CN100494165C - Preparation method of D-para-hydroxybenzol gylcine - Google Patents
Preparation method of D-para-hydroxybenzol gylcine Download PDFInfo
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- CN100494165C CN100494165C CNB200610025197XA CN200610025197A CN100494165C CN 100494165 C CN100494165 C CN 100494165C CN B200610025197X A CNB200610025197X A CN B200610025197XA CN 200610025197 A CN200610025197 A CN 200610025197A CN 100494165 C CN100494165 C CN 100494165C
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- camphorsulfonic acid
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Abstract
This invention relates to a preparation method of D - para hydroxybenzene glycine. It takes (+) - 3 - bromo-camphor ammonium sulphonate salt as resolution agent, under protection of 2 - nitryl - benzaldehyde and N2, split raceme para hydroxybenzene glycine to obtain D -glycine.
Description
Technical field
The present invention relates to a kind of preparation method of D-D-pHPG, more specifically relate to a kind of method of producing high purity D-D-pHPG by asymmetric conversion fractionation DL-D-pHPG racemic modification.
Background technology
D-pHPG is a kind of amino acid by the chemical synthesis process preparation.Have optically active D-pHPG and have important medicinal use, chirality D-pHPG and derivative thereof have broad application prospects in field such as antimicrobial, antiviral.Wherein the D-D-pHPG can be used for Broad spectrum antibioticss such as synthetic amoxycillin, amoxycillin cephalo, cefoperazone, cephalo Luo Qi and SKF-60771, and the L-D-pHPG has the effect of diseases such as assisting therapy ischemic heart disease, heart failure, diabetes.Ordinary method synthetic D-pHPG is the racemic modification with chirality, need split DL-D-pHPG racemic modification to prepare the chirality D-pHPG.
At present report pass through split DL-D-pHPG racemic modification and produce the method for D-D-pHPG and comprise that mainly crystal seed induces Split Method and asymmetric transformation approach.Crystal seed induces Split Method to refer to split the DL-D-pHPG by the method that adds chiral crystal in oversaturated racemize solution, because the solubleness of DL-D-pHPG in water, ethanol equal solvent is little, so generally select the salt of D-pHPG or derivative to carry out the crystal seed method fractionation.The defective of this method is that low, the resulting product of once through yield is not high because of mixing enantiomorph purity.Yamada etc. make salt with aromatic sulphonic acid and DL-D-pHPG, carry out induced crystallization with crystal seed then, and the once through yield of this method is 22%～28%, and polarimetry purity is 96.2%～98%.(Agric?Biol?Chem.，1978，42：1521
-1526)
Reports such as Yang Fan, with (+)-3-bromo-camphor sulfonic acid ammonium salt is resolving agent, with the salicylic aldehyde is catalyzer, in the presence of an amount of Glacial acetic acid, adopt asymmetric transformation approach to obtain D-D-pHPG double salt, double salt neutralizes in methanol solvate and obtains the D-D-pHPG, and total recovery is 70%, optical purity reaches 99% (Chinese Journal of Pharmaceuticals, 2005 (4): 199
-200).Defectives such as this method reaction times reaches 22 hours, has long reaction time, and yield is lower.
Summary of the invention
The preparation method who the purpose of this invention is to provide the short D-D-pHPG of a kind of yield height, reaction times is to overcome the deficiencies in the prior art.
The inventive method adopts the asymmetric method of walking around, and is resolving agent with (+)-3-bromo-8-camphorsulfonic acid ammonium salt, and its characteristics are to adopt 2-nitro-phenyl aldehyde as catalyzer, carry out asymmetric conversion reaction under protection of nitrogen gas, and the inventive method may further comprise the steps:
(1) adding mol ratio in acetate is (+)-3-bromo-8-camphorsulfonic acid ammonium salt and the DL-D-pHPG of 1:1, at N
2Under the condition of protection and continuously stirring, be warming up to 60～90 ℃, add 2-nitro-phenyl aldehyde behind the dropping sulfuric acid, reaction 3
-9 hours, be cooled to 10 ℃, behind the sufficient crystallising after filtration, washing, drying obtain D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt;
(2) add salt of wormwood after D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt is dissolved in the 50%v/v aqueous ethanolic solution, reacted 2～4 hours under 50～55 ℃ of temperature, be cooled to 20 ℃, filtration, washing, drying obtain the D-D-pHPG.
In the aforesaid method, the purity of DL-D-pHPG adopts single stage method synthetic, concrete operations reference literature method (Jin Tongshou etc., chemical reagent, 1997,19 (2): 120～121) greater than 98%; By weight, the consumption of acetate is 9～10 times of DL-D-pHPG; In mole, the vitriolic consumption is 0.5 times of DL-D-pHPG; By weight, the consumption of 2-nitro-phenyl aldehyde is 3%～7% of a DL-D-pHPG, wherein preferred 5%; The preferred reaction times is 4～6 hours in the step (1); By weight, the consumption of 50%v/v aqueous ethanolic solution is 2.5 times of D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt; The consumption mol ratio of D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt and salt of wormwood is 2: 1.
The D-D-pHPG that the inventive method makes, purity reaches more than 99.3%, and productive rate is higher than 90%.
According to the present invention, all right recovery set solvent and resolving agent, thus reduce cost.A preferred embodiment of the present invention is that recycling step (1) separates the filtrate that obtains, and after acetic acid fraction is reclaimed in distillation, can be used as resolution solvent and recycles.
Another preferred embodiment of the present invention is that recycling step (2) separates the filtrate obtain, through underpressure distillation, collects 60～65 ℃ of cuts be used as in and the solvent cycle use; Bottoms after filtration, after the washing, cure under 90～100 ℃ and obtained solid (+)-3-bromo-8-camphorsulfonic acid sylvite in 2 hours and recycle as resolving agent.
Beneficial effect
1, the inventive method adopts nitrogen protection, has reduced the generation of side reaction, and product purity is up to more than 99.3%.
2. the inventive method is a catalyzer with 2-nitro-phenyl aldehyde, makes the reaction times foreshorten to 3-9 hour, and yield is brought up to more than 90%.
3. the inventive method resolving agent waste is few, and recyclable applying mechanically, and avoids using valuable organic solvent simultaneously, uses nontoxic hydrophilic solvent system, and is cheap, is easy to reclaim.
4. the inventive method recycles the fractionation mother liquor, thereby reduces the usage quantity of solvent, reduces production costs.
Embodiment
Below by embodiment the inventive method is further elaborated, but does not limit the present invention:
Adopt the purity of high-efficient liquid phase chromatogram technique analysis D-D-pHPG among the following embodiment, measure its specific rotation with polarimeter (the digital automatic polarimeter of wzz-2s type).Liquid-phase chromatographic analysis uses Aglient 1100 type liquid chromatographs, chromatographic column be Chirosil SCA (-) chiral column (150*4.6mm, 5um, 100A); (2002 (4): 97～99), spectrum peak tie substance comes qualitative with reference material analytical procedure reference literature method for Song Huimin etc., Nanjing University of Technology's journal.
Embodiment 1
In the 80ml Glacial acetic acid, add 8.5 gram (0.05mol) DL-D-pHPGs and 16.9 gram (0.05mol) (+)-3-bromo-8-camphorsulfonic acid ammonium salts, at N
2Under protection and the agitation condition, be warming up to 70 ℃, slowly drip 2.5g (0.025mol) sulfuric acid after forming white suspension liquid; after treating that sulfuric acid dropwises, add 0.4 gram 2-nitro-phenyl aldehyde, after reaction is carried out 6 hours; slowly be cooled to 10 ℃, fully separate out formed double salt.D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid that filtration under diminished pressure obtains 24.58 gram white crystals shapes claims double salt, and yield is 97%, after the small amount of acetic acid washing, places vacuum drying oven dry.Get filtrate 80 grams, join in the matrass, oil bath heats up, and distillation temperature is controlled between 120 ℃～140 ℃, collects acetic acid fraction, and distillation finishes when treating not have overhead product substantially, obtains about 64 grams of cut altogether, reclaims and obtains alcohol solvent.
Take by weighing 24.5 gram exsiccant D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt, be dissolved in the aqueous ethanolic solution of 60ml50v/v%, add 3.6 gram salt of wormwood then, warming while stirring to 50 ℃ was reacted after 2 hours, was cooled to 20 ℃, filtration under diminished pressure gets filtrate and white depositions, white depositions is washed with small amount of ethanol, obtains 8.05 gram D-D-pHPGs through vacuum-drying, and yield is 94.1%.
Chemical purity is 99.9%.
Filtrate 78 grams after the neutralization reaction join in the matrass, and temperature is controlled between 70 ℃～80 ℃ at the bottom of the still, keeps vacuum tightness to be not less than 40Kpa, and distillation does not finish when having overhead product substantially, collect about 50 grams of cut; Material cools to 20 ℃ in the bottle, filter, obtain the white miscellany of 20 gram resolving agent (+)-3-bromo-8-camphorsulfonic acid sylvite and volatile salts, this mixture is placed under 100 ℃ of the Ma Fulu cured 2 hours, reclaim and obtain 17.6 gram (+)-3-bromo-8-camphorsulfonic acid sylvite.
Embodiment 2
In the 50ml Glacial acetic acid, add (+)-3-bromo-8-camphorsulfonic acid sylvite and 5 gram DL-D-pHPGs mixing that 10.5 gram embodiment 1 are recovered to, at N
2Under protection and the agitation condition, be warming up to 70 ℃, slowly drip 1.5g (0.015mol) sulfuric acid after forming white suspension liquid; after treating that sulfuric acid dropwises, add 0.24 gram 2-nitro-phenyl aldehyde, after reaction is carried out 6 hours; slowly be cooled to 10 ℃, fully separate out formed double salt.Filtration under diminished pressure obtains D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt of 14.3 gram white crystals shapes, be dissolved in the aqueous ethanolic solution of 35ml 50v/v%, add 2.1 gram salt of wormwood then, warming while stirring to 50 ℃, react after 2 hours, be cooled to 20 ℃, filtration under diminished pressure gets filtrate and white depositions, white depositions is washed with small amount of ethanol, makes D-D-pHPG 4.68 grams at last through vacuum-drying.Yield 93.8%.
Chemical purity is 99.3%.
Embodiment 3
In the 80ml Glacial acetic acid, add 8.5 gram (0.05mol) DL-D-pHPGs and 16.9 gram (0.05mol) (+)-3-bromo-8-camphorsulfonic acid ammonium salts, at N
2Under protection and the agitation condition, be warming up to 60 ℃, slowly drip 2.5g (0.025mol) sulfuric acid after forming white suspension liquid; after treating that sulfuric acid dropwises, add 0.24 gram 2-nitro-phenyl aldehyde, after reaction is carried out 9 hours; slowly be cooled to 10 ℃, fully separate out formed double salt.Filtration under diminished pressure obtains D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt of 23.8 gram white crystals shapes, and yield is 93.9%, after the small amount of acetic acid washing, places vacuum drying oven dry.
Take by weighing 23.8 gram exsiccant D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt, be dissolved in the aqueous ethanolic solution of 58ml 50v/v%, add 3.5 gram salt of wormwood then, warming while stirring to 50 ℃ was reacted after 2 hours, was cooled to 20 ℃, filtration under diminished pressure gets filtrate and white depositions, white depositions is washed with small amount of ethanol, makes D-D-pHPG 4.55 grams after vacuum-drying, yield 91.2%.
Chemical purity is 99.5%.
Embodiment 4
In the 80ml Glacial acetic acid, add 8.5 gram (0.05mol) DL-D-pHPGs and 16.9 gram (0.05mol) (+)-3-bromo-8-camphorsulfonic acid ammonium salts, at N
2Under protection and the agitation condition, be warming up to 90 ℃, slowly drip 2.5g (0.025mol) sulfuric acid after forming white suspension liquid; after treating that sulfuric acid dropwises, add 0.56 gram 2-nitro-phenyl aldehyde, after reaction is carried out 4 hours; slowly be cooled to 10 ℃, fully separate out formed double salt.Filtration under diminished pressure obtains D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt of 24.1 gram white crystals shapes, and yield is 94.8%, after the small amount of acetic acid washing, places vacuum drying oven dry.
Take by weighing 24.1 gram exsiccant D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt, be dissolved in the aqueous ethanolic solution of 60ml50v/v%, add 3.45 gram salt of wormwood then, warming while stirring to 50 ℃ was reacted after 2 hours, was cooled to 20 ℃, filtration under diminished pressure gets filtrate and white depositions, white depositions is washed with small amount of ethanol, makes D-D-pHPG 4.51 grams after vacuum-drying, yield 90.7%.
Chemical purity is 99.3%.
Claims (10)
1. the preparation method of a D-D-pHPG; with (+)-3-bromo-8-camphorsulfonic acid ammonium salt is resolving agent; under the catalysis of catalyzer; the resolution of racemic D-pHPG; obtain the D-D-pHPG; it is characterized in that catalyzer adopts 2-nitro-phenyl aldehyde, under nitrogen protection, react, may further comprise the steps:
(1) adding mol ratio in acetate is (+)-3-bromo-8-camphorsulfonic acid ammonium salt and the DL-D-pHPG of 1:1, under the condition of nitrogen protection and continuously stirring, be warming up to 60～90 ℃, add 2-nitro-phenyl aldehyde after dripping sulfuric acid, reacted 3-9 hour, be cooled to 10 ℃, behind the sufficient crystallising after filtration, washing, drying obtain D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt;
(2) add salt of wormwood after D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt is dissolved in the 50%v/v aqueous ethanolic solution, reacted 2～4 hours under 50～55 ℃ of temperature, be cooled to 20 ℃, filtration, washing, drying obtain the D-D-pHPG.
2. the preparation method of D-D-pHPG according to claim 1 is characterized in that by weight, and the consumption of 2-nitro-phenyl aldehyde is 3%～7% of a DL-D-pHPG.
3. the preparation method of D-D-pHPG according to claim 2 is characterized in that by weight, and the consumption of 2-nitro-phenyl aldehyde is 5% of a DL-D-pHPG.
4. the preparation method of D-D-pHPG according to claim 1 is characterized in that the reaction times is 4～6 hours in the step (1).
5. the preparation method of D-D-pHPG according to claim 1 is characterized in that by weight, and the consumption of acetate is 9～10 times of DL-D-pHPG; In mole, the vitriolic consumption is 0.5 times of DL-D-pHPG.
6. the preparation method of D-D-pHPG according to claim 1 is characterized in that by weight, and the consumption of 50%v/v aqueous ethanolic solution is 2.5 times of D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt.
7. the preparation method of D-D-pHPG according to claim 1 is characterized in that the consumption mol ratio of D-D-pHPG (+)-3-bromo-8-camphorsulfonic acid double salt and salt of wormwood is 2: 1.
8. the preparation method of D-D-pHPG according to claim 1 is characterized in that recovery set solvent and resolving agent.
9. the preparation method of D-D-pHPG according to claim 6 is characterized in that recycling step (1) separates the filtrate that obtains, and after acetic acid fraction is reclaimed in distillation, recycles as resolution solvent.
10. the preparation method of D-D-pHPG according to claim 6 is characterized in that recycling step (2) separates the filtrate obtain, through underpressure distillation, collects 60～65 ℃ of cuts be used as in and the solvent cycle use; Bottoms after filtration, after the washing, cure under 90～100 ℃ and obtained solid (+)-3-bromo-8-camphorsulfonic acid sylvite in 2 hours and recycle as resolving agent.
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| CN101747219A (en) * | 2008-12-01 | 2010-06-23 | 上海华理生物医药有限公司 | Synthesis of clopidogrel impurity intermediate |
| CN101955438B (en) * | 2010-08-20 | 2014-06-25 | 金沂蒙集团有限公司 | Method for preparing L-(+)-alpha-phenylglycine |
| JP5767346B2 (en) | 2012-02-15 | 2015-08-19 | ホーナン ニューランド ファーマシューティカル カンパニー リミテッド | Method for synthesizing levorotatory p-hydroxyphenylglycine compound |
| CN104557674B (en) * | 2015-01-13 | 2017-06-16 | 江苏中邦制药有限公司 | The preparation method of the hydroxy piperidines of one kind (S) N Boc 3 |
| CN105418443A (en) * | 2015-11-06 | 2016-03-23 | 安徽赛诺制药有限公司 | Method for synthesizing left-handed p-hydroxyphenyl glycine |
| CN105596345B (en) * | 2016-01-04 | 2017-05-17 | 四川制药制剂有限公司 | Preparation method for drug composition of cefoperazone sodium and sulbactam sodium |
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