A kind of synthetic method of 1,2-cyclopentanedicarboximide

Abstract

The present application belongs to the technical field of pharmaceutical intermediate synthesis, and specifically is a method for synthesizing 1,2-cyclopentanedicarboximide, comprising the following steps: (1) condensation reaction: using cyclohexanone and dimethyl carbonate as raw materials, 2-oxocyclohexanecarboxylic acid methyl ester, i.e., compound R3, is prepared under the action of a solid base catalyst; (2) halogenation reaction: R3 is dissolved in a solvent, subjected to halogenation reaction, cooled to 0-5°C, crystallized, and centrifuged to obtain 3-X-2-oxocyclohexanecarboxylic acid methyl ester, i.e., compound R4; (3) rearrangement reaction: R4 is dissolved in an alcohol ammonia solution, subjected to an amination rearrangement reaction, and then subjected to cooling, crystallization, and filter press to obtain cyclopentanecarboxylic acid methyl ester, i.e., compound R5; (4) cyclization reaction: R5 is placed in methanol, and cyclized under the action of a catalyst to obtain 1,2-cyclopentanedicarboxylic acid methyl ester, i.e., compound R6.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical intermediate synthesis, and specifically relates to a method for synthesizing 1,2-cyclopentanedicarboximide. Background Art

[0002] Gliclazide is a second-generation sulfonylurea oral hypoglycemic drug with the dual effects of lowering blood sugar and improving coagulation function. It is suitable for non-insulin-dependent diabetes mellitus and has been widely used clinically. The quality of its key intermediate 1,2-cyclopentanedicarboximide (abbreviated as: imide) directly affects the quality of gliclazide.

[0003] The existing methods for synthesizing 1,2-cyclopentanedicarboximide are as follows:

[0004] (1) In his paper “Key Intermediates of Gliclazide”, Zhang Kehua disclosed that cyclohexanone and urea were used as raw materials to first react to form spirocyclic ring R8, which was then hydrolyzed to R9 and chlorinated to R10. After rearrangement and condensation, 1,2-cyclopentanedicarboxamide R11 was obtained, and then cyclized to obtain 1,2-cyclopentanedicarboximide. The specific synthetic route is as follows:

[0005] ;

[0006] The method for synthesizing 1,2-cyclopentanedicarboximide has too many steps, a low total yield, and produces a large amount of high-salt wastewater during the synthesis process, resulting in too high environmental protection costs;

[0007] (2) Cyclohexanone is used as a raw material, and a two-step reaction is performed to obtain a bromide R15 at the α position of the ketone, and then a Favorski rearrangement condensation is performed to obtain glutaric acid R16, and then a two-step reaction is performed to obtain 1,2-cyclopentanedicarboximide R6. The specific synthetic route is:

[0008] ;

[0009] This method has too many steps, low overall yield and high raw material cost;

[0010] (3) Cyclopentadiene R18 is used as a raw material to first obtain R19 through cyclization, then hydrolyze to obtain R20, and then reduce to obtain R21, and finally cyclize to obtain 1,2-cyclopentanedicarboximide R6. The specific synthetic route is:

[0011] ;

[0012] The method has too many steps, low total yield, difficult treatment of the three wastes during the synthesis process, too high a cost for treatment of the three wastes, and high raw material costs. Summary of the invention

[0013] In order to solve the problems of the prior art, the present application provides a method for synthesizing 1,2-cyclopentanedicarboximide, which is achieved through the following scheme:

[0014] A method for synthesizing 1,2-cyclopentanedicarboximide, wherein the synthetic route is:

[0015] ;

[0016] The following steps are involved:

[0017] (1) Condensation reaction: Cyclohexanone and dimethyl carbonate are used as raw materials, and a reflux reaction is carried out under the action of a solid base catalyst to obtain methyl 2-oxocyclohexanecarboxylate, i.e., compound R3;

[0018] (2) Halogenation reaction: dissolving methyl 2-oxocyclohexanecarboxylate, i.e. compound R3, in a solvent, and reacting with a halogenating agent at 0°C-15°C for halogenation. After the halogenation, the reaction is cooled to 0-5°C, crystallized, and centrifuged to obtain methyl 3-X-2-oxocyclohexanecarboxylate, i.e. compound R4, wherein X is chlorine or bromine.

[0019] (3) Rearrangement reaction: Compound R4 is dissolved in an alcohol-ammonia solution to carry out an amination rearrangement reaction, followed by cooling, crystallization, and filter pressing to obtain the rearrangement product cyclopentylamide formate methyl ester, i.e., compound R5;

[0020] (4) Cyclization reaction: Methyl cyclopentylamide formate, i.e., compound R5, is placed in methanol and undergoes cyclization in the presence of a catalyst to obtain 1,2-cyclopentyldicarboximide, i.e., compound R6.

[0021] Furthermore, the condensation reaction time of step (1) is 6-8 hours, and the reaction temperature is 100°C-140°C.

[0022] Furthermore, in step (1), the mass ratio of cyclohexanone, dimethyl carbonate and solid base catalyst 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.

[0023] Furthermore, in the step (1), the mass ratio of cyclohexanone, dimethyl carbonate and solid base catalyst is 1:4.5:0.1, and the solid base catalyst is magnesium hydroxide.

[0024] Furthermore, in the step (2), the mass ratio of compound R3, solvent and 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°C-15°C, and the halogenating time is 4-15 min.

[0025] Furthermore, in the step (2), the mass ratio of compound R3, solvent and halogenating agent is 1:6.5:0.8, and the solvent is dichloroethane.

[0026] Furthermore, in the step (3), the mass ratio of compound R4 to 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°C-10°C, and the time of the rearrangement reaction is 2-10 hours.

[0027] Furthermore, in step (3), the mass ratio of compound R4 to alcohol ammonia solution is 1:4.5.

[0028] Furthermore, in the step (4), the mass ratio of compound R5, methanol and catalyst is 1:10-30:0.3-1, and the catalyst is sodium methoxide.

[0029] Furthermore, in step (4), the mass ratio of compound R5, methanol and catalyst is 1:20:0.5.

[0030] The beneficial effects of the present invention are as follows: the present invention provides a method for preparing 1,2-cyclopentanedicarboximide, wherein cyclohexanone and dimethyl carbonate are used as raw materials to prepare 1,2-cyclopentanedicarboximide, and alcohol as a byproduct in the reaction process can be recovered as a solvent. Compared with the traditional process, the environmental pollution problem caused by "three wastes" can be effectively reduced, and the environmental protection investment cost can be reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for the description of the embodiments are briefly introduced below. Obviously, the drawings described below are only some of the preferred embodiments of the present application, not all of the embodiments. For the preferred embodiments in the present application, for ordinary technicians in this field, other embodiments and drawings can be obtained based on these embodiments and drawings without creative work, and they all belong to the protection scope of the present application.

[0032] Figure 1 This is the liquid phase detection spectrum of the finished product 1,2-cyclopentanedicarboximide of Example 1;

[0033] Figure 2 This is the liquid phase detection spectrum of the finished product 1,2-cyclopentanedicarboximide of Example 2;

[0034] Figure 3 This is the liquid phase detection spectrum of the finished product 1,2-cyclopentanedicarboximide of Example 3. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solutions and advantages of the present application clearer, the embodiments of the present application will be further described in detail below. It should be understood that the orientation or position relationship indicated by the terms "upper", "lower", "top", "bottom", "inside", "outside", etc. is based on the orientation or position relationship shown in the accompanying drawings. The above definitions are only for the convenience of describing the present application and simplifying the description, and do not indicate or imply that the structure referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on the present application. Example 1

[0036] A method for synthesizing 1,2-cyclopentanedicarboximide, the preparation method comprising the following steps:

[0037] (1) Condensation reaction: add 50 g of cyclohexanone, 225 g of dimethyl carbonate and 5 g of magnesium hydroxide to a reaction kettle, reflux and condense at 100°C-140°C for 6-8 hours, cool to 70-80°C and filter after reflux; after filtration, distill the filtrate under reduced pressure to distill the reaction solvent, raise the temperature to 120°C-140°C, collect the fractions and obtain 90.3 g of colorless transparent liquid, methyl 2-oxocyclohexanecarboxylate, i.e., compound R3, with a yield of 72.31%;

[0038] (2) Halogenation reaction: 50 g of methyl 2-oxocyclohexanecarboxylate was dissolved in 325 g of dichloroethane, cooled to 0°C-15°C, and chlorine gas was introduced for 8 h. The total amount of chlorine gas introduced was 24 g. The reaction solution after the reaction was added to 160 g of water, stirred for 1 hour, and then cooled to 0-5°C for crystallization for 2 hours. The mixture was centrifuged and dried to obtain 53.02 g of compound R4 with a yield of 93.25%.

[0039] (3) Rearrangement reaction: 50 g of compound R4 and 230 g of methanol were placed in a reaction kettle, then cooled to 0-10°C, and liquid nitrogen was added for 5 hours. The amount of liquid nitrogen added was 15.4 g. The temperature was then raised to 25-30°C and kept warm for 5 hours. After the insulation, the temperature was lowered to 0-5°C and kept warm for 2 hours. The mixture was filtered and dried to obtain 32.5 g of cyclopentylamide formate, i.e., compound R5, with a yield of 68.75%;

[0040] (4) Cyclization reaction: 50 g of methyl cyclopentylamide formate, i.e., compound R5, was placed in a reaction vessel in two batches. 300 g of methanol was added to the reaction vessel, and the temperature was raised to 45-55°C. 12 g of sodium methoxide was slowly added, and the temperature was kept for 6 hours. After the temperature was kept, the methanol was distilled under reduced pressure. After the distillation, 200 g of toluene was added to the reaction bottle, and the temperature was raised to 70-75°C. The mixture was filtered. After the filtration, the temperature was lowered to 0-5°C and kept for 2 hours. The mixture was centrifuged and dried to obtain 35 g of 1,2-cyclopentanedicarboximide with a yield of 72.14%. Example 2

[0041] (1) Condensation reaction: add 50 g of cyclohexanone, 225 g of dimethyl carbonate and 5 g of magnesium hydroxide to a reaction kettle, and reflux for condensation reaction at 100°C-140°C for 6-8 hours. After reflux, cool to 70-80°C and filter. After filtration, distill the filtrate under reduced pressure to distill the reaction solvent. The temperature is raised to 120°C-140°C and the fraction is collected to obtain 90.3 g of colorless transparent liquid, methyl 2-oxocyclohexanecarboxylate, i.e., compound R3, with a yield of 73.25%.

[0042] (2) Halogenation reaction: 50 g of methyl 2-oxocyclohexanecarboxylate was dissolved in 325 g of dichloroethane, cooled to 0°C-15°C, and bromine was added dropwise for 6 hours. The total amount of bromine added was 36 g. The reaction solution was added to 160 g of water, stirred for 1 hour, and then cooled to 0-5°C for crystallization for 2 hours. The mixture was centrifuged and dried to obtain 58.19 g of compound R4 with a yield of 94.47%;

[0043] (3) Rearrangement reaction: 50 g of compound R4 and 230 g of methanol were placed in a reaction kettle, then cooled to 0-10°C, and liquid nitrogen was added for 5 hours. The amount of liquid nitrogen added was 15.4 g. The temperature was then raised to 25-30°C and kept warm for 5 hours. After the insulation, the temperature was lowered to 0-5°C and kept warm for 2 hours. The mixture was filtered and dried to obtain 32.5 g of cyclopentylamide formate, i.e., compound R5, with a yield of 71.13%;

[0044] (4) Cyclization reaction: 50 g of methyl cyclopentylamide formate, i.e., compound R5, was placed in a reaction vessel in two batches. 300 g of methanol was added to the reaction vessel, and the temperature was raised to 45-55°C. 12 g of sodium methoxide was slowly added, and the temperature was kept for 6 hours. After the temperature was kept, the methanol was distilled under reduced pressure. After the distillation, 200 g of toluene was added to the reaction bottle, and the temperature was raised to 70-75°C. The mixture was filtered. After the filtration, the temperature was lowered to 0-5°C and kept for 2 hours. The mixture was centrifuged and dried to obtain 35 g of 1,2-cyclopentanedicarboximide with a yield of 71.78%. Example 3

[0045] (1) Condensation reaction: add 50 g of cyclohexanone, 225 g of dimethyl carbonate and 5 g of magnesium hydroxide to a reaction kettle, and reflux for condensation reaction at 100°C-140°C for 6-8 hours. After reflux, cool to 70-80°C and filter. After filtration, distill the filtrate under reduced pressure to distill the reaction solvent. The temperature is raised to 120°C-140°C and the fraction is collected to obtain 90.3 g of colorless transparent liquid, methyl 2-oxocyclohexanecarboxylate, i.e., compound R3, with a yield of 74.85%.

[0046] (2) Halogenation reaction: 50 g of methyl 2-oxocyclohexanecarboxylate was dissolved in 325 g of dichloroethane, cooled to 0°C-15°C, and 26 g of thionyl chloride was added dropwise for 8 hours. The reaction solution was added to 160 g of water, stirred for 1 hour, and then cooled to 0-5°C for crystallization for 2 hours. The mixture was centrifuged and dried to obtain 55.29 g of compound R4 with a yield of 70.12%.

[0047] (3) Rearrangement reaction: 50 g of compound R4 and 230 g of methanol were placed in a reaction kettle, then cooled to 0-10°C, and liquid nitrogen was added for 5 hours. The amount of liquid nitrogen added was 15.4 g. The temperature was then raised to 25-30°C and kept warm for 5 hours. After the insulation was completed, the temperature was lowered to 0-5°C and kept warm for 2 hours. The mixture was filtered and dried to obtain 32.5 g of methyl cyclopentylamide formate, i.e., compound R5, with a yield of 70.62%.

[0048] (4) Cyclization reaction: 50 g of methyl cyclopentylamide formate, i.e., compound R5, was placed in a reaction vessel in two batches. 300 g of methanol was added to the reaction vessel, and the temperature was raised to 45-55°C. 12 g of sodium methoxide was slowly added, and the temperature was kept for 6 hours. After the temperature was kept, the methanol was distilled under reduced pressure. After the distillation, 200 g of toluene was added to the reaction bottle, and the temperature was raised to 70-75°C. The mixture was filtered. After the filtration, the temperature was lowered to 0-5°C and kept for 2 hours. The mixture was centrifuged and dried to obtain 35 g of 1,2-cyclopentanedicarboximide with a yield of 74.06%.

[0049] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present application and are not intended to limit it. Although the present application has been described in detail with reference to the preferred embodiments, a person of ordinary skill in the art should understand that the technical solution of the present application can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present application, which should be included in the scope of the claims of the present application.

Claims

1. A method for synthesizing 1,2-cyclopentanedicarboximide, characterized in that: The following steps are involved: (1) Condensation reaction: Cyclohexanone and dimethyl carbonate are used as raw materials, and a reflux reaction is carried out under the action of a solid base catalyst to obtain methyl 2-oxocyclohexanecarboxylate, i.e., compound R3; (2) Halogenation reaction: dissolving methyl 2-oxocyclohexanecarboxylate, i.e. compound R3, in a solvent, and reacting with a halogenating agent at 0°C-15°C for halogenation. After the halogenation, the reaction is cooled to 0-5°C, crystallized, and centrifuged to obtain methyl 3-X-2-oxocyclohexanecarboxylate, i.e. compound R4, wherein X is chlorine or bromine. (3) Rearrangement reaction: Compound R4 is dissolved in an alcohol-ammonia solution to carry out an amination rearrangement reaction, followed by cooling, crystallization, and filter pressing to obtain the rearrangement product cyclopentylamide formate methyl ester, i.e., compound R5; (4) Cyclization reaction: methyl cyclopentylamide formate, i.e. compound R5, is placed in methanol and cyclized under the action of a catalyst to obtain 1,2-cyclopentyl dicarboximide, i.e. compound R6; The synthetic route is: 。 2. A method for synthesizing 1,2-cyclopentanedicarboximide as claimed in claim 1, characterized in that: The condensation reaction time of step (1) is 6-8 hours, and the reaction temperature is 100°C-140°C.

3. A method for synthesizing 1,2-cyclopentanedicarboximide as claimed in claim 1, characterized in that: In the step (1), the mass ratio of cyclohexanone, dimethyl carbonate and solid base catalyst 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. A method for synthesizing 1,2-cyclopentanedicarboximide as claimed in claim 1, characterized in that: In the step (1), the mass ratio of cyclohexanone, dimethyl carbonate and solid base catalyst is 1:4.5:0.1, and the solid base catalyst is magnesium hydroxide.

5. The method for synthesizing 1,2-cyclopentanedicarboximide according to claim 1, characterized in that: In the step (2), the mass ratio of compound R3, solvent and 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°C-15°C, and the halogenating time is 4-15 min.

6. The method for synthesizing 1,2-cyclopentanedicarboximide according to claim 1, characterized in that: In the step (2), the mass ratio of compound R3, solvent and halogenating agent is 1:6.5:0.8, and the solvent is dichloroethane.

7. The method for synthesizing 1,2-cyclopentanedicarboximide according to claim 1, characterized in that: In the step (3), the mass ratio of compound R4 to 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°C-10°C, and the time of the rearrangement reaction is 2-10 hours.

8. The method for synthesizing 1,2-cyclopentanedicarboximide according to claim 1, characterized in that: In the step (3), the mass ratio of compound R4 to alcohol ammonia solution is 1:4.

5.

9. The method for synthesizing 1,2-cyclopentanedicarboximide according to claim 1, characterized in that: In the step (4), the mass ratio of compound R5, methanol and catalyst is 1:10-30:0.3-1, and the catalyst is sodium methoxide.

10. The method for synthesizing 1,2-cyclopentanedicarboximide according to claim 1, characterized in that: In step (4), the mass ratio of compound R5, methanol and catalyst is 1:20:0.5.

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