阅读说明：本技术 一种盐酸阿罗洛尔杂质及其制备方法与应用 (Arotinolol hydrochloride impurity and preparation method and application thereof ) 是由 冯谦 于 2021-07-08 设计创作，主要内容包括：本发明公开了一种盐酸阿罗洛尔杂质及其制备方法与应用,属于化学制药技术领域。盐酸阿罗洛尔杂质的化学名称为5-[2-[[[3-(1,1-二甲基乙基)氨基]-2-丙烯基]硫基]-4-噻唑基]-2-噻吩甲酰胺,结构式如式1；制备方法如下：以叔丁基乙醇胺为原料,经氯代反应、游离反应、磷叶立德反应,获得中间体3；以5-(2-巯基-4-噻吩基)噻吩-2-甲酰胺为原料,经甲酰化反应,获得中间体4；中间体3与中间体4经Witting反应,获得盐酸阿罗洛尔杂质。通过合成盐酸阿罗洛尔杂质,提升了盐酸阿罗洛尔成品检测分析对杂质的准确定位性和定性,本发明提供的制备方法,原料便宜易得,操作简单、所得产品纯度＞95%。式1。(The invention discloses an arotinolol hydrochloride impurity, a preparation method and application thereof, and belongs to the technical field of chemical pharmacy. The chemical name of the arotinolol hydrochloride impurity is 5- [2- [ [ [3- (1, 1-dimethylethyl) amino group]-2-propenyl group]Sulfur based radicals]-4-thiazolyl]-2-thiophenecarboxamide, formula 1; the preparation method comprises the following steps: taking tert-butyl ethanolamine as a raw material, and carrying out chlorination reaction, dissociation reaction and phosphorus ylide reaction to obtain an intermediate 3; using 5- (2-mercapto-4-thienyl) thiophene-2-formamide as a raw material, and performing formylation reaction to obtain an intermediate 4; and carrying out Witting reaction on the intermediate 3 and the intermediate 4 to obtain the arotinolol hydrochloride impurity. The method improves the accurate positioning and qualitative of the arotinolol hydrochloride finished product on impurities by synthesizing the arotinolol hydrochloride impurities, and the preparation method provided by the invention has the advantages of cheap and easily obtained raw materials, simple operation and high purity of the obtained product of more than 95%. Formula 1。)

1. The arotinolol hydrochloride impurity is characterized in that the chemical name of the arotinolol hydrochloride impurity is 5- [2- [ [ [3- (1, 1-dimethylethyl) amino ] -2-propenyl ] thio ] -4-thiazolyl ] -2-thiophenecarboxamide;

the structural formula is as follows:

。

2. a process for the preparation of the arotinolol hydrochloride impurity of claim 1 characterized in that it is prepared as follows: taking tert-butyl ethanolamine as a raw material, and carrying out chlorination reaction, dissociation reaction and phosphorus ylide reaction to obtain an intermediate 3; using 5- (2-mercapto-4-thienyl) thiophene-2-formamide as a raw material, and performing formylation reaction to obtain an intermediate 4; and carrying out Witting reaction on the intermediate 3 and the intermediate 4 to obtain the arotinolol hydrochloride impurity.

3. The method for preparing the arotinolol hydrochloride impurity according to claim 2, characterized in that the chlorination reaction is specifically operated as follows: dissolving tert-butyl ethanolamine in an organic solvent, adding thionyl chloride, and carrying out heat preservation reaction to obtain an intermediate 1;

wherein the molar ratio of the tert-butyl ethanolamine to the thionyl chloride is as follows: 1: 1.0-2.0;

the reaction temperature is 0-77 ℃.

4. The method for preparing the arotinolol hydrochloride impurity according to claim 3, characterized in that the specific operation of the free reaction is as follows: adding the intermediate 1 into an aqueous solution of an alkali compound, dissociating, extracting and concentrating to obtain an intermediate 2;

wherein the molar ratio of the intermediate 1 to the alkali compound is as follows: 1: 1.0-1.5.

5. The method for preparing the arotinolol hydrochloride impurity according to claim 4, characterized in that the specific operation of the phosphorus ylide reaction is as follows: dissolving the intermediate 2 in an organic solvent, adding triphenylphosphine, and carrying out heat preservation reaction to obtain an intermediate 3;

wherein the molar ratio of the intermediate 2 to the triphenylphosphine is as follows: 1: 1.5-2.5;

the reaction temperature is 77-153 ℃.

6. The method for preparing arotinolol hydrochloride impurity according to claim 2, wherein in the formylation reaction, the formylation system is formic acid/acetic anhydride system, and the molar ratio of acetic anhydride to formic acid is: 1: 1.0-2.0.

7. The method for preparing arotinolol hydrochloride impurity according to claim 6, wherein the mole ratio of 5- (2-mercapto-4-thienyl) thiophene-2-carboxamide to acetic anhydride in the formylation reaction is: 1: 5.0-10;

the reaction temperature is 56-110 ℃.

8. The method for preparing the arotinolol hydrochloride impurity according to claim 2, wherein in the Witting reaction, the molar ratio of the intermediate 4 to the intermediate 3 is as follows: 1: 1.5-2.0;

the reaction temperature is 60-153 ℃.

9. The method for preparing the arotinolol hydrochloride impurity according to claim 2,

after the Witting reaction is finished, purifying by adopting a column chromatography, wherein an eluent is as follows: ethyl acetate: triethylamine =50: 1.

10. Use of the arotinolol hydrochloride impurity of claim 1 as an impurity control in an arotinolol hydrochloride end product assay.

Technical Field

The invention belongs to the technical field of chemical pharmacy, and particularly relates to an arotinolol hydrochloride impurity and a preparation method and application thereof.

Background

Arotinolol Hydrochloride (Arotinolol Hydrochloride) was first marketed in japan in 1985, and was developed by japan society of medicine and society of japan. The chemical name of the compound is 5- {2- [ (2RS) -3- (1, 1-dimethylethyl) amino-2- (hydroxypropyl) thio-4 thiazolyl]Thiophene-2-carboxamide hydrochloride, a selective beta₁Adrenoceptor antagonists, mainly used clinically for the treatment of mild to moderate essential hypertension, angina pectoris, rapid cardiac arrhythmiaFrequent primary tremor, etc. Selective inhibition of beta-adrenoceptor, simultaneously with alpha₁The adrenergic receptor has slight blocking effect, so as to reduce the tension of sympathetic nerves, and the effect of reducing blood pressure is more ideal.

Arotinolol hydrochloride can generate degradation impurities in the preparation and storage processes, and the impurities can be remained in the arotinolol hydrochloride final product to influence the quality of the product. However, the related art does not have a public report of the impurity, nor a reference substance of the impurity; therefore, the content of the impurity in the final product cannot be accurately controlled, and potential safety hazards are brought to the production of the arotinolol hydrochloride.

Disclosure of Invention

The invention aims to provide an arotinolol hydrochloride impurity and a preparation method and application thereof, wherein the synthesized arotinolol hydrochloride impurity can be used as an impurity reference substance in arotinolol hydrochloride finished product detection analysis, so that the accurate positioning and qualitative performance of the arotinolol hydrochloride finished product detection analysis on the impurity are improved, the control on the impurity is favorably enhanced, and the quality of the arotinolol hydrochloride finished product is improved.

In a first aspect, the present invention provides an arotinolol hydrochloride impurity having a chemical name of 5- [2- [ [ [3- (1, 1-dimethylethyl) amino ] -2-propenyl ] thio ] -4-thiazolyl ] -2-thiophenecarboxamide.

By adopting the technical scheme, the chemical name and the chemical formula of the arotinolol hydrochloride impurity are determined, the impurity can be used as an impurity reference substance in the detection and analysis of the arotinolol hydrochloride finished product, and the quality of the arotinolol hydrochloride finished product is improved by measuring the content of the impurity in the arotinolol hydrochloride finished product.

In a second aspect, the invention provides a preparation method of arotinolol hydrochloride impurity, which comprises the following steps of taking tert-butyl ethanolamine as a raw material, and carrying out chlorination reaction, dissociation reaction and triphenylphosphine reaction to obtain an intermediate 3; using 5- (2-mercapto-4-thienyl) thiophene-2-formamide as a raw material, and performing formylation reaction to obtain an intermediate 4; the intermediate 3 and the intermediate 4 are reacted by a one-pot method to obtain the arotinolol hydrochloride impurity.

Preferably, the chlorination reaction is carried out in the following specific steps: dissolving tert-butyl ethanolamine in an organic solvent, adding thionyl chloride, and carrying out heat preservation reaction to obtain an intermediate 1; the molar ratio of the tert-butyl ethanolamine to the thionyl chloride is as follows: 1: 1.0-2.0, preferably 1: 1.37; the reaction temperature is 0-77 ℃, and preferably 55-60 ℃. Wherein, the organic solvent can be one of dichloromethane, chloroform, ethyl acetate and acetone, preferably chloroform. The progress of the reaction was monitored by TLC (DCM: MeOH ═ 10:1), and after completion of the reaction the work-up was: filtering, washing and drying the filter cake to obtain the product.

In one embodiment, the molar ratio of tert-butyl ethanolamine to thionyl chloride may also be 1: 1:5, 1:2.

in one embodiment, the reaction temperature may be 77 ℃ or 0 to 10 ℃.

The chemical reaction formula of the chlorination reaction is as follows:

preferably, the specific operation of the dissociation reaction is: adding the intermediate 1 into an aqueous solution of an alkali compound, dissociating, extracting and concentrating to obtain an intermediate 2; the molar ratio of the intermediate 1 to the alkali compound is as follows: 1: 1.0-1.5, preferably 1: 1.2; the alkali compound can be one of inorganic alkali compound and organic alkali compound, preferably sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine, and more preferably sodium carbonate.

In one embodiment, the molar ratio of intermediate 1 to base compound may also be 1:1. 1:5.

the chemical reaction formula of the dissociation reaction is as follows:

preferably, the specific operation of the phosphorus ylide reaction is as follows: dissolving the intermediate 2 in an organic solvent, adding triphenylphosphine, and carrying out heat preservation reaction to obtain an intermediate 3; the molar ratio of the intermediate 2 to the triphenylphosphine was: 1: 1.5-2.5, preferably 1: 1.5; the reaction temperature is 77-153 ℃, and preferably 10 ℃; the organic solvent can be one of dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, methanol, ethanol, toluene and DMF, preferably toluene. The treatment after the reaction is as follows: cooling, crystallizing, filtering, washing and drying a filter cake to obtain the product.

In one embodiment, the molar ratio of intermediate 2 to triphenylphosphine may also be 1:2, 1: 2.5.

In one embodiment, the reaction temperature may also be 77 ℃ 153 ℃.

The chemical reaction formula of the phosphorus ylide reaction is as follows:

preferably, the formylation reaction is performed in the following specific steps: reacting 5- (2-mercapto-4-thienyl) thiophene-2-formamide serving as a raw material with a formylation reagent (formic acid/acetic anhydride) to obtain an intermediate 4; the molar ratio of the 5- (2-mercapto-4-thienyl) thiophene-2-formamide to the acetic anhydride is as follows: 1: 5.0-10, preferably 1: 5.5; the molar ratio of acetic anhydride to formic acid is: 1: 1.0-2.0, preferably 1: 1.26; the reaction temperature is 56-110 ℃, and preferably 60-65 ℃; the organic solvent can be one of dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, toluene and DMF, preferably DMF. The treatment after the reaction is as follows: crystallizing, filtering, washing and drying a filter cake to obtain the product.

In one embodiment, the molar ratio of 5- (2-mercapto-4-thienyl) thiophene-2-carboxamide to acetic anhydride may also be 1:5.9, 1:8, 1: 10.

In one embodiment, the molar ratio of acetic anhydride to formic acid may also be 1:1.5, 1:2.

In one embodiment, the reaction temperature may also be 56 ℃, 110 ℃.

The chemical reaction of the formylation reaction is as follows:

preferably, the Witting reaction: reacting the intermediate 3 with the intermediate 4 by a one-pot method under an alkaline condition to obtain target impurities; the molar ratio of the intermediate 4 to the intermediate 3 is as follows: 1: 1.5-2.0, preferably 1: 1.53; the reaction temperature is 60-153 ℃, and preferably 65 ℃; the alkali compound can be one of inorganic alkali compound and organic alkali compound, and is preferably sodium hydroxide, potassium hydroxide, sodium carbonate and triethylamine, preferably sodium hydroxide; the organic solvent can be one of methanol, absolute ethanol and DMF, and is preferably methanol.

In one embodiment, the molar ratio of intermediate 4 to intermediate 3 may also be 1:1.81, 1:2.

In one embodiment, the reaction temperature may also be 65 ℃ 153 ℃.

The chemical reaction formula of Witting reaction is as follows:

by adopting the technical scheme, the preparation route of the arotinolol hydrochloride impurity is as follows:

reacting tert-butyl ethanolamine with thionyl chloride to convert hydroxyl in the tert-butyl ethanolamine into chlorine to prepare an intermediate 1; dissociating, extracting and concentrating the intermediate 1 to obtain an intermediate 2; the intermediate 2 reacts with triphenylphosphine to prepare an intermediate 3, and the intermediate 3 can be used as a phosphorus ylide reagent. 5- (2-mercapto-4-thienyl) thiophene-2-formamide is subjected to formylation reaction, and formyl is introduced to prepare a reactant intermediate 4 required by Witting reaction. And then carrying out Witting reaction on the intermediate 4 and the intermediate 3, converting carbonyl in the intermediate 4 into olefin, and preparing 5- [2- [ [ [3- (1, 1-dimethylethyl) amino ] -2-propenyl ] thio ] -4-thiazolyl ] -2-thiophenecarboxamide, wherein the preparation method is simple to operate, the reaction condition is mild, and the purity of the arotinolol hydrochloride impurity obtained by preparation is more than 95%.

Preferably, after the Witting reaction is finished, the purification is carried out by adopting a column chromatography, and an eluent is as follows: ethyl acetate: triethylamine 50: 1.

By adopting the technical scheme, the treatment after the Witting reaction is finished is as follows: extracting, separating liquid, drying the organic phase, filtering, concentrating the filtrate under reduced pressure, and purifying to obtain the final product. The eluent is: ethyl acetate: the ratio of triethylamine to triethylamine is 50:1,

in a third aspect, the invention provides an application of the arotinolol hydrochloride impurity as an impurity reference substance in the detection and analysis of an arotinolol hydrochloride finished product.

In conclusion, the invention has the following beneficial effects:

1. the invention discloses an arotinolol hydrochloride impurity (5- [2- [ [ [3- (1, 1-dimethylethyl) amino ] -2-propenyl ] thio ] -4-thiazolyl ] -2-thiophenecarboxamide), and discloses a chemical structural formula and a preparation method thereof for the first time.

2. The preparation method of the arotinolol hydrochloride impurity has the advantages of simple operation, cheap and easily obtained raw materials and high purity (more than 95 percent).

3. According to the process conditions of the invention, the prepared impurity reference substance meets the quality requirements of Chinese pharmacopoeia, namely the purity is more than 95 percent; the method can be applied to the quality control of the arotinolol hydrochloride bulk drug and the preparation, can also provide a reliable monitoring means for the process research, promotes the process optimization and determination process, and has good application prospect.

Drawings

FIG. 1 is an HPLC chromatogram of the arotinolol hydrochloride impurity prepared in example 1;

FIG. 2 shows the arotinolol hydrochloride impurity prepared in example 1¹HNMR atlas.

Detailed Description

The 5- [2- [ [ [3- (1, 1-dimethylethyl) amino ] -2-propenyl ] thio ] -4-thiazolyl ] -2-thiophenecarboxamide prepared by the present invention is supposed to be an impurity generated by degradation of arotinolol hydrochloride during the preparation and storage processes.

Source of raw materials

Raw materials	Source
		Tert-butyl ethanolamine	Beijing Bailingwei science and technology Co., Ltd., 98%
Thionyl chloride	Beijing chemical plant, 98%
		Triphenylphosphine	Beijing coupled technologies, Inc., 98%
5- (2-mercapto-4-thienyl) thiophene-2-carboxamide	98 percent of Jiangsu Huayu chemical industry Co., Ltd
		Acetic anhydride	Beijing chemical plant, 98%
Formic acid	Beijing chemical plant, 98%

The present invention will be described in further detail with reference to the following examples and the accompanying drawings.

Examples

Example 1

S1, chlorination: to a 1L reaction flask, 30.00g of t-butyl ethanolamine (0.256mol) and 300ml of chloroform were sequentially added. Adding 41.90g of thionyl chloride (0.352mol) into the system at 0-10 ℃, heating to 55-60 ℃, and carrying out heat preservation reaction. After the reaction, filtration was carried out, the filter cake was rinsed with 90ml of acetone and the filter cake was air-dried at 50 ℃ to give N- (2-chloroethyl) -2-methylpropan-2-amine hydrochloride (intermediate 1, off-white solid, 32.60 g). The yield thereof was found to be 74.0%.

S2, free reaction: to a 500ml reaction flask, 16.26g of sodium carbonate (0.153mol) was dissolved in 200ml of purified water. 22.00g of intermediate 1(0.128mol) and 300ml of ethyl acetate were added to the above system, and the mixture was extracted and separated. The organic phase was dried over 20.00g of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40-45 ℃ to give N- (2-chloroethyl) -2-methylpropan-2-amine (intermediate 2, oil, 11.00 g). Yield: 63.43 percent.

S3, phosphorus ylide reaction: to a 250ml reaction flask, 11.00g of intermediate 2(0.081mol), 32.00g of triphenylphosphine (0.122mol), and 120ml of toluene were sequentially added. The temperature is raised to 110 ℃ and the mixture is refluxed and reacted for 10 hours. After the reaction is finished, cooling to 0-10 ℃, and stirring for crystallization; filtering; the filter cake was rinsed with 10ml of toluene and the filter cake was air-dried at 60 ℃ to give (N-ethyl-2-methylpropan-2-amino) triphenylphosphonium chloride (intermediate 3, off-white solid, 3.69 g). The yield thereof was found to be 11.37%.

S4, formylation: 10.85g of 5- (2-mercapto-4-thienyl) thiophene-2-formamide (0.0447mol), 27.00g of acetic anhydride (0.264mol), 15.38g of formic acid (0.334mol) and 120ml of DMF are sequentially added into a 250ml reaction bottle, the temperature is raised to 60-65 ℃, and the reaction is carried out under the condition of heat preservation. After the reaction, filtering, adding 120ml of purified water into the filtrate, and stirring for crystallization. Filtration, rinsing of the filter cake with 20ml of purified water and forced air drying of the filter cake at 60 ℃. S-4- (5-carbamoylthiophen-2-yl) thiazol-2-yl-thioformate (intermediate 4, off-white solid, 7.94g) was obtained. The yield thereof was found to be 65.62%.

S5, Witting reaction: to a 1L reaction flask, 10.00g of intermediate 4(0.037mol), 20.08g of intermediate 3(0.056mol), 7.40g of sodium hydroxide (0.185mol), and 200ml of methanol were sequentially added. The temperature is raised to 65 ℃ and the reflux is carried out, and the reaction is carried out for 15 hours. After the reaction is finished, cooling to 20-30 ℃. Concentrated at 30 ℃ under reduced pressure and the residue extracted with 300ml of dichloromethane and 100ml of purified water. Liquid separation; the organic phase was dried by adding 50.00g of anhydrous sodium sulfate. Filtration was carried out, the filtrate was concentrated under reduced pressure at 30 ℃ and the residue was purified by column chromatography (ethyl acetate: triethylamine ═ 50: 1) to give 5- [2- [ [ [3- (1, 1-dimethylethyl) amino ] -2-propenyl ] thio ] -4-thiazolyl ] -2-thiophenecarboxamide (target impurity, off-white solid, 4.00 g). The yield thereof was found to be 30.58%.

The purity was 98.26% by HPLC, and the HPLC profile is shown in FIG. 1.

¹H-NMR (400MHz, DMSO). delta: 7.970ppm (s, 2H) delta: 7.406-7.706ppm (s, 3H) delta: 3.273-3.307ppm (m, 2H) delta: 2.849-2.883ppm (m, 2H) delta: 1.897-1.988ppm (s, 1H). The hydrogen spectrum is shown in FIG. 2.

Example 2

S1, chlorination: to a 500mL reaction flask, 15.00g of t-butyl ethanolamine (0.128mol) and 200m of ethyl acetate were added in this order. Adding 22.84g of thionyl chloride (0.192mol) into the system at 0-10 ℃, heating to 77 ℃ for reflux, and carrying out heat preservation reaction. After the reaction, the mixture was concentrated under reduced pressure. Pulping the residue with 100ml acetone, and filtering; the filter cake was rinsed with 50ml acetone and the filter cake was air dried at 50 ℃ to give N- (2-chloroethyl) -2-methylpropan-2-amine hydrochloride (intermediate 1, off-white solid, 15.08 g). The yield thereof was found to be 68.46%.

S2, free reaction: to a 250ml reaction flask, 100ml of methylene chloride was added, and 10.00g of intermediate 1(0.0581mol) was added with stirring. Cooling to 0-10 ℃, dropwise adding 5.90g of triethylamine (0.0583mol), and preserving heat for 1 hour after dropwise adding. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 20 to 30 ℃ to give N- (2-chloroethyl) -2-methylpropan-2-amine (intermediate 2, oily substance, 4.38 g). Yield: 55.60 percent.

S3, phosphorus ylide reaction: to a 500ml reaction flask were added 13.50g of intermediate 2(0.10mol), 52.45g of triphenylphosphine (0.20mol), and 250ml of ethyl acetate in this order. The temperature was raised to 77 ℃ and the mixture was refluxed for 20 hours. After the reaction is finished, cooling to 0-10 ℃, and stirring for crystallization; filtering; the filter cake was rinsed with 10ml of ethyl acetate and the filter cake was air-dried at 60 ℃ to give (N-ethyl-2-methylpropan-2-amino) triphenylphosphonium chloride (intermediate 3, off-white solid, 3.17 g). The yield thereof was found to be 8.00%.

S4, formylation: to a 500ml reaction flask were added 24.20g of 5- (2-mercapto-4-thienyl) thiophene-2-carboxamide (0.10mol), 81.67g of acetic anhydride (0.80mol), 55.23g of formic acid (1.20mol), and 200ml of acetone in this order, and the mixture was refluxed at 56 ℃ and then reacted while maintaining the temperature. After the reaction, 200ml of purified water was added, and the mixture was stirred for crystallization. Filtration, rinsing of the filter cake with 50ml of purified water and forced air drying of the filter cake at 60 ℃ gave S-4- (5-carbamoylthiophen-2-yl) thiazol-2-yl-thioformate (intermediate 4, off-white solid, 16.27 g). The yield thereof was found to be 60.19%.

S5, Witting reaction: to a 1L reaction flask, 10.00g of intermediate 4(0.037mol), 26.50g of intermediate 3(0.067mol), 18.71g of triethylamine (0.185mol), and 200ml of DMF were sequentially added. The reaction was refluxed at 153 ℃ for 5 hours. After the reaction is finished, cooling to 20-30 ℃. Adding 400ml of dichloromethane and 100ml of purified water for extraction; liquid separation; the organic phase was dried by adding 50.00g of anhydrous sodium sulfate. Filtration was carried out, the filtrate was concentrated under reduced pressure at 30 ℃ and the residue was purified by column chromatography (ethyl acetate: triethylamine ═ 50: 1) to give 5- [2- [ [ [3- (1, 1-dimethylethyl) amino ] -2-propenyl ] thio ] -4-thiazolyl ] -2-thiophenecarboxamide (target impurity, off-white solid, 2.14 g). The yield thereof was found to be 18.50%.

Purity by HPLC was 96.20%.

Example 3

S1, chlorination: 10.00g of t-butyl ethanolamine (0.0853mol) and 120mL of methylene chloride were sequentially added to a 250mL reaction flask, and 20.30g of thionyl chloride (0.171mol) was added to the above system at 0 to 10 ℃ and the reaction was carried out while maintaining the temperature. After the reaction, the mixture was concentrated under reduced pressure. Pulping the residue with 30ml acetone, and filtering; the filter cake was rinsed with 10ml acetone and the filter cake was air dried at 60 ℃ to give N- (2-chloroethyl) -2-methylpropan-2-amine hydrochloride (intermediate 1, off-white solid, 8.88 g). The yield thereof was found to be 60.47%.

S2, free reaction: to a 500ml reaction flask, 6.00g (0.15mol) of sodium hydroxide was dissolved in 50ml of purified water. 17.20g of intermediate 1(0.10mol) and 220ml of ethyl acetate were added to the above system to extract liquid separation. The organic phase was dried by adding 20.00g of anhydrous sodium sulfate. Filtration and concentration of the filtrate at 40-45 ℃ under reduced pressure gave N- (2-chloroethyl) -2-methylpropan-2-amine (intermediate 2, oil, 7.90 g). Yield: 58.26 percent.

S3, phosphorus ylide reaction: to a 500ml reaction flask, 20.00g of intermediate 2(0.147mol), 96.68g of triphenylphosphine (0.368mol) and 200ml of DMF were added in this order. The reaction was carried out at 153 ℃ under reflux for 10 hours. After the reaction is finished, cooling to 0-10 ℃, and stirring for crystallization; filtering; the filter cake was rinsed with 50ml of ethyl acetate and the filter cake was air-dried at 60 ℃ to give (N-ethyl-2-methylpropan-2-amino) triphenylphosphonium chloride (intermediate 3, off-white solid, 2.64 g). The yield thereof was found to be 4.50%.

S4, formylation: to a 500ml reaction flask were added 24.20g of 5- (2-mercapto-4-thienyl) thiophene-2-carboxamide (0.10mol), 102.09g of acetic anhydride (1.0mol), 92.06g of formic acid (2.0mol), and 200ml of toluene in this order. Heating to 110 deg.c for reflux and maintaining the temperature for reaction. After the reaction is finished, decompressing to 60-65 ℃ and concentrating. 50ml of absolute ethanol and 150ml of water were added to the residue, and the mixture was stirred to crystallize. Filtration, rinsing of the filter cake with 50ml of purified water and forced air drying of the filter cake at 60 ℃. S-4- (5-carbamoylthiophen-2-yl) thiazol-2-yl-thioformate (intermediate 4, off-white solid, 14.20g) was obtained. The yield thereof was found to be 52.53%.

S5, Witting reaction: to a 1L reaction flask, 10.00g of intermediate 4(0.037mol), 29.44g of intermediate 3(0.074mol), 18.71g of triethylamine (0.18mol), and 200ml of DMF were sequentially added. Heating to 60-65 ℃ for reflux, and reacting for 15 hours. After the reaction is finished, cooling to 20-30 ℃. 400ml of methylene chloride and 100ml of purified water were added for extraction. Liquid separation; the organic phase was dried by adding 50.00g of anhydrous sodium sulfate. Filtration was carried out, the filtrate was concentrated under reduced pressure at 30 ℃ and the residue was purified by column chromatography (ethyl acetate: triethylamine ═ 50: 1) to give 5- [2- [ [ [3- (1, 1-dimethylethyl) amino ] -2-propenyl ] thio ] -4-thiazolyl ] -2-thiophenecarboxamide (target impurity, off-white solid, 3.10 g). The yield thereof was found to be 23.72%.

Purity by HPLC was 95.05%.

The present embodiment is only for explaining the present invention, and it is not limited to the present invention, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present invention.