CN101139272A - Method for synthesizing vitamin K2 - Google Patents
Method for synthesizing vitamin K2 Download PDFInfo
- Publication number
- CN101139272A CN101139272A CNA2006101287803A CN200610128780A CN101139272A CN 101139272 A CN101139272 A CN 101139272A CN A2006101287803 A CNA2006101287803 A CN A2006101287803A CN 200610128780 A CN200610128780 A CN 200610128780A CN 101139272 A CN101139272 A CN 101139272A
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- vitamin
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- transition metal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/10—Quinones the quinoid structure being part of a condensed ring system containing two rings
- C07C50/14—Quinones the quinoid structure being part of a condensed ring system containing two rings with unsaturation outside the ring system, e.g. vitamin K1
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a synthesis method of the vitamin K <SUB > 2 </ SUB> represented by the vitamin K<SUB>2(10)</SUB>, K<SUB>2(20)</SUB> and K<SUB>2(45)</SUB>. Specifically the present invention is a synthesis method of the vitamin K <SUB > 2 </ SUB>, which is characterized in the condensation reaction of the vitamin K<SUB>3</SUB> and the halide of the plant alcohol with the influence of the transition metal elements.
Description
Invention field
The present invention relates to the organic medicinal chemistry field, particularly, the present invention relates to vitamin K
2Synthetic method.
Background technology
Vitamin K (Vitamin K) has another name called vitamin K, vitamin K
2It is the essential material that the liver blood coagulation forms.Vitamin K
2Be mainly used in treatment new biochemical period and young infant digestive tract hemorrhage and intracranial hemorrhage etc., and can prevent the liver cirrhosis progress to be liver cancer (JAMA, 292:358-361,2004), vitamin K
2Effect more and more paid attention to by people, this compound is present in nature, also can synthetic.
1958, Isler etc. (Helv.Chim.Acta 41,786,1958) are the chemosynthesis vitamin K at first
2Series.
At numerous vitamin Ks
2In the study on the synthesis, 2-bromo-3-methyl isophthalic acid is arranged, on the 4-dimethoxy-naphthalene main ring, carry out grignard reaction and the coupling of polyisoamylene base (1. SynderC D, J.Am.Chem.Soc., 13 (7): 8046-8054,1974; 2. Chanard B L, J.Org.Chem, 45 (3): 378-384,1980; 3. Syper L.Tetrahedron, 36 (1): 123-129,1979) its intermediate 2-bromo-3-methyl isophthalic acid, the 4-methoxynaphthalene is to be raw material with the 2 methyl naphthoquinone, through bromo, and reduction, methoxylation, produced a coupling side chain thus, but the reaction of many step demethyls has a negative impact to quality product and yield.
Hamamura in 1994 etc. (U.S.Pat 5,412, and 124; 5,476,995); Proposed the method for vitamin k4-cyclopentadiene adduction synthesise vitamins, yield is higher, but technology or more complicated, be through D-A addition and contrary D-A reaction.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, a kind of vitamin K of using is provided
3(be vitamin k4, menadione) and the halogenide of pohytol, the vitamin K that in the presence of transition metal, carries out condensation reaction
2Synthetic method.
Before this, be isoprene or n isoprene chain unit (n=1～10) with 3-bromo-2 methyl naphthoquinone, isoprene unit carries out addition and synthesizes VK one by one
2 (20)Or VK
2 (45), possible in theory, but technology is numerous and diverse during actually operating, and defectives such as separation difficulty and yield are low are arranged, and make it industrialization become impossible.
The present invention has overcome above-mentioned defective through research repeatedly, and a kind of reaction process simple possible is provided, and purity is good, the manufacture method that yield is high.
The present invention represents with following equation, methyl naphthoquinone, i.e. and 2-methyl isophthalic acid, the halogenide of 4-naphthoquinones and pohytol carries out condensation, is in the presence of metal catalyst, and need not redox processes, and directly prepare VK
2Method.
Wherein X is halogens such as chlorine, bromine, n=1～10 integers
Resultant: during n=2, be vitamin K
2 (10), i.e. MK2
During n=4, be vitamin K
2 (20), i.e. MK4
During n=9, the time vitamin K
2 (45), i.e. MK9
To should be mentioned that especially, not see in the past with the synthetic VK of this method
2 (45), i.e. MK9.And the raw material eggplant Buddhist nun alcohol of the present invention's use, to extract in the waste tobacco leaf, supply is arranged on market.Eggplant Buddhist nun alcohol is provided by the great day Bioisystech Co., Ltd in Xi'an.
Generally speaking the present invention at first adds solvent, charges into rare gas element, because VK
3Easily oxidation has made it an oxygen-free environment; Add VK then as early as possible
3, metal-powder adds the halogenide of pohytol again, and in 40-90 ℃ of stirring heating backflow 2-10 hour, reaction finished, and carries out separating treatment.
Starting raw material of the present invention is a vitamin K
3, the intermediate of side chain is the halogenide of pohytol: pohytol chlorine, pohytol bromine, geranyl chloride, the geranyl bromine, geranyl geranyl chloride, geranyl geranyl bromine, eggplant Thessaloniki chlorine, eggplant Thessaloniki bromine, the decyl alcohol muriate, the decyl alcohol bromide, but be not limited to the halides of above-mentioned pohytol.
The solvent that uses is: anhydrous tetrahydro furan, and isopropyl ether, dioxane, glycol dimethyl ether, particularly anhydrous tetrahydro furan are preferred.
As metal catalyst, can be iron, cobalt, copper, zinc, transition element such as tin.Wherein zinc is preferred.Metallic substance can powder, and is granular, sheet, and particularly pulverous is preferred.
The present invention is with previous synthetic VK
2Method relatively needn't be carried out redox reaction, also needn't carry out D-A addition and contrary D-A reaction; By VK
3Add pohytol halogenide one-step synthesis, product purity is good, and the yield height is very advantageous in suitability for industrialized production.
The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, down preparation method's of the present invention simple modifications is all belonged to the scope of protection of present invention in advance in design of the present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
Embodiment one, vitamin K
2 (10)Preparation
In the 1000ml three-necked flask, drop into solvent 600ml anhydrous tetrahydro furan, charge into nitrogen, drop into geranyl bromine 86.8 (0.4mol), zinc powder 25.6g (0.4mol) drops into vitamin K at last
368.8g (0.4mol), reflux is 6 hours while stirring, and the pressure reducing and steaming tetrahydrofuran (THF) adds the 400ml hexane, will remove by filter by insolubles in hexane.Again hexane solution is concentrated,, uses hexane residual oily matter silica gel column chromatography: ethanol=1: 1 eluant solution, separate VK
2(10) 91.8g, yield 74.5%, purity (HPLC): 98.6%.Confirm no VK
3Detect.
Embodiment two, vitamin V K
2 (20)Preparation
In the 1000ml three-necked flask, drop into anhydrous tetrahydro furan 400ml, add zinc powder 12.8g (0.2m), geranyl geranyl bromine 124.0g (0.2ml) charges into nitrogen, adds vitamin K as early as possible
334.4g (0.2mol), reflux is 5 hours while stirring, and reaction is finished.The pressure reducing and steaming tetrahydrofuran (THF) adds hexane and removes by filter insolubles, concentrates hexane solution, and oily matter is carried out silica gel column chromatography, and use ethanol: hexane=1: 1 wash-out obtains vitamin K
2 (20)52.3g, yield 58.8g%, purity (HPLC): 98.2%, confirm no VK
3Detect.
Embodiment three, vitamin K
2 (45)Preparation
In the 1000ml three-necked flask, drop into anhydrous isopropyl ether 400ml, add glass putty 35.8g (0.2mol) and eggplant Thessaloniki bromine 139.0g (0.2mol), charge into nitrogen, add VK as early as possible
334.4g (0.2mol), reflux 6 hours, reaction finishes, and the pressure reducing and steaming isopropyl ether adds hexane, and the overanxious insolubles of removing concentrates hexane solution, and oily matter is carried out silica gel column chromatography, and use ethanol: hexane=1: 1 wash-out obtains vitamin K
2 (45)88.7g, yield 56.6g%, purity (HPLC): 98.3%, VK
3≤ 0.5%.
Claims (5)
1. with vitamin K
3With the halogenide of pohytol, in the presence of transition metal and reaction solvent, inflated with nitrogen stream carries out the vitamin K that condensation reaction is a feature
2Synthetic method.Wherein temperature of reaction is 60-90 ℃, and the reaction times is 2-10 hour.
Wherein X is a halogen, n=1～10 integers;
Resultant: during n=2, be vitamin K
2 (10), i.e. MK2;
During n=4, be vitamin K
2 (20), i.e. MK4;
During n=9, be vitamin K
2 (45), i.e. MK9.
2. according to claim 1, transition metal is as the preparation synthetic method of metallicity.
3. according to claim 1, transition metal is an iron, cobalt, copper, zinc and tin.
4. according to claim 1, reaction solvent is a tetrahydrofuran (THF), isopropyl ether, dioxane, glycol dimethyl ether.
5. according to claim 1, wherein halogen is a chlorine, bromine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101287803A CN101139272A (en) | 2006-09-08 | 2006-09-08 | Method for synthesizing vitamin K2 |
| PCT/CN2006/002614 WO2008031283A1 (en) | 2006-09-08 | 2006-10-08 | Method for synthesizing of vitamin k2 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101287803A CN101139272A (en) | 2006-09-08 | 2006-09-08 | Method for synthesizing vitamin K2 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101139272A true CN101139272A (en) | 2008-03-12 |
Family
ID=39183366
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006101287803A Pending CN101139272A (en) | 2006-09-08 | 2006-09-08 | Method for synthesizing vitamin K2 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101139272A (en) |
| WO (1) | WO2008031283A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104513149A (en) * | 2013-09-29 | 2015-04-15 | 天津瑞安医药科技发展有限公司 | Synthetic method of menatetrenone |
| CN104513148A (en) * | 2013-09-29 | 2015-04-15 | 天津瑞安医药科技发展有限公司 | Column chromatography purifying method of menatetrenone |
| CN113264818A (en) * | 2021-05-25 | 2021-08-17 | 湖北工业大学 | Method for carbon-carbon cross-coupling reaction of quinone compound and alcohol under catalysis of silver |
| CN114031490A (en) * | 2021-11-26 | 2022-02-11 | 安徽先和医药研究有限公司 | Method for synthesizing VK2 by one-step method |
| CN114262264A (en) * | 2021-10-29 | 2022-04-01 | 太阳树(莆田)生物医药有限公司 | Vitamin K1Heck reaction synthesis method |
| CN114276225A (en) * | 2021-10-29 | 2022-04-05 | 太阳树(莆田)生物医药有限公司 | Vitamin K1Synthetic method of organic zinc reagent |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150216820A1 (en) | 2012-09-07 | 2015-08-06 | Edison Pharmaceuticals, Inc. | Quinone derivatives for use in the modulation of redox status of individuals |
-
2006
- 2006-09-08 CN CNA2006101287803A patent/CN101139272A/en active Pending
- 2006-10-08 WO PCT/CN2006/002614 patent/WO2008031283A1/en active Application Filing
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104513149A (en) * | 2013-09-29 | 2015-04-15 | 天津瑞安医药科技发展有限公司 | Synthetic method of menatetrenone |
| CN104513148A (en) * | 2013-09-29 | 2015-04-15 | 天津瑞安医药科技发展有限公司 | Column chromatography purifying method of menatetrenone |
| CN113264818A (en) * | 2021-05-25 | 2021-08-17 | 湖北工业大学 | Method for carbon-carbon cross-coupling reaction of quinone compound and alcohol under catalysis of silver |
| CN113264818B (en) * | 2021-05-25 | 2022-07-05 | 湖北工业大学 | Method for carbon-carbon cross-coupling reaction of quinone compound and alcohol under catalysis of silver |
| CN114262264A (en) * | 2021-10-29 | 2022-04-01 | 太阳树(莆田)生物医药有限公司 | Vitamin K1Heck reaction synthesis method |
| CN114276225A (en) * | 2021-10-29 | 2022-04-05 | 太阳树(莆田)生物医药有限公司 | Vitamin K1Synthetic method of organic zinc reagent |
| CN114276225B (en) * | 2021-10-29 | 2024-03-19 | 太阳树(莆田)生物医药有限公司 | Vitamin K 1 Method for synthesizing organic zinc reagent |
| CN114031490A (en) * | 2021-11-26 | 2022-02-11 | 安徽先和医药研究有限公司 | Method for synthesizing VK2 by one-step method |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008031283A1 (en) | 2008-03-20 |
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Open date: 20080312 |