CN101029003A - Method for synthesizing vitamin k solanine - Google Patents
Method for synthesizing vitamin k solanine Download PDFInfo
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- CN101029003A CN101029003A CN 200710065417 CN200710065417A CN101029003A CN 101029003 A CN101029003 A CN 101029003A CN 200710065417 CN200710065417 CN 200710065417 CN 200710065417 A CN200710065417 A CN 200710065417A CN 101029003 A CN101029003 A CN 101029003A
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- methyl
- alpha
- solanesol
- trans
- tetrahydrochysene
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Abstract
A process for synthesizing VK2 from solanesol includes such steps as purifying solaneol, dissolving 2-methyl-1,4-naphthylquinone in methanol, adding cyclopentadiee and Lewis acid or protonic acid, reaction to obtain the compound A (1,4,4a,9a-tetrahydro-9a alpha-methyl-1 alpha, 4 alpha-methyl bridge anthraquinone), dissolving solaneol in hexane, adding PBr3, extracting in petroether to obtain solanylbromine, dissolving it in tetrahydrofuran, dripping in said compound A, adding solvanylbromine, reaction to obtain compound B, dissolving it in toluene, and reflux to obtain VK2.
Description
Technical field
The present invention relates to a kind of methodology of organic synthesis, specifically relate to a kind of with solanesol synthesise vitamins K
2Method.
Background technology
Vitamin K
2Being series compound, is flaxen solid, and mainly synthetic by intestinal bacteria, the length difference that goes up isoprene side chains according to C-3 has 14 kinds of forms, represents that with MK-n wherein n refers to the number of isoprene unit on the side chain.This series compound all has thermotolerance, but to light and alkali sensitivity.Its chemical structure is as shown in the figure:
Menaquinone (MK-n, vitamin K
2)
Vitamin K
2Having formation of promotion bone and the inhibition effect by the caused bone resorption of osteoclast, is exclusive feature medicine, and wherein promoting bone to form is the vitamin K that produces by osteocyte
2The γ of dependent protein-carboxylated realizes.Vitamin K
2Also have the blood coagulation of promotion, improve arteriosclerotic effect.
Solanesol is a kind of polyisoprene alcohol, and English solanesol by name mainly is present in the plant of Solanaceae, and content is particularly outstanding in tobacco leaf, accounts for the 0.3%-4.0% of tobacco leaf dry weight.Its molecular formula is as shown in the figure:
The polyisoprene structure of solanesol can be used as vitamin K
2The side chain of structural unit, shortening reduce reaction cost directly with the single step that connects of isoprene.
Because the production technology of high purity solanesol is monopolized by Japan for a long time, the high purity solanesol of therefore present China is dependence on import almost completely, the cost height.Adopt the lower solanesol of purity to reduce cost, help industrialization.
Solanesol exists with free state and two kinds of forms of chemical combination attitude usually, and wherein free state accounts for main component, and the solanesol of chemical combination attitude generally exists with the form of fatty acid ester.Saponification reaction can make the solanesol of chemical combination attitude discharge, and improves the extraction yield of solanesol, and helps to improve the purity of solanesol.
Hamamura, (EP0613877, open day: on February 28th, 1994) disclose with naphthoquinones-cyclopentadiene and add legal synthetic MK-4 such as Kimio.This method does not need to make catalyzer with transition metal, and the alkylation under alkaline condition can keep the steric configuration of two keys in the side chain preferably, and the auxiliary cyclopentadiene is easy to recycle.But the defective of this method maximum is having the product of the prosposition of a great deal of to be substituted simultaneously in the alkylating process for the first time, thereby has reduced output, has also increased the difficulty of separation and purification.
Summary of the invention
The purpose of this invention is to provide a kind of with raw material solanesol synthesise vitamins K
2(MK-9) method is by this method synthetic vitamin K
2Yield height and cost are low.
Provided by the present invention with solanesol synthesise vitamins K
2(MK-9) method may further comprise the steps:
(1) purification of solanesol
Is saponification in the mixed solvent of 1: 1～1: 5 methyl alcohol and acetone with the solanesol crude product of purity 15～20% in volume ratio, and temperature is 30～60 ℃, adds sodium hydroxide, its consumption is 10～50% of a solanesol crude product weight, reacted 2～10 hours, decolouring obtains purity 60～75% solanesols;
(2) depolymerization of dicyclopentadiene
Dicyclopentadiene is heated to 170～220 ℃, depolymerization, the collection cut is a cyclopentadiene;
(3) 1,4,4a, 9a-tetrahydrochysene-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinones synthetic
With the 2-methyl isophthalic acid, 4-naphthoquinones dissolve with methanol adds the cyclopentadiene that step (2) obtains, with lewis acid or proton acid as catalyst, reacted 4～16 hours, 25～40 ℃ of temperature of reaction obtain 1,4,4a, 9a-tetrahydrochysene-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinones;
(4) trans-Solanesyl bromide is synthetic
Solanesol n-hexane dissolution with step (1) obtains under-10～0 ℃ of condition, adds pyridine, drips phosphorus tribromide then, stirs 1～3 hour at 0～5 ℃, and reaction solution is poured in the frozen water, with 30～60 ℃ of petroleum ether extractions, obtains trans-Solanesyl bromide;
(5) 1,4,4a, 9a-tetrahydrochysene-4a α-(trans-Solanesyl bromide)-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinones synthetic
Potassium tert.-butoxide is dissolved with tetrahydrofuran (THF), drip the product that step (3) obtains down at 0～5 ℃, under nitrogen protection, drip the product trans-Solanesyl bromide of step (4), reacted 1～3 hour, reaction product is poured in the hydrochloric acid,, obtained 1 with the toluene extraction, 4,4a, 9a-tetrahydrochysene-4a α-(trans-Solanesyl bromide)-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinones;
(6) vitamin K
2Synthetic
The product of step (5) is dissolved with toluene, under the nitrogen protection, refluxed 0.5～2 hour, obtain vitamin K
2
The inventive method is compared with existing method has following beneficial effect:
(a) be that 60～75% solanesols are raw material synthesise vitamins K with purity behind the purifying
2, its purification process is simple, has reduced cost, helps industrialization.
(b) synthesizing 1,4,4a, 9a-tetrahydrochysene-9a Alpha-Methyl-1 α during 4 Alpha-Methyl bridge anthraquinones, with Lewis acid or proton acid as catalyst, has shortened the reaction times, has improved reaction efficiency.
Embodiment
Embodiment 1
(1) the solanesol crude product of 5g 16% is 1: 3 mixing solutions dissolving with 120ml methyl alcohol and acetone ratio, adds 1.5g sodium hydroxide, saponification 6h down at 40 ℃.Suction filtration is removed insoluble substance, freezes 24 hours in refrigerator and cooled, separates out solid.With solid 100ml acetone solution, stirred 4 hours down at 40 ℃, remove insoluble material, add gac, continue to stir 2 hours, suction filtration, refrigerator and cooled is frozen and was separated out flaxen solid 0.85g in 24 hours, and purity is 66.0%, and its yield is 70.1%.
(2) add the 50ml dicyclopentadiene in the round-bottomed flask of 100ml, be warming up to 200 ℃, stir, 40-42 ℃ cut is collected in the rectifying column fractionation.The yield of cyclopentadiene is 70%, and purity is 96.7% (detecting through gas chromatograph).
(3) in the round-bottomed flask of 100ml, add the 2-methyl isophthalic acid, 4-naphthoquinones 0.5g uses the 30ml dissolve with methanol, stirs, and temperature rises to 30 ℃, adds cyclopentadiene 2ml, drips boron trifluoride diethyl etherate 2ml, continues to stir.Follow the tracks of reaction with thin-layer chromatography (TLC), reaction in 7 hours finishes, and with the reaction solution concentrating under reduced pressure, pours in the water, stirs, and separates out linen solid, filters drying.Use recrystallizing methanol, obtain white 1,4,4a, 9a-tetrahydrochysene-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinone 0.59g, its yield is 85.3%.
(4) in the round-bottomed flask of 50ml, add the 0.70g solanesol, with the dissolving of 6ml anhydrous n-hexane, drip several pyridines ,-10 ℃ are stirred half an hour, drip the hexane solution of the 3ml of 105 μ l phosphorus tribromides in 30 minutes, temperature is warming up to 0 ℃ then, continues to stir 2 hours.Reaction solution is poured in the frozen water, stirred 15 minutes, use 30-60 ℃ petroleum ether extraction three times respectively, merge organic phase, wash four times, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains trans-Solanesyl bromide 0.65g, and its yield is 84.4%.
(5) in the there-necked flask of 100ml; the potassium tert.-butoxide that adds 0.4g, with the dissolving of 20ml tetrahydrofuran (THF), 0 ℃ was stirred 20 minutes down; nitrogen protection; with 1,4 of 0.2g, 4a; 9a-tetrahydrochysene-9a Alpha-Methyl-1 α; the tetrahydrofuran solution of the 6ml of 4 Alpha-Methyl bridge anthraquinones is added drop-wise in the reaction, dropwises in 30 minutes, continues to stir 30 minutes.The 0.8g trans-Solanesyl bromide with the dilution of 6ml tetrahydrofuran (THF), is added drop-wise in the reaction system, dropwised in 30 minutes.Continue reaction 1 hour.Reaction system is poured in the hydrochloric acid, regulated the pH value, toluene extraction, anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains 1,4,4a, and 9a-tetrahydrochysene-4a α-(trans-Solanesyl bromide)-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinone 0.68g, yield is 69.3%.
(6) in the there-necked flask of 100ml, add 1,4,4a, 9a-tetrahydrochysene-4a α-(trans-Solanesyl bromide)-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinone 0.8g with the toluene dissolving, under nitrogen protection, refluxed 30 minutes, and concentrating under reduced pressure obtains xanchromatic oily matter then.Yellow oil is purified through column chromatography, freeze in refrigerator and cooled and separate out faint yellow solid, obtain vitamin K
20.67g.Yield is 90.3%.
Embodiment 2
The methyl alcohol in the step (1) and the ratio of acetone are 1: 1, when temperature is 40 ℃, get faint yellow solid 0.70g, and purity is 61.9%, and yield is 54.2%, and other step is with embodiment 1.
Embodiment 3
Temperature is 35 ℃ in the step (1), and the ratio of methyl alcohol and acetone is 1: 2, gets faint yellow solid 0.61g, and purity is 61.9%, and yield is 47.2%, and other step is with embodiment 1.
Embodiment 4
The methyl alcohol in the step (1) and the ratio of acetone are 1: 3, and temperature is 40 ℃, and the amount of sodium hydroxide is 2.0g, get faint yellow solid 0.67g, and purity is 63.7%, and yield is 53.3%, and other step is with embodiment 1.
Embodiment 5
The methyl alcohol in the step (1) and the ratio of acetone are 1: 4, and temperature is 55 ℃, get faint yellow solid 0.51g, and purity is 61.0%, and yield is 38.9%, and other step is with embodiment 1.
Embodiment 6
When the temperature of reaction in the step (3) was 35 ℃, the reaction times was 4 hours, got 1,4,4a, and 9a-tetrahydrochysene-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthracene 0.54g, yield is 78.1%, other step is with embodiment 1.
Embodiment 7
Catalyzer in the step (3) is a Glacial acetic acid, and temperature of reaction is 35 ℃, and the reaction times is 13 hours, gets 1,4,4a, and 9a-tetrahydrochysene-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinone 0.64g, yield is 92.5%, other step is with embodiment 1.
Embodiment 8
Catalyzer in the step (3) is a Glacial acetic acid, and when temperature of reaction was 30 ℃, the reaction times was 16 hours, gets 1,4,4a, and 9a-tetrahydrochysene-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinone 0.6g, yield is 87.5%, other step is with embodiment 1.
Claims (3)
1. one kind with solanesol synthesise vitamins K
2Method, may further comprise the steps:
(1) purification of solanesol
Is saponification in the mixed solvent of 1: 1～1: 5 methyl alcohol and acetone with the solanesol crude product of purity 15～20% in volume ratio, and temperature is 30～60 ℃, adds sodium hydroxide, its consumption is 10～50% of a solanesol crude product weight, reacted 2～10 hours, decolouring obtains purity 60～75% solanesols;
(2) depolymerization of dicyclopentadiene
Dicyclopentadiene is heated to 170～220 ℃, depolymerization, the collection cut is a cyclopentadiene;
(3) 1,4,4a, 9a-tetrahydrochysene-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinones synthetic
With the 2-methyl isophthalic acid, 4-naphthoquinones dissolve with methanol adds the cyclopentadiene that step (2) obtains, with lewis acid or proton acid as catalyst, reacted 4～16 hours, 25～40 ℃ of temperature of reaction obtain 1,4,4a, 9a-tetrahydrochysene-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinones;
(4) trans-Solanesyl bromide is synthetic
Solanesol n-hexane dissolution with step (1) obtains under-10～0 ℃ of condition, adds pyridine, drips phosphorus tribromide then, stirs 1～3 hour at 0～5 ℃, and reaction solution is poured in the frozen water, with 30～60 ℃ of petroleum ether extractions, obtains trans-Solanesyl bromide;
(5) 1,4,4a, 9a-tetrahydrochysene-4a α-(trans-Solanesyl bromide)-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinones synthetic
Potassium tert.-butoxide is dissolved with tetrahydrofuran (THF), drip the product that step (3) obtains down at 0～5 ℃, under nitrogen protection, drip the product trans-Solanesyl bromide of step (4), reacted 1～3 hour, reaction product is poured in the hydrochloric acid,, obtained 1 with the toluene extraction, 4,4a, 9a-tetrahydrochysene-4a α-(trans-Solanesyl bromide)-9a Alpha-Methyl-1 α, 4 Alpha-Methyl bridge anthraquinones;
(6) vitamin K
2Synthetic
The product of step (5) is dissolved with toluene, under the nitrogen protection, refluxed 0.5～2 hour, obtain vitamin K
2
2. according to the method for claim 1, the saponification temperature that it is characterized in that step (1) is 30～40 ℃.
3. according to the method for claim 1, it is characterized in that the described lewis acid of step (3) is boron trifluoride diethyl etherate, protonic acid is a Glacial acetic acid.
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|---|---|---|---|
| CN 200710065417 CN101029003A (en) | 2007-04-13 | 2007-04-13 | Method for synthesizing vitamin k solanine |
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|---|---|---|---|
| CN 200710065417 CN101029003A (en) | 2007-04-13 | 2007-04-13 | Method for synthesizing vitamin k solanine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2463981A (en) * | 2008-09-24 | 2010-04-07 | Syntavit As | Processes for the preparation of Vitamin K2 derivatives |
| CN102351677A (en) * | 2011-09-16 | 2012-02-15 | 重庆大学 | Method for chemical synthesis of vitamin K2 |
| 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 |
| WO2021071372A1 (en) * | 2019-10-07 | 2021-04-15 | Sieć Badawcza Łukasiewicz - Instytut Farmaceutyczny | Process of vitamin k2 derivatives preparation |
| WO2022184938A1 (en) * | 2021-03-05 | 2022-09-09 | Kappa Bioscience As | Process for the preparation of vitamin k2 and novel intermediates |
-
2007
- 2007-04-13 CN CN 200710065417 patent/CN101029003A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2463981A (en) * | 2008-09-24 | 2010-04-07 | Syntavit As | Processes for the preparation of Vitamin K2 derivatives |
| GB2463981B (en) * | 2008-09-24 | 2011-05-25 | Syntavit As | Process for the preparation of vitamin K2 |
| US10472314B2 (en) | 2008-09-24 | 2019-11-12 | Kappa Bioscience As | Process for the preparation of vitamin K2 |
| CN102351677A (en) * | 2011-09-16 | 2012-02-15 | 重庆大学 | Method for chemical synthesis of vitamin K2 |
| CN102351677B (en) * | 2011-09-16 | 2014-04-09 | 重庆大学 | Method for chemical synthesis of vitamin K2 |
| 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 |
| WO2021071372A1 (en) * | 2019-10-07 | 2021-04-15 | Sieć Badawcza Łukasiewicz - Instytut Farmaceutyczny | Process of vitamin k2 derivatives preparation |
| WO2022184938A1 (en) * | 2021-03-05 | 2022-09-09 | Kappa Bioscience As | Process for the preparation of vitamin k2 and novel intermediates |
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