CN113651796A - Preparation method of sertaconazole nitrate intermediate - Google Patents
Preparation method of sertaconazole nitrate intermediate Download PDFInfo
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- CN113651796A CN113651796A CN202110819628.4A CN202110819628A CN113651796A CN 113651796 A CN113651796 A CN 113651796A CN 202110819628 A CN202110819628 A CN 202110819628A CN 113651796 A CN113651796 A CN 113651796A
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- chlorobenzo
- thiophene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Abstract
The invention discloses a preparation method of a sertaconazole nitrate intermediate, which takes cyclohexane as a reaction solvent, and leads 3-methyl-7-chlorobenzo [ b ] thiophene to react with a bromination reagent in the presence of benzoyl peroxide to generate 3-bromomethyl-7-chlorobenzo [ b ] thiophene. The invention uses cyclohexane as reaction solvent to carry bromination reaction for preparing 3-bromomethyl-7-chlorobenzo [ b ] thiophene. Cyclohexane is less toxic than carbon tetrachloride and does not react with ozone and destroy the atmosphere. And the use of the method is not limited, and the method is more favorable for industrial production.
Description
Technical Field
The invention relates to the technical field of preparation of medical intermediates, in particular to a preparation method of a sertaconazole nitrate intermediate.
Background
Sertaconazole nitrate, molecular formula: c20H15Cl3N2OS·HNO3Chemical name 1- [2- (7-chlorobenzo [ b ]]Thiophen-3-yl) methoxy-2- (2, 4-dichlorobenzene) ethyl]-1H-imidazole nitrate, which is an artificial imidazole broad-spectrum antifungal drug and can be used for treating dermatophytes, microzyme and candidaAnd aspergillus has the effects of inhibiting and killing, and has strong antibacterial effect on gram-positive bacteria.
The common synthesis process of sertaconazole nitrate is to make 1- (2, 4-dichlorobenzene) -2- (1-imidazole) ethanol and 3-bromomethyl-7-chlorobenzo [ b ] thiophene undergo the process of salt-forming reaction to prepare sertaconazole nitrate.
For the intermediate 3-bromomethyl-7-chlorobenzo [ b ] thiophene of sertaconazole nitrate, patent document CN112694470A describes the following preparation process: the 3-bromomethyl-7-chlorobenzo [ b ] thiophene is obtained by taking o-chlorothiophenol and chloropropanone as initial raw materials through acylation, cyclization and bromination. Wherein, in the bromination step, carbon tetrachloride is used as a reaction solvent.
As is well known, after carbon tetrachloride is volatilized, gas molecules react with ozone under illumination to consume the ozone, so that the ozone layer becomes thin and the whole atmosphere is damaged, and therefore, the use of carbon tetrachloride is gradually limited in practical industrial production due to the requirement of environmental protection.
In view of the above, it is important to find other suitable solvents for use in the bromination reaction described above instead of carbon tetrachloride, for the preparation of 3-bromomethyl-7-chlorobenzo [ b ] thiophene.
Disclosure of Invention
Through continuous research and test, the inventor of the invention finds that cyclohexane can be used as a solvent to replace carbon tetrachloride for preparing 3-bromomethyl-7-chlorobenzo [ b ] thiophene. More unexpectedly, the present inventors have found that when cyclohexane is used as a reaction solvent, the yield and purity of 3-bromomethyl-7-chlorobenzo [ b ] thiophene are significantly improved as compared with carbon tetrachloride, and based on this, have completed the present invention.
The specific technical scheme is as follows.
The invention provides a preparation method of a sertaconazole nitrate intermediate, which takes cyclohexane as a reaction solvent, and leads 3-methyl-7-chlorobenzo [ b ] thiophene to react with a bromination reagent in the presence of benzoyl peroxide to generate 3-bromomethyl-7-chlorobenzo [ b ] thiophene.
In some embodiments of the invention, the brominating reagent is N-bromosuccinimide.
In some embodiments of the invention, the molar ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to brominating reagent is 1: (1-1.1).
In some embodiments of the invention, the molar ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to brominating reagent is 1: 1.05.
in some embodiments of the invention, the molar ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to benzoyl peroxide is 1: (0.04-0.1).
In some embodiments of the invention, the molar ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to benzoyl peroxide is 1: 0.05.
in some embodiments of the invention, the mass ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to cyclohexane is 1: (6-10).
In some embodiments of the invention, the mass ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to cyclohexane is 1: (7-8).
In some embodiments of the invention, the method comprises the steps of:
adding 3-methyl-7-chlorobenzo [ b ] thiophene into cyclohexane, irradiating with a bulb,
adding benzoyl peroxide under stirring, heating to boil,
adding the brominating agent in batches, and after the adding is finished, continuously stirring for 4-6 hours under the boiling condition.
In some embodiments of the invention, the method further comprises: after stirring, cooling, filtering, concentrating the filtrate until precipitate is separated out, standing for 3-5 hours, filtering, and washing the filter cake with petroleum ether.
Advantageous effects
The invention uses cyclohexane as reaction solvent to carry bromination reaction for preparing 3-bromomethyl-7-chlorobenzo [ b ] thiophene. Cyclohexane is less toxic than carbon tetrachloride and does not react with ozone and destroy the atmosphere. And the use is not limited, and the method is more suitable for industrial production.
More importantly, after the reaction solvent is replaced by cyclohexane, the yield and the purity of the 3-bromomethyl-7-chlorobenzo [ b ] thiophene are obviously improved, and unexpected technical effects are generated.
Drawings
FIG. 1 is a nuclear magnetic spectrum of 3-bromomethyl-7-chlorobenzo [ b ] thiophene prepared in example 3;
FIG. 2 is a chromatogram of the HPLC purity of 3-bromomethyl-7-chlorobenzo [ b ] thiophene prepared in example 3;
FIG. 3 is a chromatogram of HPLC purity of 3-bromomethyl-7-chlorobenzo [ b ] thiophene prepared in comparative example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present application more apparent, the technical solutions of the present application will be clearly and completely described below through specific embodiments.
In the following examples, those not indicated with specific conditions were performed according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
EXAMPLE 1 preparation of 3-methyl-7-chlorobenzo [ b ] thiophene
(1) Preparation of o-chlorobenzene thioacetone
Adding 80kg of purified water into a reaction kettle, stirring, adding 2.92kg of sodium hydroxide while stirring to completely dissolve the sodium hydroxide to obtain 3.6 wt% sodium hydroxide solution, adding 10.4kg of o-chlorothiophenol, and stirring at room temperature for 30 min; adding 6.66kg of chloropropanone under stirring, stirring again for reacting for 60min, standing after the reaction is finished, and layering into water layer and oil layer. Then, 21.36kg of ether was added to extract the aqueous layer, and the mixture was washed with water 3 times. The ether layer was collected by layering, combined with the oil layer and distilled under reduced pressure, ether was recovered to obtain 12.14kg of o-chlorobenzenethiol.
(2) Preparation of 3-methyl-7-chlorobenzo [ b ] thiophene
Adding 121.4kg of polyphosphoric acid into the reaction kettle A, stirring, adding 12.14kg of o-chlorothiophenyl acetone, heating to 120 ℃, preserving the temperature for 5 hours, and controlling the temperature to be 120-140 ℃. And adding water into the other reaction kettle B, and cooling for later use. Discharging the reaction liquid in the reaction kettle A, and slowly adding the reaction liquid into the other reaction kettle B for dilution. Adding 86.20kg of ether for extraction, standing for layering, and taking an ether layer. Washing the ether layer with water, concentrating, and distilling under reduced pressure; collecting 135-137 deg.C/10 mmHg fraction to obtain 16.72kg of 3-methyl-7-chlorobenzo [ b ] thiophene.
EXAMPLE 2 examination of bromination reaction solvent
The following procedure was conducted using 3-methyl-7-chlorobenzo [ b ] thiophene prepared in example 1 as a substrate, N-bromosuccinimide (NBS) as a brominating agent, and benzoyl peroxide as an initiator to examine the preparation of 3-bromomethyl-7-chlorobenzo [ b ] thiophene in the presence of various organic solvents as reaction solvents.
The specific preparation process is as follows:
adding solvent and 3-methyl-7-chlorobenzo [ b ] thiophene into a reaction bottle, irradiating by a 200W bulb, adding benzoyl peroxide while stirring, heating to boil, adding N-bromosuccinimide in batches, and continuously stirring for 4 hours while boiling.
The feeding proportion of the reaction is as follows:
| raw materials | Feed amount | Amount of substance | Molar ratio of |
| 3-methyl-7-chlorobenzo [ b]Thiophene(s) | 29.3g | 0.16 |
1 |
| Benzoyl peroxide | 1.76g | 0.0072mol | 0.045 |
| N-bromosuccinimide | 29.89g | 0.168mol | 1.05 |
| Solvent(s) | 230g | —— | —— |
The screening method comprises the following steps:
after the N-bromosuccinimide is added, the organic solvent is screened in the following way:
(1) after stirring for an additional 2 hours, Thin Layer Chromatography (TLC) analysis was performed using Petroleum Ether (PE) as a developing solvent to monitor the progress of the reaction and to determine whether bromination of the substrate had occurred. If it is determined from the thin-layer chromatography analysis that the bromination reaction has not occurred, this indicates that the organic solvent cannot serve as a bromination reaction solvent.
(2) Under the condition that the bromination reaction is confirmed to be capable of occurring, a reaction conversion path is tracked by adopting High Performance Liquid Chromatography (HPLC) (area normalization method) on the reaction liquid after stirring for 4 hours; and determining the relative retention time of each component in the reaction solution through product and substrate (sample application) positioning analysis, and inspecting the influence of each solvent on the reaction process, thereby determining whether other byproducts, namely dibromo and tribromo, exist in the reaction solution besides the target product, namely monobromo, is generated. If dibromide and tribromide are generated, the organic solvent influences the selectivity of bromination reaction and is not suitable for being used as a bromination reaction solvent.
The results of the examination are shown in the following table.
As can be seen from the above table, when dichloromethane, acetonitrile, 1, 2-dichloroethane were used as the reaction solvent, bromination reaction of 3-methyl-7-chlorobenzo [ b ] thiophene did not occur.
When chloroform, dimethylformamide, acetone, propylene oxide, dimethylacetamide, propyl acetate, or ethyl acetate is used as a reaction solvent, 3-methyl-7-chlorobenzo [ b ] thiophene can undergo bromination reaction, but the selectivity of bromination reaction is poor, and a large amount of dibromide and/or tribromide is produced in addition to the monobromide as a target product, and thus it is not suitable as a reaction solvent in the present invention.
When cyclohexane and benzene are used as the reaction solvent, the bromination reaction can be carried out with good selectivity, and dibromo-and/or tribromide is not substantially produced except for monobromide as the target product, so cyclohexane and benzene can be used as the bromination reaction solvent from the viewpoint of chemical reaction. But considering that benzene is more toxic than carbon tetrachloride as an organic solvent, cyclohexane is selected as a reaction solvent in the present invention from the viewpoint of environmental protection.
Preparation of 3-bromomethyl-7-chlorobenzo [ b ] thiophene
Example 3 the solvent was cyclohexane
228.54g of cyclohexane, 29.30g of 3-methyl-7-chlorobenzo [ b ] thiophene and 200W of lamp bulb are added into a reaction flask, 1.94g of benzoyl peroxide are added under stirring, the mixture is heated to boiling, 29.89g N-bromosuccinimide is added in portions, and the mixture is stirred for 5 hours under boiling. Cooling, filtering, concentrating the filtrate until precipitate is separated out, standing for 4 hr, filtering, washing the filter cake with 21.8g petroleum ether (II) to obtain 23.92g yellow 3-bromomethyl-7-chlorobenzo [ b ] thiophene powder, the nuclear magnetic spectrum of which is shown in FIG. 1.
Comparative example 1 the solvent was carbon tetrachloride
Comparative example 1 differs from example 3 only in that the solvent cyclohexane in example 3 is replaced by carbon tetrachloride, and the other steps are the same as example 3.
The properties, molar yields and HPLC purities of the products of example 3 and comparative example 1 are shown in the table below.
| Product traits | HPLC purity | Molar yield | |
| Example 3 | Deep yellow crystal | 98.1％ | 57％ |
| Comparative example 1 | Deep yellow crystal | 94.0％ | 54％ |
The chromatograms of HPLC purities of example 3 and comparative example 1 are shown in fig. 2 and 3, respectively. HPLC detection was performed according to the general rules 0512 of the four departments of the 2015 edition of pharmacopoeia of the people's republic of China.
Molar yield ═ moles of product 3-bromomethyl-7-chlorobenzo [ b ] thiophene/moles of substrate 3-methyl-7-chlorobenzo [ b ] thiophene.
As can be seen from the above table, in example 3, compared to comparative example 1, the yield and purity were significantly improved after replacing carbon tetrachloride with cyclohexane as the reaction solvent. And the cyclohexane has lower toxicity, can not react with ozone to damage the atmosphere, is not limited in use and is more beneficial to industrial production.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (10)
1. A preparation method of sertaconazole nitrate intermediate is characterized in that 3-methyl-7-chlorobenzo [ b ] thiophene is reacted with a bromination reagent in the presence of benzoyl peroxide by using cyclohexane as a reaction solvent to generate 3-bromomethyl-7-chlorobenzo [ b ] thiophene.
2. The method of claim 1, wherein the brominating agent is N-bromosuccinimide.
3. The process according to claim 2, wherein the molar ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to brominating agent is 1: (1-1.1).
4. The process according to claim 3, wherein the molar ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to brominating agent is 1: 1.05.
5. the process according to claim 4, wherein the molar ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to benzoyl peroxide is 1: (0.04-0.1).
6. The process according to claim 5, wherein the molar ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to benzoyl peroxide is 1: 0.05.
7. the production method according to any one of claims 1 to 6, wherein the mass ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to cyclohexane is 1: (6-10).
8. The production method according to claim 7, wherein the mass ratio of 3-methyl-7-chlorobenzo [ b ] thiophene to cyclohexane is 1: (7-8).
9. The method of claim 8, wherein the method comprises the steps of:
adding 3-methyl-7-chlorobenzo [ b ] thiophene into cyclohexane, irradiating with a bulb,
adding benzoyl peroxide under stirring, heating to boil,
adding the brominating agent in batches, and after the adding is finished, continuously stirring for 4-6 hours under the boiling condition.
10. The method of claim 9, further comprising: after stirring, cooling, filtering, concentrating the filtrate until precipitate is separated out, standing for 3-5 hours, filtering, and washing the filter cake with petroleum ether.
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| CN202110819628.4A CN113651796A (en) | 2021-07-20 | 2021-07-20 | Preparation method of sertaconazole nitrate intermediate |
| PCT/CN2021/114846 WO2023000435A1 (en) | 2021-07-20 | 2021-08-26 | Method for preparing sertaconazole nitrate intermediate |
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| CN202110819628.4A CN113651796A (en) | 2021-07-20 | 2021-07-20 | Preparation method of sertaconazole nitrate intermediate |
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| CN112694470A (en) * | 2020-12-30 | 2021-04-23 | 海南海神同洲制药有限公司 | Preparation process of sertaconazole nitrate |
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| JP5269766B2 (en) * | 2006-05-09 | 2013-08-21 | ノボ・ノルデイスク・エー／エス | Insulin derivative |
| US9840485B1 (en) * | 2016-09-27 | 2017-12-12 | Sekisui Chemical Co., Ltd. | Bisfuran dihalide, method for producing bisfuran dihalide, and method for producing bisfuran diacid, bisfuran diol or bisfuran diamine using bisfuran dihalide |
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| CN112694470A (en) * | 2020-12-30 | 2021-04-23 | 海南海神同洲制药有限公司 | Preparation process of sertaconazole nitrate |
Non-Patent Citations (1)
| Title |
|---|
| VENKATESWARLU RAYUDU等: "An Easy, Efficient and Improved Synthesis of Sertaconazole Nitrate", 《RUSSIAN JOURNAL OF ORGANIC CHEMISTRY》 * |
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