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VK2 synthesis method

A synthesis method and dropwise addition technology are applied in the field of chemical synthesis of vitamin K2, which can solve the problems of low purity, low yield, flammability and explosion, and achieve the effects of shortening reaction time, reducing cost and simplifying steps.

Pending Publication Date: 2022-03-08
安徽先和医药研究有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] (1) The synthesis time from compound 1 to compound 3 is long, and the purification of compound 3 is troublesome, and it is not easy to obtain compound 3 with high purity, which often contains compound 1
[0007] (2) The yield of compound 5 is low, and the purity is not high, and there is a large amount of compound 3 in it that the reaction is not completed, which directly leads to the low purity of the synthesized VK2, and the yield is very low (total yield is about 15%)
[0008] (3) The depolymerization of cyclopentadiene in this process is more dangerous, it is flammable and explosive, and the depolymerization produces a large amount of solid waste and volatile gas

Method used

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Experimental program
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Effect test

Embodiment 1

[0026] Add 5g (29mmol) menadione to 50ml EA (ethyl acetate), then add 6g (34.5mmol) sodium hydrosulfite (sodium dithionite), add 1.3g (72.2mmol) pure water with a syringe under nitrogen protection, The reaction was carried out overnight (about 10 hours) at room temperature. When the reaction solution becomes milky white and turbid completely, add 5.2g (36.6mmol) boron trifluoride ether dropwise under nitrogen protection, heat up to 60 degrees Celsius, slowly add 10.4g (35.8mmol) geranyllinalool dropwise, and control the temperature React for 3 hours. Get the reaction solution and send it to the liquid phase for detection, and the HPLC detection result is as follows: figure 2 , wherein the main impurity is unreacted menadione, which can be recovered by means of purification. After the reaction, the reaction solution can be poured into water to flush, then extracted twice with ethyl acetate, backwashed with saturated brine, dried over sodium sulfate, concentrated to dryness, ...

Embodiment 2

[0028] Add 15g (87mmol) of menadione to 150ml of EA (ethyl acetate), then add 18g (103.4mmol) of hydrosulfite (sodium dithionite), add 4g (222.2mmol) of pure water with a syringe under nitrogen protection conditions, and keep at room temperature The reaction was left overnight (about 10 hours). When the reaction solution becomes milky white turbidity completely, add 15.6g (109.8mmol) boron trifluoride ether dropwise under nitrogen protection, heat up to 60 degrees Celsius, slowly add 31.2g (107.4mmol) geranyllinalool dropwise, and control the temperature React for 3 hours. After the reaction, the reaction solution can be poured into water to flush, then extracted twice with ethyl acetate, backwashed with saturated brine, dried over sodium sulfate, concentrated to dryness, mixed with silica gel and purified by column, the eluent is ethyl acetate : Petroleum ether=1:10, v / v. 13.3 g of product were obtained after purification. 99% pure.

Embodiment 3

[0030] Add 30g (174mmol) of menadione to 250ml of EA (ethyl acetate), then add 36g (206.8mmol) of hydrosulfite (sodium dithionite), add 8g (444.4mmol) of purified water with a syringe under the condition of nitrogen protection, at room temperature The reaction was left overnight (about 10 hours). When the reaction liquid becomes milky white turbidity completely, add 31.2g (219mmol) boron trifluoride ether dropwise under nitrogen protection, heat up to 60 degrees Celsius, slowly add 62.4g (214.8mmol) geranyl linalool dropwise, and react under temperature control 3 hours. After the reaction, the reaction solution can be poured into water to flush, then extracted twice with ethyl acetate, backwashed with saturated brine, dried over sodium sulfate, concentrated to dryness, mixed with silica gel and purified by column, the eluent is ethyl acetate : Petroleum ether=1:10, v / v. 27.5 g of product were obtained after purification. 99% pure.

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Abstract

The invention discloses a VK2 synthesis method, which comprises: dissolving menadione in EA, adding sodium hydrosulfite, adding water under an anaerobic condition, and carrying out a room temperature reaction for 6-15 h; dropwise adding boron trifluoride diethyl etherate under the protection of nitrogen when the reaction liquid becomes milk white turbid, heating to 50-80 DEG C after dropwise adding, slowly dropwise adding geranyl linalool, carrying out temperature-controlled reaction for 1-6 hours, and carrying out post-treatment purification. According to the method, VK2 is synthesized in one step by adopting a one-pot method, so that the reaction steps are greatly simplified, the reaction time is shortened, the yield and the purity of a target product are relatively high, and the price of used reagents is low, so that the production cost is greatly reduced.

Description

technical field [0001] The invention relates to a chemical synthesis method of vitamin K2 (VK2). Background technique [0002] Vitamin K is a class of compounds with a quinone structure, including five types of compounds with different structures, namely vitamin K1, K2, K3, K4, and K5. Studies have shown that vitamin K2 has an osteogenic effect, promotes calcium metabolism, and can also inhibit bone resorption caused by osteoclasts, thereby increasing bone density and preventing osteoporosis. Vitamin K2 Chemicalbook is a series of compounds, which are pale yellow crystals and are mainly synthesized by intestinal bacteria. There are 14 types according to the length of the isoprene side chain on C3. Vitamin K2 is mainly used to treat osteoporosis (20) , that is, menadione tetraenol. Menatetrenone is an oily substance, and it is easy to decompose when exposed to light, so it is suitable for making soft capsule dosage forms. [0003] Currently, the commonly used chemical synt...

Claims

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Application Information

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IPC IPC(8): C07C46/00C07C50/14
CPCC07C46/00C07C37/07C07C2602/10C07C50/14C07C39/14
Inventor 王俊姚欣张晓倩袁毅
Owner 安徽先和医药研究有限公司
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