CN101792398B - Method for preparing optical pure p-hydroxy phenyl glycine by separation method - Google Patents
Method for preparing optical pure p-hydroxy phenyl glycine by separation method Download PDFInfo
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- CN101792398B CN101792398B CN 201010120393 CN201010120393A CN101792398B CN 101792398 B CN101792398 B CN 101792398B CN 201010120393 CN201010120393 CN 201010120393 CN 201010120393 A CN201010120393 A CN 201010120393A CN 101792398 B CN101792398 B CN 101792398B
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- resolving agent
- phpg
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Abstract
The invention discloses a method for preparing optical pure p-hydroxy phenyl glycine by a separation method, and belongs to the field of separating racemic compounds. In the method, laevo-rotation cycle phosphoric acid serving a main separating agent and cycle phosphoric acid serving as an auxiliary separating agent are used together to separate DL-p-Hydroxyphenylglycine, and particularly, the DL-p-Hydroxyphenylglycine and the combined cycle phosphoric acid separating agent are reacted in a water-containing organic solvent, the reaction solution is heated and refluxed until the reaction solution is clear, the reaction solution is stirred and cooled to precipitate crystals, the reaction solution is filterer and washed, the obtained filter cakes are treated to form the D-(-)-p-hydroxy phenyl glycine, and the filtrate and the water-washing solution are treated to obtain the L-(+)-p-hydroxy phenyl glycine. The method has the advantages of high yield, high optical purity, high separation efficiency, easy and convenient operation, and the like.
Description
Technical field
The present invention relates to a kind of method that Split Method prepares the optical purity D-pHPG, be specifically related to a kind of fractionation racemization D-pHPG and prepare its L-(+)-and the method for D-(-)-D-pHPG isomer.
Background technology
The photolytic activity D-pHPG has important purposes, can be used for the synthetic of Broad spectrum antibiotics, assisting therapy ischemic heart disease, heart failure, the treatment of the diseases such as diabetes.
The preparation method of photolytic activity D-pHPG comprises biological enzyme, chemical resolution method and induced crystallization method.
At present industrially mainly prepare by the o-toluene sulfonic acid of the D-pHPG of racemization or tosilate are carried out induced crystallization the D-pHPG that light is lived, the method is with low cost, but efficient is too low.After biological enzyme prepares the photolytic activity D-pHPG, extraction process is loaded down with trivial details, the higher and difficult removal of the protein content that produces in process and cause the quality of photolytic activity D-pHPG to be subject to impact.
1998, during the people such as Wynberg and Vries is applied to combinational chemistry split first, invented the method for family approach, they adopt resolving agent family (family resolvingagents) to replace single chiral resolving agent that racemic compound is split, and this is a great breakthrough on method for splitting.They adopt equimolar ratio is that CP1, CP2, the CP3 that the light of 1: 1: 1 is lived makes resolving agent, splits the D-pHPG of racemization, the D-pHPG that the light that obtains is lived, and its e.e. value is 95%.But the resolution reagent that uses in aforesaid method is optical purity, and need three kinds to use simultaneously, split with traditional classical and use a kind of optical purity resolution reagent to compare, increased the requirement to resolving agent, also greatly increased the cost of resolving agent simultaneously on the basis of improving fractionation efficient.
Summary of the invention
The object of the present invention is to provide that a kind of yield is high, optical purity is high, split the method that efficient is high, Split Method that operation is simple prepares the optical purity D-pHPG, prepare its L-(+)-and the method for D-(-)-isomer also referred to as splitting the racemization D-pHPG.
For achieving the above object, the present invention is by the following technical solutions:
A kind of Split Method of the present invention prepares the method for optical purity D-pHPG, comprises the steps:
Be left-handed cyclic phosphoric acid and help the resolving agent cyclic phosphoric acid to combine for the fractionation of racemization D-pHPG with main resolving agent.Racemization D-pHPG and associative ring phosphoric acid resolving agent are reacted in moisture organic solvent, and reflux to solution is clarified, stir, and cooling, crystallize out filters, washing, filter cake obtains D-(-)-D-pHPG after processing; Obtain L-(+)-D-pHPG after filtrate and washings processing.
The molar content n of the left-handed cyclic phosphoric acid of main resolving agent in described associative ring phosphoric acid resolving agent
1Its span is 50%≤n
1＜100%, help resolving agent molar content n
2Its span is: 0%＜n
2≤ 50%.
Described main resolving agent is not the same compound with helping resolving agent, and described main resolving agent is left-handed optical purity cyclic phosphoric acid, and helping resolving agent is the optical purity cyclic phosphoric acid, perhaps is the cyclic phosphoric acid of racemization.The cyclic phosphoric acid that adopts is lower array structure.Substituent R is H, Cl, OMe.
For ease of describing, different according to substituting group, be H, Cl, OMe called after CP1, CP2, CP3 successively artificially with substituent R.
Described main resolving agent is (-)-4-(2-chloro-phenyl-)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (CP2) or (-)-4-(2-p-methoxy-phenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (CP3).
The described resolving agent that helps is 4-phenyl-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (CP1), 4-(2-chloro-phenyl-)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (CP2), 4-(2-p-methoxy-phenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3, a kind of in 2-dioxaphosphorinane (CP3).
Described main resolving agent and help resolving agent for the same compound, refer to when described main resolving agent be left-handed rotation live CP2 the time, helping resolving agent can or be optical purity CP1 or CP3 for CP1 or the CP3 of racemization; When helping resolving agent, opticity can be consistent with main resolving agent, also can be opposite as optical purity CP1 or CP3.When described main resolving agent be left-handed rotation live CP3 the time, the CP1 or the CP2 that help resolving agent to can be racemization also can be optically pure CP1 or CP2, when helping resolving agent, opticity can be consistent with main resolving agent, also can be opposite as optical purity CP1 or CP2.
The mol ratio of described racemization D-pHPG and associative ring phosphoric acid resolving agent is 1: x, wherein the x span is 0.5＜x≤1, and the mol ratio of main resolving agent and racemization D-pHPG is more than or equal to 0.5, less than 1.
Described organic solvent is the organic solvent miscible with water, can be a kind of in methyl alcohol, ethanol, Virahol, acetone or ether or several mixture wherein.Organic solvent can adopt a kind of, can be also that multiple organic solvent mixes use, and wherein effect mixed with water is better separately with a kind of organic solvent, and cost is lower.
Described filter cake is molten in strong acid, stirs, and filters, and reclaims the cyclic phosphoric acid resolving agent; Transfer filtrate pH=5.3～6.0 with alkali, filter, washing, drying gets D-(-)-D-pHPG.Its optical purity is: [α]
20 D-156 °--158 ° (c=1,1N HCl).Described strong acid is inorganic proton acid or organic acid, example hydrochloric acid, sulfuric acid or phosphoric acid etc., and described alkali can be mineral alkali or organic bases, as NaOH, KOH, Na
2CO
3, ammoniacal liquor, triethylamine, methylamine etc.
Described filtrate and water lotion merge, concentrate, and add strong acid, separate out the cyclic phosphoric acid resolving agent, filter; Transfer filtrate to regulate pH=pH=5.3～6.0 with alkali and filter, washing, drying gets L-(+)-D-pHPG.Its optical purity is: [α]
20 D+ 156 °-+158 ° (c=1,1N HCl).Described strong acid is inorganic proton acid or organic acid, example hydrochloric acid, sulfuric acid, phosphoric acid etc., and described alkali can be mineral alkali or organic bases, as NaOH, KOH, Na
2CO
3, ammoniacal liquor, triethylamine, methylamine etc.
The present invention has invented the new combination of a kind of cyclic phosphoric acid on the basis of existing technology as resolution reagent, i.e. associative ring phosphoric acid resolving agent is for the preparation of the photolytic activity D-pHPG.Use the molar content n of the main resolving agent of associative ring phosphoric acid resolving agent
1Be 50%≤n
1＜100%, help resolving agent molar content n
2For: 0%＜n
2≤ 50%.
Described main resolving agent is not the same compound with helping resolving agent, and described main resolving agent is left-handed optical purity cyclic phosphoric acid, helps resolving agent to can be the optical purity cyclic phosphoric acid, also can be the cyclic phosphoric acid of racemization.The aforesaid combination cyclic phosphoric acid splits D-pHPG, with classical split to compare greatly improved fractionation efficient, use simultaneously with three kinds of resolving agents of the people such as Wynberg in 1998 and Vries and compare, reduced the requirement to optical agents, reduced cost.
CP2 or CP3 that described associative ring phosphoric acid resolving agent adopts left-handed rotation to live are main resolving agent, then add that another light is lived or racemization help resolving agent, the D-pHPG of racemization is split.The D-pHPG that this associative ring phosphoric acid resolving agent can be bordering on the selectivity of 100%e.e. and racemization promptly forms the crystallization of diastereomer, obtain thereby split the D-pHPG that light is lived, yield reaches more than 95%, and optical purity reached＞more than 98%ee, split efficient very high.
In addition, resolving agent can recycling use, has reduced production cost.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.
CP1 in embodiment 1-5 is 4-phenyl-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane;
CP2 is 4-(2-chloro-phenyl-)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane;
CP3 is 4-(2-p-methoxy-phenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane.
Embodiment 1
(1) (volume ratio is 1: 1) adds the D-pHPG of 167g (1mol) racemization in the 450mL ethanol/water solution, 276.46g (1mol) associative ring phosphoric acid resolving agent reflux to solution is clarified, stir 1h, be cooled to 50 ℃, have crystal to separate out, filter, with 56mL frozen water washing leaching cake, drying gets filter cake 218.4g, 230 ℃-232 ℃ of fusing points.
Main resolving agent in described associative ring phosphoric acid resolving agent is (-)-CP2, and helping resolving agent is (±)-CP3, and both mol ratios are 99: 1.
(2) with above-mentioned filter cake, molten in 50mL36% hydrochloric acid, stirring at room 4h separates out a large amount of solid filterings, reclaims the cyclic phosphoric acid resolving agent, filtrate is regulated pH=5.4 with NaOH solution, filter, with the washing of 15mL frozen water, drying, get D-(-)-D-pHPG 81.33g, yield is 97.4%.[α]
20 D-158°(c＝1，1N?HCl)。
(3) filtrate in step (1) and water lotion are merged, concentrate, add 40mL 36% hydrochloric acid, stirring at room 4h separates out the cyclic phosphoric acid resolving agent, filters; Filtrate is regulated pH=6.0 with NaOH solution, filters, and with the washing of 15mL frozen water, drying gets L-(+)-D-pHPG 80.33g, yield 96.2%.[α]
20 D+156°(c＝1，1N?HCl)。
(4) resolution reagent of above-mentioned steps (2) and (3) recovery is total to 268.83g, and the rate of recovery is 97.24%, and the resolving agent that reclaims is combined to be recycled.
Embodiment 2
(1) in the 400mL isopropanol/water solution (volume ratio is 1: 1), the D-pHPG that adds 167g (1mol) racemization, 276.41g (1mol) associative ring phosphoric acid resolving agent, reflux to solution is clarified, stir 1h, be cooled to 50 ℃, have crystal to separate out, filter, with 53mL frozen water washing leaching cake, drying gets filter cake 214.6g, 231 ℃-233 ℃ of fusing points.
Main resolving agent in described associative ring phosphoric acid resolving agent is (-)-CP2, and helping resolving agent is (-)-CP3, and both mol ratios are 98: 2.
(2) with above-mentioned filter cake, molten in 45mL phosphoric acid, stirring at room 4h separates out a large amount of solid filterings.Reclaim the cyclic phosphoric acid resolving agent, filtrate is regulated pH=5.4 with KOH solution, filters, and with the washing of 14mL frozen water, drying gets D-(-)-D-pHPG 79.78g, and yield is 95.54%.[α]
20 D-157°(c＝1，1N?HCl)。
(3) filtrate in step (1) and water lotion are merged, concentrate, add 50mL phosphoric acid, stirring at room 4h separates out the cyclic phosphoric acid resolving agent, filters; Filtrate is regulated pH=6.0 with KOH solution, filters, and uses the 13mL water washing, and drying gets L-(+)-D-pHPG 79.38g, yield 95.06%.[α]
20 D+155°(c＝1，1N?HCl)。
(4) resolution reagent of above-mentioned steps (2) and (3) recovery is total to 267.7g, and the rate of recovery is 96.85%, and the resolving agent that reclaims is combined to be recycled.
Embodiment 3
(1) in the 450mL methanol/water solution (volume ratio is 1: 1), the D-pHPG that adds 167g (1mol) racemization, 272.02g (1mol) associative ring phosphoric acid resolving agent, reflux to solution is clarified, stir 1h, be cooled to 50 ℃, have crystal to separate out, filter, with 50mL frozen water washing leaching cake, drying gets filter cake 214g, 226 ℃-258 ℃ of fusing points.
Main resolving agent in described associative ring phosphoric acid resolving agent is (-)-CP3, and helping resolving agent is (±)-CP2, and both mol ratios are 99.5: 0.5.
(2) with above-mentioned filter cake, molten in the 48mL18% dilute sulphuric acid, stirring at room 4h separates out a large amount of solid filterings.Reclaim the cyclic phosphoric acid resolving agent, filtrate is used Na
2CO
3Solution is regulated pH=5.4, filters, and with the washing of 11mL frozen water, drying gets D-(-)-D-pHPG 79.87g, and yield is 95.65%.[α]
20 D-158°(c＝1，1N?HCl)。
(3) filtrate in step (1) and water lotion are merged, concentrate, add the 50mL18% dilute sulphuric acid, stirring at room 4h separates out the cyclic phosphoric acid resolving agent, filters; Filtrate is used Na
2CO
3Solution is regulated pH=6.0, filters, and with the washing of 10mL frozen water, drying gets L-(+)-D-pHPG 79.56g, yield 95.28%.[α]
20 D+156°(c＝1，1N?HCl)。
(4) resolution reagent of above-mentioned steps (2) and (3) recovery is total to 261.28g, and the rate of recovery is 96.05%, and the resolving agent that reclaims is combined to be recycled.
Embodiment 4
(1) in 450mL acetone/water solution (volume ratio is 1: 1), the D-pHPG that adds 167g (1mol) racemization, 231.43g (0.85mol) associative ring phosphoric acid resolving agent, reflux to solution is clarified, stir 1h, be cooled to 50 ℃, have crystal to separate out, filter, 70ml frozen water washing leaching cake, drying gets filter cake 212.65g, 226 ℃-228 ℃ of fusing points.
Main resolving agent in described associative ring phosphoric acid resolving agent is (-)-CP3, and helping resolving agent is (-)-CP2, and both mol ratios are 16: 1.
(2) with above-mentioned filter cake, molten in 40mL36% hydrochloric acid, stirring at room 4h separates out a large amount of solid filterings.Reclaim resolving agent, filtrate is regulated pH=5.4 with ammonia soln, filters, and with the washing of 16mL frozen water, drying gets D-(-)-D-pHPG 79.7g, and yield is 95.45%.[α]
20 D-157°(c＝1，1N?HCl)。
(3) filtrate in step (1) and water lotion are merged, concentrate, add 40mL 36% hydrochloric acid, stirring at room 4h separates out the cyclic phosphoric acid resolving agent, filters; Filtrate is regulated pH=6.0 with ammonia soln, filters, and with the washing of 17mL frozen water, drying gets L-(+)-D-pHPG 79.51g, yield 95.22%.[α]
20 D+156°(c＝1，1N?HCl)。
(4) resolution reagent of above-mentioned steps (2) and (3) recovery is total to 227.03g, and the rate of recovery is 98.1%, and the resolving agent that reclaims is combined to be recycled.
Embodiment 5
(1) in 400mL ether/ethanol/aqueous solution (volume ratio is 2: 50: 48), the D-pHPG that adds 167g (1mol) racemization, 186.65g (0.7mol) associative ring phosphoric acid resolving agent, reflux to solution is clarified, and stirs 1h, be cooled to 50 ℃, there is crystal to separate out, filters 60mL frozen water washing leaching cake, drying gets filter cake 212.88g.
Main resolving agent in described associative ring phosphoric acid resolving agent is (-)-CP2, and helping resolving agent is (-)-CP1, and both mol ratios are 5: 2.
(2) with above-mentioned filter cake, molten in 50mL 36% hydrochloric acid, stirring at room 4h separates out a large amount of solid filterings.Reclaim the cyclic phosphoric acid resolving agent, filtrate is regulated pH=5.4 with methylamine solution, filters, and with the washing of 12mL frozen water, drying gets D-(-)-D-pHPG 79.44g, and yield is 95.14%.[α]
20 D-156°(c＝1，1N?HCl)。
(3) filtrate in step (1) and water lotion are merged, concentrate, add 50mL 36% hydrochloric acid, stirring at room 4h separates out the cyclic phosphoric acid resolving agent, filters; Filtrate is regulated pH=6.0 with methylamine solution, filters, and with the washing of 11mL frozen water, drying gets L-(+)-D-pHPG 79.38g, yield 95.07%.[α]
20 D+155°(c＝1，1N?HCl)。
(4) resolution reagent of above-mentioned steps (2) and (3) recovery is total to 179.18g, and the rate of recovery is 96%, and the resolving agent that reclaims is combined to be recycled.
Embodiment 6
(1) in 400mL methanol/ethanol/aqueous solution (volume ratio is 0.5: 0.5: 1), the D-pHPG that adds 167g (1mol) racemization, 276.28g (1mol) associative ring phosphoric acid resolving agent, reflux to solution is clarified, stir 1h, be cooled to 50 ℃, have crystal to separate out, filter, 50mL frozen water washing leaching cake, drying gets filter cake 218.42g, 232 ℃-233 ℃ of fusing points.
Main resolving agent in described associative ring phosphoric acid resolving agent is (-)-CP2, and helping resolving agent is (+)-CP3, and both mol ratios are 95: 5.
(2) with above-mentioned filter cake, molten in 50mL 36% hydrochloric acid, stirring at room 4h filters.Reclaim the cyclic phosphoric acid resolving agent, filtrate is regulated pH=5.4 with triethylamine solution, filters, and with the washing of 13mL frozen water, drying gets D-(-)-D-pHPG 80.69g, and yield is 96.63%.[α]
20 D-156°(c＝1，1N?HCl)。
(3) filtrate in step (1) and water lotion are merged, concentrate, add 50mL 36% hydrochloric acid, stir 4h, separate out the cyclic phosphoric acid resolving agent, filter; Filtrate is regulated pH=6.0 with triethylamine solution, filters, and with the washing of 12mL frozen water, drying gets L-(+)-D-pHPG 80.22g, yield 96.07%.[α]
20 D+155°(c＝1，1N?HCl)。
(4) resolution reagent of above-mentioned steps (2) and (3) recovery is total to 269.1g, and the rate of recovery is 97.4%, and the resolving agent that reclaims is combined to be recycled.
Claims (3)
1. a Split Method prepares the method for optical purity D-pHPG, it is characterized in that comprising the steps:
Be left-handed cyclic phosphoric acid and help the resolving agent cyclic phosphoric acid to combine for the fractionation of racemization D-pHPG with main resolving agent, racemization D-pHPG and associative ring phosphoric acid resolving agent are reacted in moisture organic solvent, reflux to solution is clarified, stir, cooling, crystallize out filters, washing, filter cake obtains D-(-)-D-pHPG after processing; Obtain L-(+)-D-pHPG after filtrate and washings processing;
Described main resolving agent is not the same compound with helping resolving agent, and described main resolving agent is left-handed optical purity cyclic phosphoric acid, and helping resolving agent is the cyclic phosphoric acid of optical purity or racemization;
Described main resolving agent is (-)-4-(2-chloro-phenyl-)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane or (-)-4-(2-p-methoxy-phenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3, the 2-dioxaphosphorinane;
The described resolving agent that helps is that light is lived or the 4-phenyl of racemization-2-hydroxyl-5,5-dimethyl-2-oxo-1,3, the 4-(2-chloro-phenyl-) of 2-dioxaphosphorinane, light work or racemization-2-hydroxyl-5,5-dimethyl-2-oxo-1,3, the 4-(2-p-methoxy-phenyl) of 2-dioxaphosphorinane or light work or racemization-2-hydroxyl-5,5-dimethyl-2-oxo-1,3, a kind of in the 2-dioxaphosphorinane;
Described organic solvent is a kind of in methyl alcohol, ethanol, Virahol, acetone or ether or several mixture wherein;
Described filter cake is molten in strong acid, stirs, and filters, and reclaims resolving agent; Transfer filtrate pH=5.3～6.0 with alkali, filter, washing, drying gets D-(-)-D-pHPG;
Described filtrate and water lotion merge, concentrate, and add strong acid, separate out the cyclic phosphoric acid resolving agent, filter; Transfer filtrate to regulate pH=5.3～6.0 with alkali, filter, washing, drying gets L-(+)-D-pHPG;
Described strong acid is inorganic proton acid or organic acid, and described alkali is mineral alkali or organic bases.
2. Split Method according to claim 1 prepares the method for optical purity D-pHPG, it is characterized in that the molar content n of main resolving agent in described associative ring phosphoric acid resolving agent
1Its span is 50%≤n
1＜100%, help resolving agent molar content n
2Its span is: 0%＜n
2≤ 50%.
3. Split Method according to claim 1 prepares the method for optical purity D-pHPG, the mol ratio that it is characterized in that described racemization D-pHPG and associative ring phosphoric acid resolving agent is 1: x, wherein the x span is 0.5＜x≤1, and the mol ratio of main resolving agent and racemization D-pHPG is more than or equal to 0.5, less than 1.
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| CN102070469B (en) * | 2010-12-31 | 2013-11-20 | 河北科技大学 | Resolution method for preparing optically pure metoprolol |
| CN102391138B (en) * | 2011-10-14 | 2014-09-10 | 山东谛爱生物技术股份有限公司 | Method for preparing D-valine by using asymmetric transformation method |
| CN102603449B (en) * | 2012-02-15 | 2015-07-15 | 河南新天地药业股份有限公司 | Synthesis method of levo-p-hydroxy phenylglycine compound |
| CN103755582B (en) * | 2014-01-26 | 2015-04-08 | 河北科技大学 | Preparation method according to D-serine through splitting method |
| CN104876856B (en) * | 2015-05-05 | 2017-11-21 | 河北凯力昂生物科技有限公司 | A kind of method that Split Method prepares (R) (+) 3 amino piperidine dihydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0180276B1 (en) * | 1984-10-24 | 1988-12-28 | Stamicarbon B.V. | Dioxaphosphorinanes, their preparation and use for resolving optically active compounds |
| CN1182068A (en) * | 1996-10-23 | 1998-05-20 | Dsm有限公司 | Process for separation of mixture of enantiomers |
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2010
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0180276B1 (en) * | 1984-10-24 | 1988-12-28 | Stamicarbon B.V. | Dioxaphosphorinanes, their preparation and use for resolving optically active compounds |
| CN1182068A (en) * | 1996-10-23 | 1998-05-20 | Dsm有限公司 | Process for separation of mixture of enantiomers |
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Application publication date: 20100804 Assignee: Shanxi Xinbaoyuan Pharmaceutical Co.,Ltd. Assignor: Hebei University of Science and Technology Contract record no.: 2015310000075 Denomination of invention: Method for preparing optical pure p-hydroxy phenyl glycine by separation method Granted publication date: 20130626 License type: Exclusive License Record date: 20150707 |
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