CN1203042C - Preparation of optical pure D-malic acid - Google Patents
Preparation of optical pure D-malic acid Download PDFInfo
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- CN1203042C CN1203042C CN 03135236 CN03135236A CN1203042C CN 1203042 C CN1203042 C CN 1203042C CN 03135236 CN03135236 CN 03135236 CN 03135236 A CN03135236 A CN 03135236A CN 1203042 C CN1203042 C CN 1203042C
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- oxysuccinic acid
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- resolving agent
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Abstract
The present invention relates to a process for preparing optical pure D-malic acid. D-(-)-2-amino-1-(4-nitrophenyl)-1, 3-propanediol in industrial production is used as a resolution agent and can react with malic acid racemate in a mixed solution of low-molecular alcohol and water. A pair of generated diastereoisomer salt has different dissolvability in the solvent and can separate the resolution agent and the malic acid racemate, wherein the slat of the D-malic acid is processed via crystallization, recrystallization, alkali decomposition and ion exchange resin, so the D-malic acid with optically pure is obtained, and the optical purity is more than 99%. The present invention has the characteristics of abundant resolution agent source, simple preparation process, easy operation, high optical purity, etc.
Description
Technical field
The invention belongs to the organic synthesis field, specifically be to use the optically pure resolving agent of a kind of configuration to obtain the method for optically pure D-oxysuccinic acid.
Background technology
The D-oxysuccinic acid is a chirality synthetic intermediate useful in the organic synthesis, is widely used in fields such as chiral drug, chiral additives, chiral auxiliary(reagent), has important development and application prospect.But there is not optical purity D-oxysuccinic acid in occurring in nature, and it is too high to use the synthetic and enzyme process of chemical process to obtain the cost of D-oxysuccinic acid, and about the fractionation of D, L MALIC ACID, rarely has report abroad, and does not domesticly almost have.The report that uses the chlorination cinchonine to split the oxysuccinic acid racemic modification is arranged in the document, but also can only obtain the lower L MALIC ACID of optical purity through recrystallize repeatedly; In addition, phenylethylamine also is used to the fractionation of oxysuccinic acid racemic modification, and is poor because of the malate optical purity, needs repeatedly recrystallize, and yield is low; In addition, Japanese Patent [JP56030952 (1981)] and United States Patent (USP) [US 54330484 (1982)] have reported that use optical activity 2-amino butanol is as resolving agent, be primarily aimed at L MALIC ACID and split, it is low to have resolving agent toxicity, and the higher rate of recovery is arranged.But weak point be salt that this resolving agent and oxysuccinic acid generates difficulty crystallize out, cause separation difficulty.
Summary of the invention
The object of the present invention is to provide a kind of preparation of optical purity D-oxysuccinic acid, he is with optically pure D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol is a resolving agent, in low mass molecule alcohol solution, split the oxysuccinic acid racemic modification, finally obtain optical purity D-oxysuccinic acid, e.e. value reaches more than 99%, has obtained satisfied fractionation effect.
The present invention is achieved like this: at first, with chiral separation agent D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol splits the oxysuccinic acid of racemization, again resultant of reaction is carried out crystallization, recrystallization purifying, decompose through alkali again, storng-acid cation exchange resin is handled, and obtains optically pure D-oxysuccinic acid.
In the above-mentioned resolution reaction, resolving agent is D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol, and its structure is:
In the above-mentioned resolution reaction, the mol ratio of resolving agent and oxysuccinic acid racemic modification is 1: 2～2: 1.
In the above-mentioned resolution reaction, the solvent that uses is lower than the low mass molecule alcohol solution that 40% (weight) is preferably lower than 20% (weight) as water content, and alcohol is methyl alcohol, ethanol etc., and mother liquor can be left to when splitting next time and recycle after each crystallization.
In the above-mentioned resolution reaction, obtaining the used ion exchange resin of free D-oxysuccinic acid at last is strongly acidic styrene type cation exchange resin (001 * 7) 732.
Resolving agent recycling step of the present invention is: make the filtrate (PH=8～11 are preferably PH=10) under alkaline condition that splits in post crystallization and the recrystallization operation, resolving agent is separated out, filter, reclaim, and can recycle.
Used alkali is ammonia soln in the said process.
Usefulness of the present invention is: the resolving agent of use is the intermediate of industrial production paraxin, and is cheap and easy to get, and resolving agent can reclaim well, and can recycle.Preparation optical purity D-oxysuccinic acid processing method is easy among the present invention, raw material is easy to get, yield is higher, resolving agent is easy to be recycled; solvent for use also can be recycled during fractionation; thereby the cost and the protection that has strengthened environment of reduction preparation optical purity D-oxysuccinic acid; these all help the big production that this invention realizes modernization industryization, satisfy the demand of people to it.
Embodiment
Be embodiments of the invention below.Among the embodiment, the yield of product is that benchmark calculates with raw material oxysuccinic acid racemic modification all.
Embodiment one:
Oxysuccinic acid racemic modification 1.34g (0.01mol) is joined in 20ml ethanol and the 5ml distilled water, add D-(-)-2-amino-1-(4-nitrophenyl)-1 down in reflux state, the quick stirring, ammediol 2.12g, continue stirring and refluxing after 1 hour, stir crystallisation by cooling, to room temperature, in 12～15 ℃ of water-baths, cool off again.Suction filtration oven dry and weigh D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol-D-(+)-oxysuccinic acid 2.5g, yield are 47.8%.Filtrate continuation stirs cool overnight, and the suction filtration drying gets D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol-L-(-)-oxysuccinic acid, and this is used for further reclaiming resolving agent.
Embodiment two:
In the 1000ml three-necked bottle that mechanical stirrer and reflux condensing tube are housed, add oxysuccinic acid racemic modification 50g (0.373mol), methyl alcohol 650ml.Add D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol 79.2g (0.373mol) down in reflux state, the quick stirring.The very fast dissolving of solid, the adularescent solid is separated out behind the several minutes, and more and more.Continued stirring and refluxing 1 hour, filtered while hot, the filter cake suction filtration press dry, drying weigh D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol-D-(+)-oxysuccinic acid 99g, optical purity is 42%, yield is 47%.Filtrate continuation stirs cool overnight, and the suction filtration drying gets D-(-)-2-amino-1-(4-nitrophenyl)-1, and ammediol-L-(-)-oxysuccinic acid is for use in further reclaiming resolving agent.
Embodiment three:
With D-(-)-2-amino-1-(4-nitrophenyl)-1 that obtains among the embodiment two, ammediol-D-(+)-oxysuccinic acid 99g adds 73ml distilled water and 250ml ethanol, after the reflux dissolving, stir crystallisation by cooling, suction filtration oven dry and weigh solid 87g, optical purity is 85%, and the recrystallization yield is 87.9%.The gained crystal is dissolved in 64ml distilled water and the 190ml ethanol again, stirs crystallisation by cooling, the suction filtration oven dry and weigh solid 80g, optical purity is 94%, the recrystallization yield is 91.9%, total recovery is 38.5%.The methyl alcohol in the mother liquor is reclaimed in distillation.The resolving agent total yield is more than 90%.
Embodiment four:
In the 1000ml three-necked bottle that mechanical stirrer and reflux condensing tube are housed, add oxysuccinic acid racemic modification 50g (0.373mol), methyl alcohol 350ml.Add D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol 118.6g (0.560mol) down in reflux state, the quick stirring.The very fast dissolving of solid, the adularescent solid is separated out behind the several minutes, and more and more.Continued stirring and refluxing 1 hour, filtered while hot, the filter cake suction filtration press dry, drying weigh D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol-D-(+)-oxysuccinic acid 125g, optical purity is 35%, yield is 60%.Filtrate continuation stirs cool overnight, and the suction filtration drying gets D-(-)-2-amino-1-(4-nitrophenyl)-1, and ammediol-L-(-)-oxysuccinic acid is used for further reclaiming resolving agent.
Embodiment five:
With D-(-)-2-amino-1-(4-nitrophenyl)-1 that obtains among the embodiment four, ammediol-D-(+)-oxysuccinic acid 120g adds 75ml distilled water and 250ml methyl alcohol, after the reflux dissolving, stirs crystallisation by cooling.Suction filtration oven dry and weigh solid 89.3g, optical purity is 82%, the recrystallization yield is 74.4%.The gained crystal is dissolved in 67ml distilled water and the 200ml methyl alcohol again, stirs crystallisation by cooling, the suction filtration oven dry and weigh solid 79.8g, optical purity is 93.8%, the recrystallization yield is 89.4%, total recovery is 38.3%.The methyl alcohol in the mother liquor is reclaimed in distillation.The resolving agent total yield is more than 90%.
Embodiment six:
In the 1000ml three-necked bottle that mechanical stirrer and reflux condensing tube are housed, add oxysuccinic acid racemic modification 50g (0.373mol), methyl alcohol 430ml.Add D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol 158.21g (0.746mol) down in reflux state, the quick stirring.The very fast dissolving of solid, the adularescent solid is separated out behind the several minutes, and more and more.Continued stirring and refluxing 1 hour, filtered while hot, the filter cake suction filtration press dry, drying weigh D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol-D-(+)-oxysuccinic acid 130g, optical purity is 33.2%.Yield is 62.4%.Filtrate continuation stirs cool overnight, and the suction filtration drying gets D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol-L-(-)-oxysuccinic acid 74g, and yield is 35.5%, is used for further reclaiming resolving agent.Mother liquor is left to when splitting next time and recycles.
Embodiment seven:
50g (0.373mol) oxysuccinic acid racemic modification is joined embodiment six stay in the mother liquor, and add methyl alcohol maintenance solvent volume at 450ml.Add D-(-)-2-amino-1-(4-nitrophenyl)-1 that is reclaimed among embodiment three and the embodiment five, ammediol 158.21g (0.746mol) down in reflux state, the quick stirring.The very fast dissolving of solid, the adularescent solid is separated out behind the several minutes, and more and more.Continued stirring and refluxing 1 hour, filtered while hot, the filter cake suction filtration press dry, drying weigh D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol-D-(+)-oxysuccinic acid 140g, optical purity is 30.7%.Yield is 67.2%.Filtrate continuation stirs cool overnight, and the suction filtration drying gets D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol-L-(-)-oxysuccinic acid 75g, and yield is 36%, is used for further reclaiming resolving agent.Mother liquor is left to when splitting next time and recycles.
Embodiment eight:
With D-(-)-2-amino-1-(4-nitrophenyl)-1 that obtains among the embodiment six, ammediol-D-(+)-oxysuccinic acid 130g 100ml distilled water heating for dissolving, add 250ml methyl alcohol then, after the reflux dissolving, stir crystallisation by cooling, suction filtration oven dry and weigh solid 97g, optical purity is 80.6%, the recrystallization yield is 74.6%.Use distilled water 60ml, methyl alcohol 175ml recrystallization again, suction filtration, the oven dry weigh solid 89g, optical purity is 91%, the recrystallization yield is 91.7%.Use distilled water 55ml, methyl alcohol 175ml recrystallization again, suction filtration, the oven dry weigh solid 80g, optical purity is more than 99%, the recrystallization yield is 90%, total recovery is 38.4%.The mother liquor concentrating under reduced pressure of preceding twice recrystallization removes desolvate back and D-(-)-2-amino-1-(4-nitrophenyl)-1, and ammediol-L-(-)-oxysuccinic acid merges.The mother liquor concentrating under reduced pressure of recrystallization removes desolvate back and next D-(-)-2-amino-1-(4-nitrophenyl)-1 for the third time, and ammediol-D-(+)-oxysuccinic acid merges.
Embodiment nine:
With gained D-(-) among the embodiment eight-2-amino-1-(4-nitrophenyl)-1, ammediol-D-(+)-oxysuccinic acid 80g heating is dissolved in the 100ml distilled water, and transferring pH value with ammoniacal liquor is 10.The cooling suction filtration.Filtrate decompression concentrates and removes unnecessary ammonia, obtains the ammonia salts solution of D-oxysuccinic acid, is used for following further processing.D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol-L-(-)-oxysuccinic acid is handled in the same way.D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol reclaims air-dry, and the rate of recovery is greater than 90%.Its specific rotation light value is [α]
25=-30.8 ° (c=2 is among 1N HCl) need not be further purified and just can be directly used in fractionation next time.
D-oxysuccinic acid-ammonia salts solution is used the distilled water wash-out by the 170-200g732# cation exchange resin column, and the PH detection paper is collected acidic components.Solution decompression is concentrated into dried, gets D-(+)-oxysuccinic acid white crystal 19g, and yield is 92.6%, [α]
25=+27 °～+ 28 ° (c=2 is in the pyridine).
Claims (8)
1, the preparation of optical purity D-oxysuccinic acid, it is characterized in that, with the racemic modification oxysuccinic acid is raw material, adopt optically pure D-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol splits the racemic modification of oxysuccinic acid as resolving agent in the low mass molecule alcohol solution of C1-C2, resultant of reaction is carried out crystallization, recrystallization purifying, decomposes through alkali again, storng-acid cation exchange resin is handled, and obtains optically pure D-oxysuccinic acid.
2, the preparation of optical purity D-oxysuccinic acid according to claim 1 is characterized in that, resolving agent system selects the intermediate of industrial production paraxin for use.
3, the preparation of optical purity D-oxysuccinic acid according to claim 1 is characterized in that, the mol ratio of resolving agent and oxysuccinic acid racemic modification is 1: 2～2: 1.
4, the preparation of optical purity D-oxysuccinic acid according to claim 1 is characterized in that, reaction solvent is methyl alcohol or the ethanol that water content is lower than 40% weight content, and can be recycled.
5, the preparation of optical purity D-oxysuccinic acid according to claim 1 is characterized in that, used ion exchange resin is strongly acidic styrene type cation exchange resin.
6, the preparation of optical purity D-oxysuccinic acid according to claim 1 is characterized in that, also comprises the resolving agent recycling step:
A. make the filtrate that splits in the post crystallization operation under alkaline condition, resolving agent is separated out, filter, reclaim;
B. make the filtrate that splits in the recrystallization operation of back under alkaline condition, resolving agent is separated out, filter, reclaim.
7, the preparation of optical purity D-oxysuccinic acid according to claim 6 is characterized in that, alkaline condition was PH=8～11 when resolving agent reclaimed, and resolving agent can be recycled.
8, the preparation of optical purity D-oxysuccinic acid according to claim 1 is characterized in that, the used alkali of the decomposition of D-malate is ammonia soln.
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| CN 03135236 CN1203042C (en) | 2003-06-18 | 2003-06-18 | Preparation of optical pure D-malic acid |
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| CN 03135236 CN1203042C (en) | 2003-06-18 | 2003-06-18 | Preparation of optical pure D-malic acid |
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| CN1203042C true CN1203042C (en) | 2005-05-25 |
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| CN102126979A (en) * | 2009-12-15 | 2011-07-20 | 中国科学院成都有机化学有限公司 | Preparation method of optically pure 3-(carbamoylmethyl)-5-methyl-hexanoic acid |
| CN104447273B (en) * | 2014-10-27 | 2016-02-03 | 天津华津制药有限公司 | A kind of recovery method of Zopiclone resolving agent D-(+)-oxysuccinic acid |
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