CN119285528B - A kind of synthetic method of 1,2-cyclopentanedicarboximide - Google Patents
A kind of synthetic method of 1,2-cyclopentanedicarboximide Download PDFInfo
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- CN119285528B CN119285528B CN202411820231.7A CN202411820231A CN119285528B CN 119285528 B CN119285528 B CN 119285528B CN 202411820231 A CN202411820231 A CN 202411820231A CN 119285528 B CN119285528 B CN 119285528B
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Abstract
The application belongs to the technical field of synthesis of medical intermediates, and particularly relates to a synthesis method of 1, 2-cyclopentanedicarboximide, which comprises the following steps of (1) condensation reaction, namely, preparing 2-oxo-cyclohexanecarboxylic acid methyl ester, namely, a compound R3, by taking cyclohexanone and dimethyl carbonate as raw materials under the action of a solid base catalyst, (2) halogenation reaction, namely, dissolving R3 in a solvent, cooling to 0-5 ℃ for crystallization and centrifugation, namely, 3-X-2-oxo-cyclohexanecarboxylic acid methyl ester, namely, a compound R4, (3) rearrangement reaction, namely, dissolving R4 in an alcohol ammonia solution for ammoniation rearrangement reaction, then cooling, crystallizing and press-filtering to obtain cyclopentanamide methyl ester, namely, a compound R5, and (4) cyclization reaction, namely, placing R5 in methanol, and carrying out cyclization under the action of a catalyst to obtain the 1, 2-cyclopentanedicarboximide, namely, the compound R6.
Description
Technical Field
The application belongs to the technical field of synthesis of medical intermediates, and particularly relates to a synthesis method of 1, 2-cyclopentanediimide.
Background
Gliclazide is a second-generation sulfonylurea oral hypoglycemic agent, has double functions of reducing blood sugar and improving blood coagulation, is suitable for non-insulin dependent diabetes mellitus, has been widely used clinically, and the quality of a key intermediate 1, 2-cyclopentanecarboximide (abbreviated as imide) directly influences the quality of gliclazide.
The prior method for synthesizing the 1, 2-cyclopentanediimide comprises the following steps:
(1) Zhang Kehua in the paper gliclazide key intermediate discloses that cyclohexane and urea are used as raw materials to react to generate spiro R8, then hydrolyze to R9, chloridize to R10, 1, 2-cyclopentanediamide R11 is obtained through rearrangement condensation, and then cyclized to obtain 1, 2-cyclopentanediimide, wherein the specific synthetic route is as follows:
;
The method for synthesizing the 1, 2-cyclopentanediimide has the advantages of overlong steps, low total yield, large amount of high-salt wastewater generated in the synthesis process, and high environmental protection cost;
(2) The method comprises the steps of reacting cyclohexanone serving as a raw material in two steps to obtain alpha bromide R15 of ketone, then carrying out Favorsky rearrangement condensation to obtain glutaric acid R16, and then carrying out two steps to obtain 1, 2-cyclopentanimide R6, wherein the specific synthetic route is as follows:
;
the method has the advantages of overlong steps, low total yield and high raw material cost;
(3) The preparation method comprises the steps of taking cyclopentadiene R18 as a raw material, carrying out cyclization to obtain R19, then carrying out hydrolysis to obtain R20, carrying out reduction to obtain R21, and finally carrying out cyclization to obtain 1, 2-cyclopentanediimide R6, wherein the specific synthetic route is as follows:
;
the method has the advantages of overlong steps, low total yield, difficult treatment of three wastes in the synthesis process, high cost for treating the three wastes and high cost of raw materials.
Disclosure of Invention
In order to solve the problems in the prior art, the application provides a synthesis method of 1, 2-cyclopentanediimide, which is realized by the following scheme:
The synthesis method of the 1, 2-cyclopentadiformyl imine comprises the following synthetic routes:
;
The method comprises the following steps:
(1) The condensation reaction is that cyclohexanone and dimethyl carbonate are used as raw materials, and reflux reaction is carried out under the action of a solid base catalyst to prepare 2-oxo cyclohexane carboxylic acid methyl ester, namely a compound R3;
(2) The halogenation reaction is that 2-oxo cyclohexane carboxylic acid methyl ester, namely a compound R3, is dissolved in a solvent, and is subjected to halogenation reaction with a halogenating reagent at the temperature of 0 ℃ to 15 ℃, and after halogenation, 3-X-2-oxo cyclohexane carboxylic acid methyl ester, namely a compound R4, is obtained by cooling to 0 ℃ to 5 ℃ in sequence, crystallizing and centrifuging, wherein X is chlorine or bromine;
(3) Dissolving a compound R4 in an alcohol ammonia solution for ammoniation rearrangement reaction, and then cooling, crystallizing and press-filtering to obtain a rearranged substance methyl cyclopentanamide formate, namely a compound R5;
(4) And (3) cyclization reaction, namely placing the methyl cyclopentylamide formate, namely the compound R5, in methanol, and cyclizing under the action of a catalyst to obtain the 1, 2-cyclopentanediimide, namely the compound R6.
Further, the time of the condensation reaction in the step (1) is 6-8 hours, and the reaction temperature is 100-140 ℃.
Further, the mass ratio of cyclohexanone, dimethyl carbonate and solid base catalyst in the step (1) is 1:3-6:0.05-0.2, and the solid base catalyst is one or more of magnesium hydroxide, basic zinc carbonate, potassium fluoride/aluminum oxide and zinc hydroxide.
Further, in the step (1), the mass ratio of cyclohexanone to dimethyl carbonate to the solid base catalyst is 1:4.5:0.1, and the solid base catalyst is magnesium hydroxide.
Further, in the step (2), the mass ratio of the compound R3 to the solvent to the halogenating agent is 1:5-7:0.5-1, the solvent is dichloroethane or dichloromethane, the halogenating agent is one or more of chlorine, bromine, phosphorus trichloride, thionyl chloride and sulfuryl chloride, the halogenating temperature is 0-15 ℃, and the halogenating time is 4-15min.
Further, in the step (2), the mass ratio of the compound R3 to the solvent to the halogenating agent is 1:6.5:0.8, and the solvent is dichloroethane.
Further, in the step (3), the mass ratio of the compound R4 to the alcohol ammonia solution is 1:3-5.5, the alcohol ammonia solution is methanol ammonia solution or ethanol ammonia solution, the mass concentration of ammonia in the alcohol ammonia solution is 10-15%, the temperature of the rearrangement reaction is 0-10 ℃, and the time of the rearrangement reaction is 2-10 hours.
Further, the mass ratio of the compound R4 to the alcohol ammonia solution in the step (3) is 1:4.5.
Further, in the step (4), the mass ratio of the compound R5 to the methanol to the catalyst is 1:10-30:0.3-1, and the catalyst is sodium methoxide.
Further, in the step (4), the mass ratio of the compound R5 to the methanol to the catalyst is 1:20:0.5.
The invention has the beneficial effects that the invention provides the preparation method of the 1, 2-cyclopentanediimide, which takes cyclohexanone and dimethyl carbonate as raw materials to prepare the 1, 2-cyclopentanediimide, and the byproduct, namely alcohol, can be recovered as a solvent in the reaction process, so that the environmental pollution problem caused by three wastes can be effectively reduced compared with the traditional process, and the environmental protection investment cost is reduced.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are required for the description of the embodiments will be briefly described below, and it is apparent that the drawings in the following description are only some of the preferred embodiments of the present application, but not all of the embodiments. In the preferred embodiments of the present application, it will be apparent to those skilled in the art from this disclosure that other embodiments and drawings can be made without undue burden, and still fall within the scope of the present application.
FIG. 1 is a liquid phase detection pattern of the finished 1, 2-cyclopentanedicarboximide of example 1;
FIG. 2is a liquid phase detection pattern of the finished 1, 2-cyclopentanediimide product of example 2;
FIG. 3 is a liquid phase detection pattern of the finished 1, 2-cyclopentanedicamide product of example 3.
Detailed Description
In order to make the objects, technical solutions and advantages of the present application more apparent, embodiments of the present application will be described in further detail below. It is to be understood that the terms "upper," "lower," "top," "bottom," "inner," "outer," and the like are used in relation to the orientation or position shown in the drawings. The foregoing definitions are provided merely to facilitate the description of the application and to simplify the description and do not indicate or imply that the structures referred to must have a particular orientation, be constructed and operate in a particular orientation, and are not to be construed as limiting the application.
Example 1
A synthesis method of 1, 2-cyclopentanediimide comprises the following steps:
(1) Adding 50g of cyclohexanone, 225g of dimethyl carbonate and 5g of magnesium hydroxide into a reaction kettle, carrying out reflux condensation reaction for 6-8 hours at 100-140 ℃, reducing the temperature to 70-80 ℃ after reflux, filtering, carrying out reduced pressure distillation on the filtrate after filtering, distilling the reacted solvent, and collecting fractions at 120-140 ℃ to obtain 90.3g of colorless transparent liquid, namely compound R3, wherein the yield is 72.31%;
(2) The halogenation reaction comprises the steps of dissolving 50g of methyl 2-oxo-cyclohexane carboxylate in 325g of dichloroethane, cooling to 0-15 ℃, introducing chlorine for 8h, introducing the total amount of the chlorine to be 24g, adding the reacted reaction solution into 160g of water, stirring for 1 hour, cooling to 0-5 ℃ for crystallization for 2 hours, centrifuging, and drying to obtain 53.02g of compound R4, wherein the yield is 93.25%;
(3) Placing 50g of compound R4 and 230g of methanol in a reaction kettle, cooling to 0-10 ℃, adding liquid nitrogen for 5 hours, wherein the addition amount of the liquid nitrogen is 15.4g, heating to 25-30 ℃ and preserving heat for 5 hours, after preserving heat, cooling to 0-5 ℃ and preserving heat for 2 hours, press-filtering, and drying to obtain 32.5g of methyl cyclopentylamide formate, namely compound R5, and the yield is 68.75%;
(4) And (3) cyclization reaction, namely placing 50g of methyl cyclopentylamide formate, namely a compound R5, in a reaction kettle in two batches, adding 300g of methanol into the reaction kettle, heating to 45-55 ℃, slowly adding 12g of sodium methoxide, then preserving heat for 6 hours, preserving heat, distilling methanol under reduced pressure, adding 200g of toluene into a reaction bottle after distillation, heating to 70-75 ℃, filtering, cooling to 0-5 ℃ after filtering, preserving heat for 2 hours, centrifuging, drying to obtain 35g of 1, 2-cyclopentanediimide, and obtaining the yield of 72.14%.
Example 2
(1) Adding 50g of cyclohexanone, 225g of dimethyl carbonate and 5g of magnesium hydroxide into a reaction kettle, carrying out reflux condensation reaction for 6-8 hours at 100-140 ℃, reducing the temperature to 70-80 ℃ after reflux, filtering, carrying out reduced pressure distillation on the filtrate after filtering, distilling the reacted solvent, and collecting fractions at 120-140 ℃ to obtain 90.3g of colorless transparent liquid, namely compound R3, with the yield of 73.25%;
(2) The halogenation reaction comprises the steps of dissolving 50g of methyl 2-oxo-cyclohexane carboxylate in 325g of dichloroethane, cooling to 0-15 ℃, dropwise adding bromine for 6h, adding 36g of total bromine, adding the reacted reaction solution into 160g of water, stirring for 1 hour, cooling to 0-5 ℃ for crystallization for 2 hours, centrifuging, and drying to obtain 58.19g of compound R4, wherein the yield is 94.47%;
(3) Placing 50g of compound R4 and 230g of methanol in a reaction kettle, cooling to 0-10 ℃, adding liquid nitrogen for 5 hours, wherein the addition amount of the liquid nitrogen is 15.4g, heating to 25-30 ℃ and preserving heat for 5 hours, after the heat preservation, cooling to 0-5 ℃ and preserving heat for 2 hours, press-filtering, and drying to obtain 32.5g of methyl cyclopentylamide formate, namely compound R5, and the yield is 71.13%;
(4) And (3) carrying out cyclization reaction, namely placing 50g of methyl cyclopentanamide formate, namely a compound R5, in a reaction kettle in two batches, adding 300g of methanol into the reaction kettle, heating to 45-55 ℃, slowly adding 12g of sodium methoxide, then preserving heat for 6 hours, preserving heat, distilling methanol under reduced pressure, adding 200g of toluene into a reaction bottle after distillation, heating to 70-75 ℃, filtering, cooling to 0-5 ℃ after filtration, preserving heat for 2 hours, centrifuging, drying to obtain 35g of 1, 2-cyclopentanecarboximide, and obtaining the yield of 71.78%.
Example 3
(1) Adding 50g of cyclohexanone, 225g of dimethyl carbonate and 5g of magnesium hydroxide into a reaction kettle, carrying out reflux condensation reaction for 6-8 hours at 100-140 ℃, reducing the temperature to 70-80 ℃ after reflux, filtering, carrying out reduced pressure distillation on the filtrate after filtering, distilling the reacted solvent, and collecting fractions at 120-140 ℃ to obtain 90.3g of colorless transparent liquid, namely compound R3, with the yield of 74.85%;
(2) The halogenation reaction comprises the steps of dissolving 50g of methyl 2-oxo-cyclohexane carboxylate in 325g of dichloroethane, cooling to 0-15 ℃, dropwise adding thionyl chloride for 8 hours, wherein the addition amount of the thionyl chloride is 26g, adding the reacted reaction solution into 160g of water, stirring for 1 hour, cooling to 0-5 ℃ for crystallization for 2 hours, centrifuging, and drying to obtain 55.29g of compound R4, wherein the yield is 70.12%;
(3) The rearrangement reaction comprises placing 50g of compound R4 and 230g of methanol in a reaction kettle, cooling to 0-10deg.C, adding liquid nitrogen for 5h, adding liquid nitrogen 15.4g, heating to 25-30deg.C, maintaining for 5h, maintaining for 2 h, press-filtering, and drying to obtain 32.5g of methyl cyclopentylamide formate (compound R5) with yield of 70.62%
(4) And (3) carrying out cyclization reaction, namely placing 50g of methyl cyclopentanamide formate, namely a compound R5, in a reaction kettle in two batches, adding 300g of methanol into the reaction kettle, heating to 45-55 ℃, slowly adding 12g of sodium methoxide, then preserving heat for 6 hours, preserving heat, distilling methanol under reduced pressure, adding 200g of toluene into a reaction bottle after distillation, heating to 70-75 ℃, filtering, cooling to 0-5 ℃ after filtration, preserving heat for 2 hours, centrifuging, drying to obtain 35g of 1, 2-cyclopentanecarboximide, and obtaining the yield of 74.06%.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present application and not for limiting the same, and although the present application has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present application, which is intended to be covered by the scope of the claims of the present application.
Claims (10)
1. A method for synthesizing 1, 2-cyclopentanediimide, which is characterized by comprising the following steps:
(1) The condensation reaction is that cyclohexanone and dimethyl carbonate are used as raw materials, and reflux reaction is carried out under the action of a solid base catalyst to prepare 2-oxo cyclohexane carboxylic acid methyl ester, namely a compound R3;
(2) The halogenation reaction is that 2-oxo cyclohexane carboxylic acid methyl ester, namely a compound R3, is dissolved in a solvent, and is subjected to halogenation reaction with a halogenating reagent at the temperature of 0 ℃ to 15 ℃, and after halogenation, 3-X-2-oxo cyclohexane carboxylic acid methyl ester, namely a compound R4, is obtained by cooling to 0 ℃ to 5 ℃ in sequence, crystallizing and centrifuging, wherein X is chlorine or bromine;
(3) Dissolving a compound R4 in an alcohol ammonia solution for ammoniation rearrangement reaction, and then cooling, crystallizing and press-filtering to obtain a rearranged substance methyl cyclopentanamide formate, namely a compound R5;
(4) The cyclization reaction is to put methyl cyclopentylamide formate, namely a compound R5, into methanol, and cyclize under the action of a catalyst to obtain 1, 2-cyclopentanediimide, namely a compound R6;
The synthetic route is as follows:
。
2. the method for synthesizing 1, 2-cyclopentanediimide according to claim 1, wherein the condensation reaction in step (1) takes 6 to 8 hours at a reaction temperature of 100 ℃ to 140 ℃.
3. The method for synthesizing 1, 2-cyclopentanediimide according to claim 1, wherein the mass ratio of cyclohexanone, dimethyl carbonate and solid base catalyst in the step (1) is 1:3-6:0.05-0.2, and the solid base catalyst is one or more of magnesium hydroxide, basic zinc carbonate, potassium fluoride/aluminum oxide and zinc hydroxide.
4. The method for synthesizing 1, 2-cyclopentanediimide according to claim 1, wherein the mass ratio of cyclohexanone, dimethyl carbonate and solid base catalyst in step (1) is 1:4.5:0.1, and the solid base catalyst is magnesium hydroxide.
5. The method for synthesizing 1, 2-cyclopentanediimide according to claim 1, wherein in the step (2), the mass ratio of the compound R3 to the solvent to the halogenating agent is 1:5-7:0.5-1, the solvent is dichloroethane or dichloromethane, the halogenating agent is one or more of chlorine, bromine, phosphorus trichloride, thionyl chloride and sulfuryl chloride, the halogenating temperature is 0-15 ℃, and the halogenating time is 4-15min.
6. The method for synthesizing 1, 2-cyclopentadicarboximide according to claim 1, wherein the mass ratio of the compound R3, the solvent and the halogenating agent in the step (2) is 1:6.5:0.8, and the solvent is dichloroethane.
7. The method for synthesizing 1, 2-cyclopentanediimide according to claim 1, wherein the mass ratio of the compound R4 to the alcohol ammonia solution in the step (3) is 1:3-5.5, the alcohol ammonia solution is methanol ammonia solution or ethanol ammonia solution, the mass concentration of ammonia in the alcohol ammonia solution is 10-15%, the temperature of the rearrangement reaction is 0-10 ℃, and the time of the rearrangement reaction is 2-10 hours.
8. The method for synthesizing 1, 2-cyclopentanediimide according to claim 1, wherein the mass ratio of the compound R4 to the alcohol ammonia solution in the step (3) is 1:4.5.
9. The method for synthesizing 1, 2-cyclopentanediimide according to claim 1, wherein in the step (4), the mass ratio of the compound R5 to methanol to the catalyst is 1:10-30:0.3-1, and the catalyst is sodium methoxide.
10. The method for synthesizing 1, 2-cyclopentanediimide according to claim 1, wherein the mass ratio of the compound R5, methanol and catalyst in the step (4) is 1:20:0.5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102014927A (en) * | 2008-03-06 | 2011-04-13 | 安纳考尔医药公司 | Boron-containing small molecules as anti-inflammatory agents |
| CN108059599A (en) * | 2018-01-22 | 2018-05-22 | 凯方医药科技（上海）有限公司 | A kind of preparation method of Wei Naituoke key intermediates |
| CN108569994A (en) * | 2018-06-01 | 2018-09-25 | 滨海博大化工有限公司 | The synthetic method of 1,2- of one kind rings, penta dicarboximide |
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| CN102850257B (en) * | 2012-09-17 | 2015-09-30 | 山东方明药业集团股份有限公司 | The preparation method of 1,2-cyclopentanediformylandne |
| FR2999179A1 (en) * | 2012-12-07 | 2014-06-13 | Servier Lab | PROCESS FOR THE SYNTHESIS OF A SALT FOR ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID OF 4- {3- [CIS-HEXAHYDROCYCLOPENTA [C] PYRROL-2 (1H) -YL] PROPOXY} BENZAMIDE, AND ASSOCIATED CRYSTALLINE FORMS |
| CN116589399A (en) * | 2023-05-29 | 2023-08-15 | 济南大学 | Preparation method of 3-methoxy-2-nitropyridine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102014927A (en) * | 2008-03-06 | 2011-04-13 | 安纳考尔医药公司 | Boron-containing small molecules as anti-inflammatory agents |
| CN108059599A (en) * | 2018-01-22 | 2018-05-22 | 凯方医药科技（上海）有限公司 | A kind of preparation method of Wei Naituoke key intermediates |
| CN108569994A (en) * | 2018-06-01 | 2018-09-25 | 滨海博大化工有限公司 | The synthetic method of 1,2- of one kind rings, penta dicarboximide |
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