CN111518055A - Preparation method of benzothiazepine oxide, product prepared by preparation method and application of product - Google Patents
Preparation method of benzothiazepine oxide, product prepared by preparation method and application of product Download PDFInfo
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- CN111518055A CN111518055A CN202010415813.2A CN202010415813A CN111518055A CN 111518055 A CN111518055 A CN 111518055A CN 202010415813 A CN202010415813 A CN 202010415813A CN 111518055 A CN111518055 A CN 111518055A
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Abstract
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.
Description
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
Examples
In order to explain the technical content, the objects and the effects of the present invention in detail, the following description will be given in conjunction with the embodiments.
The raw materials according to the present invention are all commercially available, and the type and source of each raw material are shown in table 1.
TABLE 1 type and Source of raw materials
Example 1
A preparation method of benzothiazepine oxide comprises the following steps:
preparation of S1 tert-butyloxycarbonylaminoethanethiol: weighing 100g of aminoethanethiol hydrochloride, transferring the aminoethanethiol hydrochloride into a 2000mL three-neck flask, adding 1000mL of dichloromethane, stirring at the rotating speed of 300 r/min, adding 262g of triethylamine and 311g of di-tert-butyl dicarbonate, and reacting at room temperature for 16 h; 500mL of water was added to the reaction solution to dilute the reaction solution, followed by liquid separation, washing the organic phase with 200mL of a 10% (balance water) aqueous citric acid solution three times each time, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to remove the solvent, thereby obtaining 174g of 2-t-butoxycarbonylaminoethanethiol with a yield of 75.7%.
The reaction of step S1 is schematically as follows:
s2 benzoic acid esterification: weighing 46g of 2-fluoro-4-chlorobenzoic acid, adding the weighed 2-fluoro-4-chlorobenzoic acid into a 1000mL three-neck flask, adding 500mL of methanol, putting the three-neck flask into a circulating refrigerator to cool the reaction solution to 0 ℃, stirring at the rotating speed of 200 revolutions per minute, dropwise adding 92g of thionyl chloride, heating to 60 ℃ after the dropwise adding is finished, continuing stirring, monitoring the reaction progress by TLC (thin layer chromatography (developing solvent is 5: 1 petroleum ether/ethyl acetate solvent) and displaying the completion of the reaction by TLC after the reaction is carried out for 120 min. The reaction solution was concentrated under reduced pressure to remove the solvent, to obtain 42g of methyl 4-chloro-2-fluorobenzoate as a white solid in a yield of 82.5%, and the product was directly fed to the next step.
The reaction of step S2 is schematically as follows:
s3 fluorochemical thio: transferring 39g of 4-chloro-2-fluorobenzoic acid methyl ester prepared in the step S2 into a 1000mL single-neck bottle, adding 700mL of N, N-dimethylformamide, adding 48g of 2-tert-butoxycarbonylaminoethanol thiol prepared in the step S1 and 205g of cesium carbonate, stirring at the rotating speed of 250 revolutions per minute, heating to 60 ℃, stirring for reaction, monitoring the reaction progress by TLC (a developing solvent is a petroleum ether/ethyl acetate solvent with the volume ratio of 8: 1), and after reacting for 16 hours, indicating that the reaction is finished by TLC; 2100mL of ethyl acetate was added to the reaction mixture for dilution, the organic phase was washed three times with 700mL of saturated brine each time, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, to give 42.8g of methyl 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoate as a white solid in 59.8% yield.
The reaction of step S3 is schematically as follows:
s4 acid hydrolysis of tert-butyloxycarbonylamino: 42.8g of methyl 2- ((2- ((tert-butoxycarbonyl (amino) ethyl) thio) -4-chlorobenzoate prepared in the step S3 is transferred into a 500mL single-neck bottle, 300mL of dichloromethane and 93mL of dioxane hydrochloride solution with the hydrogen chloride concentration of 4mol/L are added, stirring is carried out at the rotating speed of 200 r/min, reaction is carried out for 3h at room temperature, white solid is gradually separated out, filtering is carried out, filter cake is collected, 300mL of methanol is added into the filter cake, 60g of sodium carbonate is added, stirring is carried out for 30min at room temperature, 300mL of dichloromethane is added, stirring is carried out, filtering is carried out, the filtrate is decompressed and concentrated to remove the solvent, and 22.3g of methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate is prepared and is in a yellow solid state, and the yield is 73.3.
The reaction of step S4 is schematically as follows:
s5 amine ester ring closure: taking 22.24g of the methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate prepared in the step S4, transferring the methyl 2- ((2-aminoethyl) thio) -4-chlorobenzoate into a 500mL single-mouth bottle, adding 200mL of tetrahydrofuran and 182mL of 1mol/L lithium bistrimethylsilyl amide tetrahydrofuran solution, stirring at the rotating speed of 200 r/min, heating to 70 ℃ for reaction, monitoring the reaction progress by TLC (a developing agent is ethyl acetate), and after the reaction is carried out for 300min, displaying the completion of the reaction by TLC; cooling the reaction solution to 0 ℃, dropwise adding 20mL of saturated ammonium chloride solution to carry out quenching reaction, adding 100mL of water for dilution, extracting with 200mL of ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to remove the solvent, purifying by chromatography silica gel column chromatography (the eluent is petroleum ether/ethyl acetate solvent with the volume ratio of 1: 4), and concentrating under reduced pressure to remove the solvent to obtain 8.2g of 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone which is in a yellow solid state with the yield of 42.4%.
The reaction of step S5 is schematically as follows:
s6 carbonyl reduction: adding 8.2g of 8-chloro-3, 4-dihydrobenzo-1, 4-thiazepin-5 (2H) -ketone prepared in the step S5 into a 250mL single-mouth bottle, adding 100mL of tetrahydrofuran, adding 1.9g of lithium aluminum hydride in five batches, stirring at the room temperature at the rotating speed of 150 r/min for reaction, monitoring the reaction progress by TLC (a developing agent is a dichloromethane/methanol solvent with the volume ratio of 20: 1), and after reacting for 16H, indicating the reaction is finished by TLC; the reaction was quenched by adding 2.47g of sodium sulfate decahydrate in five portions on average, filtered, and the filtrate was collected. To prepare 8-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine, and directly putting the reaction solution into the next step.
The reaction of step S6 is schematically as follows:
s7 amine protection: adding 17.5g of di-tert-butyl dicarbonate and 7.4g of triethylamine into the reaction solution prepared in S6, stirring at the room temperature at the rotating speed of 150 revolutions per minute for reaction, monitoring the reaction progress by TLC (a developing agent is a petroleum ether/ethyl acetate solvent with the volume ratio of 5: 1), and after reacting for 120min, monitoring by TLC to show that the reaction is finished; adding 50mL of water into the reaction solution for dilution, and extracting with 200mL of ethyl acetate; the organic phase was dried over anhydrous sodium sulfate with 50mL of saturated aqueous sodium chloride solution, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure to remove the solvent, purified by silica gel column chromatography (eluent was a petroleum ether/ethyl acetate solvent in a volume ratio of 10: 1), and concentrated under reduced pressure to remove the solvent, to give 6.3g of tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate as a white solid with a yield of 51.2%.
The reaction of step S7 is schematically as follows:
s8 oxidation of benzothiepin: taking 2.6g of tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate prepared in the step S7, transferring the tert-butyl-8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate into a 250mL single-neck bottle, adding 100mL of dichloromethane and 7.5g of m-chloroperoxybenzoic acid, stirring and reacting at the room temperature at the rotating speed of 100 r/min, monitoring the reaction progress by TLC (a developing agent is a petroleum ether/ethyl acetate solvent with the volume ratio of 5: 1), and after reacting for 180min, monitoring by TLC to show that the reaction is; adding 100mL of sodium carbonate aqueous solution into the reaction solution, and adding 100mL of dichloromethane for extraction; the organic phase was washed with 100mL of saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was collected and concentrated under reduced pressure to remove the solvent, to give 2.0g of 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide as a pale yellow solid with a yield of 69.5%.
The reaction of step S8 is schematically as follows:
deprotection of the S9 amine group: taking 2g of 8-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide prepared in the step S8, transferring the mixture into a 100mL single-mouth bottle, adding 20mL of dichloromethane and 4.57mL of hydrochloric acid dioxane solution with the hydrogen chloride concentration of 4mol/L, stirring the mixture at room temperature at the rotating speed of 100 revolutions/minute for reaction, monitoring the reaction progress by using an LCMS (liquid Crystal display System), and after the reaction is carried out for 240min, monitoring the reaction by using the LCMS to show that the reaction is finished; filtering the reaction solution, and collecting a filter cake; adding 20mL of methanol into the filter cake, adding ammonia water to adjust the pH to 9, and concentrating under reduced pressure to remove the solvent; the crude product was subjected to medium pressure liquid phase preparation (medium pressure liquid phase preparation conditions: C18 column, mobile phase: phase A is 0.05% (v/v) ammonia, phase B is acetonitrile) to give 1.03g of benzothiazepine oxide, which was a white solid, yield: 73.8 percent.
The reaction of step S9 is schematically as follows:
examples 2 to 8
Examples 2-8 differ from example 1 in the amounts of starting materials added and the process parameters of examples 2-8.
The amounts of the 2-fluoro-4-chlorobenzoic acids added in examples 2 to 8 were 46g, and 2.6g of the product obtained in step S7 was used in the synthesis experiment in step S8, and 39g of the product obtained in step S2 was used in the synthesis experiment in step S3; the products of steps S3, S4, S5, S6 and S8 were all used in subsequent step experiments. The purification scheme for each step of examples 2-8 was consistent with example 1, and the manner of addition and experimental conditions for each step of examples 2-8 were consistent with example 1. The solvent amounts in the respective steps of examples 2 to 8 were kept the same as in example 1 except for the amount of methanol used in step S2 (see Table 2 for the amount of methanol used in step S2 of examples 2 to 8).
The feeds of the various starting materials of examples 2 to 8 are shown in Table 2, and the process parameters of examples 2 to 8 are shown in Table 3.
TABLE 2 addition of the starting materials of examples 2 to 8
TABLE 3 parameters in the various steps of examples 2-8
Calculation of yield
The weights of the intermediate products and the final products in each step are recorded in each group of experimental processes, the reaction yield and the total yield are calculated, and the reaction yield results are shown in table 4.
TABLE 4 comparison of the reaction yields in the different examples
As shown in the above table, the above table shows the reaction yield and the total yield of each step in examples 1 to 8 of the present invention. 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. The invention selects proper alkaline reagent, dehydrating agent, organic base, acid reagent, reducing agent, non-nucleophilic indicator and oxidant, and selects proper process conditions in each step, thereby improving the reaction conversion rate in each step, improving the product yield, reducing the process cost and the raw material cost, improving the market value of the product, and expanding the application range of the product.
In the invention, TLC is a thin-layer chromatography and is used for tracking the progress of chemical reaction in the experimental process; the LCMS is a liquid chromatogram-mass spectrometer detection method, and the liquid chromatogram-mass spectrometer used in the invention is an instrument which is manufactured by Shimadzu instruments of Japan and has the model of LCMS-2020.
The embodiments of the present invention are preferred embodiments of the present invention, and the scope of the present invention is not limited by these embodiments, so: all equivalent changes made according to the structure, shape and principle of the invention are covered by the protection scope of the invention.
Claims (10)
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.
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| WO1998005657A1 (en) * | 1996-08-02 | 1998-02-12 | Knoll Aktiengesellschaft | 2,3-dihydro-1,4-benzothiazepines, their preparation and their use as intermediates |
| CN103717589A (en) * | 2011-08-11 | 2014-04-09 | 弗·哈夫曼-拉罗切有限公司 | Compounds for the treatment and prophylaxis of respiratory syncytial virus disease |
| CN102361860B (en) * | 2009-03-20 | 2014-09-10 | 瑟维尔实验室 | Benzothiadiazepine derivatives used as AMPA and NMDA receptor modulators |
| CN109879837A (en) * | 2014-01-24 | 2019-06-14 | 豪夫迈·罗氏有限公司 | Prepare the method for preventing and treating the compound of RSV |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1998005657A1 (en) * | 1996-08-02 | 1998-02-12 | Knoll Aktiengesellschaft | 2,3-dihydro-1,4-benzothiazepines, their preparation and their use as intermediates |
| CN102361860B (en) * | 2009-03-20 | 2014-09-10 | 瑟维尔实验室 | Benzothiadiazepine derivatives used as AMPA and NMDA receptor modulators |
| CN103717589A (en) * | 2011-08-11 | 2014-04-09 | 弗·哈夫曼-拉罗切有限公司 | Compounds for the treatment and prophylaxis of respiratory syncytial virus disease |
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