production.

Detailed Description

The present invention will be further described with reference to the following examples. The various chemicals and reagents used in the examples were all commercially available unless otherwise specified.

(1) Synthesis of 2-amino-4-ethoxycarbonyl-1, 3-thiazole (intermediate 1)

In a reaction flask, 600g of 2,4, 5-trimethoxybenzoic acid was added to 3L of anhydrous toluene, and 250mL of thionyl chloride and 1.2mL of N, N-dimethylformamide were added at room temperature, and the reaction was stirred at 80 ℃ for 1.5 hours. And then cooling to 40-50 ℃, decompressing and evaporating the solvent, and slowly raising the vacuum degree in the initial stage to prevent material flushing. And then distilling twice with anhydrous toluene, wherein the dosage is 580mL each time, and redundant thionyl chloride, hydrogen chloride and sulfur dioxide are brought out in the distillation process.

To the resulting product was added 5.4L of 1, 2-dichloroethane, 448g of 2-amino-4-ethoxycarbonyl-1, 3-thiazole, stirring was started and the reaction was refluxed for 6 hours. And after the reaction is finished, cooling to 15-25 ℃, stirring for crystallization for 2-3 hours, filtering, washing with 1, 2-dichloroethane twice, wherein the dosage is 580mL each time, and drying the obtained solid at room temperature. And dissolving the dried solid into 9.6L of deionized water and 2.4L of ice-water mixed solution, dropwise adding a sodium hydroxide solution at the temperature of 0-8 ℃, and adjusting the pH to 7.5. Then stirring and crystallizing for 4-5 hours at 15-25 ℃, filtering and washing twice by using 2.2L deionized water. And drying the obtained solid for 6-8 hours under the conditions of vacuum (-0.1MPa) and temperature of 40-50 ℃ to obtain 910g of the solid, namely the 2-amino-4-ethoxycarbonyl-1, 3-thiazole (the intermediate 1), with the yield of 90%.

(2) Synthesis of 2- [ N- (2,4, 5-trimethoxybenzoyl) amino ] -4-carboxy-1, 3-thiazole (intermediate 2)

And (3) adding 50g of the intermediate 1 and 100mL of methanol into a reaction bottle, dropwise adding a sodium hydroxide solution when the temperature is controlled to be 0-5 ℃, and heating to room temperature for reaction for 4-5 hours after dropwise adding. When the HPLC monitors that the raw material residue is less than 0.3 percent, the temperature is reduced to-10 to-5 ℃, and hydrochloric acid which is cooled in advance is dripped. And then controlling the temperature to be 0-5 ℃, adjusting the pH to be about 4, and stirring to separate out a solid. And (3) performing suction filtration after 2-3 hours of crystallization, washing a filter cake by using 5L of water and 2L of ethanol, and drying under reduced pressure at the temperature of 35-45 ℃ for more than 12 hours to obtain about 40g of a product, namely 2- [ N- (2,4, 5-trimethoxybenzoyl) amino ] -4-carboxyl-1, 3-thiazole.

(3) Synthesis of acotiamide hydrochloride

Under nitrogen atmosphere, 20g of intermediate 2, 8.44g of thionyl chloride and 200mL of dichloroethane are added into a three-port reaction flask, the mixture is stirred and heated to a weak reflux state, after the reaction is finished, the dichloroethane is evaporated by decompression, 50mL of acetonitrile is added respectively and is dried for 2 times under pressure, and the thionyl chloride is removed completely as much as possible.

Then adding 100mL of acetonitrile, cooling to 0 ℃, dropwise adding 9.38g of N, N-diisopropyl ethylenediamine, heating to room temperature after the dropwise adding is finished, and reacting for 5-6 hours until the reaction is finished. 100mL of methylene chloride was added with stirring, and the mixture was washed twice with 3L of saturated brine, separated, and the organic phase was dried over 10g of anhydrous sodium sulfate for 12 hours. And (3) carrying out suction filtration, carrying out reduced pressure concentration on the filtrate to dryness, adding 50mL of acetonitrile into the obtained product, stirring and dissolving, controlling the temperature to be 10-20 ℃, dropwise adding hydrochloric acid to adjust the pH to be 1-2, continuing stirring for 4-5 hours after dropwise adding, adding 100mL of isopropyl ether to crystallize, and drying under reduced pressure at the temperature of 40-50 ℃ for more than 12 hours to obtain about 18g of light yellow powder solid, namely acotiamide hydrochloride.

Therefore, the preparation method of the acotiamide hydrochloride impurity has the characteristics of mild reaction conditions, simplicity in operation, low cost, good product stability, high purity, high yield, suitability for industrial production and the like.

Finally, it should be noted that: the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting the same, and although the present invention is described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that: modifications and equivalents may be made to the invention without departing from the spirit and scope of the invention.