CN104311393A - Preparation method of R-1-(3-chlorphenyl) ethanol and ester thereof - Google Patents
Preparation method of R-1-(3-chlorphenyl) ethanol and ester thereof Download PDFInfo
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- CN104311393A CN104311393A CN201410534057.XA CN201410534057A CN104311393A CN 104311393 A CN104311393 A CN 104311393A CN 201410534057 A CN201410534057 A CN 201410534057A CN 104311393 A CN104311393 A CN 104311393A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/095—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of organic acids
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/62—Carboxylic acid esters
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The invention relates to a synthesis method of R-1-(3-chlorphenyl) ethanol and ester thereof. According to the synthesis method, 1-(3-chlorphenyl) ethanol is used as a raw material, lipase is used as a biological resolution catalyst, acidic resin is used as a recemization catalyst and p-chlorophenol is used as an acyl donor, R-1-(3-chlorphenyl) ethanol ester is obtained by dynamic kinetic resolution, and R-1-(3-chlorphenyl) ethanol is obtained through hydrolysis by LiOH. The synthesis method has the advantages that the synthesis method is mild in reaction and environment-friendly, and R-1-(3-chlorphenyl) ethanol is good in yield and high in selectivity, the used recemization catalyst is low in price and easily available, and the like, so that the synthesis method has an extremely high application value in the industrial production.
Description
Technical field
The present invention relates to the preparation method of a kind of optical homochiral alcohol and ester, especially the Dynamic Kinetic Resolution preparation method of R-1-(3-chloro-phenyl-) ethanol and ester thereof.
Background technology
Chiral drug is significant in the control of numerous disease, after medicine circle " reaction stops event ", the study on the synthesis of chiral drug in human body medicine, agricultural chemicals, veterinary drug more and more by national governments, enterprise pay attention to.Chiral alcohol and chiral ester are the chipal compounds that wherein a class is important, can be applied to the synthesis of medicine and fine chemicals as important chiral intermediate and raw material.
R-1-(3-chloro-phenyl-) ethanol of current report and ester thereof are mainly obtained by biological resolution raceme alcohol, and biological resolution method can be divided into kinetic resolution and Dynamic Kinetic Resolution again.The theoretical yield that general dynamics splits only has 50%, and the method for Dynamic Kinetic Resolution can obtain optically pure chiral alcohol compound with the productive rate of 100% in theory, but the reaction that R-1-(3-chloro-phenyl-) ethanol ester is prepared in the fractionation of the Dynamic Kinetic of existing report generally will use rhodium, and the noble metal catalysts such as ruthenium are as the racemization catalyst in Dynamic Kinetic Resolution process.Greatly improve the cost of reaction, the production of industry words is realized to technique there is great restriction.
Summary of the invention
The present invention, on the basis being lipase kinetic resolution, introduces acidic resins as racemization catalyst, carries out Dynamic Kinetic Resolution 1-(3-chloro-phenyl-) ethanol and prepare R-1-(3-chloro-phenyl-) ethanol ester.Gained R-1-(3-chloro-phenyl-) ethanol ester can obtain R-1-(3-chloro-phenyl-) ethanol by hydrolysis again.In the process splitting preparation R-1-(3-chloro-phenyl-) ethanol ester, adopt acidic resins as racemization catalyst, both overcome the problem that product yield is low, and in turn ensure that the cheap and easy to get of catalyzer, and can reuse, and be easy to realize suitability for industrialized production.
Concrete operation step is as follows:
1) ratio in 1:1-1.2:1-1.2:0.01-0.05 in methylene dichloride adds organic acid successively, para-chlorophenol, DCC, DMAP, and stirring at normal temperature is reacted, and after some plate detection reaction terminates, filters, concentrated, crossing post, to obtain pure para-chlorophenol ester stand-by as acry radical donor.2) in toluene solvant, add the para-chlorophenol ester after 1-(3-chloro-phenyl-) ethanol and purifying in the ratio of 1:1-1.5, then add the acidic resins after lipase CRL and process in the ratio of 1-(3-chloro-phenyl-) ethanol massfraction 5%-20%.System is put in the shaking table of 35-70 DEG C and reacts.After reaction certain hour, 1-(3-chloro-phenyl-) ethanol completely dissolve can be detected, be converted into R-1-(3-chloro-phenyl-) ethanol ester completely, and the optical purity of product is greater than 99%.Reacted product carries out filtering, concentrate, cross column chromatography can obtain pure R-1-(3-chloro-phenyl-) ethanol ester.3) in step 2, the pure R-1-of gained (3-chloro-phenyl-) ethanol ester joins the alcohol of 10 times of volumes and LiOH(concentration is 1mol/L) be hydrolyzed in mixing solutions, the volume ratio of alcohol and LiOH is 1:1.After reflux certain hour, the completely dissolve of R-1-(3-chloro-phenyl-) ethanol ester can be detected, be converted into R-1-(3-chloro-phenyl-) ethanol.Final system methylene dichloride repeatedly extracts, after separatory, combined dichloromethane, carry out drying, concentrated after, obtain R-1-(3-chloro-phenyl-) ethanol.
Use the present invention prepare R-1-(3-chloro-phenyl-) ethanol and ester thereof not only mild condition, environmental friendliness, product yield is good, selectivity is higher, and racemization catalyst used is cheap and easy to get, this makes this technique have high using value in the industrial production.
Specific implementation method
1) preparation of acry radical donor para-chlorophenol ester
The methylene dichloride of 500ml is added in the round-bottomed flask of 1000ml.Add 128g (1mol) para-chlorophenol more successively, 72g (1.2mol) acetic acid, 247.5g (1.2mol) DCC, 2.44g(0.02mol) DMAP.Stirred at ambient temperature 10 hours, some plate detects para-chlorophenol and disappears, then react end.Solution carries out filtering, concentrating, and then crosses post and can obtain pure para-chlorophenol acetic ester 162.5g, yield 95.6%.
Other para-chlorophenol propionic esters, para-chlorophenol butanic acid ester, the positive valerate of para-chlorophenol etc. also can example preparation according to this.
2) Dynamic Kinetic Resolution prepares R-1-(3-chloro-phenyl-) ethanol ester
In the triangular flask of 500ml, add 250ml toluene, then add 78g (0.5mol) 1-(3-chloro-phenyl-) ethanol successively, 93.5g (1.1mol) para-chlorophenol acetic ester, 3g CRL, 6g acidic resins CD550.Add complete, Erlenmeyer flask sealing is put into 45 degree of constant-temperature tables and is reacted.After 12 hours, reaction terminates, and 1-(3-chloro-phenyl-) ethanol is converted into R-1-(3-chloro-phenyl-) alcohol, acetic acid ester completely, and detecting its ee value is 99.8%.After end, solution is filtered, concentrated, cross post pure R-1-(3-chloro-phenyl-) alcohol, acetic acid ester 92.3g, yield 93.2%.
Other are with para-chlorophenol propionic ester, and para-chlorophenol butanic acid ester, the positive valerate of para-chlorophenol etc. is prepared R-1-(3-chloro-phenyl-) ethanol ester for acry radical donor and can example be carried out according to this.
3) R-1-(3-chloro-phenyl-) ethanol Ester hydrolysis prepares R-1-(3-chloro-phenyl-) ethanol
1000ml methyl alcohol is first added and LiOH(concentration is 1mol/L in 2000ml round-bottomed flask) mixing solutions of 1:1 preparation by volume, then add 99gR-1-(3-chloro-phenyl-) alcohol, acetic acid ester reflux and react.Point plate detects the completely dissolve of R-1-(3-chloro-phenyl-) alcohol, acetic acid ester, then react end.System carries out underpressure distillation removing methyl alcohol, after cooling, adds 200ml methylene dichloride and extracts, and after separatory, dichloromethane solution carried out drying, concentrate to obtain R-1-(3-chloro-phenyl-) ethanol 71.3g, yield 91.4%, and ee value is 99.2%.
Other are hydrolyzed R-1-(3-chloro-phenyl-) ethanol propionic ester, R-1-(3-chloro-phenyl-) ethanol butanic acid ester, the preparation such as R-1-(3-chloro-phenyl-) ethanol positive valerate R-1-(3-chloro-phenyl-) ethanol can example carry out according to this.
Claims (3)
- The synthetic method of 1.R-1-(3-chloro-phenyl-) ethanol and ester thereof, it is characterized in that its step is as follows: the ratio 1) in 1:1-1.2:1-1.2:0.01-0.05 in methylene dichloride adds organic acid successively, para-chlorophenol, DCC, DMAP, stirring at normal temperature is reacted, and after some plate detection reaction terminates, filters, concentrated, crossing post, to obtain pure para-chlorophenol ester stand-by as acry radical donor; 2) in toluene solvant, add the para-chlorophenol ester after 1-(3-chloro-phenyl-) ethanol and purifying in the ratio of 1:1-1.5, then add the acidic resins after lipase CRL and process in the ratio of 1-(3-chloro-phenyl-) ethanol massfraction 5%-20%; System is put in the shaking table of 35-70 DEG C and reacts; After reaction certain hour, the synthesis completely dissolve of 1-(3-chloro-phenyl-) ethanol and ester thereof can be detected, be converted into R-1-(3-chloro-phenyl-) ethanol ester completely, and the optical purity of product is greater than 99%; Reacted product carries out filtering, concentrate, cross column chromatography can obtain pure R-1-(3-chloro-phenyl-) ethanol ester; 3) in step 2, the pure R-1-of gained (3-chloro-phenyl-) ethanol ester joins the alcohol of 10 times of volumes and LiOH(concentration is 1mol/L) be hydrolyzed in mixing solutions, the volume ratio of alcohol and LiOH is 1:1; After reflux certain hour, the completely dissolve of R-1-(3-chloro-phenyl-) ethanol ester can be detected, be converted into R-1-(3-chloro-phenyl-) ethanol; Final system methylene dichloride repeatedly extracts, after separatory, combined dichloromethane, carry out drying, concentrated after, obtain R-1-(3-chloro-phenyl-) ethanol.
- 2. according to claim 1, the synthetic method of optical purity R-1-(3-chloro-phenyl-) ethanol and ester thereof, is characterized in that step 2) described in biological resolution catalyzer have lipase CRL, racemization catalyst is acidic resins CD550.
- 3. according to claim 1, the synthetic method of optical purity R-1-(3-chloro-phenyl-) ethanol and ester thereof, is characterized in that hydrolysis R-1-phenylglycollic ester used in step 3) alkali used is LiOH solution.
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Citations (2)
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US7026144B2 (en) * | 2000-07-07 | 2006-04-11 | Csir | Process for preparing (-) menthol and similar compounds |
CN101503729A (en) * | 2008-12-08 | 2009-08-12 | 浙江大学 | Enzymatic resolution method of dl 1-phenylethanol compounds |
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- 2014-10-12 CN CN201410534057.XA patent/CN104311393A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7026144B2 (en) * | 2000-07-07 | 2006-04-11 | Csir | Process for preparing (-) menthol and similar compounds |
CN101503729A (en) * | 2008-12-08 | 2009-08-12 | 浙江大学 | Enzymatic resolution method of dl 1-phenylethanol compounds |
Non-Patent Citations (2)
Title |
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戴晓庭 等: "酰基供体结构对褶皱念珠菌脂肪酶(CRL)催化芳香仲醇动力学拆分立体选择性的影响", 《生物加工过程》, vol. 11, no. 1, 31 January 2013 (2013-01-31), pages 12 - 16 * |
陈永军: "化学酶法催化仲醇的动态动力学拆分", 《中国优秀硕士学位论文全文数据库-工程科技I辑》, no. 5, 15 May 2012 (2012-05-15), pages 014 - 102 * |
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