CN111620838A - Preparation method of chloro-benzothiepin compound, product prepared by preparation method and application of chloro-benzothiepin compound - Google Patents
Preparation method of chloro-benzothiepin compound, product prepared by preparation method and application of chloro-benzothiepin compound Download PDFInfo
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- 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
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- 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
Abstract
The invention discloses a preparation method of a chloro-benzothiepin compound, a prepared product and application thereof, relating to the technical field of chemical synthesis; a preparation method of a chlorobenzenethiazine compound takes 2-chloro-6-fluoro-benzaldehyde as an initial raw material, and prepares a chlorobenzenethiazine compound product of 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide through steps of sulfo-group, aldehyde-amine condensation, amine-carbon addition, amino protection, oxidation, amino deprotection and the like; the preparation method of the chloro-benzothiepin compound has the advantage of convenient introduction of chlorine element; the chloro-benzothiepin compound product has the advantage of expanding the application range of the product to a certain extent.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of a chlorobenzothiazepine compound, a product prepared by the preparation method and application of the product.
Background
The benzothiazepine compound is an important drug synthesis intermediate, and the drug synthesized by taking the benzothiazepine compound as the intermediate has better pharmacological activity and physiological activity and has the effects of resisting blood coagulation, resisting atherosclerosis, resisting ischemia, resisting depression, resisting fungi and the like. Has wide application in the field of drug synthesis.
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 halogen on molecules are available, the introduction of halogen, especially chlorine, on the medical intermediates is beneficial to expanding the application range of the medical intermediates, and no report is available at present that chlorine is introduced on the benzene ring of 2,3,4, 5-tetrahydro-1, 4-benzothiepin-1, 1-dioxide intermediates.
Disclosure of Invention
In view of the defects of the prior art, the first object of the invention is to provide a preparation method of chlorobenzenethiazine compound, which has the advantage of convenient introduction of chlorine element.
The second purpose of the invention is to provide a chlorobenzenethiazine compound which has the advantage of expanding the application range of the product to a certain extent.
The third purpose of the invention is to provide an application of the chlorobenzenethiazine compound, 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 a chlorobenzenethiazepine compound has the following reaction scheme:
which comprises the following steps:
s1 thio: under the action of alkali carbonate, 2-chloro-6-fluoro-benzaldehyde reacts with 2-tert-butyloxycarbonylaminoethanethiol to prepare tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate;
s2 condensation of aldehyde with amine: under the action of an acid reagent, carrying out an aldehyde-amine condensation reaction on tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate to prepare 6-chloro-2, 3-dihydro-1, 4-benzothiazepine;
s3 amine carbon addition: under the action of a reducing agent, 6-chloro-2, 3-dihydro-1, 4-benzothiazepine is subjected to addition reaction to prepare 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine;
s4 amine protection: carrying out ester exchange reaction on di-tert-butyl dicarbonate and 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine to prepare tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate;
s5 oxidation: under the action of an oxidant, tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate undergoes an oxidation reaction to prepare 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide;
deprotection of the S6 amine group: under the action of an acidic reagent, 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide undergoes acidolysis reaction to prepare a chlorobenzenethiazole compound product.
By adopting the technical scheme, 2-chloro-6-fluoro-benzaldehyde is used as an initial raw material, reacts with 2-tert-butoxycarbonylaminoethanethiol under the action of alkali metal carbonate to generate tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate, then generates an aldehyde-amine condensation reaction under the action of an acidic reagent to prepare 6-chloro-2, 3-dihydro-1, 4-benzothiazepine, generates an addition reaction under the action of a reducing agent to prepare 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine, and oxidizes sulfur on molecules with an oxidizing agent under the protection of di-tert-butyl dicarbonate to prepare 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide, then preparing a chlorobenzenetetrazol compound of 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide through an amino deprotection step, preparing the 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide through a series of chemical reactions, and the compound can be used as an intermediate for synthesizing various medicaments, thereby expanding the application range of benzothiazepine compounds to a certain extent.
Preferably, the method comprises the following steps:
s1 thio: under the action of alkali carbonate, 2-chloro-6-fluoro-benzaldehyde reacts with 2-tert-butyloxycarbonylaminoethanethiol at 65-75 ℃ for 280-320 min, and the tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate is prepared after purification; the reaction materials are fed according to the following molar ratio: 2-chloro-6-fluoro-benzaldehyde: 2-tert-Butoxycarbonylaminoethanethiol: alkali metal carbonate ═ 1: 1.8-2.2: 2.2-2.8;
s2 condensation of aldehyde with amine: under the action of an acidic reagent, reacting tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate at room temperature for 12-20 h, and purifying to obtain 6-chloro-2, 3-dihydro-1, 4-benzothiazepine;
s3 amine carbon addition: reacting 6-chloro-2, 3-dihydro-1, 4-benzothiazepine at room temperature for 20min to 50min under the action of a reducing agent to prepare 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine; the reaction materials are fed according to the following molar ratio: 6-chloro-2, 3-dihydro-1, 4-benzothiazepine: reducing agent 1: 1.3-1.7;
s4 amine protection: reacting di-tert-butyl dicarbonate with 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine at room temperature for 40min to 80min, and purifying to obtain tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate; the reaction materials are fed according to the following molar ratio: 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine: di-tert-butyl dicarbonate 1: 1-1.2;
s5 oxidation: under the action of an oxidant, tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate is subjected to oxidation reaction at room temperature for 8h to 12h, and then purified to obtain 6-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-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate: oxidant 1: 2.8-3.2;
deprotection of the S6 amine group: under the action of an acidic reagent, reacting 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide at room temperature for 280-320 min, and purifying to obtain the chloro benzothiazepine compound product.
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 alkali metal carbonate is cesium carbonate.
By adopting the technical scheme, the cesium carbonate with moderate alkalinity and activity is used in the step S1, which is beneficial to controlling the reaction rate of the thionation reaction in the step S1, so that the step S1 is carried out under mild reaction conditions, thereby being convenient for improving the conversion rate, reducing the production of byproducts, improving the reaction yield, reducing the synthesis cost of products, improving the market competitiveness of the products, improving the market value of the products and expanding the application range of the products.
Preferably, the reducing agent is sodium borohydride.
By adopting the technical scheme, the sodium borohydride reducing agent with proper activity is selected, and the reducing agent with high activity is not selected, so that the reaction rate of the S3 addition reaction is favorably controlled, the step S3 is carried out under the mild condition of room temperature, the reaction is prevented from being too violent, the occurrence of side reactions is reduced, the conversion rate is improved, the product synthesis cost is reduced, the product market competitiveness is improved, the product market value is improved, and the product application range is enlarged.
Preferably, the oxidizing agent is m-chloroperoxybenzoic acid.
By adopting the technical scheme, the m-chloroperoxybenzoic acid oxidant with proper activity is selected instead of the oxidant with violent reaction or slow reaction, so that the step S5 is subjected to oxidation reaction at room temperature, the oxidation reaction is prevented from being carried out at high temperature or low temperature, the energy consumption is prevented from being improved due to the atmosphere needing high temperature or low temperature reaction, 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 acidic reagent is hydrogen chloride solution with the concentration of 4mol/L hydrochloric acid dioxane (the rest is dioxane).
By adopting the technical scheme, the use of the dioxane solution can provide an acidic environment required by the acidolysis reaction in the steps S2 and S6, and simultaneously improves the compatibility of an acidic reagent with each raw material and reaction solvent in the steps S2 and S6, the reaction rate, the reaction yield, the synthesis cost, the product market competitiveness, the product market value and the product application range.
Preferably, the ratio of tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate to hydrogen chloride in step S2 is 1:0.9-1.1 (molar ratio); in the step S6, the ratio of 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide to hydrogen chloride is 1:4.2-4.8 (molar ratio).
By adopting the technical scheme, the aldehyde-amine condensation reaction in the step S2 is beneficial to promoting the acidolysis of tert-butyl ester, less acid reagent is used in the step S2, and the weak alkaline sodium bicarbonate can be used for neutralizing the residual acidity of the reaction system in the post-treatment process of the step S2, so that the use of ammonia water which is unfavorable to human health and has pungent smell is avoided, and the environmental protection property is improved; the acidolysis reaction in the step S6 is slow, and more acidic reagents are needed, so that the reaction conversion rate is improved, the product yield is improved, the synthesis cost is reduced, the product market competitiveness is improved, the product market value is improved, and the product application range is expanded.
In order to achieve the second object, the invention provides the following technical scheme: a chlorobenzenethiazepine compound is prepared by the preparation method of the chlorobenzenethiazepine compound.
By adopting the technical scheme, the chloro-benzothiazepine compound prepared by the preparation method of the chloro-benzothiazepine compound disclosed by the invention can be used as an intermediate for synthesizing various medicines, and the application range of the chloro-benzothiazepine compound is expanded to a certain extent.
In order to achieve the third object, the invention provides the following technical solutions: the application of the chlorobenzenethiazepine compound as an intermediate in preparing active components of RSV preventing and treating medicines.
By adopting the technical scheme, the chloro-benzothiepin compound is used as an intermediate for preparing the active component of the medicament for preventing and treating RSV, has certain preventing and treating effects, and enlarges the application range of the product to a certain extent.
In summary, the invention includes at least one of the following beneficial technical effects:
1. the method takes 2-chloro-6-fluoro-benzaldehyde as an initial raw material, the initial raw material reacts with 2-tert-butyloxycarbonylaminoethanethiol under the action of an alkaline reagent to generate tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate, then under the action of an acidic reagent, an aldehyde-amine condensation reaction is carried out to prepare 6-chloro-2, 3-dihydro-1, 4-benzothiazepine, 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine is prepared through an addition reaction, under the protection of di-tert-butyl dicarbonate, an oxidant is used to oxidize sulfur on molecules to prepare 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide, then preparing a chloro-benzothiazepine compound of 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide through an amido deprotection step, preparing 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide through a series of chemical reactions, being capable of being used as an intermediate for synthesizing various medicaments, and expanding the application range of benzothiazepine compounds to a certain extent;
2. the invention uses proper alkali carbonate, reducer, oxidant and acid reagent to make each step of reaction under mild reaction condition, thus reducing process cost, improving reaction yield, reducing synthesis cost, improving product market competitiveness, improving product market value and expanding product application range;
3. according to the invention, the aldehyde-amine condensation reaction in the step S2 is beneficial to promoting the acidolysis of tert-butyl ester, less acidic reagent is used in the step S2, and the weak alkaline sodium bicarbonate can be used in the post-treatment process of the step S2 to neutralize the residual acidity of the reaction system, so that the use of ammonia water which is unfavorable to human health and has pungent smell is avoided, and the environmental protection property is improved; the acidolysis reaction in the step S6 is slow, and more acidic reagents are needed, so that the reaction conversion rate is improved, the product yield is improved, the synthesis cost is reduced, the product market competitiveness is improved, the product market value is improved, and the product application range is expanded.
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 |
| 2-chloro-6-fluoro-benzaldehyde | Purity 98% | DUCHUANG (SHANGHAI) MEDICINE TECHNOLOGY Co.,Ltd. |
| 2-Boc-aminoethanethiol | Purity 98% | DUCHUANG (SHANGHAI) MEDICINE TECHNOLOGY Co.,Ltd. |
| Cesium carbonate | Purity of 99% | Shanghai Yixue chemical Co Ltd |
| N, N-dimethylformamide | Purity of 99% | TIANJIN DAMAO CHEMICAL REAGENT FACTORY |
| Dioxane solution of hydrochloric acid | 4mol/L | Shanghai Yingshuo New Material science and technology Co Ltd |
| Methylene dichloride | Purity of 99% | TIANJIN DAMAO CHEMICAL REAGENT FACTORY |
| Sodium borohydride | Purity 95% | Sai' an Keluo glass Instrument Co Ltd |
| Methanol | Purity of 99% | TIANJIN DAMAO CHEMICAL REAGENT FACTORY |
| Di-tert-butyl dicarbonate | Purity 98% | BIDE PHARMATECH Ltd. |
| Meta-chloroperoxybenzoic acid | The purity is 85 percent | Shanghai Yixue chemical Co Ltd |
Example 1
A preparation method of chloro-benzothiepin compounds comprises the following steps:
s1 thio: weighing 15g of 2-chloro-6-fluoro-benzaldehyde, adding the 2-chloro-6-fluoro-benzaldehyde into a 500mL three-neck flask, adding 200mL of dimethylformamide, stirring at the rotating speed of 200 revolutions per minute, adding 34g of 2-tert-butoxycarbonylaminoethanethiol and 77g of cesium carbonate, heating to 70 ℃, continuing stirring, monitoring the reaction progress by TLC (a developing agent is a petroleum ether/ethyl acetate solvent with the volume ratio of 20: 1), and after reacting for 300min, indicating that the reaction is finished by TLC; filtering, collecting filtrate, adding 500mL of water into the filtrate, extracting with 400mL of ethyl acetate for three times, combining organic phases, and concentrating under reduced pressure to remove the solvent; the crude product was purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate solvent at a volume ratio of 5: 1), and concentrated under reduced pressure to remove the solvent, to give 24.0g of tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate as a yellow solid in 80% yield.
The reaction of step S1 is schematically as follows:
s2 condensation of aldehyde with amine: dissolving 24.0g of tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate prepared in the step S1 in 250mL of N, N-dimethylformamide, stirring at the rotating speed of 150 revolutions per minute, cooling to 5 ℃ in an ice-water bath, and adding 25mL of 4mol/L dioxane hydrochloride solution; raising the temperature to room temperature, monitoring the reaction progress by LCMS, reacting for 16h, and monitoring by LCMS to show that the reaction is finished; concentrating under reduced pressure to remove organic solvent; adding 300mL of methanol into the solid obtained by vacuum concentration, adding 60g of sodium bicarbonate, stirring for 30min, and neutralizing to remove hydrochloric acid in the system; filtering, collecting filtrate, and concentrating the filtrate under reduced pressure to remove solvent to obtain 6-chloro-2, 3-dihydro-1, 4-benzothiazepine, wherein the crude product is directly fed into the next step.
The reaction of step S2 is schematically as follows:
s3 amine carbon addition: and (2) dissolving 15.0g of 6-chloro-2, 3-dihydro-1, 4-benzothiazepine prepared in the step S2 in 200mL of methanol, stirring at the rotating speed of 100 revolutions per minute, cooling to 5 ℃ in an ice water bath, adding 4.2g of sodium borohydride in five batches on average, 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 5: 1), after reacting for 30min, monitoring by TLC to show that the reaction is finished to prepare the 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine, and directly feeding the reaction solution to the next step.
The reaction of step S3 is schematically as follows:
s4 amine protection: directly adding 18.2g of di-tert-butyl dicarbonate into the reaction solution prepared in the step S3, stirring at the room temperature at the rotating speed of 150 revolutions per minute, 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 60min, monitoring by TLC to show that the reaction is finished; concentrating the reaction solution under reduced pressure to remove the solvent; the crude product was purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate solvent at a volume ratio of 3: 1), and the solvent was removed by concentration under reduced pressure to give 15.1g of tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate as a colorless oil.
The reaction of step S4 is schematically as follows:
s5 oxidation: taking 2g of tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate prepared in the step S4, transferring the tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate into a 100mL reaction bottle, adding 20mL of dichloromethane, stirring at a rotating speed of 50 revolutions/minute, cooling the mixture to 5 ℃ in an ice water bath, adding 5.2g of m-chloroperoxybenzoic acid in five batches on average, heating the mixture to room temperature for reaction, monitoring the reaction progress by LCMS, and after the reaction is carried out for 10 hours, monitoring by; filtering, recovering the mother liquor, adding 30mL of saturated sodium bicarbonate aqueous solution, layering, and collecting an organic phase; the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (eluent ethyl acetate) and concentrated under reduced pressure to remove the solvent, yielding 1.4g of 6-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 68%.
The reaction of step S5 is schematically as follows:
deprotection of the S6 amine group: taking 1.5g of 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide prepared in the step S5, transferring the 1.5g of 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester into a 100mL reaction bottle, adding 30mL of dichloromethane, stirring at the rotating speed of 100 revolutions per minute, cooling to 5 ℃ in an ice water bath, adding 6mL of 4mol/L dioxane hydrochloride solution, heating to room temperature to continue reaction, monitoring the reaction progress by LCMS, and after reacting for 300min, monitoring by LCMS to show that the reaction is finished; concentrating the reaction solution under reduced pressure to remove the solvent, adding 30mL of methanol for dissolving, 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 water, phase B is acetonitrile) to give 0.7g of chlorobenzothiazepine compound product as a white solid with a yield of 70%.
The reaction of step S6 is schematically as follows:
examples 2 to 8
Examples 2 to 8 were different from example 1 in the amount of each raw material added and the process parameters were different in examples 2 to 8, 15g of each 2-chloro-6-fluoro-benzaldehyde of examples 2 to 8 was added, 2.5g of t-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate obtained in step S4 was used in the subsequent step of step S5, all the products obtained in the previous step were used in the subsequent step of experiment, the purification schemes in examples 2 to 8 were the same as in example 1, and the feeding modes and feeding experimental conditions in examples 2 to 8 were the same as in example 1. 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 weight of the intermediate product and the final product in the steps S1, S5 and S6 were recorded during each set of experiments, and the reaction yield and the total yield were calculated, and the results of the reaction yields are shown in Table 4.
TABLE 4 comparison of the reaction yields in the different examples
| Experiment number | Step S1 yield (%) | Steps S2 to S5 yield (%) | Step S6 yield (%) | Total yield (%) |
| Example 1 | 80 | 68 | 70 | 38.08 |
| Example 2 | 79.5 | 69.2 | 71.2 | 39.17 |
| Example 3 | 80.3 | 69.7 | 70.6 | 39.51 |
| Example 4 | 80.6 | 67.4 | 69.4 | 37.70 |
| Example 5 | 79.8 | 66.3 | 69.8 | 36.93 |
| Example 6 | 81.3 | 69.9 | 68.5 | 38.93 |
| Example 7 | 78.6 | 70.3 | 68.1 | 37.63 |
| Example 8 | 79.4 | 66.8 | 71.6 | 37.98 |
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 takes 2-chloro-6-fluoro-benzaldehyde as an initial raw material, the initial raw material reacts with 2-tert-butyloxycarbonylaminoethanethiol to generate tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate, then aldehyde-amine condensation reaction is carried out to obtain 6-chloro-2, 3-dihydro-1, 4-benzothiazepine, 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine is prepared by addition reaction, under the protection action of di-tert-butyl dicarbonate, sulfur on molecules is oxidized by an oxidant to obtain 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide, then preparing a chloro-benzothiazepine compound of 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide through an amido deprotection step, preparing 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1, 1-dioxide through a series of chemical reactions, being capable of being used as an intermediate for synthesizing various medicaments, and expanding the application range of benzothiazepine compounds to a certain extent. The invention selects proper alkali metal carbonate, reducer, oxidant and acid reagent to make each step of reaction proceed under mild reaction condition, which reduces process cost, and selects proper process condition to improve reaction yield, reduce synthesis cost, improve product market competitiveness, improve product market value and enlarge product application range.
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 (9)
1. The preparation method of the chlorobenzenethiazine compound is characterized in that the reaction is as follows:
which comprises the following steps:
s1 thio: under the action of alkali carbonate, 2-chloro-6-fluoro-benzaldehyde reacts with 2-tert-butyloxycarbonylaminoethanethiol to prepare tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate;
s2 condensation of aldehyde with amine: under the action of an acid reagent, carrying out an aldehyde-amine condensation reaction on tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate to prepare 6-chloro-2, 3-dihydro-1, 4-benzothiazepine;
s3 amine carbon addition: under the action of a reducing agent, 6-chloro-2, 3-dihydro-1, 4-benzothiazepine is subjected to addition reaction to prepare 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine;
s4 amine protection: carrying out ester exchange reaction on di-tert-butyl dicarbonate and 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine to prepare tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate;
s5 oxidation: under the action of an oxidant, tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate undergoes an oxidation reaction to prepare 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide;
deprotection of the S6 amine group: under the action of an acidic reagent, 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide undergoes acidolysis reaction to prepare a chlorobenzenethiazole compound product.
2. The method for preparing chlorobenzenethiazepine compounds according to claim 1, which comprises the following steps:
s1 thio: under the action of alkali carbonate, 2-chloro-6-fluoro-benzaldehyde reacts with 2-tert-butyloxycarbonylaminoethanethiol at 65-75 ℃ for 280-320 min, and the tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate is prepared after purification; the reaction materials are fed according to the following molar ratio: 2-chloro-6-fluoro-benzaldehyde: 2-tert-Butoxycarbonylaminoethanethiol: alkali metal carbonate ═ 1: 1.8-2.2: 2.2-2.8;
s2 condensation of aldehyde with amine: under the action of an acidic reagent, reacting tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate at room temperature for 12-20 h, and purifying to obtain 6-chloro-2, 3-dihydro-1, 4-benzothiazepine;
s3 amine carbon addition: reacting 6-chloro-2, 3-dihydro-1, 4-benzothiazepine at room temperature for 20min to 50min under the action of a reducing agent to prepare 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine; the reaction materials are fed according to the following molar ratio: 6-chloro-2, 3-dihydro-1, 4-benzothiazepine: reducing agent 1: 1.3-1.7;
s4 amine protection: reacting di-tert-butyl dicarbonate with 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine at room temperature for 40min to 80min, and purifying to obtain tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate; the reaction materials are fed according to the following molar ratio: 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine: di-tert-butyl dicarbonate 1: 1-1.2;
s5 oxidation: under the action of an oxidant, tert-butyl-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-formate is subjected to oxidation reaction at room temperature for 8h to 12h, and then purified to obtain 6-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-6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylate: oxidant 1: 2.8-3.2;
deprotection of the S6 amine group: under the action of an acidic reagent, reacting 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-tert-butyl formate-1, 1-dioxide at room temperature for 280-320 min, and purifying to obtain the chloro benzothiazepine compound product.
3. The method for preparing a chlorobenzenethiazepine compound according to claim 2, wherein: the alkali metal carbonate is cesium carbonate.
4. The method for preparing a chlorobenzenethiazepine compound according to claim 2, wherein: the reducing agent is sodium borohydride.
5. The method for preparing a chlorobenzenethiazepine compound according to claim 2, wherein: the oxidant is m-chloroperoxybenzoic acid.
6. The method for preparing a chlorobenzenethiazepine compound according to claim 2, wherein: the acidic reagent is hydrochloric acid dioxane solution with the concentration of hydrogen chloride of 4mol/L (the rest is dioxane).
7. The method for preparing a chlorobenzenethiazepine compound according to claim 5, wherein: the ratio of tert-butyl (2- ((3-chloro-2-formylphenyl) thio) ethyl) carbamate to hydrogen chloride in said step S2 is 1:0.9-1.1 (molar ratio); in the step S6, the ratio of 6-chloro-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-4-carboxylic acid tert-butyl ester-1, 1-dioxide to hydrogen chloride is 1:4.2-4.8 (molar ratio).
8. A chlorobenzenethiazepine compound is characterized in that: prepared by the method for preparing the chlorobenzenethiazepine compound as claimed in any one of claims 1 to 7.
9. Use of a chlorobenzenethiazepine compound as claimed in claim 8, wherein: the chloro-benzo-thiazepine compound is used as an intermediate for preparing an active component of a medicament for preventing and treating RSV.
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| CN111548325A (en) * | 2020-05-16 | 2020-08-18 | 西安都创医药科技有限公司 | Preparation method of halogenated benzothiazepine compound, product prepared by preparation method and application of product |
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