CN116969903B - Efficient preparation method of thiazate - Google Patents
Efficient preparation method of thiazate Download PDFInfo
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- CN116969903B CN116969903B CN202311240774.7A CN202311240774A CN116969903B CN 116969903 B CN116969903 B CN 116969903B CN 202311240774 A CN202311240774 A CN 202311240774A CN 116969903 B CN116969903 B CN 116969903B
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- Prior art keywords
- thiazate
- reaction
- methyl thiosalicylate
- chloroethylamine hydrochloride
- catalyst
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- BAQGCWNPCFABAY-UHFFFAOYSA-N methyl 2-sulfanylbenzoate Chemical compound COC(=O)C1=CC=CC=C1S BAQGCWNPCFABAY-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000002156 mixing Methods 0.000 claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 claims description 5
- 229940103494 thiosalicylic acid Drugs 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 9
- 239000002904 solvent Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000002360 explosive Substances 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- ISJBQSJDQZLCSF-UHFFFAOYSA-N (4-chlorophenyl)azanium;chloride Chemical compound [Cl-].[NH3+]C1=CC=C(Cl)C=C1 ISJBQSJDQZLCSF-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to a high-efficiency preparation method of a sulfur nitrogen heterocycle, belonging to the technical field of chemical synthesis; the method comprises the following steps: obtaining methyl thiosalicylate; mixing the methyl thiosalicylate and the chloroethylamine hydrochloride in a solvent, and carrying out a first reaction under the condition of a first catalyst to obtain a sulfur nitrogen heterocycle; the method adopts the methyl thiosalicylate and the chloroethylamine hydrochloride as raw materials to prepare the thiazate, and the methyl thiosalicylate and the chloroethylamine hydrochloride are all easily available raw materials, so that expensive and difficultly available reagents are avoided, the industrial production of the thiazate is facilitated, and the aim of improving the problem that the existing thiazate is difficult to realize industrial production is fulfilled.
Description
Technical Field
The application relates to the technical field of chemical synthesis, in particular to a high-efficiency preparation method of a sulfur nitrogen heterocycle.
Background
Currently, there are three main routes for the preparation of thiazates.
The first path:
the second path:
third path:
it can be seen that in each current preparation route, a water and air sensitive flammable and explosive reagent such as NaH is used in the first step of the first route, which makes the whole preparation process dangerous. The second route would employ more expensive and less available reagents such asThe yield of the third route is low, resulting in difficulty in realizing industrial mass production.
Disclosure of Invention
The application provides a high-efficiency preparation method of a sulfur-nitrogen heterocycle, which aims to solve the problem that the existing sulfur-nitrogen heterocycle is difficult to realize industrial production.
The application provides a high-efficiency preparation method of a sulfur nitrogen heterocycle, which comprises the following steps:
obtaining methyl thiosalicylate;
mixing the methyl thiosalicylate and the chloroethylamine hydrochloride in a solvent, and carrying out a first reaction under the condition of a first catalyst to obtain the thiazate.
As an alternative embodiment, the first catalyst comprises sodium methoxide.
As an alternative embodiment, the temperature of the reaction is 15-25 ℃.
As an alternative embodiment, the reaction time is 7.5-8.5 h.
As an alternative embodiment, the solvent comprises anhydrous methanol.
As an alternative embodiment, said mixing said methyl thiosalicylate and triethylamine hydrochloride in a solvent, and performing a first reaction under first catalyst conditions, to obtain a thiazate comprises:
mixing the methyl thiosalicylate and sodium methoxide in absolute methanol, and adding the chloroethylamine hydrochloride in batches to perform a first reaction to obtain the thiazate.
As an alternative embodiment, the obtaining methyl thiosalicylate includes:
mixing methanol and thiosalicylic acid, and carrying out a second reaction under the condition of a second catalyst to obtain the methyl thiosalicylate.
As an alternative embodiment, the second catalyst comprises concentrated sulfuric acid.
As an alternative embodiment, the temperature of the second reaction is 20-30 ℃.
As an alternative embodiment, the second reaction time is 19 to 21 hours.
Compared with the prior art, the technical scheme provided by the embodiment of the application has the following advantages:
according to the method provided by the embodiment of the application, the methyl thiosalicylate and the chloroethylamine hydrochloride are used as raw materials to prepare the thiazate, and are all easily available raw materials, so that expensive and difficultly available reagents are avoided, the industrial production of the thiazate is facilitated, and the aim of improving the problem that the existing thiazate is difficult to realize industrial production is fulfilled.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the application and together with the description, serve to explain the principles of the application.
In order to more clearly illustrate the embodiments of the application or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, and it will be obvious to a person skilled in the art that other drawings can be obtained from these drawings without inventive effort.
FIG. 1 is a flow chart of a method provided by an embodiment of the present application;
FIG. 2 is a liquid spectrum of methyl thiosalicylate provided in example 1 of the present application;
FIG. 3 is a chart showing the nuclear magnetic resonance spectrum of the thiazate provided in example 7 of the present application;
fig. 4 is a liquid phase diagram of a thiazate provided in example 7 of the present application.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present application more apparent, the technical solutions of the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments of the present application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
Unless otherwise specifically indicated, the various raw materials, reagents, instruments, equipment and the like used in the present application are commercially available or may be prepared by existing methods.
Currently, there are three main routes for the preparation of thiazates. Some use of flammable and explosive reagents such as NaH, which are sensitive to water and air, makes the whole preparation process dangerous. Some use relatively expensive and difficult reagents such as 2-oxazolidinone (497-25-6), azido-monopolyethylene glycol-MS (75178-70-0), etc., and some routes have low yields, resulting in difficulty in realizing industrial mass production.
As shown in fig. 1, the embodiment of the application provides a method for efficiently preparing a sulfur nitrogen heterocycle, which comprises the following steps:
s1, obtaining methyl thiosalicylate;
in some embodiments, the obtaining methyl thiosalicylate comprises: mixing methanol and thiosalicylic acid, and carrying out a second reaction under the condition of a second catalyst to obtain the methyl thiosalicylate.
In some embodiments, the second catalyst comprises concentrated sulfuric acid. The temperature of the second reaction is 20-30 ℃. The second reaction time is 19-21 h.
Specifically, in this example, methanol is added into a four-mouth bottle under the protection of nitrogen at a temperature of 25 ℃, thiosalicylic acid is added, concentrated sulfuric acid is added for catalysis, and the temperature is raised until the reflux reaction is completed for 20 hours. After concentrating under reduced pressure, dissolving with ethyl acetate, washing twice with water, concentrating the organic phase under reduced pressure until no fraction flows out. To obtain light yellow oily matter, namely methyl thiosalicylate.
S2, mixing the methyl thiosalicylate and the chloroethylamine hydrochloride in a solvent, and carrying out a first reaction under the condition of a first catalyst to obtain the thiazate.
In some embodiments, the first catalyst comprises sodium methoxide. The reaction temperature is 15-25 ℃. The reaction time is 7.5-8.5 h. The solvent comprises anhydrous methanol.
In some embodiments, the mixing the methyl thiosalicylate and the chloroethylamine hydrochloride in a solvent and performing a first reaction under first catalyst conditions to obtain a thiazate comprises: mixing the methyl thiosalicylate and sodium methoxide in absolute methanol, and adding the chloroethylamine hydrochloride in batches to perform a first reaction to obtain the thiazate.
Specifically, in this example, anhydrous methanol was added to a four-necked flask under nitrogen protection, and methyl thiosalicylate and sodium methoxide solution were added with stirring. And controlling the temperature to be 20 ℃, adding the chloroethylamine hydrochloride into the reaction system in batches, and preserving the heat for 8 hours until the reaction is complete. Concentrating under reduced pressure until no fraction flows out, adding isopropyl acetate dissolved solid into a reaction system, washing twice with water, concentrating under reduced pressure, adding heptane, stirring for crystallization for 1h, and performing suction filtration and drying to obtain white powdery solid, namely thiazate.
The whole reaction process is as follows:
the method adopts MeONa to replace NaH and other reagents which are sensitive to water and air and are inflammable and explosive as catalysts, improves the production safety and the yield, adopts chloroethylamine hydrochloride to replace 2-oxazolidone (497-25-6), azido-monopolyethylene glycol-MS (75178-70-0) and other expensive reagents, and reduces the cost.
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental procedures, which are not specified in the following examples, are generally determined according to national standards. If the corresponding national standard does not exist, the method is carried out according to the general international standard, the conventional condition or the condition recommended by the manufacturer.
Example 1
Under the protection of nitrogen, the temperature is controlled at 25 ℃, 2kg of methanol is added into a 5L four-mouth bottle, 500g of thiosalicylic acid is added, 20g of concentrated sulfuric acid is added for catalysis, and the temperature is raised until the reflux reaction is carried out for 20 hours until the reaction is complete. After concentrating under reduced pressure, dissolving with ethyl acetate, washing twice with 2kg of water, concentrating the organic phase under reduced pressure until no fraction flows out. 520g of light yellow oily matter is obtained, the purity is more than 98.0%, and the yield is 95%.
The reaction process is as follows:
characterization of the product structure: 1 H NMR(400 MH Z ;CDCl 3 ): δ3.84（s,1H）, δ3.97（s,3H）, δ7.20-7.74（brs,3H）, δ8.05（d,1H）。
example 2
In this example, the amount of concentrated sulfuric acid was 0.01kg, and the remainder was the same as in example 1, and the purity of the product in this example was 97% and the yield was 93%.
Example 3
In this example, the amount of concentrated sulfuric acid was 0.04kg, and the remainder was the same as in example 1, and the purity of the product in this example was 98% and the yield thereof was 95%.
Example 4
In this example, the amount of concentrated sulfuric acid was 0.06kg, and the remainder was the same as in example 1, and the purity of the product in this example was 98% and the yield was 95%.
Example 5
In this example, the amount of methanol used was 3kg, and the remainder was the same as in example 1, and the purity of the product in this example was 98% and the yield was 95%.
Example 6
In this example, the amount of methanol used was 3kg, the flow rate of concentrated sulfuric acid was 0.04kg, and the other matters were the same as in example 1, but the purity of the product in this example was 98%, and the yield of the product was 95%.
Example 7
To a 2L four-necked flask, 400ml of anhydrous methanol was added under nitrogen protection, and 200g of methyl thiosalicylate and 640g of sodium methoxide solution (26% by mass) were added under stirring. 166g of chloroethylamine hydrochloride is added into the reaction system in batches at the temperature of 20 ℃ for 8 hours until the reaction is complete. Concentrating under reduced pressure until no fraction flows out, adding 1000ml of isopropyl acetate dissolved solid into a reaction system, washing twice with 2kg of water, concentrating under reduced pressure until 500ml of isopropyl acetate is obtained, adding 600ml of heptane, stirring for crystallization for 1h, and carrying out suction filtration and drying to obtain 173g of white powdery solid with purity of more than 99% and yield of 81%.
The reaction process is as follows:
characterization of the product structure: 1 H NMR(400 MH Z ;CDCl 3 ): δ3.10-3.20（m,2H）, δ3.33-3.44（m,2H）, δ7.27（brs,1H）, δ7.35-7.75（m,4H）。
example 8
The amount of the added chloroaniline hydrochloride in this example was 153g, and the other matters were the same as in example 7, and the purity of the product in this example was 99%, and the yield of the product was 76%.
Example 9
The amount of the added chloroaniline hydrochloride in this example was 146g, and the other contents were the same as in example 7, and the purity of the product in this example was 99%, and the yield of the product was 70%.
Example 10
The sodium methoxide solution (26% by mass) of this example was added in an amount of 430g, and the remainder was the same as in example 7, but the purity of the product of this example was 99% and the yield of the product was 70%.
Example 11
The sodium methoxide solution (26% by mass) of this example was added in an amount of 540g, and the remainder was the same as in example 7, but the purity of the product of this example was 99% and the yield of the product was 74%.
Example 12
The sodium methoxide solution (26% by mass) of this example was added in an amount of 740g, and the remainder was the same as in example 7, and the purity of the product of this example was 99% and the yield of the product was 81%.
Various embodiments of the application may exist in a range of forms; it should be understood that the description in a range format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the application; it is therefore to be understood that the range description has specifically disclosed all possible sub-ranges and individual values within that range. For example, it should be considered that a description of a range from 1 to 6 has specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single numbers within the range, such as 1, 2, 3, 4, 5, and 6, wherever applicable. In addition, whenever a numerical range is referred to herein, it is meant to include any reference number (fractional or integer) within the indicated range.
In the present application, unless otherwise specified, terms such as "upper" and "lower" are used specifically to refer to the orientation of the drawing in the figures. In addition, in the description of the present specification, the terms "include", "comprising" and the like mean "including but not limited to". Relational terms such as "first" and "second", and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Herein, "and/or" describing an association relationship of an association object means that there may be three relationships, for example, a and/or B, may mean: a alone, a and B together, and B alone. Wherein A, B may be singular or plural. Herein, "at least one" means one or more, and "a plurality" means two or more. "at least one", "at least one" or the like refer to any combination of these items, including any combination of single item(s) or plural items(s). For example, "at least one (individual) of a, b, or c," or "at least one (individual) of a, b, and c," may each represent: a, b, c, a-b (i.e., a and b), a-c, b-c, or a-b-c, wherein a, b, c may be single or multiple, respectively.
The foregoing is only a specific embodiment of the application to enable those skilled in the art to understand or practice the application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the application. Thus, the present application is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (3)
1. A method for efficiently preparing a sulfur nitrogen heterocycle comprises the following reaction processes:characterized in that the method comprises:
obtaining methyl thiosalicylate;
mixing the methyl thiosalicylate and sodium methoxide in absolute methanol, and adding chloroethylamine hydrochloride in batches to perform a first reaction to obtain a thiazate;
the method for obtaining the methyl thiosalicylate comprises the following steps:
mixing methanol and thiosalicylic acid, and performing a second reaction under a second catalyst to obtain methyl thiosalicylate;
the temperature of the first reaction is 15-25 ℃;
the time of the first reaction is 7.5-8.5 hours;
the second catalyst is selected from concentrated sulfuric acid.
2. The efficient preparation method of the thiazate according to claim 1, wherein the temperature of the second reaction is 20-30 ℃.
3. The efficient preparation method of the thiazate according to claim 1, wherein the time of the second reaction is 19-21 h.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311240774.7A CN116969903B (en) | 2023-09-25 | 2023-09-25 | Efficient preparation method of thiazate |
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| CN202311240774.7A CN116969903B (en) | 2023-09-25 | 2023-09-25 | Efficient preparation method of thiazate |
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| CN116969903B true CN116969903B (en) | 2023-12-12 |
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| Title |
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| Discovery of Benzoazepinequinoline (BAQ) Derivatives as Novel, Potent, Orally Bioavailable Respiratory Syncytial Virus Fusion Inhibitors;Xiufang Zheng, et al;《J. Med. Chem.》;第61卷;第10228−10241页 * |
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