Preparation method of vitamin K1 with different cis-trans isomer proportions and intermediate halogenated phytol thereof

A technology of cis-trans isomerization and phytoalcohol, which is applied in the preparation of halogenated hydrocarbons, organic compounds, quinones, etc. It can solve the problem of uncontrollable isomer ratio and achieve the effect of simple operation and low purification difficulty

Active Publication Date: 2020-05-15
NANJING HANXIN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The object of the present invention is to provide a vitamin K with different cis and trans isomer ratios 1 The preparation method of halogenated phytoalcohols and intermediates thereof solves the problem of uncontrollable ratio of isomers existing in the prior art

Method used

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  • Preparation method of vitamin K1 with different cis-trans isomer proportions and intermediate halogenated phytol thereof
  • Preparation method of vitamin K1 with different cis-trans isomer proportions and intermediate halogenated phytol thereof
  • Preparation method of vitamin K1 with different cis-trans isomer proportions and intermediate halogenated phytol thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]Add 200g of phytoalcohol and 10g of phosphoric acid into 1.2L of n-hexane and stir, cool down to -10-0°C, add 240g of phosphorus tribromide dropwise, and keep the internal temperature under control not higher than 0°C. After 3 hours of monitoring by TLC, the reaction of the raw materials was complete, quenched by adding methanol, separated into layers, spin-dried to remove the solvent, and bromophytol was obtained.

[0042] Add 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into the reaction flask and stir, cool down to -20~-10°C, add 60g of cyclopentadienylmenadione, and slowly add bromophytol dropwise. After 2 hours of monitoring by TLC, the reaction of the raw materials was complete, quenched by adding hydrochloric acid, and the tetrahydrofuran was removed by rotary evaporation. The remaining aqueous phase was extracted with 0.5 L of methyl tert-butyl ether, separated, and the solvent was removed by rotary evaporation to obtain an oily substance. Dissolv...

Embodiment 2

[0044] Add 200g of phytoalcohol and 40g of phosphoric acid into 1.2L of n-hexane and stir, cool down to -10-0°C, add 240g of phosphorus tribromide dropwise, and control the internal temperature to not higher than 0°C. After 2.5 hours of monitoring by TLC, the reaction of the raw materials was complete, quenched by adding methanol, separated into layers, spin-dried to remove the solvent, and bromophytol was obtained.

[0045] Add 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into the reaction flask and stir, cool down to -20~-10°C, add 60g of cyclopentadienylmenadione, and slowly add bromophytol dropwise. After 2 hours of monitoring by TLC, the reaction of the raw materials was complete, quenched by adding hydrochloric acid, and the tetrahydrofuran was removed by rotary evaporation. The remaining aqueous phase was extracted with 0.5 L of methyl tert-butyl ether, separated, and the solvent was removed by rotary evaporation to obtain an oily substance. Dissolve the...

Embodiment 3

[0047] Add 200g of phytoalcohol and 60g of phosphoric acid into 1.2L of n-hexane and stir, lower the temperature to -10-0°C, add 240g of phosphorus tribromide dropwise, and keep the internal temperature under control not higher than 0°C. After 2 hours of monitoring by TLC, the reaction of the raw materials was complete, quenched by adding methanol, separated into layers, spin-dried to remove the solvent, and bromophytol was obtained.

[0048] Add 11.5g of potassium tert-butoxide and 1.2L of tetrahydrofuran into the reaction flask and stir, cool down to -20~-10°C, add 60g of cyclopentadienylmenadione, and slowly add bromophytol dropwise. After 2 hours of monitoring by TLC, the reaction of the raw materials was complete, quenched by adding hydrochloric acid, and the tetrahydrofuran was removed by rotary evaporation. The remaining aqueous phase was extracted with 0.5 L of methyl tert-butyl ether, separated, and the solvent was removed by rotary evaporation to obtain an oily substa...

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Abstract

The invention discloses a preparation method of vitamin K1 with different cis-trans isomer proportions and an intermediate halogenated phytol thereof. The method comprises the following steps: carrying out a halogenation reaction on a raw material phytol and phosphorus trihalide under the catalysis of phosphoric acid to obtain halogenated phytol, reacting the halogenated phytol with cyclopentadienyl menadione, and carrying out high-temperature depolymerization to obtain the vitamin K1. The addition amount of phosphoric acid in the halogenation reaction can be controlled, so that the proportionof the obtained vitamin K1 cis-isomer can be regulated between 1% and 21%.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a vitamin K with different cis-trans isomer ratios 1 The preparation method of its intermediate halogenated phytoalcohol. Background technique [0002] Vitamin K 1 (Vitamin K 1 ), the chemical name is 2-methyl-3-(3,7,11,15-tetramethylhexadec-2-enyl)-1,4-naphthoquinone, which belongs to vitamin drugs, and there are A double bond, so there are cis and trans isomers. Chemically synthesized vitamin K 1 It is a mixture of cis and trans isomers, and the cis isomer has almost no physiological activity. Therefore, after the 1980s, the pharmacopoeias of various countries have all listed vitamin K as 1 The cis-isomer of the specified limit (cis-isomer ≤ 21.0%). [0003] At present, domestic vitamin K 1 The main preparation methods are 1) Friedel-Crafts alkylation method; 2) menadione-cyclopentadiene method. The disadvantages of the Friedel-Crafts alkylation method are low yield,...

Claims

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Application Information

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IPC IPC(8): C07C17/16C07C21/14C07C21/04C07C46/00C07C50/14
CPCC07B2200/09C07C17/16C07C46/00C07C2602/10C07C2603/86C07C21/14C07C21/04C07C50/14C07C50/22
Inventor 徐奎年夫宇徐勇刚陈松张昊宁
Owner NANJING HANXIN PHARMA TECH CO LTD
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