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Preparation method of vitamin K2 compounds

A compound and metal compound technology, applied in the field of organic drug synthesis, can solve problems such as unsuitable for industrial production, harsh conditions, and cumbersome operations, and achieve the effects of easy separation and purification, mild reaction conditions, and reduced pollution

Active Publication Date: 2014-10-22
天津康鸿医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The conditions of this method are harsh, the operation is cumbersome, and the yield is low, so it is not suitable for industrial production
Xavier Garcias et al. used 2-methyl-3-bromo-1,4-naphthalenediol and geranylgeranial as raw materials to synthesize vitamin K2 through condensation, elimination, deprotection and other reactions. This method uses sensitive chemicals For n-butyllithium, column chromatography is required during the operation, which is cumbersome to operate, has great potential safety hazards, and the yield is very low, so it is not suitable for industrial production

Method used

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  • Preparation method of vitamin K2 compounds
  • Preparation method of vitamin K2 compounds
  • Preparation method of vitamin K2 compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] (1) Synthesis of compound shown in formula 3

[0051] Add 500ml of methanol and 100g of 2-methyl-1,4-naphthoquinone into a 1L four-neck flask, cool down to 0°C, add 111.7g of bromine dropwise at a temperature of 0-10°C, and pay attention to connecting the alkali absorption device. After dripping, keep warm at 10-30°C for 3-5 hours, slowly heat up to reflux and react for 3 hours, cool down to room temperature naturally, then cool to 0-5°C for natural crystallization for 10 hours, suction filter, reduce at 25-30°C Drying under pressure gave 124.4 g of white solid with a yield of 91%.

[0052] (2) Synthesis of compound shown in formula 4

[0053] A. Add 87g of tri-n-butyltin hydrogen and 200ml of tetrahydrofuran into a 1L dry four-necked bottle, cool down to -10°C, and add 100g of geranylgeranyl bromide in 300ml of tetrahydrofuran solution dropwise at -10°C to 10°C. Warm to 20-25°C until the reaction is complete, and filter until dry to obtain 163.2 g of a yellow solid, ...

Embodiment 2

[0058] (1) Synthesis of compound shown in formula 3

[0059] Add 500ml of toluene, 100g of 2-methyl-1,4-naphthoquinone, 49.5g of ethylene glycol into a 1L four-neck flask, and after refluxing for 3 hours, cool down to 0°C, and dropwise add the Phosphorus oxybromide 200g tetrahydrofuran solution 100ml, pay attention to connect the alkali absorption device. After dripping, keep warm at 10-30°C for 3-5 hours, slowly heat up to reflux and react for 3 hours, cool down to room temperature naturally, then cool to 0-5°C for natural crystallization for 10 hours, suction filter, reduce at 25-30°C Drying under pressure gave 120.3 g of white solid with a yield of 89%.

[0060] (2) Synthesis of compound shown in formula 4

[0061] A. Add 50g of elemental magnesium, 1g of elemental iodine, 600ml of tetrahydrofuran and 100g of geranylgeranyl bromide into a 1L dry four-necked bottle, slowly heat to reflux for 10h, and naturally cool down to room temperature, that is, the geranylgeranyl magn...

Embodiment 3

[0066] (1) Synthesis of compound shown in formula 3

[0067] Add 500ml of toluene, 100g of 2-methyl-1,4-naphthoquinone, and 75.5g of ethanedithiol into a 1L four-neck flask. After refluxing for 3 hours, cool down to 0°C and add dropwise at 0-10°C. 100ml of tetrahydrofuran solution containing 200g of phosphorus oxybromide, pay attention to connect the alkali absorption device. After dripping, keep warm at 10-30°C for 3-5 hours, slowly heat up to reflux and react for 3 hours, cool down to room temperature naturally, then cool to 0-5°C for natural crystallization for 10 hours, suction filter, reduce at 25-30°C Drying under pressure gave 143 g of white solid with a yield of 89%.

[0068] (2) Synthesis of compound shown in formula 4

[0069] A. Add 50g of elemental zinc, 1g of elemental iodine, 600ml of toluene and 100g of geranylgeranyl bromide into a 1L dry four-necked bottle, slowly heat to reflux for 10 hours, and naturally cool down to room temperature, that is, the geranylg...

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Abstract

The invention provides a preparation method of a vitamin K2 compound. The preparation method comprises the following steps that a compound shown by the formula 2, a carbonyl protective agent and a bromination agent undergo a reaction to produce a compound shown in the formula 3; the compound shown in the formula 3 and a long-chain olefin metal compound undergo a reaction in the presence of catalysts to produce a compound shown in the formula 4; and the compound shown in the formula 4 reacts under an acid catalysis condition to produce a compound shown in the formula 1, wherein n represents an integer of 0 to 10, such as 1, 3, 6 or 8; and R represents C1-C4 of O,O-, O,S- and S,S-ketal and acetal (comprising annular ketal and acetal), O,O,O-orthoester, O,S,S-orthoester, S,S,S-orthoester, alkenyl ether, sulfo-alkenyl ether and enamine. The preparation method has the advantages of mild reaction conditions, less side reactions, poor product decomposability, relatively simple deprotection reaction conditions and high yield.

Description

technical field [0001] The invention belongs to the field of organic medicine synthesis, and in particular relates to a synthesis method of vitamin K2 compounds. Background technique [0002] In 1934, Danish scientists first discovered vitamin K and confirmed that it is a fat-soluble vitamin. Vitamin K is a class of naphthoquinone derivatives with biological activity of phylloquinone, and is one of the indispensable and important vitamins in the human body. Naturally occurring vitamins K1 and K2, among which vitamin K1 is widely found in green plants and is an important source of vitamin K in food; vitamin K2 is mainly synthesized by intestinal bacteria. [0003] Vitamin K2 can be used to treat and prevent osteoporosis, increase bone density, prevent fractures; prevent liver cirrhosis from developing into liver cancer; treat vitamin K2 deficiency hemorrhage, promote the formation of prothrombin, accelerate coagulation, and maintain normal coagulation time; It also has a di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C50/14C07C46/00
Inventor 郭建锋孙歆慧邹美香吴疆薛艳萍张彩霞
Owner 天津康鸿医药科技发展有限公司
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