Method for producing 6-ethylidene chenodeoxycholic acid by continuous flow micro reactor

A technology of chenodeoxycholic acid and micro-reactor, which is applied in the field of production of 6-ethylene chenodeoxycholic acid, can solve the problems of increased side reactions, decreased product system purity, increased difficulties, etc., and achieves easy operation and control, Easy-to-sync amplification and simple post-processing effects

Active Publication Date: 2018-07-20
ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, when the reaction is scaled up to 500g to 1Kg level, the amplification effect is obvious. Because the mass transfer and heat transfer process cannot be scaled up simultaneously, the control of the reaction becomes very difficult, especially the stirring effect of the material is quite different from that of the small-scale reaction, and the side reaction There is a relatively obvious increase, and the content of 7-ketocholelithic acid in the reaction system will always have a greater increase
When the same reaction conditions are scaled up to 1Kg level, the content of 7-ketocholelithic acid will rise to more than 5%, which will cause great trouble to the purification of 6-ethylenecholelithic acid
And many other types of side reactions also increase significantly during the amplification process, resulting in a significant decrease in the purity of the product system
Further magnification, the difficulty due to the magnification effect increases further

Method used

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  • Method for producing 6-ethylidene chenodeoxycholic acid by continuous flow micro reactor
  • Method for producing 6-ethylidene chenodeoxycholic acid by continuous flow micro reactor
  • Method for producing 6-ethylidene chenodeoxycholic acid by continuous flow micro reactor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The cyclohexane solution of 0.5mol / L enol silyl ether S1, (274g S1 is dissolved in cyclohexane to make a total volume of 1 liter of cyclohexane solution), cooled to a solution temperature of about 0 degrees Celsius, passed The plunger pump P1 described in accompanying drawing 3 is pumped into a stainless steel pipe with an inner diameter of 0.2 mm, the linear velocity of the fluid in the pipe is 0.1-1 m / s, and the volume flow rate V1 is 3.14*10 - 8 m 3 / S, 1.84ml / min, Mol flow rate is 0.92mmol / min. This section of stainless steel pipe is immersed in a cold bath with a temperature of -35 degrees Celsius. The length of this section of pipe should ensure that the temperature of the fluid at the end of this section of pipe is lower than -30 degrees Celsius. Liquid anhydrous acetaldehyde flows through a stainless steel pipe immersed in a cold bath at -35 degrees Celsius, cooled to below -30 degrees Celsius, and then pumped into the pipeline reaction system through a plunge...

Embodiment 2

[0055] ingredients of each material. The sequence and flow process of flowing into the reactor are as in Example 1. Only the inner diameter of the main reaction mixing section and the main reaction section of the reactor is enlarged to 2mm. Keep the linear velocity of the fluid in the pipeline constant. The inner diameter of the reaction pipe in the supplementary reaction section is enlarged to 20mm. After the expansion of the reaction device, the cooling measures of each section should be appropriately strengthened, and the cooling bath should have a faster forced flow to ensure that the heat energy generated by the reaction in the pipeline can be exported in time.

[0056] It can produce about 40g of 6-ethylene chenodeoxycholic acid per minute, and can produce about 50Kg of 6-ethylene chenodeoxycholic acid per day in continuous operation. When the reactor is expanded to this specification, the impurities in the reaction system do not increase significantly.

Embodiment 3

[0058] Each material composition is consistent with Example 1, only the order of each material flowing into the reactor is changed: the boron trifluoride acetonitrile solution is first pumped in, after cooling, it is mixed with acetaldehyde in the mixer M1, and then in the high-efficiency mixer M2 is mixed with the cyclohexane solution of enol silyl ether, and the subsequent reaction and supplementary reaction process and temperature remain unchanged.

[0059] In this embodiment, the reaction mixture leaving the continuous flow reactor is clear and transparent, with very little impurity content, relatively simple post-treatment, and extremely high yield. A single set of reaction device can produce about 0.4g of 6-ethylene chenodeoxycholic acid per minute, and can produce about 50Kg of 6-ethylene chenodeoxycholic acid per day in continuous operation.

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Abstract

The invention discloses a method for producing 6-ethylidene chenodeoxycholic acid by a continuous flow micro reactor. According to the method, pumping and conveying a solution of silyl enol ether intoa pipeline reactor through a pump; after cooling, mixing the solution with the cooled acetaldehyde solution in a mixer; then, continuously performing cooling in a pipeline reactor; next, mixing the materials with the cooled catalyst solution in another mixer; then, completing the reaction in the pipeline reactor. The operation is simple; the operation and the control of the production are easy; byproducts in the production process are few; the yield is high; the synchronous amplification is easy.

Description

technical field [0001] The invention relates to a method for producing 6-ethylenechenodeoxycholic acid using a continuous flow microreactor. Background technique [0002] 6-Ethylenechenodeoxycholic acid is a key intermediate for the preparation of obeticholic acid. The preparation of this key intermediate is generally based on commercially available chenodeoxycholic acid (CDCA) or 7-ketocholic acid (7-KLCA) as a raw material, after protecting the 3-position hydroxyl group, and enolizing the 7-position keto group Prepare the corresponding enol silyl ether, enol silyl ether undergoes a Mukaiyama-type strong condensation reaction with anhydrous acetaldehyde under the catalysis of Lewis acid, and the product is automatically dehydrated under appropriate conditions such as the presence of excess Lewis acid to generate 3-protected 6-ethylene chenodeoxycholic acid, and then remove the 3-position protecting group to obtain the key intermediate 6-ethylene chenodeoxycholic acid for t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCC07J9/005Y02P20/55
Inventor 欧松吴黎雄杨琳钟可玲彭延春王明宗梁代亮娄良阮宇峰
Owner ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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