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Preparation method of (R)-3-cyclohexeneformic acid

A technology of cyclohexene carboxylic acid and dimethyl ring, which is applied in the field of preparation of -3-cyclohexene carboxylic acid, can solve the problems of expensive raw materials, cumbersome reaction process, and difficult filtration of salt, and achieve high atom utilization rate and reaction Simple operation effect

Active Publication Date: 2021-04-13
安徽英特美科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] There are two methods for synthesizing (R)-3-cyclohexenecarboxylic acid in the existing public literature. The first method is the racemate resolution method (Tetrahedron, 2017, 73, 1381-1388), mainly using (S)- α-Phenylethylamine is resolved, but the obtained salt is not easy to filter and requires repeated recrystallization to achieve qualified products, the yield is 29-33%, and the amount of resolving agent is large
The second method is asymmetric synthesis (Tetrahedron, 2011, 67, 2044-2050). This method mainly uses chiral substances as raw materials, and obtains products through multi-step reactions. , difficult to industrialize

Method used

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  • Preparation method of (R)-3-cyclohexeneformic acid

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Experimental program
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Effect test

Embodiment 1

[0020] Synthesis of (R)-3-cyclohexenecarboxylic acid

[0021]

[0022] Into a 2000mL reaction flask, add 200.0g 3-cyclohexenecarboxylic acid (1.585mol) and 1000mL ethyl acetate, control the temperature to 45-50℃, and add 112.8g (1S, 2S)-N,N′-di A solution formed by dissolving methylcyclohexanediamine (0.793mol, 0.5eq) in 200mL ethyl acetate took 2.5 hours. After the dropwise addition, the temperature was raised to reflux for 4.0 hours, and the temperature was gradually lowered to 10-15°C. Filtration gave white crystalline solid (R)-3-cyclohexenecarboxylic acid-(1S,2S)-N,N'-dimethylcyclohexanediamine salt. Put the filter cake back into the reaction flask, add ethyl acetate and 6M hydrochloric acid aqueous solution, adjust the pH=1-2, stir for 0.5 hours, and separate layers when the pH value does not change. The organic layer was dried over anhydrous sodium sulfate, concentrated by filtration, added 40g of sulfolane, and distilled under reduced pressure (-0.099Mpa, 79~85°C)...

Embodiment 2

[0024]

[0025] Into a 2000mL reaction flask, add 200.0g 3-cyclohexenecarboxylic acid (1.585mol) and 800mL 2-methyltetrahydrofuran and mix, control the temperature to 45~50℃, add 112.8g (0.793mol, 0.5eq) (1S ,2S)-N,N′-Dimethylcyclohexanediamine was dissolved in 200mL 2-methyltetrahydrofuran to form a solution. After the dropwise addition, the temperature was raised to reflux for 4 hours, and the temperature was gradually lowered to 5-10°C. The white crystalline solid (R)-3-cyclohexenecarboxylic acid-(1S,2S)-N,N'-dimethylcyclohexanediamine salt was obtained by filtration. Put the filter cake back into the reaction flask, add 500mL 2-methyltetrahydrofuran, control the temperature not to exceed 20°C, slowly add 20% sulfuric acid aqueous solution dropwise, adjust the pH=2-3, stir for 0.5 hours, and separate when the pH value does not change . The organic layer was dried over anhydrous sodium sulfate, concentrated by filtration, added 40g of sulfolane, and distilled under reduc...

Embodiment 3

[0027]

[0028] Add 200.0g of 3-cyclohexenecarboxylic acid (1.585mol) and 800mL of 2-methyltetrahydrofuran into a 2000mL reaction flask, mix them, control the temperature to 45-50°C, and add 112.8g (0.793mol, 0.5eq) (1S ,2S)-N,N′-Dimethylcyclohexanediamine was dissolved in 200mL of ethyl acetate to form a solution. After the dropwise addition, the temperature was raised to reflux for 4 hours, and the temperature was gradually lowered to 5-10°C. The white crystalline solid (R)-3-cyclohexenecarboxylic acid-(1S,2S)-N,N'-dimethylcyclohexanediamine salt was obtained by filtration. Put the filter cake back into the reaction flask, add 500mL ethyl acetate, control the temperature not to exceed 20°C, slowly add 6M hydrochloric acid aqueous solution dropwise, adjust the pH=1-2, stir for 0.5 hours, and separate when the pH value does not change. The organic layer was dried over anhydrous sodium sulfate, concentrated by filtration, added 40g of sulfolane, and distilled under reduced p...

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Abstract

The invention discloses a preparation method of (R)-3-cyclohexenecarboxylic acid, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: refluxing 3-cyclohexenecarboxylic acid and 0.5 eq(1S, 2S)-N, N'-dimethyl cyclohexanediamine in an organic solvent to form salt, and adding acid for dissociation to obtain the (R)-3-cyclohexenecarboxylic acid. According to the method, the reaction steps are few, the raw materials are easy to obtain, the operation is simple and convenient, the one-time resolution yield is 42-43%, the product purity and enantioselectivity are up to 99.5% or above, and the resolving agent can be recycled and reused, so that the method has a potential industrial amplification prospect.

Description

technical field [0001] The invention relates to a preparation method of (R)-3-cyclohexenecarboxylic acid, belonging to the technical field of pharmaceutical intermediates. Background technique [0002] (R)-3-Cyclohexene-carboxylic acid, English name: (R)-3-Cyclohexene-1-carboxylic acid, CAS5709-98-8, its chemical structure is: (R)-3-cyclohexenecarboxylic acid, as an important structural functional group, has good biological activity and is also the starting material of edoxaban. [0003] (R)-3-Cyclohexenecarboxylic acid is an important chemical reagent and organic intermediate, widely used in many fields such as medicine and chemical industry, such as in the blood coagulation factor Xa inhibitor, is 3,4-diaminocyclic Important starting material for hexanecarboxylic acid derivatives. [0004] There are two methods for synthesizing (R)-3-cyclohexenecarboxylic acid in the existing public literature. The first method is the racemate resolution method (Tetrahedron, 2017, 73, 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/41C07C51/02C07C51/44C07C61/22C07C209/68C07C211/36
CPCC07C51/412C07C51/02C07C51/44C07C209/68C07B2200/07C07C2601/16C07C61/22C07C211/36
Inventor 刘洪强杨忆魏佳玉王松松年成成朱克明
Owner 安徽英特美科技有限公司
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