CN1680565A - Preparation of chiral epichlorohydrin - Google Patents
Preparation of chiral epichlorohydrin Download PDFInfo
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- CN1680565A CN1680565A CN 200510023852 CN200510023852A CN1680565A CN 1680565 A CN1680565 A CN 1680565A CN 200510023852 CN200510023852 CN 200510023852 CN 200510023852 A CN200510023852 A CN 200510023852A CN 1680565 A CN1680565 A CN 1680565A
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- epoxy chloropropane
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- epoxide hydrolase
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Abstract
A process of preparing handing chloroepoxy propane. Chloroepoxy hydrolase is as accelerating agent. racemic chloroepoxy propane, organic solvent, water and phase transfer catalyst reacts in reaction bulb. Add alkalescent buffer solution to react at pH 3-10,-20-30deg.C for 1-10days. Then add beta-caritinoid and stir for 1-10h before separating. Chloroepoxy propane and 3-Cl-1,2- propylene glvcol is obtained by way of distillation.
Description
Technical field
The present invention relates to the preparation method's of epoxy chloropropane, particularly a kind of chiral epichlorohydrin preparation method.
Background technology
The optics chiral epichlorohydrin is the important chiral intermediate of synthetic many chiral medicinals.As use chiral epichlorohydrin to synthesize treatment cardiovascular disorder, antibacterial-anti-inflammatory drugs such as beta-blocker, R-carnitine, the general naphthalene of S-Lip river system, sharp naphthalene oxazolone.At present, the method that the racemation epoxy chloropropane is split is divided two classes:
1. chemical resolution method
Mainly by the Salen cobalt catalyst of Jacobsen E.N. invention to the racemation epoxy chloropropane split (Science 277 (5328), 1997:936.J.Am.Chem.Soc.121 (17), 1999:447).This method is at first made chirality Salen metal complex catalysts.This chiral catalyst under the effect of water with the epoxy chloropropane generation hydrolysis reaction of corresponding configuration, generate the 3-chloro-1 of configuration of the same race, the 2-propylene glycol and the epoxy chloropropane of configuration in addition.Utilize the difference of the two boiling point, can easily they be separated by underpressure distillation.It is simple that this method has production technique, the efficient advantages of higher.But, there is certain environmental pollution because the Salen catalyzer uses heavy metal elements such as cobalt metal.And the chiral epichlorohydrin that every production is 1 ton will produce the waste material that contains heavy metals such as Salen cobalt more than 2 tons.
2. biological enzyme Split Method
1. (1992:97.J.Ind.Microbcol.10 1993:37) isolates two kinds of bacterial classifications to Kasai etc. for Agric.Biol.Chem.54,1990:3185.J.Ind.Microbcol.9.A kind of is pseudomonas (Pseudomonas) Sp OS-K-29, another kind of for having a liking for alkali bacterium (Alcaligenes) SP.DS-K-S38, can absorb S type and R type epoxy compounds respectively, thereby obtain the optics chirality body of single configuration.But it is wasteful that this kind method exists raw material, the shortcoming that reaction yield is low.Almost the substrate more than 70% is absorbed by microbial strains.Aftertreatment technology complexity in addition, the loss of activity of enzyme is big, and industrialized production efficient is not high.
2. permitted to build and wait and isolate a class epoxide hydrolase bacterium (J.Molecular Catal.B:Enzymatic13,2001:61.Enzyme and Micro.Tech.33,2003:527.J.Molecular Catal.B:Enzymatic 27,2004:155.Biotech.Lett.26,2004:1217), the hydrolysis of racemize htrb gene epoxy compounds can be split as a kind of compound of configuration and the corresponding glycol product of another kind of configuration.
Much lower because of the boiling point of epoxy compounds with the boiling point of its corresponding glycol, can easily both be separated by distillating method thus.This kind method has been taken into account the advantage of aforementioned two kinds of methods, and production efficiency height, starting material expend few, and production cost is low, and aftertreatment is easy etc., and environmentally friendly, and certain industrialization development prospect is arranged.
But utilize epoxide hydrolase ECU1001, ECU1040 to split epoxy chloropropane, obtain the epoxy chloropropane industrialization product of chiral purity.Have following problem: because the chemical property of macro-radical epoxy compounds and epoxy chloropropane has certain difference, especially the existence of chlorine element may make poisoning by enzyme and lose activity on the one hand; As adopting the water react system, because the concentration of substrate epoxy chloropropane is very low, it will be very difficult that processing is extracted in the back on the other hand, and energy consumption is big, the production cost height.
Summary of the invention
The technical problem to be solved in the present invention is the activity of protection epoxide hydrolase, improves reaction conversion ratio, makes the preparation method who separates easy a kind of high purity chiral epichlorohydrin.This method has rate of recovery height, byproduct is pure, production cost is low and free of contamination advantage.
Technical scheme of the present invention comprises the steps:
(1) catalyzer epoxide hydrolase, epoxy chloropropane, organic solvent, water, phase-transfer catalyst are placed reaction flask, add the buffered soln insulation reaction of organic amine and ammoniacal liquor preparation, pH value is 3～10 ,-20～30 ℃, reacts 1～10 day;
The add-on of epoxide hydrolase is an epoxide hydrolase: epoxy chloropropane=1: the add-on of (2～50) (weight ratio) phase-transfer catalyst is a phase-transfer catalyst: epoxy chloropropane=0.01～0.1: 1 (mol ratio); As catalyzer, can obtain S-epoxy chloropropane and R-3-chloro-1, the 2-propylene glycol with epoxide hydrolase ECU1001 (2005/01/17 China Committee for Culture Collection of Microorganisms common micro-organisms center/CGMCC No:1293);
As catalyzer, can obtain R-epoxy chloropropane and S-3-chloro-1, the 2-propylene glycol with epoxide hydrolase ECU1040 (2005/01/17 China Committee for Culture Collection of Microorganisms common micro-organisms center/CGMCC No:1292);
Optimum temps is-5～10 ℃;
Organic solvent is selected from one or more mixtures of sherwood oil, hexanaphthene, normal hexane, tetrahydrofuran (THF), Pyrrolidine, acetone, isopropyl ether;
Phase-transfer catalyst is: benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, 4-butyl ammonium hydrogen sulfate, palmityl trimethyl ammonium chloride, cetyl trimethylammonium bromide, Ethyltriphenylphosphonium brimide;
Phase-transfer catalyst: the epoxy chloropropane optimum quantity is 0.03～0.05: 1 (mol ratio);
The best pH value of buffered soln is 7～9;
Organic amine is quadrol, diethanolamine or triethylamine;
(2) before the separation and Extraction, add the additive β-Hu Luobusu, after the adding, stirred 1～10 hour, after adopting the ordinary method concentration of reaction solution, separate epoxy chloropropane and 3-chloro-1,2-propylene glycol with vacuum distillation method, use the dichloromethane extraction β-Hu Luobusu, the activity of recovering epoxide hydrolase is in order to recycling later on; The β-Hu Luobusu add-on is a β-Hu Luobusu: epoxide hydrolase=1: 1.0～30 (mass ratio); β-Hu Luobusu: the epoxide hydrolase optimum proportion is 1: 10～15 (mass ratioes); Best churning time is 2～5 hours.
Because the chlorine element in the epoxy chloropropane can make the epoxide hydrolase poisoning and deactivation, the inventive method adopts a rational hydrolysis reaction system, makes free chlorine element that hydrolysis reaction produces in time by in the alkaline media and absorb the activity of protective enzyme.
Employing is based on little water react system of organic solvent.An a spot of water part participates in the hydrolysis reaction of epoxy chloropropane in the system, and another part promotes the hydrolytic activity of enzyme.Because organic solvent is different with the boiling point of product, water, reaction can adopt the simple distillation method that various different substancess are separated easily after finishing.
Because the mutual solubility of reaction substrate epoxy chloropropane and water is very poor, therefore can in reaction process, add a kind of to the enzyme gentleness, the phase-transfer catalyst of no deactivation, thoroughly the dispersion situation of thing is hanged down in improvement, the raising reaction conversion ratio.
After hydrolysis reaction reaches requirement, in the fractionation by distillation process, because enzyme high temperature continues to take place hydrolysis down, can make the optical purity epoxy chloropropane of a part of target product configuration continue to be hydrolyzed to glycol, so not only reduce product yield, also reduced 3-chloro-1, the optical purity of 2-propylene glycol simultaneously.The present invention selects β-Hu Luobusu as additive, in time adds the activity of inhibitory enzyme in sepn process, ends the hydrolysis reaction of enzyme.After separation and Extraction finishes, it is extracted from aqueous phase with organic solvent, make lytic enzyme recover active.
Take the preparation method of chiral epichlorohydrin of the present invention, not only can obtain the optics chiral purity and reach 99%ee above R or S epoxy chloropropane, also can obtain the S about optical purity 85%ee or the 3-chloro-1 of R configuration simultaneously, the 2-propylene glycol.The chiral epichlorohydrin yield reaches 40%, and production cost has obvious reduction, and byproduct 3-chloro-1,2-propylene glycol also have the above optics chiral purity of 85%ee, can utilize other optical homochiral intermediate of preparation.The essentially no generation of waste materials of whole preparation method, non-environmental-pollution has good industrial prospect.
Embodiment
Embodiment 1
(1) with 100g oxygen chloropropane, 20g epoxide hydrolase ECU1001,56g water, 1L sherwood oil, 2.5g benzyltriethylammoinium chloride place reaction flask, mixed solution (quadrol: strong aqua=2: 1 with quadrol and strong aqua, mass ratio) solution is transferred pH value 8.5～9, stirring reaction 48 hours, temperature of reaction are 0～6 ℃.Acidometer monitoring pH value in the reaction.When being lower than 8.5, pH value adds quadrol and ammonia water mixture.(2) add 22g carotene, stirring reaction 2 hours is with reacting liquid filtering.Filtrate is used the 50g anhydrous magnesium sulfate drying, and after refiltering, normal pressure steams sherwood oil, steams the S-epoxy chloropropane then under 45 ℃ of 2mmHg vapor phase temperatures.Under the 1mmHg, 90 ℃ steam R-3-chloro-1,2-propylene glycol 62.31g.After steaming the S-ring chlorine chlorine alkane layering that part is taken out of in the moisture content, merge the 43.82g that weighs, yield 43.82% (theoretical yield 50%) with the epoxy chloropropane that steams subsequently.Gas-chromatography mapping examination chemical purity is 99.32%, and the chirality optical purity is 99.56%ee.
Chirality optical purity testing method is as follows: use Agilent (Agilent) γ of company-225 type chiral column (30m * 0.25mm * 0.25um), use CH
2Cl
2Make solvent.80 ℃ of column temperatures, 250 ℃ of sample introduction temperature.To R-3-chloro-1, the 2-propylene glycol carries out test analysis, and chemical purity is 99.26%, and chiral purity is 85.86%ee.Its chiral purity testing method is:
At first the acetone with 25ml mixes with the water of 25ml, splashes into the 1ml vitriol oil and mixes, and after the cooling, with the R-3-chloro-1 of 2ml, reaction is 12 hours under the 2-propylene glycol room temperature, adds the yellow soda ash termination reaction then, filters, and boils off acetone, gets the acetonylidene product.
Reaction formula:
Detect acetonylidene with chiral column γ-225 type and get chiral purity.
Condition:
Column：GAMMA?DEX
TM?225
30m×0.25mm×0.25μm
Oven：75℃
Embodiment 2
(1) 200g epoxy chloropropane, 30g epoxide hydrolase ECU1040,80g water, 1.5L methyl alcohol were placed the reaction flask stirring reaction 35 hours, temperature of reaction is 0～6 ℃.Embodiment 1 is pressed in other operation
(2), add 30g-carotene, stirring reaction 2 hours with reacting liquid filtering.Reprocessing analysis is with embodiment 1.Get the 90.36gR-epoxy chloropropane.Chemical purity 99.56%; Chirality optical purity 99.72%e.e.Yield 45.18% (theoretical yield 50%).Get 126.73g S-3-chloro-1,2-propylene glycol, chemical purity 98.33%; Chirality optical purity 86.51%e.e.
Embodiment 3
(1) with the 80g epoxy chloropropane, 20g epoxide hydrolase ECU1001,56g water, 1L hexanaphthene, 3.2g benzyltriethylammoinium chloride place reaction flask, mixed solution (quadrol: strong aqua=2: 1 with quadrol and strong aqua, mass ratio) solution is transferred pH value 8.0～9, stirring reaction 72 hours, temperature of reaction are-3～9 ℃.Acidometer monitoring pH value in the reaction.When being lower than 8.0, pH value adds quadrol and ammonia water mixture.(2) add 17g carotene, stirring reaction 4 hours is with reacting liquid filtering.Filtrate is used the 45g anhydrous magnesium sulfate drying, and after refiltering, normal pressure steams sherwood oil, steams the S-epoxy chloropropane then under 45 ℃ of 2mmHg vapor phase temperatures.Under the 1mmHg, 90 ℃ steam R-3-chloro-1,2-propylene glycol 62.31g.After steaming the S-ring chlorine chlorine alkane layering that part is taken out of in the moisture content, merge the 35.69g that weighs, yield 44.61% (theoretical yield 50%) with the epoxy chloropropane that steams subsequently.Gas-chromatography mapping examination chemical purity is 99.32%, and the chirality optical purity is 99.56%ee.
Chirality optical purity testing method is as follows: use Agilent (Agilent) γ of company-225 type chiral column (30m * 0.25mm * 0.25um), use CH
2Cl
2Make solvent.80 ℃ of column temperatures, 250 ℃ of sample introduction temperature.To R-3-chloro-1, the 2-propylene glycol carries out test analysis, and chemical purity is 99.26%, and chiral purity is 85.86%ee.
Embodiment 4
(1) with the 116g Ethylene Oxide, 25g epoxide hydrolase ECU1001,52g water, 1L methylene dichloride, 4.8g Ethyltriphenylphosphonium brimide place reaction flask, mixed solution (quadrol: strong aqua=2: 1 with quadrol and strong aqua, mass ratio) solution is transferred pH value 8.5～9, stirring reaction 38 hours, temperature of reaction are 0～6 ℃.Acidometer monitoring pH value in the reaction.When being lower than 8.5, pH value adds quadrol and ammonia water mixture.(2) add 20g carotene, stirring reaction 3 hours is with reacting liquid filtering.Filtrate is used the 50g anhydrous magnesium sulfate drying, and after refiltering, normal pressure steams methylene dichloride, steams the S-propylene oxide then under 40 ℃ of normal pressures.Under the 5mmHg, 90 ℃ steam R-1,2-propylene glycol 65.31g.Yield 85.82%.Gas-chromatography mapping examination chemical purity is 99.53%, and the chirality optical purity is 99.12%ee.
Chirality optical purity test R-1,2-propylene glycol method is as follows: use Agilent (Agilent) γ of company-120 type chiral column (30m * 0.25mm * 0.25um), use CH
2Cl
2Make solvent.80 ℃ of column temperatures, 250 ℃ of sample introduction temperature.
Claims (8)
1. the preparation method of a chiral epichlorohydrin is characterized in that comprising the steps:
(1) catalyzer epoxide hydrolase, epoxy chloropropane, organic solvent, water, phase-transfer catalyst are placed reaction flask, add the buffered soln insulation reaction of organic amine and ammoniacal liquor preparation, pH value is 3～10 ,-20～30 ℃, reacts 1～10 day;
Epoxide hydrolase: epoxy chloropropane=1: (2～50) (weight ratio);
Phase-transfer catalyst: epoxy chloropropane=0.01～0.1: 1 (mol ratio);
(2) before the separation and Extraction, add the additive β-Hu Luobusu, stirred 1～10 hour, behind the employing ordinary method concentration of reaction solution, separate epoxy chloropropane and 3-chloro-1,2-propylene glycol with vacuum distillation method;
β-Hu Luobusu: epoxide hydrolase=1: 1.0～30 (mass ratio).
2. the preparation method of a kind of chiral epichlorohydrin according to claim 1, it is characterized in that: described epoxide hydrolase ECU1001 is as catalyzer, can obtain S-epoxy chloropropane and R-3-chloro-1, the 2-propylene glycol, described epoxide hydrolase ECU1040 is as catalyzer, can obtain R-epoxy chloropropane and S-3-chloro-1, the 2-propylene glycol.
3. the preparation method of a kind of chiral epichlorohydrin according to claim 1, it is characterized in that: described buffered soln pH value is 7～9, insulation reaction temperature-5～10 ℃.
4. the preparation method of a kind of chiral epichlorohydrin according to claim 1, it is characterized in that: described organic solvent is selected from sherwood oil, hexanaphthene, normal hexane, tetrahydrofuran (THF), Pyrrolidine, acetone and isopropyl ether.
5. the preparation method of a kind of chiral epichlorohydrin according to claim 1, it is characterized in that: described phase-transfer catalyst is benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, 4-butyl ammonium hydrogen sulfate, palmityl trimethyl ammonium chloride, cetyl trimethylammonium bromide or Ethyltriphenylphosphonium brimide; Described phase-transfer catalyst: epoxy chloropropane is 0.03～0.05: 1 (mol ratio).
6. the preparation method of a kind of chiral epichlorohydrin according to claim 1, it is characterized in that: described organic amine is quadrol, diethanolamine or triethylamine.
7. the preparation method of a kind of chiral epichlorohydrin according to claim 1, it is characterized in that: described β-Hu Luobusu: epoxide hydrolase is 1: 10～15 (mass ratioes), and described churning time is 2～5 hours.
8. according to the preparation method of claim 1 or 3 described a kind of chiral epichlorohydrins, it is characterized in that: described buffered soln pH value is 8～9, and insulation reaction temperature-3～8 ℃ was reacted 24-72 hour.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102242085A (en) * | 2011-04-12 | 2011-11-16 | 华东理工大学 | Epoxy hydrolase, gene thereof and application thereof |
| CN102391239A (en) * | 2011-09-14 | 2012-03-28 | 上海科利生物医药有限公司 | Preparation method of (R)-propene carbonate |
| CN101462947B (en) * | 2009-01-05 | 2012-07-25 | 上海柏鼎医药技术有限公司 | Preparation of (R) -4-phenyl-2-hydroxybutyrate |
| CN104151494A (en) * | 2014-08-27 | 2014-11-19 | 贵州一当科技有限公司 | Epoxy chain extender and preparation method thereof |
| CN111943805A (en) * | 2020-09-16 | 2020-11-17 | 安徽工业大学 | Preparation method of (R) -3-chloro-1, 2-propanediol |
| CN112730683A (en) * | 2020-12-25 | 2021-04-30 | 石家庄四药有限公司 | Method for detecting epichlorohydrin isomer |
| CN113943206A (en) * | 2021-10-25 | 2022-01-18 | 华今(山东)新材料科技有限公司 | Preparation method of high-quality (R) -3-chloro-1, 2-propanediol |
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2005
- 2005-02-05 CN CNB2005100238523A patent/CN100335645C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101462947B (en) * | 2009-01-05 | 2012-07-25 | 上海柏鼎医药技术有限公司 | Preparation of (R) -4-phenyl-2-hydroxybutyrate |
| CN102242085A (en) * | 2011-04-12 | 2011-11-16 | 华东理工大学 | Epoxy hydrolase, gene thereof and application thereof |
| CN102242085B (en) * | 2011-04-12 | 2013-04-24 | 华东理工大学 | Epoxy hydrolase, gene thereof and application thereof |
| CN102391239A (en) * | 2011-09-14 | 2012-03-28 | 上海科利生物医药有限公司 | Preparation method of (R)-propene carbonate |
| CN102391239B (en) * | 2011-09-14 | 2013-08-21 | 上海科利生物医药有限公司 | Preparation method of (R)-propene carbonate |
| CN104151494A (en) * | 2014-08-27 | 2014-11-19 | 贵州一当科技有限公司 | Epoxy chain extender and preparation method thereof |
| CN111943805A (en) * | 2020-09-16 | 2020-11-17 | 安徽工业大学 | Preparation method of (R) -3-chloro-1, 2-propanediol |
| CN112730683A (en) * | 2020-12-25 | 2021-04-30 | 石家庄四药有限公司 | Method for detecting epichlorohydrin isomer |
| CN113943206A (en) * | 2021-10-25 | 2022-01-18 | 华今(山东)新材料科技有限公司 | Preparation method of high-quality (R) -3-chloro-1, 2-propanediol |
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