阅读说明：本技术 一种苯并硫氮杂卓氧化物的制备方法及其制备的产品及其应用 (Preparation method of benzothiazepine oxide, product prepared by preparation method and application of product ) 是由 单玉庆 张辉 帅宝奎 于 2020-05-16 设计创作，主要内容包括：本发明公开了一种苯并硫氮杂卓氧化物的制备方法及其制备的产品及其应用,涉及化学合成的技术领域；一种苯并硫氮杂卓氧化物的制备方法,以2-氟-4-氯苯甲酸为初始原料,经叔丁氧羰基氨基乙硫醇制备、苯甲酸酯化、氟化物硫代、叔丁氧羰氨基酸解、胺酯闭环、羰基还原、胺基保护、苯并硫杂卓氧化和胺基脱保护等步骤,制得8-氯-2,3,4,5-四氢-1,4-苯并硫氮杂卓-1,1-二氧化物的苯并硫氮杂卓氧化物产品；苯并硫氮杂卓氧化物的制备方法具有便于引入氯元素的优点；苯并硫氮杂卓氧化物产品具有可以一定程度上扩大产品应用范围的优点,苯并硫氮杂卓氧化物作为中间体用于制备预防和治疗RSV药物的活性组分。(The invention discloses a preparation method of benzothiazepine oxide, a product prepared by the preparation method and application of the benzothiepine oxide, and relates to the technical field of chemical synthesis; a preparation method of benzothiazepine oxide takes 2-fluoro-4-chlorobenzoic acid as an initial raw material, and comprises the steps of tert-butoxycarbonylaminoethanethiol preparation, benzoic acid esterification, fluoride sulfo-hydrolysis, tert-butoxycarbonylamino acid hydrolysis, amine ester ring closure, carbonyl reduction, amino protection, benzothiazepine oxidation, amino deprotection and the like to prepare benzothiazepine oxide products of 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide; the preparation method of the benzothiazepine oxide has the advantage of convenient introduction of chlorine element; the benzothiazepine oxide product has the advantage of expanding the application range of the product to a certain extent, and the benzothiazepine oxide is used as an intermediate for preparing active components of medicaments for preventing and treating RSV.)

1. The preparation method of the benzothiazepine oxide is characterized in that the reaction is as follows:

which comprises the following steps:

preparation of S1 tert-butyloxycarbonylaminoethanethiol: under the action of organic alkali, aminoethanethiol hydrochloride reacts with di-tert-butyl dicarbonate to prepare 2-tert-butoxycarbonylaminoethanethiol;

s2 benzoic acid esterification: under the action of a dehydrating agent, carrying out esterification reaction on 2-fluoro-4-chlorobenzoic acid and methanol to prepare 4-chloro-2-fluorobenzoic acid methyl ester;

s3 fluorochemical thio: under the action of an alkaline reagent, carrying out a thio reaction on the 4-chloro-2-fluorobenzoic acid methyl ester prepared in the step S2 and the 2-tert-butoxycarbonylaminoethanethiol prepared in the step S1 to prepare 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoic acid methyl ester;

s4 acid hydrolysis of tert-butyloxycarbonylamino: carrying out acidolysis reaction on methyl 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoate under the action of an acid reagent to prepare methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate;

s5 amine ester ring closure: under the action of a non-nucleophilic strong base reagent, a primary amine group and an ester group on a methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate molecule undergo a ring-closure reaction to prepare 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone;

s6 carbonyl reduction: under the action of a reducing agent, ketone carbonyl on 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone molecules is subjected to reduction reaction to prepare 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine;

s7 amine protection: under the action of organic alkali, di-tert-butyl dicarbonate and 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine are subjected to ester exchange reaction to prepare tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate;

s8 oxidation of benzothiepin: under the action of an oxidant, tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate undergoes an oxidation reaction to prepare 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide;

deprotection of the S9 amine group: under the action of an acidic reagent, carrying out acidolysis reaction on 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide to prepare a benzothiazepine oxide product.

2. The method of claim 1, comprising the steps of:

preparation of S1 tert-butyloxycarbonylaminoethanethiol: under the action of organic base, aminoethanethiol hydrochloride and di-tert-butyl dicarbonate react for 14h to 18h at room temperature, and then 2-tert-butoxycarbonylaminoethanethiol is prepared after purification; the reaction materials are fed according to the following molar ratio: aminoethanethiol hydrochloride: di-tert-butyl dicarbonate: organic base ═ 1: 1.05-1.15: 1.8-2.2;

s2 benzoic acid esterification: reacting 2-fluoro-4-chlorobenzoic acid with methanol at 58-62 ℃ for 100-150 min under the action of a dehydrating agent, and purifying to obtain 4-chloro-2-fluorobenzoic acid methyl ester; the reaction materials are fed according to the following molar ratio: 2-fluoro-4-chlorobenzoic acid: methanol: 1, dehydrating agent: 45-50: 2.8-3.2;

s3 fluorochemical thio: under the action of an alkaline reagent, 4-chloro-2-fluorobenzoic acid methyl ester prepared in the step S2 and 2-tert-butoxycarbonylaminoethanethiol prepared in the step S1 react at the temperature of 58-62 ℃ for 14-18 h, and the reaction product is purified to obtain 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoic acid methyl ester, wherein the reaction materials are fed according to the following molar ratio of 4-chloro-2-fluorobenzoic acid methyl ester to 2-tert-butoxycarbonylaminoethanethiol: 1: 1.25-1.35: 2.8-3.2;

s4 acid hydrolysis of tert-butyloxycarbonylamino: under the action of an acid reagent, 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoic acid methyl ester reacts at room temperature for 150min-200min, and is purified to prepare 2- ((2-aminoethyl) thio) -4-chlorobenzoic acid methyl ester, wherein the reaction materials are fed according to the following molar ratio of 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoic acid methyl ester to the acid reagent of 1: 2.8-3.2;

s5 amine ester ring closure: under the action of a non-nucleophilic strong base reagent, reacting a primary amine group and an ester group on a methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate molecule at 68-72 ℃ for 280-320 min, and purifying to obtain 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone; the reaction materials are fed according to the following molar ratio: methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate: non-nucleophilic strong base reagent ═ 1: 1.8-2.2;

s6 carbonyl reduction: under the action of a reducing agent, 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone reacts at room temperature for 14H-18H, and is purified to prepare 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine; the reaction materials are fed according to the following molar ratio: 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepin-5 (2H) -one: reducing agent 1: 1.25-1.35;

s7 amine protection: under the action of organic alkali, di-tert-butyl dicarbonate and 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine react at room temperature for 100min to 150min, and the tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate is prepared after purification; the reaction materials are fed according to the following molar ratio: 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine: di-tert-butyl dicarbonate: organic base ═ 1: 1.8-2.2: 1.8-2.2;

s8 oxidation of benzothiepin: under the action of an oxidant, tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate is subjected to oxidation reaction at room temperature for 150min to 200min, and then purified to obtain 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide; the reaction materials are fed according to the following molar ratio: tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate: oxidant 1: 4.8-5.2;

deprotection of the S9 amine group: under the action of an acidic reagent, 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide reacts at room temperature for 220min to 280min, and is purified to prepare benzothiazepine oxide products; the reaction materials are fed according to the following molar ratio: 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide: acid reagent 1: 2.8-3.2.

3. The method of claim 2, wherein the method comprises: the organic base is triethylamine.

4. The method of claim 2, wherein the method comprises: the dehydrating agent is thionyl chloride.

5. The method of claim 2, wherein the method comprises: the alkaline reagent is cesium carbonate.

6. The method of claim 2, wherein the method comprises: the acid reagent is a dioxane solution of hydrochloric acid with the hydrogen chloride concentration of 4mol/L (the rest is dioxane); methyl 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoate: hydrogen chloride 1: 2.8-3.2 (molar ratio) in the step S4, and tert-butyl 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate-1, 1-dioxide: hydrogen chloride 1: 2.8-3.2 (molar ratio) in the step S9.

7. The method of claim 2, wherein the method comprises: the non-nucleophilic strong base reagent is bis-trimethylsilyl lithium amide; the reducing agent is lithium aluminum hydride.

8. The method of claim 2, wherein the method comprises: the oxidant is m-chloroperoxybenzoic acid.

9. A benzothiazepine oxide characterized by: prepared by the method for preparing benzothiazepine oxide according to any one of claims 1 to 8.

10. Use of a benzothiazepine oxide according to claim 9, wherein: the benzothiazepine oxide is used as an intermediate for preparing an active ingredient of a medicament for preventing and treating RSV.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of benzothiazepine oxide, a product prepared by the preparation method and application of the product.

Background

The benzoazepine oxide compound is an important heterocyclic compound, and a medicament synthesized by taking the benzoazepine oxide as an intermediate has better pharmacological activity and has wide application as an active component of medicaments for relaxing blood vessels, resisting arrhythmia, treating hypertension, resisting fungi and the like.

Application publication No. CN109879837A discloses a method for preparing a compound for preventing and treating RSV, which is characterized in that N- [ (3-aminooxetan-3-yl) methyl ] -2- (1, 1-dioxo-3, 5-dihydro-1, 4-benzothiazepine-4-yl) -6-methyl-quinazolin-4-amine is synthesized by taking 2,3,4, 5-tetrahydro-1, 4-benzothiazacycloheptatriene-1, 1-dioxide as an intermediate, and is used for preventing and treating Respiratory Syncytial Virus (RSV) infection in mammals or humans. According to the technical scheme, thiophenol sodium is used as a raw material and reacts with 2-chloroethylamine hydrochloride to generate 2-phenylthioethylamine, then the 2-phenylthioethylamine reacts with acetic anhydride to generate N- (2-phenylthioethyl) acetamide, then 1- (3, 5-dihydro-2H-1, 4-benzothiepin-4-yl) ethanone is prepared, 1- (1, 1-dioxo-2, 3-dihydro-1, 4-benzothiepin-4 (5H) -yl) ethanone is prepared through oxidation, and then the 2,3,4, 5-tetrahydro-1, 4-benzothiepin-1, 1-dioxide intermediate is generated through reaction.

More and more medical intermediates containing chlorine elements on molecules are available, the introduction of chlorine elements on the medical intermediates can change the treatment effect of medicines and is beneficial to expanding the application range of the medical intermediates, and no report is provided for introducing chlorine elements on the benzene ring of 2,3,4, 5-tetrahydro-1, 4-benzothiepin-1, 1-dioxide intermediates at present.

Disclosure of Invention

In view of the defects of the prior art, the first object of the present invention is to provide a method for preparing benzothiazepine oxide, which has the advantage of easy introduction of chlorine.

The second purpose of the invention is to provide a benzothiazepine oxide which has the advantage that the application range of the product can be expanded to a certain extent.

The third purpose of the invention is to provide an application of benzothiazepine oxide, which has the advantage that the application range of the product can be expanded to a certain extent.

In order to achieve the first object, the invention provides the following technical scheme: a preparation method of benzothiazepine oxide has the following reaction scheme:

which comprises the following steps:

preparation of S1 tert-butyloxycarbonylaminoethanethiol: under the action of organic alkali, aminoethanethiol hydrochloride reacts with di-tert-butyl dicarbonate to prepare 2-tert-butoxycarbonylaminoethanethiol;

s2 benzoic acid esterification: under the action of a dehydrating agent, carrying out esterification reaction on 2-fluoro-4-chlorobenzoic acid and methanol to prepare 4-chloro-2-fluorobenzoic acid methyl ester;

s3 fluorochemical thio: under the action of an alkaline reagent, carrying out a thio reaction on the 4-chloro-2-fluorobenzoic acid methyl ester prepared in the step S2 and the 2-tert-butoxycarbonylaminoethanethiol prepared in the step S1 to prepare 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoic acid methyl ester;

s4 acid hydrolysis of tert-butyloxycarbonylamino: carrying out acidolysis reaction on methyl 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoate under the action of an acid reagent to prepare methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate;

s5 amine ester ring closure: under the action of a non-nucleophilic strong base reagent, a primary amine group and an ester group on a methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate molecule undergo a ring-closure reaction to prepare 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone;

s6 carbonyl reduction: under the action of a reducing agent, ketone carbonyl on 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone molecules is subjected to reduction reaction to prepare 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine;

s7 amine protection: under the action of organic alkali, di-tert-butyl dicarbonate and 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine are subjected to ester exchange reaction to prepare tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate;

s8 oxidation of benzothiepin: under the action of an oxidant, tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate undergoes an oxidation reaction to prepare 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide;

deprotection of the S9 amine group: under the action of an acidic reagent, carrying out acidolysis reaction on 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide to prepare a benzothiazepine oxide product.

By adopting the technical scheme, 2-fluoro-4-chlorobenzoic acid is used as an initial raw material to generate 4-chloro-2-fluorobenzoic acid methyl ester through an esterification reaction with methanol, then the 4-chloro-2-fluorobenzoic acid methyl ester and 2-tert-butoxycarbonyl aminoethanethiol prepared in the step S1 are subjected to a thioreaction to prepare 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoic acid methyl ester, then the 2- ((2-aminoethyl) thio) -4-chlorobenzoic acid methyl ester is prepared through an acid hydrolysis reaction, amino groups on the aminoethanethiol are protected, 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone is prepared through an amine ester ring-closing step, and the ketocarbonyl on the molecule is reduced to prepare 8-chloro-2, oxidizing sulfur on molecules under the condition of amino protection, and then performing amino deprotection to obtain a benzothiazepine oxide product of 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide. According to the invention, through a series of synthesis steps, chlorine element is introduced into a specific position on a benzene ring of the benzothiazepine compound, so that the physicochemical properties of the benzothiazepine compound are changed, the benzothiazepine compound can be used as an intermediate to synthesize various medicines, and the application range of the benzothiazepine compound is expanded to a certain extent.

Preferably, the method comprises the following steps:

preparation of S1 tert-butyloxycarbonylaminoethanethiol: under the action of organic base, aminoethanethiol hydrochloride and di-tert-butyl dicarbonate react for 14h to 18h at room temperature, and then 2-tert-butoxycarbonylaminoethanethiol is prepared after purification; the reaction materials are fed according to the following molar ratio: aminoethanethiol hydrochloride: di-tert-butyl dicarbonate: organic base ═ 1: 1.05-1.15: 1.8-2.2;

s2 benzoic acid esterification: reacting 2-fluoro-4-chlorobenzoic acid with methanol at 58-62 ℃ for 100-150 min under the action of a dehydrating agent, and purifying to obtain 4-chloro-2-fluorobenzoic acid methyl ester; the reaction materials are fed according to the following molar ratio: 2-fluoro-4-chlorobenzoic acid: methanol: 1, dehydrating agent: 45-50: 2.8-3.2;

s3 fluorochemical thio: under the action of an alkaline reagent, 4-chloro-2-fluorobenzoic acid methyl ester prepared in the step S2 and 2-tert-butoxycarbonylaminoethanethiol prepared in the step S1 react at the temperature of 58-62 ℃ for 14-18 h, and the reaction product is purified to obtain 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoic acid methyl ester, wherein the reaction materials are fed according to the following molar ratio of 4-chloro-2-fluorobenzoic acid methyl ester to 2-tert-butoxycarbonylaminoethanethiol: 1: 1.25-1.35: 2.8-3.2;

s4 acid hydrolysis of tert-butyloxycarbonylamino: under the action of an acid reagent, 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoic acid methyl ester reacts at room temperature for 150min-200min, and is purified to prepare 2- ((2-aminoethyl) thio) -4-chlorobenzoic acid methyl ester, wherein the reaction materials are fed according to the following molar ratio of 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoic acid methyl ester to the acid reagent of 1: 2.8-3.2;

s5 amine ester ring closure: under the action of a non-nucleophilic strong base reagent, reacting a primary amine group and an ester group on a methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate molecule at 68-72 ℃ for 280-320 min, and purifying to obtain 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone; the reaction materials are fed according to the following molar ratio: methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate: non-nucleophilic strong base reagent ═ 1: 1.8-2.2;

s6 carbonyl reduction: under the action of a reducing agent, 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone reacts at room temperature for 14H-18H, and is purified to prepare 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine; the reaction materials are fed according to the following molar ratio: 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepin-5 (2H) -one: reducing agent 1: 1.25-1.35;

s7 amine protection: under the action of organic alkali, di-tert-butyl dicarbonate and 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine react at room temperature for 100min to 150min, and the tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate is prepared after purification; the reaction materials are fed according to the following molar ratio: 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine: di-tert-butyl dicarbonate: organic base ═ 1: 1.8-2.2: 1.8-2.2;

s8 oxidation of benzothiepin: under the action of an oxidant, tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate is subjected to oxidation reaction at room temperature for 150min to 200min, and then purified to obtain 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide; the reaction materials are fed according to the following molar ratio: tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate: oxidant 1: 4.8-5.2;

deprotection of the S9 amine group: under the action of an acidic reagent, 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide reacts at room temperature for 220min to 280min, and is purified to prepare benzothiazepine oxide products; the reaction materials are fed according to the following molar ratio: 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide: acid reagent 1: 2.8-3.2.

By adopting the technical scheme, the product yield can be improved, the product production cost can be reduced, the product market competitiveness can be improved, the product market value can be improved, and the product application range can be enlarged by using proper proportion and reaction conditions.

Preferably, the organic base is triethylamine.

By adopting the technical scheme, acidic hydrogen chloride byproducts are generated in the preparation process of the tert-butyloxycarbonylaminoethanethiol in the step S1, basic triethylamine is added to react with the hydrogen chloride byproducts to generate triethylamine hydrochloride which is separated out from an organic synthesis system in a solid state, the chemical balance forward movement of the ester exchange reaction in the step S1 is promoted, the conversion rate in the step S1 is improved, the reaction yield in the step S1 is improved, the product synthesis cost is reduced, the product market value is improved, and the product application range is expanded.

Preferably, the dehydrating agent is thionyl chloride.

By adopting the technical scheme, in the benzoic acid esterification reaction process of the step S2, by-product water can be generated, the added thionyl chloride dehydrating agent can react with water to generate hydrogen chloride and sulfur dioxide with strong volatility, under the heating reaction condition of the step S2, the hydrogen chloride and the sulfur dioxide are removed from the reaction system due to volatilization, the water content in the reaction system is reduced, the chemical balance forward movement in the benzoic acid esterification reaction process is promoted, the conversion rate of the step S2 is improved, the reaction yield of the step S2 is improved, the product synthesis cost is reduced, the product market value is improved, and the product application range is expanded.

Preferably, the alkaline agent is cesium carbonate.

By adopting the technical scheme, in the fluoride thioreaction process of the step S3, an acidic hydrogen fluoride byproduct is generated and reacts with alkaline cesium carbonate to generate cesium fluoride, the concentration of hydrogen fluoride in a system is reduced, the chemical balance of the fluoride thioreaction process of the step S3 is pushed to move in the positive direction, the conversion rate of the step S3 is improved, the reaction yield of the step S3 is improved, the product synthesis cost is reduced, the product market value is improved, and the product application range is expanded.

Preferably, the acidic reagent is dioxane hydrochloride solution with the hydrogen chloride concentration of 4mol/L (the rest is dioxane); methyl 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoate: hydrogen chloride 1: 2.8-3.2 (molar ratio) in the step S4, and tert-butyl 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate-1, 1-dioxide: hydrogen chloride 1: 2.8-3.2 (molar ratio) in the step S9.

By adopting the technical scheme, the dioxane solution of hydrochloric acid is added in the acidolysis reaction processes of the steps S4 and S9, so that on one hand, an acidic environment required by the acidolysis reaction is provided, on the other hand, the intersolubility of the acidic solvent and S4 and S9 organic synthesis systems is improved, protons in the acidic reagent are enabled to be more easily close to nitrogen atoms in reaction raw materials, the reaction activity is improved, the acidolysis reaction is completed under mild conditions, the process cost is reduced, the market value of products is improved, and the application range of the products is expanded.

Preferably, the non-nucleophilic strong base reagent is lithium bis (trimethylsilyl) amide; the reducing agent is lithium aluminum hydride.

By adopting the technical scheme, the non-nucleophilic strong base reagent and the reducing agent with proper activity are selected, so that the conversion rate and the reaction yield of the step S5 and the step S6 can be improved, the cost is reduced, the market value of the product is improved, and the application range of the product is expanded.

Preferably, the oxidizing agent is m-chloroperoxybenzoic acid.

By adopting the technical scheme, the m-chloroperoxybenzoic acid with proper oxidation performance is used, so that the step S8 is completed under the mild room temperature condition, extra energy consumption is not needed, the process cost is reduced, the market value of the product is improved, and the application range of the product is expanded.

In order to achieve the second object, the invention provides the following technical scheme: a benzothiazepine oxide is prepared by the preparation method of the benzothiazepine oxide.

By adopting the technical scheme, the benzothiepin oxide prepared by the invention introduces chlorine element into the specific position of the benzothiepin compound, changes the physical and chemical properties of the benzothiepin compound, and expands the application range of the benzothiepin compound to a certain extent.

In order to achieve the third object, the invention provides the following technical solutions: the use of benzothiazepine oxides as intermediates for the preparation of active ingredients of medicaments for the prophylaxis and treatment of RSV.

By adopting the technical scheme, the benzothiepin oxide prepared by the invention is used as an intermediate for preparing active components of medicines for preventing and treating RSV, and the application range of the benzothiepin compound is expanded to a certain extent.

In summary, the invention includes at least one of the following beneficial technical effects:

1. the method comprises the steps of carrying out esterification reaction on 2-fluoro-4-chlorobenzoic acid serving as an initial raw material and methanol to generate 4-chloro-2-fluorobenzoic acid methyl ester, carrying out thioreaction on the 4-chlorobenzoic acid methyl ester and a product prepared in the step S1 to prepare 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoic acid methyl ester, carrying out acidolysis reaction to prepare 2- ((2-aminoethyl) thio) -4-chlorobenzoic acid methyl ester, protecting amino groups on aminoethanethiol, carrying out amine ester ring-closing step to prepare 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone, reducing ketone carbonyl groups on molecules to prepare 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine, oxidizing sulfur on molecules under the condition of amino protection, and then performing amino deprotection to obtain a benzothiazepine oxide product of 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide; according to the invention, through a series of synthesis steps, chlorine element is introduced into a specific position on a benzene ring of the benzothiazepine compound, so that the physicochemical properties of the benzothiazepine compound are changed, the benzothiazepine compound can be used as an intermediate to synthesize various medicines, and the application range of the benzothiazepine compound is expanded to a certain extent;

2. according to the invention, basic triethylamine is added in the step S1, and reacts with the acidic hydrogen chloride byproduct generated in the step S1 to generate triethylamine hydrochloride which is separated out from an organic synthesis system in a solid state form, so that the chemical equilibrium forward shift of the ester exchange reaction in the step S1 is promoted, the conversion rate in the step S1 is improved, and the reaction yield in the step S1 is improved; adding a thionyl chloride dehydrating agent into the step S2 to react with byproduct water to generate hydrogen chloride and sulfur dioxide with strong volatility, wherein the hydrogen chloride and the sulfur dioxide are removed from a reaction system due to volatilization under the heating reaction condition of the step S2, so that the water content in the reaction system is reduced, the chemical balance of the benzoic acid esterification reaction process is pushed to move forward, the conversion rate of the step S2 is improved, the reaction yield of the step S2 is improved, the product synthesis cost is reduced, the product market value is improved, and the product application range is expanded;

3. the invention selects proper alkaline reagent, acid reagent, reducing agent, non-nucleophilic indicator and oxidant, and selects proper proportion and process condition in each step, thereby improving the reaction conversion rate in each step, improving the product yield, reducing the process cost and raw material cost, improving the product market value, and expanding the product application range.

Detailed Description