CN111574475B - Preparation method of halogenated benzothiepin oxide, product prepared by preparation method and application of product - Google Patents
Preparation method of halogenated benzothiepin oxide, product prepared by preparation method and application of product Download PDFInfo
- Publication number
- CN111574475B CN111574475B CN202010493832.7A CN202010493832A CN111574475B CN 111574475 B CN111574475 B CN 111574475B CN 202010493832 A CN202010493832 A CN 202010493832A CN 111574475 B CN111574475 B CN 111574475B
- Authority
- CN
- China
- Prior art keywords
- reaction
- tlc
- chloro
- solvent
- tetrahydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
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 to a certain extent.
Description
Technical Field
The invention relates to the technical field of chemical intermediate synthesis, in particular to a preparation method of halogenated benzothiepin oxide, a product prepared by the preparation method and application of the product.
Background
The benzoazepine compound is an important heterocyclic compound, has good pharmacological activity, and has certain application value as an active component of medicaments for resisting mental disorder, epilepsy, hyperlipidemia, cardiovascular and fungi and the like.
Application publication No. CN106414436A discloses a method for preparing N- [ (3-aminooxetan-3-yl) methyl ] -2- (1, 1-dioxo-3, 5-dihydro-1, 4-benzothiazepine-4-yl) -6-methyl-quinazolin-4-amine, which uses 2,3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide as an intermediate to prepare N- [3- [ [ [2- (1, 1-dioxo-3, 5-dihydro-1, 4-benzothiazepine-4-yl) -6-methyl-quinazolin-4-yl ] amino ] methyl ] oxetane -3-yl ] carbamic acid (4-methoxyphenyl) methyl ester for the prevention and treatment of Respiratory Syncytial Virus (RSV) infection in a mammal or a human. 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 the 1- (3, 5-dihydro-2H-1, 4-benzothiepin-4-yl) ethanone is prepared through a ring-closing reaction, the 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 a reaction.
However, since 2,3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide does not contain a polar functional group on the benzene ring, 2,3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide has poor water solubility and is not easily absorbed by the human body, and the pharmaceutical effect of a drug prepared using 2,3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide as an intermediate is reduced to some extent.
Disclosure of Invention
In view of the disadvantages of the prior art, the first object of the present invention is to provide a method for preparing a halogenated benzothiepin oxide, which has the advantage of facilitating the introduction of polar functional groups.
The second purpose of the invention is to provide a halogenated benzothiepin oxide which has the advantage of improving the water solubility of the product to a certain extent.
The third purpose of the invention is to provide an application of halogenated benzothiepin oxide, wherein the halogenated benzothiepin oxide is used as an intermediate for preparing an active component of a medicament for preventing and treating RSV (respiratory syncytial virus), and the medicament prepared by using the halogenated benzothiepin oxide prepared by the invention as the intermediate has the advantage of improving the medicament effect to a certain extent.
In order to achieve the first object, the invention provides the following technical scheme: a preparation method of halogenated benzothiepin oxide comprises the following reaction processes:
which comprises the following steps:
s1 thioalkylation: under the action of alkali metal carbonate, carrying out alkylation reaction on o-chlorothiophenol and ethyl 3-bromopropionate to prepare 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 azido trimethylsilane to obtain 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.
By adopting the technical scheme, o-chlorothiophenol is taken as an initial raw material, and is subjected to substitution reaction with ethyl 3-bromopropionate to generate ethyl 3- (2-chlorophenylthio) propionate, then hydrolysis reaction is carried out to generate 3- (2-chlorophenylthio) propionate, under the deacidification action of sulfuric acid, a carboxyl group on a molecule and hydrogen on a benzene ring are subjected to dehydration reaction to complete ring closure to generate 9-chloro-3, 4-dihydrobenzo-1-thiazepine-4 (2H) -ketone, nitrogen element is introduced through reaction with azido trimethylsilane, ketone carbonyl on the molecule is reduced to prepare 9-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine, sulfur on the molecule is oxidized under the premise of amino protection, and then 9-chloro-2 is prepared through an amino deprotection step, halogenated benzothiepin oxide products of 3,4, 5-tetrahydro-1, 4-benzothiepin-1, 1-dioxide. The halogenated benzothiepin oxide product with chlorine introduced at a specific position is prepared through a series of chemical reactions, the physicochemical properties of the benzothiepin compound are changed, a plurality of medicines can be synthesized by taking the halogenated benzothiepin oxide product prepared by the method as an intermediate, the medicine solubility can be improved, the medicine effect can be improved, and the application range of the halogenated benzothiepin oxide product is expanded to a certain extent.
Preferably, the method comprises the following steps:
s1 thioalkylation: reacting o-chlorothiophenol with ethyl 3-bromopropionate at 75-85 ℃ for 50-70 min under the action of alkali metal carbonate, and purifying to obtain ethyl 3- (2-chlorophenylthio) 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-chlorophenylthio) propionic acid prepared in the step S2 is dehydrated 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.
By adopting the technical scheme, the proper proportion and reaction conditions are used, the reaction rate is favorably controlled, the product yield is favorably adjusted, the process cost is reduced, the market competitiveness of the product is improved, the market value of the product is improved, and the application range of the product is expanded.
Preferably, the alkali metal carbonate is potassium carbonate.
By adopting the technical scheme, in the step S1, the substitution reaction of the o-chlorothiophenol and the ethyl 3-bromopropionate can generate acidic hydrogen bromide byproducts, the alkaline potassium carbonate is added to react with the hydrogen bromide byproducts, the concentration of the hydrogen bromide byproducts in a synthesis system is reduced, the chemical reaction balance in the step S1 is moved in the positive direction, the conversion rate in the step S1 is improved, the yield in the step S1 is improved, the market value of products is improved, and the application range of the products is expanded.
Preferably, the alkali metal hydroxide is sodium hydroxide.
By adopting the technical scheme, sodium hydroxide is added in the hydrolysis reaction of the step S2 to promote the hydrolysis of the 3- (2-chlorphenyl thio) ethyl propionate, the hydrolysis rate of the ester functional group is improved, the step S2 is carried out under the mild room temperature condition, the energy consumption is reduced, the process cost is reduced, the market value of the product is improved, and the application range of the product is expanded.
Preferably, the reducing agent is lithium aluminum hydride.
By adopting the technical scheme, the lithium aluminum hydride with moderate reduction performance is selected as the reducing agent for ketone carbonyl reduction in the step S5, so that the reaction condition in the step S5 can be controlled, the reaction condition is avoided under severe reaction conditions, the process cost is reduced, the market value of the product is improved, and the application range of the product is expanded.
Preferably, the organic tertiary amine reagent is triethylamine.
By adopting the technical scheme, a by-product of tert-butyl carbonate can be generated in the amino protection reaction process of the step S6, the tert-butyl carbonate reacts with triethylamine to reduce the concentration of the tert-butyl carbonate, the chemical balance of the step S6 is moved forward, the conversion rate and yield of the step S6 are improved, the product synthesis cost is reduced, the product market value is improved, and the product application range is expanded.
Preferably, the oxidizing agent is m-chloroperoxybenzoic acid.
By adopting the technical scheme, the m-chloroperoxybenzoic acid oxidant with proper activity is selected to complete the step S7 at room temperature, so that the energy consumption of the step S7 is reduced, 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 halogenated benzothiepin oxide is prepared by the preparation method of the halogenated benzothiepin oxide.
By adopting the technical scheme, the halogenated benzothiepin oxide prepared by the method changes the physical and chemical properties of the halogenated benzothiepin oxide, can be used as an intermediate to synthesize various medicaments, is beneficial to improving the medicinal effect, and expands the application range of the halogenated benzothiepin oxide to a certain extent.
In order to achieve the third object, the invention provides the following technical solutions: the application of halogenated benzothiepin oxide as an intermediate in preparing an active ingredient of a medicament for preventing and treating RSV is disclosed.
By adopting the technical scheme, the halogenated benzothiepin oxide prepared by the invention is used as an intermediate for preparing active components of medicines for preventing and treating RSV, and is beneficial to improving the solubility of the medicines, improving the drug effect to a certain extent and expanding the application range of the halogenated benzothiepin oxide 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 taking o-chlorothiophenol as an initial raw material, carrying out substitution reaction with ethyl 3-bromopropionate to generate ethyl 3- (2-chlorophenylthio) propionate, carrying out hydrolysis reaction to generate 3- (2-chlorophenylthio) propionate, carrying out dehydration reaction on carboxyl groups on molecules and hydrogen on benzene rings under the dehydration action of sulfuric acid to complete ring closure to generate 9-chloro-3, 4-dihydrobenzo-1-thiazepin-4 (2H) -ketone, introducing nitrogen elements through reaction with azido trimethylsilane, reducing ketone carbonyl on the molecules to prepare 9-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepin, oxidizing sulfur on the molecules under the premise of protecting the amino groups, carrying out deprotection on the amino groups to prepare 9-chloro-2, a halogenated benzothiepin oxide product of 3,4, 5-tetrahydro-1, 4-benzothiepin-1, 1-dioxide; according to the invention, a halogenated benzothiepin oxide product with chlorine introduced at a specific position is prepared through a series of chemical reactions, the solubility of a benzothiepin compound is changed, and a plurality of medicines can be synthesized by taking the halogenated benzothiepin oxide product prepared by the invention as an intermediate, so that the water solubility of the medicine is improved, the medicine is convenient to absorb by a human body, the medicine effect is improved, and the application range of the halogenated benzothiepin oxide product is expanded to a certain extent;
2. the invention selects proper alkali metal carbonate, alkali metal hydroxide, reducing agent, organic amine reagent, oxidant and the like, so that the steps S2-S4 and S6-S8 are completed under the room temperature condition, the severe reaction is avoided, the reaction condition is convenient to control, the energy consumption is reduced, the process cost is reduced, and the product market value is improved;
3. the benzothiepin compound prepared by the invention is used as an intermediate to prepare an active component for preventing and treating RSV (respiratory syncytial virus) medicaments, is beneficial to improving the medicament solubility, improves the medicament effect to a certain extent and enlarges the application range of halogenated benzothiepin oxide to a certain extent.
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
| Name of reagent | Specification of | Manufacturer of the product |
| O-chlorothiophenol | Purity 98% | SHANGHAI TITAN TECHNOLOGY Co.,Ltd. |
| 3-Bromopropionic acid ethyl ester | Purity 98% | BIDE PHARMATECH Ltd. |
| Di-tert-butyl dicarbonate | Purity 98% | BIDE PHARMATECH Ltd. |
| Triethylamine | Purity of 99% | Sai' an Keluo glass Instrument Co Ltd |
| Potassium carbonate | Purity of 99% | TIANJIN DAMAO CHEMICAL REAGENT FACTORY |
| Sodium hydroxide | Purity of 99% | TIANJIN DAMAO CHEMICAL REAGENT FACTORY |
| Sulfuric acid | Purity 98% | Sai' an Keluo glass Instrument Co Ltd |
| Azidotrimethylsilane | Purity 95% | SAEN CHEMICAL TECHNOLOGY (SHANGHAI) Co.,Ltd. |
| Trifluoroacetic acid | The purity is 99.5 percent | Oppocky medicine science and technology Limited |
| Dioxane solution of hydrochloric acid | The concentration of hydrogen chloride is 4mol/L | Shanghai Yingshuo New Material science and technology Co Ltd |
| Lithium aluminum hydride | Purity 98% | SHANGHAI TITAN TECHNOLOGY Co.,Ltd. |
| Meta-chloroperoxybenzoic acid | The purity is 85 percent | Shanghai Yixue chemical Co., Ltd |
| Ammonia-methanol solution | NH 3 The concentration is 7mol/L | SAEN CHEMICAL TECHNOLOGY (SHANGHAI) Co.,Ltd. |
TLC in the following examples is thin layer chromatography used to follow the progress of the 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.
Example 1
A preparation method of halogenated benzothiepin oxide comprises the following steps:
s1 thioalkylation: weighing 50g of o-chlorothiophenol, transferring the o-chlorothiophenol into a 2000mL three-neck flask, adding 1000mL of ethanol, stirring at the rotating speed of 300 r/min, adding 143.8 potassium carbonate and 94.2g of ethyl 3-bromopropionate, heating to 80 ℃ for reaction, monitoring the reaction progress by a TLC point plate (a developing solvent is a petroleum ether/ethyl acetate solvent with the volume ratio of 20: 1), and after reacting for 60min, displaying the completion of the reaction by TLC; cooling to room temperature, filtering, and concentrating the filtrate under reduced pressure to remove the solvent; the crude product was purified by column chromatography on silica gel (eluent was petroleum ether/ethyl acetate solvent at a volume ratio of 20: 1), and concentrated under reduced pressure to remove the solvent to give 82.4g of ethyl 3- (2-chlorophenylthio) propionate as a colorless oil in 97% yield.
The reaction process of step S1 is as follows:
hydrolysis of ethyl propionate S2: preparing 27.0g of sodium hydroxide and 400mL of water into a sodium hydroxide solution; weighing 82.4g of the ethyl 3- (2-chlorophenylthio) propionate prepared in the step S1, dissolving the ethyl 3- (2-chlorophenylthio) propionate in 400mL of tetrahydrofuran, stirring at the rotating speed of 200 r/min, cooling to 4 ℃ in an ice water bath, adding a sodium hydroxide solution, heating to room temperature for reaction, monitoring the reaction progress by TLC (a developing agent is a petroleum ether/ethyl acetate solvent with the volume ratio of 1: 1), and after reacting for 16h, indicating that the reaction is finished by TLC; concentrating under reduced pressure to remove the solvent, and extracting the water phase with 600mL ethyl acetate for three times to remove impurities; the aqueous phase was collected, cooled to 5 ℃ with an ice water bath, adjusted to pH 1 by the addition of 6mol/L aqueous hydrochloric acid, extracted twice with 800mL ethyl acetate, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was collected and concentrated under reduced pressure to remove the solvent to give 64.2g of 3- (2-chlorophenylthio) propanoic acid as a white solid in 87% yield.
The reaction process of step S2 is as follows:
s3 Ring closure reaction: taking 150mL of sulfuric acid, cooling to 5 ℃ in an ice-water bath, adding 64.2g of 3- (2-chlorphenylthio) propionic acid prepared in the step S2 into the sulfuric acid in five times on average, heating to room temperature for reaction, monitoring the reaction progress by TLC (a developing solvent is a petroleum ether/ethyl acetate solvent with the volume ratio of 5: 1), and after reacting for 120min, indicating that the reaction is finished by TLC; pouring the reaction solution into 1600mL of ice water (the mass ratio of ice to water is 1: 1), separating out a large amount of solid, filtering, collecting the solid, washing the solid with water to be neutral, and concentrating under reduced pressure to remove residual solvent and water in the solid; the crude product was purified by column chromatography on silica gel (eluent was petroleum ether/ethyl acetate solvent in a volume ratio of 8: 1) and concentrated under reduced pressure to remove the solvent, yielding 31.2g of 9-chloro-3, 4-dihydro-2H-1-thiochroman-4-one as a white solid in 53% yield.
The reaction process of step S3 is as follows:
s4: nitridizing reaction: dissolving 31.2g of 9-chloro-3, 4-dihydro-2H-1-benzothiopyran-4-ketone prepared in the step S3 in 160mL of trifluoroacetic acid, cooling to 5 ℃ in an ice water bath, adding 23.6g of azidotrimethylsilane in five batches on average, heating to room temperature, stirring at room temperature at 150 r/min for reaction, monitoring the reaction progress by TLC (a developing solvent is petroleum ether/ethyl acetate solvent with the volume ratio of 1: 1), reacting for 16H, and indicating the completion of the reaction by TLC; pouring the reaction solution into 600mL of 5mol/L aqueous solution of sodium hydroxide in an ice water bath, extracting with 600mL of ethyl acetate for three times, combining organic phases, and concentrating under reduced pressure to remove the solvent; the crude product was purified by column chromatography on silica gel (eluent was petroleum ether/ethyl acetate solvent at a volume ratio of 2: 1) and concentrated under reduced pressure to remove the solvent, yielding 3.2g of 9-chloro-3, 4-dihydrobenzo-1, 4-thiazepin-5 (2H) -one as a white solid with a yield of 9%.
The reaction process of step S4 is as follows:
s5 carbonyl reduction: adding 1.5g of 9-chloro-3, 4-dihydrobenzo-1, 4-thiazepin-5 (2H) -ketone into a 100mL three-neck flask, adding 30mL of tetrahydrofuran, stirring at the rotating speed of 50 r/min, cooling to 5 ℃ in an ice water bath, adding 0.8g of lithium aluminum hydride in five batches, heating to 65 ℃ for reaction, monitoring the reaction progress by TLC (a developing agent is ethyl acetate), reacting for 3H, and indicating that the reaction is complete by TLC; cooling the reaction solution to 5 ℃ by using an ice water bath, and sequentially adding 0.8mL of water, 2.4mL of a 15% sodium hydroxide aqueous solution and 0.8mL of water; filtering, collecting filtrate, concentrating the filtrate under reduced pressure to remove solvent to obtain 9-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine, and directly feeding the crude product into the next step.
The reaction process of step S5 is as follows:
s6 amine protection: taking 2.3g of the crude product prepared in the step S5, dissolving the crude product in 50mL of dichloromethane, adding 1.4g of triethylamine and 2.3g of di-tert-butyl dicarbonate, stirring at the room temperature at the rotation speed of 100 revolutions per minute for reaction, monitoring the reaction progress by TLC (a developing agent is ethyl acetate), and after reacting for 120min, indicating that the reaction is finished by TLC; concentrating the reaction solution under reduced pressure to remove the solvent; the crude product was purified by column chromatography on silica gel (eluent was petroleum ether/ethyl acetate solvent in a volume ratio of 3: 1) and concentrated under reduced pressure to remove the solvent to give 1.3g of tert-butyl-9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate as a white solid in a total yield of 61% over the two steps S5 and S6.
The reaction process of step S6 is as follows:
s7 oxidation of benzothiepin: taking 1.3g of tert-butyl-9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate prepared in the step S6, transferring the tert-butyl-9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate into a 100mL reaction bottle, adding 50mL of dichloromethane, cooling the mixture to 5 ℃ in an ice water bath, adding 2.3g of m-chloroperoxybenzoic acid in three batches, stirring the mixture at room temperature at the rotating speed of 100 r/min for reaction,monitoring the reaction progress by TLC (a developing solvent is a petroleum ether/ethyl acetate solvent with the volume ratio of 1: 1), and after reacting for 180min, monitoring by TLC to show that the reaction is finished; filtration, collection of the filtrate, addition of 50mL saturated NaHCO to the filtrate 3 Layering the aqueous solution, and collecting an organic phase; concentrating the organic phase under reduced pressure to remove the solvent; the crude product was purified by column chromatography on silica gel (eluent was petroleum ether/ethyl acetate solvent in a volume ratio of 3: 1), and concentrated under reduced pressure to remove the solvent, to give 1.2g of 9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide as a white solid with a yield of 90%.
The reaction process of step S7 is as follows:
deprotection of the S8 amine group: taking 1.2g of the 9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide prepared in the step S7, transferring the mixture into a 100mL single-mouth bottle, adding 20mL of dichloromethane, cooling the system to 5 ℃ in ice water bath, adding 4mL of dioxane hydrochloride solution with the hydrogen chloride concentration of 4mol/L, stirring the mixture at room temperature at the rotating speed of 50 revolutions/minute for reaction, monitoring the reaction progress by using an LCMS (liquid Crystal display System), and after the reaction is carried out for 120min, monitoring by using the LCMS to show that the reaction is finished; concentrating under reduced pressure to remove the solvent, dissolving the crude product in 20mL of methanol, dissolving the crude product in NH 3 The pH was adjusted to 9 with 7mol/L ammonia-methanol solution (balance methanol) and concentrated 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 water, phase B is acetonitrile) to give 520mg of white solid product with a yield of 62%.
The reaction process of step S8 is 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 o-chlorothiophenol added in examples 2 to 8 were all 50g, and 1.5g of t-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate prepared in step S4 was used in the subsequent step in step S5, and all the products prepared in the previous step were used in the subsequent step. 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 amounts of solvents used in the respective steps of examples 2 to 8 were kept the same as in example 1 except for the amount of water used in the step S2 and the amount of trifluoroacetic acid used in the step S4 (see Table 2 for the amounts of water used in the step S2 and the amount of trifluoroacetic acid used in the step S4 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 compounding ratio of each raw material 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
Example 9
Various methods for testing the inhibitory activity of Respiratory Syncytial Virus (RSV) are disclosed in the prior art, and the test was carried out according to the method described in the grant No. CN 104004042B; firstly, different medicaments are prepared according to the following method:
drug preparation experiment a: preparing 2,3,4, 5-tetrahydro-1, 4-benzothiazacycloheptatriene-1, 1-dioxide according to the method disclosed in the application publication No. CN109879837A, and preparing N- [ (3-aminooxetan-3-yl) methyl ] -2- (1, 1-dioxo-3, 5-dihydro-1, 4-benzothiazacycloheptatriene-4-yl) -6-methyl-quinazolin-4-amine which is marked as drug A from 2,3,4, 5-tetrahydro-1, 4-benzothiazacycloheptatriene-1, 1-dioxide;
drug preparation experiment B: the 2,3,4, 5-tetrahydro-1, 4-benzothiepin-1, 1-dioxide from drug preparation experiment A was replaced by an equivalent amount of the halogenated benzothiepin oxide product prepared in example 1, all of which were otherwise identical to drug preparation experiment A. Substitution of the secondary amine groups on the halogenated benzothiepin oxide with the chloro groups on the methyl N- [3- [ [ (2-chloro-6-methyl-quinazolin-4-yl) amino ] methyl ] oxetan-3-yl ] carbamate (4-methoxyphenyl) ester to give the methyl N- [3- [ [ [2- (1, 1-dioxo-9-chloro-3, 5-dihydro-1, 4-benzothiepin-4-yl) -6-methyl-quinazolin-4-yl ] amino ] methyl ] oxetan-3-yl ] carbamate (4-methoxyphenyl) ester, hydrolysis of the carbamate groups on the molecule, purifying to obtain N- [ (3-aminooxetan-3-yl) methyl ] -2- (1, 1-dioxo-9-chloro-3, 5-dihydro-1, 4-benzothiazacycloheptatrien-4-yl) -6-methyl-quinazolin-4-amine which is marked as medicine B.
Water solubility experiments were performed for drug A and drug B as follows: adding 100g of purified water into a 250mL beaker, stirring at a rotating speed of 200 rpm, adding 0.1g of the medicine, continuing stirring for 10min to completely dissolve the medicine, visually observing whether undissolved solid exists in the beaker, repeating the medicine adding process until undissolved solid exists if undissolved solid does not exist in the beaker, recording the total weight of the added medicine, calculating the solubility of the medicine, and dividing the total weight of the medicine by 100 to obtain the medicine solubility. The results are shown in Table 5.
TABLE 5 comparison of solubility of different drugs
| Medicine | Medicine A | Medicine B |
| Solubility (g/100g) | 1.8 | 11.3 |
As shown in the above table, compared with the drug a prepared from the halogen-free benzothiepin oxide, the drug B prepared from the halogenated benzothiepin oxide product prepared by the present invention as an intermediate has significantly improved water solubility, is easy to be absorbed by human body, and is helpful for improving drug efficacy.
Test experiment of Respiratory Syncytial Virus (RSV) inhibitory activity on drug A, drug B and ribavirin to test half effective concentration (IC) respectively 50 ) And half Toxic Concentration (TC) 50 ) And calculating the toxicity inhibiting index (TI), which is TC 50 /IC 50 . The results are shown in Table 6
TABLE 6 comparison of the pharmacological effects of the different compounds
| Medicine | Medicine A | Medicine B | Ribavirin |
| IC 50 (μM) | 1.56 | 0.28 | 23.52 |
| TC 50 (μM) | 35.2 | 34.6 | ﹥3000 |
| TC 50 /IC 50 | 22.56 | 123.6 | ﹥127.5 |
Test results show that the halogenated benzothiepin oxide product prepared by the invention is used as an intermediate to prepare IC of the drug B 50 The value is only 0.28 mu M, and compared with the existing drug ribavirin and the drug A prepared by using halogen-free benzothiepin oxide, the half effective concentration (IC) of the drug B prepared by using the halogenated benzothiepin oxide product prepared by the invention as an intermediate 50 ) The preparation method has the advantages that the effect is remarkably reduced, the medicine B prepared by taking the halogenated benzothiepin oxide product prepared by the preparation method as an intermediate has better efficacy, the medicine B has higher toxicity inhibiting index, and the toxicity inhibiting index (TI) exceeds 100. The medicament B prepared by taking the halogenated benzothiepin oxide product prepared by the invention as an intermediate has excellent inhibitory activity on RSV infection, can be used for preventing and treating the field of anti-RSV infection viruses, and has wide application prospect.
The embodiments of the present invention are all preferred embodiments of the present invention, and the scope of the present invention is not limited thereby, 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 (3)
1. A preparation method of 9-chloro-2, 3,4, 5-tetrahydro-1, 4-phenylpropanethiazepine-1, 1-dioxide is characterized in that the reaction process is as follows:
the method comprises the following steps:
s1 thioalkylation
Weighing 50g of o-chlorothiophenol, transferring the o-chlorothiophenol into a 2000mL three-neck flask, adding 1000mL of ethanol, stirring at the rotating speed of 300 r/min, adding 143.8 g of potassium carbonate and 94.2g of ethyl 3-bromopropionate, heating to 80 ℃ for reaction, monitoring the reaction progress by a TLC point plate, wherein the volume ratio of a TLC developing agent is 20: 1, reacting for 60min, and displaying the completion of the reaction by TLC; cooling to room temperature, filtering, and concentrating the filtrate under reduced pressure to remove the solvent;
purifying the crude product by a chromatographic silica gel column, wherein the volume ratio of eluent is 20: 1, concentrating under reduced pressure to remove the solvent to obtain 82.4g of ethyl 3- (2-chlorophenylthio) propionate as colorless oil;
hydrolysis of S2 Ethyl propionate
Preparing 27.0g of sodium hydroxide and 400mL of water into a sodium hydroxide solution; weighing 82.4g of ethyl 3- (2-chlorophenylthio) propionate prepared in the step S1, dissolving the ethyl 3- (2-chlorophenylthio) propionate in 400mL of tetrahydrofuran, stirring at the rotating speed of 200 r/min, cooling to 4 ℃ in an ice water bath, adding a sodium hydroxide solution, heating to room temperature for reaction, monitoring the reaction progress by TLC, and preparing a TLC developing agent with the volume ratio of 1:1, petroleum ether/ethyl acetate solvent, and after reacting for 16 hours, TLC shows that the reaction is finished; concentrating under reduced pressure to remove the solvent, and extracting the water phase with 600mL ethyl acetate for three times to remove impurities; collecting the water phase, cooling the water phase to 5 ℃ by using an ice water bath, adding 6mol/L hydrochloric acid aqueous solution to adjust the pH of the water phase to 1, extracting the water phase with 800mL of ethyl acetate twice each time, combining all organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, collecting filtrate, and concentrating the filtrate under reduced pressure to remove the solvent to obtain 64.2g of 3- (2-chlorphenyl thio) propionic acid which is a white solid;
s3 Ring closure reaction
Taking 150mL of sulfuric acid, cooling to 5 ℃ in an ice-water bath, adding 64.2g of 3- (2-chlorophenylthio) propionic acid prepared in the step S2 into the sulfuric acid in five times on average, heating to room temperature for reaction, monitoring the reaction progress by TLC, and developing by using TLC developing agent in a volume ratio of 5: 1, petroleum ether/ethyl acetate solvent, reacting for 120min, and displaying the completion of the reaction by TLC; the reaction was poured into 1600mL of ice water, in ice: the water mass ratio is 1:1, precipitating a large amount of solid, filtering, collecting the solid, washing the solid to be neutral by using water, and removing residual solvent and water in the solid by decompression and concentration; purifying the crude product by a chromatographic silica gel column, wherein the volume ratio of eluent is 8: 1, concentrated under reduced pressure to remove the solvent to give 31.2g of 9-chloro-3, 4-dihydro-2H-1-benzothiopyran-4-one as a white solid;
s4 Azide reaction
Dissolving 31.2g of 9-chloro-3, 4-dihydro-2H-1-benzothiopyran-4-ketone prepared in the step S3 in 160mL of trifluoroacetic acid, cooling to 5 ℃ in an ice water bath, adding 23.6g of azidotrimethylsilane in five batches on average, heating to room temperature, stirring at room temperature at 150 r/min for reaction, monitoring the reaction progress by TLC, reacting for 16H by using a TLC developing agent which is a petroleum ether/ethyl acetate solvent in a volume ratio of 1:1, and finishing the reaction by TLC; pouring the reaction solution into 600mL of 5mol/L aqueous solution of sodium hydroxide in an ice water bath, extracting with 600mL of ethyl acetate for three times, combining organic phases, and concentrating under reduced pressure to remove the solvent; purifying the crude product by a chromatographic silica gel column, wherein the volume ratio of eluent is 2: 1, concentrating under reduced pressure to remove the solvent to obtain 3.2g of 9-chloro-3, 4-dihydrobenzo-1, 4-thiazepin-5 (2H) -one as a white solid;
s5 carbonyl reduction
Adding 1.5g of 9-chloro-3, 4-dihydrobenzo-1, 4-thiazepine-5 (2H) -ketone into a 100mL three-neck flask, adding 30mL of tetrahydrofuran, stirring at the rotating speed of 50 r/min, cooling to 5 ℃ in an ice water bath, adding 0.8g of lithium aluminum hydride in five batches, heating to 65 ℃ for reaction, monitoring the reaction progress by TLC (thin layer chromatography), using ethyl acetate as a TLC developing agent, reacting for 3H, and indicating that the reaction is complete by TLC; cooling the reaction solution to 5 ℃ by using an ice water bath, and sequentially adding 0.8mL of water, 2.4mL of a 15% sodium hydroxide aqueous solution and 0.8mL of water; filtering, collecting filtrate, concentrating the filtrate under reduced pressure to remove solvent to obtain 9-chloro-2, 3,4, 5-tetrahydro-benzo-1, 4-thiazepine, and directly feeding the crude product into the next step;
s6 amino group protection
Taking 2.3g of the crude product prepared in the step S5, dissolving the crude product in 50mL of dichloromethane, adding 1.4g of triethylamine and 2.3g of di-tert-butyl dicarbonate, stirring at the room temperature at the rotation speed of 100 revolutions per minute for reaction, monitoring the reaction progress by TLC, using ethyl acetate as a TLC developing agent, and after reacting for 120min, indicating the completion of the reaction by TLC; concentrating the reaction solution under reduced pressure to remove the solvent; purifying the crude product by a chromatographic silica gel column, wherein the volume ratio of eluent is 3: 1, concentrating under reduced pressure to remove the solvent to obtain 1.3g of tert-butyl-9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate as a white solid;
s7 oxidation of benzothiepins
Taking 1.3g of tert-butyl-9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate prepared in the step S6, transferring the tert-butyl-9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate into a 100mL reaction bottle, adding 50mL of dichloromethane, cooling the temperature to 5 ℃ in an ice water bath, adding 2.3g of m-chloroperoxybenzoic acid in three batches, stirring the mixture at room temperature at the rotating speed of 100 r/min for reaction, monitoring the reaction progress by TLC, wherein a TLC developing agent is a petroleum ether/ethyl acetate solvent with the volume ratio of 1:1, and after reacting for 180min, monitoring by TLC to show that the reaction is finished; filtration, collection of the filtrate, addition of 50mL saturated NaHCO to the filtrate 3 Layering the aqueous solution, and collecting an organic phase; concentrating the organic phase under reduced pressure to remove the solvent; purifying the crude product by a chromatographic silica gel column, wherein the volume ratio of eluent is 3: 1, concentrating under reduced pressure to remove the solvent to obtain 1.2g of 9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide in the form of white solid;
deprotection of the S8 amine group
Taking 1.2g of the 9-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide prepared in the step S7, transferring the mixture into a 100mL single-mouth bottle, adding 20mL of dichloromethane, and carrying out ice-water bath to obtain a systemCooling to 5 ℃, adding 4mL of dioxane hydrochloride solution with the hydrogen chloride concentration of 4mol/L, stirring at the room temperature at the rotating speed of 50 r/min for reaction, monitoring the reaction progress by LCMS, and after reacting for 120min, monitoring by LCMS to show that the reaction is finished; concentrating under reduced pressure to remove the solvent, dissolving the crude product in 20mL of methanol, and dissolving the crude product in NH 3 Adjusting the pH value to 9 by 7mol/L ammonia-methanol solution, and decompressing and concentrating to remove the solvent; the crude product is prepared by medium-pressure liquid phase, and the medium-pressure liquid phase preparation conditions are as follows: c18 chromatographic column, mobile phase A is 0.05% (v/v) ammonia water, B is acetonitrile, and white solid product 520mg is obtained.
2. A9-chloro-2, 3,4, 5-tetrahydro-1, 4-phenylpropanethiazepine-1, 1-dioxide, characterized in that: the 9-chloro-2, 3,4, 5-tetrahydro-1, 4-phenylpropaneazazepine-1, 1-dioxide as claimed in claim 1.
3. Use of the 9-chloro-2, 3,4, 5-tetrahydro-1, 4-phenylpropaneazepine-1, 1-dioxide of claim 2, wherein: the 9-chloro-2, 3,4, 5-tetrahydro-1, 4-phenylpropaneazepine-1, 1-dioxide is used as an intermediate for preparing an active component of a medicament for preventing and treating RSV.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010493832.7A CN111574475B (en) | 2020-06-03 | 2020-06-03 | Preparation method of halogenated benzothiepin oxide, product prepared by preparation method and application of product |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010493832.7A CN111574475B (en) | 2020-06-03 | 2020-06-03 | Preparation method of halogenated benzothiepin oxide, product prepared by preparation method and application of product |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111574475A CN111574475A (en) | 2020-08-25 |
| CN111574475B true CN111574475B (en) | 2022-09-20 |
Family
ID=72118018
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010493832.7A Active CN111574475B (en) | 2020-06-03 | 2020-06-03 | Preparation method of halogenated benzothiepin oxide, product prepared by preparation method and application of product |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111574475B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998005657A1 (en) * | 1996-08-02 | 1998-02-12 | Knoll Aktiengesellschaft | 2,3-dihydro-1,4-benzothiazepines, their preparation and their use as intermediates |
| CN102361860A (en) * | 2009-03-20 | 2012-02-22 | 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 |
| CN104004042A (en) * | 2014-05-17 | 2014-08-27 | 中国海洋大学 | Steroidal compound as well as preparation method and application of steroidal compound taken as antiviral agent |
| 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 |
-
2020
- 2020-06-03 CN CN202010493832.7A patent/CN111574475B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998005657A1 (en) * | 1996-08-02 | 1998-02-12 | Knoll Aktiengesellschaft | 2,3-dihydro-1,4-benzothiazepines, their preparation and their use as intermediates |
| CN102361860A (en) * | 2009-03-20 | 2012-02-22 | 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 |
| 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 |
| CN104004042A (en) * | 2014-05-17 | 2014-08-27 | 中国海洋大学 | Steroidal compound as well as preparation method and application of steroidal compound taken as antiviral agent |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111574475A (en) | 2020-08-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2007267733B2 (en) | Compounds and compositions as channel activating protease inhibitors | |
| EP3412665B1 (en) | Suvorexant intermediates and preparation methods thereof | |
| CN102762535B (en) | Methods of synthesizing and isolating n-(bromoacetyl)-3,3-dinitroazetidine and a composition including the same | |
| AU2004259741A1 (en) | (2S,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt and anhydrous crystalline forms thereof | |
| CN105061425A (en) | Synthesis method of diazabicyclo octanone sulfuric acid monoester | |
| CN106966947A (en) | A kind of preparation method of vildagliptin | |
| CN109761924A (en) | A kind of post-processing approach of improved Valsartan reaction mixture | |
| CN111574475B (en) | Preparation method of halogenated benzothiepin oxide, product prepared by preparation method and application of product | |
| CN111606970A (en) | 1, 5-diazabicyclo [5,3,0] deca-alkanone amino acid derivative and preparation method and application thereof | |
| CN106518694A (en) | Novel preparation method of L-alanine isopropyl ester hydrochloride | |
| CN110655517A (en) | Preparation method of doriravir open-loop impurities and impurities thereof | |
| CN110204505A (en) | (S) preparation process of -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione | |
| CN103405435B (en) | Application of clinafloxacin amino derivatives and medicinal salts thereof in preparing antitubercular medicaments | |
| CN107074858A (en) | The method for preparing the carboxylic acid sodium of (2S, 5R) 6 (benzyloxy) 7 oxo 1,6 diazabicylo [3.2.1] octane 2 | |
| CN115720580A (en) | Process for preparing phthalazinone derivatives and intermediates thereof | |
| CN106946907A (en) | Method and the application of tacrolimus are isolated and purified from mycelium | |
| CN111548325A (en) | Preparation method of halogenated benzothiazepine compound, product prepared by preparation method and application of product | |
| CN106699604A (en) | Sacubitril and preparation method of midbody of sacubitril | |
| CN115304619A (en) | Crystal form of rubitinid and preparation method thereof | |
| CN111620838A (en) | Preparation method of chloro-benzothiepin compound, product prepared by preparation method and application of chloro-benzothiepin compound | |
| CN110981879B (en) | Method for preparing NS5A inhibitor-wipatasvir | |
| EP2170872B1 (en) | Process for the preparation of the n-(2-chloro-4-methyl-3-thienyl)-1h- benzimidazol-2-amine hydrochloride and intermediates thereof | |
| CN112679406A (en) | Continuous preparation method of vildagliptin | |
| CN111518055A (en) | Preparation method of benzothiazepine oxide, product prepared by preparation method and application of product | |
| EP0991630A1 (en) | Crystalline roxifiban |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |