阅读说明：本技术 卤代苯并硫杂卓氧化物的制备方法及其制备的产品及其应用 (Preparation method of halogenated benzothiepin oxide, product prepared by preparation method and application of product ) 是由 单玉庆 康康 帅宝奎 于 2020-06-03 设计创作，主要内容包括：本发明公开了卤代苯并硫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；一种卤代苯并硫杂卓氧化物的制备方法,以邻氯苯硫酚为初始原料,经硫代物烷基化、丙酸乙酯水解、闭环反应、叠氮反应、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9-氯-2,3,4,5-四氢-1,4-苯并硫氮杂卓-1,1-二氧化物的卤代苯并硫杂卓氧化物产品；卤代苯并硫杂卓氧化物的制备方法具有便于引入极性功能团的优点；卤代苯并硫杂卓氧化物产品具有可以一定程度上提高产品水溶性的优点；卤代苯并硫杂卓氧化物作为中间体用于制备预防和治疗RSV药物的活性组分具有可在一定程度上提高药物药效的优点。(The invention discloses a preparation method of halogenated benzothiepin oxide, a product prepared by the method and application of the product, and relates to the technical field of chemical synthesis; a preparation method of halogenated benzothiepin oxide takes o-chlorothiophenol as an initial raw material, and prepares a halogenated benzothiepin oxide product of 9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiepin-1, 1-dioxide through the steps of thio-compound alkylation, ethyl propionate hydrolysis, ring-closing reaction, azide reaction, carbonyl reduction, amino protection, benzothiepin oxidation, amino deprotection and the like; the preparation method of the halogenated benzothiepin oxide has the advantage of being convenient for introducing polar functional groups; the halogenated benzothiepin oxide product has the advantage of improving the water solubility of the product to a certain extent; the halogenated benzothiepin oxide used as an intermediate for preparing the active component of the medicament for preventing and treating RSV has the advantage of improving the medicament effect of the medicament to a certain extent.)

1. A preparation method of halogenated benzothiepin oxide is characterized by comprising the following reaction processes:

which comprises the following steps:

s1 thioalkylation: under the action of alkali carbonate, carrying out alkylation reaction on o-chlorothiophenol and ethyl 3-bromopropionate to obtain ethyl 3- (2-chlorophenylthio) propionate;

hydrolysis of ethyl propionate S2: under the action of alkali metal hydroxide and water, 3- (2-chlorphenyl sulfo) ethyl propionate undergoes hydrolysis reaction to prepare 3- (2-chlorphenyl sulfo) propionic acid;

s3 Ring closure reaction: dehydrating the 3- (2-chlorophenylthio) propionic acid prepared in the step S2 under the action of sulfuric acid to prepare 9-chloro-3, 4-dihydro-2H-1-benzothiopyran-4-one;

s4: nitridizing reaction: reacting 9-chloro-3, 4-dihydro-2H-1-benzothiopyran-4-one with trimethylsilyl azide to prepare 9-chloro-3, 4-dihydrobenzo-1, 4-thiazepin-5 (2H) -one;

s5 carbonyl reduction: under the action of a reducing agent, ketone carbonyl on 9-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone molecules is subjected to reduction reaction to prepare 9-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine;

s6 amine protection: under the action of an organic tertiary amine reagent, carrying out ester exchange reaction on di-tert-butyl dicarbonate and 9-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine to prepare tert-butyl-9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate;

s7 oxidation of benzothiepin: under the action of an oxidant, tert-butyl-9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate undergoes an oxidation reaction to prepare 9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide;

deprotection of the S8 amine group: under the action of an acidic reagent, carrying out acidolysis reaction on 9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide to prepare a halogenated benzothiazepine oxide product.

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

s1 thioalkylation: under the action of alkali carbonate, o-chlorothiophenol reacts with 3-bromoethyl propionate at 75-85 ℃ for 50-70 min, and the reaction product is purified to obtain 3- (2-chlorphenyl thio) ethyl propionate; the reaction materials are fed according to the following mass ratio: o-chlorothiophenol: ethyl 3-bromopropionate: alkali metal carbonate = 1: 1.45-1.55: 2.8-3.2;

hydrolysis of ethyl propionate S2: under the action of alkali metal hydroxide and water, 3- (2-chlorphenyl sulfo) ethyl propionate reacts for 14-18 h at room temperature, and is purified to obtain 3- (2-chlorphenyl sulfo) propionic acid; the reaction materials are fed according to the following mass ratio: ethyl 3- (2-chlorophenylthio) propionate: alkali metal hydroxide: water = 1: 1.8-2.2: 60-70 parts of;

s3 Ring closure reaction: under the action of sulfuric acid with the mass concentration of not less than 98 percent (the balance being water), the 3- (2-chlorphenylthio) propionic acid prepared in the step S2 is dehydrated and reacted for 100min to 150min at room temperature, and is purified to prepare 9-chloro-3, 4-dihydro-2H-1-benzothiopyran-4-one; the reaction materials are fed according to the following mass ratio: 3- (2-chlorophenylthio) propionic acid: sulfuric acid = 1: 8.5-9.5;

s4: nitridizing reaction: reacting 9-chloro-3, 4-dihydro-2H-1-benzothiopyran-4-ketone and trimethylsilyl azide at room temperature for 15H-17H by taking trifluoroacetic acid as a reaction solvent, and purifying to obtain 9-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone; the reaction materials are fed according to the following mass ratio: 9-chloro-3, 4-dihydro-2H-1-thiochroman-4-one: azidotrimethylsilane: trifluoroacetic acid = 1: 1.25-1.35: 12-15;

s5 carbonyl reduction: reacting 9-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone at 62-68 ℃ for 150-200 min under the action of a reducing agent, and purifying to obtain 9-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine; the reaction materials are fed according to the following mass ratio: 9-chloro-3, 4-dihydrobenzo-1, 4-thiazepin-5 (2H) -one: reducing agent = 1: 2.8-3.2;

s6 amine protection: under the action of an organic tertiary amine reagent, di-tert-butyl dicarbonate and 9-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine react at room temperature for 100min to 150min, and the tert-butyl-9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate is prepared after purification; the reaction materials are fed according to the following mass ratio: 9-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine: di-tert-butyl dicarbonate: organic tertiary amine reagent = 1: 2-2.5: 1.35-1.45;

s7 oxidation of benzothiepin: under the action of an oxidant, tert-butyl-9-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 9-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 mass ratio: tert-butyl-9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate: oxidant = 1: 2.8-3.2;

deprotection of the S8 amine group: carrying out acidolysis reaction on 9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide at room temperature for 100min-150min under the action of an acidic reagent, and purifying to obtain a halogenated benzothiepine oxide product; the acid reagent is a dioxane solution of hydrochloric acid with the hydrogen chloride concentration of 4mol/L (the rest is dioxane); the reaction materials are fed according to the following mass ratio: 9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide: hydrogen chloride = 1: 3.6-4.

3. The method of claim 2, wherein the halogenated benzothiepin oxide is prepared by: the alkali metal carbonate is potassium carbonate.

4. The method of claim 2, wherein the halogenated benzothiepin oxide is prepared by: the alkali metal hydroxide is sodium hydroxide.

5. The method of claim 2, wherein the halogenated benzothiepin oxide is prepared by: the reducing agent is lithium aluminum hydride.

6. The method of claim 2, wherein the halogenated benzothiepin oxide is prepared by: the organic tertiary amine reagent is triethylamine.

7. The method of claim 2, wherein the halogenated benzothiepin oxide is prepared by: the oxidant is m-chloroperoxybenzoic acid.

8. A halogenated benzothiepin oxide characterized by: the halogenated benzothiepin oxide compound of any one of claims 1 to 7, which is prepared by a process for the preparation thereof.

9. Use of a halogenated benzothiepin oxide as claimed in claim 8, characterized in that: the halogenated benzothiepin oxide is used as an intermediate for preparing an active ingredient of a medicament for preventing and treating RSV.