CN104342478A - Synthesis of R-1-(2,3-dimethyl phenyl) ethyl alcohol and ester thereof - Google Patents
Synthesis of R-1-(2,3-dimethyl phenyl) ethyl alcohol and ester thereof Download PDFInfo
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- CN104342478A CN104342478A CN201410527142.3A CN201410527142A CN104342478A CN 104342478 A CN104342478 A CN 104342478A CN 201410527142 A CN201410527142 A CN 201410527142A CN 104342478 A CN104342478 A CN 104342478A
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Abstract
The invention relates to a synthesis method of R-1-(2,3-dimethyl phenyl) ethyl alcohol and an ester thereof. The method comprises the following steps: carrying out dynamic kinetic resolution on a chlorophenol ester taken as an acyl donor by taking 1-(2,3-dimethyl phenyl) ethyl alcohol as a raw material, lipase as a biological resolution catalyst and acidic resins as an racemase catalyst so as to obtain a R-1-(2,3-dimethyl phenyl) ethyl alcohol ester; and then hydrolyzing the R-1-(2,3-dimethyl phenyl) ethyl alcohol ester with LiOH so as to obtain the R-1-(2,3-dimethyl phenyl) ethyl alcohol. The method has the advantages of mild condition, environmental friendliness, good yield and high selectivity of the R-1-(2,3-dimethyl phenyl) ethyl alcohol and the like; and the adopted racemase catalyst is low in price and is easily available. Thus, the method provided by the invention has an ultrahigh application value in 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-(2,3-3,5-dimethylphenyl) 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-(2, the 3-3,5-dimethylphenyl) 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 R-1-(2 is prepared in the fractionation of the Dynamic Kinetic of existing report, 3-3,5-dimethylphenyl) reaction of ethanol ester 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-(2,3-3,5-dimethylphenyl) ethanol and prepare R-1-(2,3-3,5-dimethylphenyl) ethanol ester.Gained R-1-(2,3-3,5-dimethylphenyl) ethanol ester can obtain R-1-(2,3-3,5-dimethylphenyl) ethanol by hydrolysis again.In the process splitting preparation R-1-(2,3-3,5-dimethylphenyl) ethanol ester, adopt acidic resins as racemization catalyst, both the problem that product yield is low had been overcome, in turn ensure that the cheap and easy to get of catalyzer, can reuse, 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, 1-(2 is added in the ratio of 1:1-1.5,3-3,5-dimethylphenyl) para-chlorophenol ester after ethanol and purifying, then the ratio of pressing 1-(2,3-3,5-dimethylphenyl) ethanol massfraction 5%-20% adds the acidic resins after lipase CRL and process.System is put in the shaking table of 35-70 DEG C and reacts.After reaction certain hour, 1-(2,3-3,5-dimethylphenyl) ethanol completely dissolve can be detected, be converted into R-1-(2,3-3,5-dimethylphenyl) 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-(2,3-3,5-dimethylphenyl) ethanol ester.3) in step 2, the pure R-1-of gained (2,3-3,5-dimethylphenyl) 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-(2,3-3,5-dimethylphenyl) ethanol ester can be detected, be converted into R-1-(2,3-3,5-dimethylphenyl) ethanol.Final system methylene dichloride repeatedly extracts, after separatory, combined dichloromethane, carry out drying, concentrated after, obtain R-1-(2,3-3,5-dimethylphenyl) ethanol.
The present invention is used to prepare R-1-(2,3-3,5-dimethylphenyl) 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, the positive valeric acid of 72g (1.2mol), 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-(2,3-3,5-dimethylphenyl) ethanol ester
In the triangular flask of 500ml, add 250ml toluene, then add 68g (0.5mol) 1-(2,3-3,5-dimethylphenyl) 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-(2,3-3,5-dimethylphenyl) ethanol is converted into R-1-(2,3-3,5-dimethylphenyl) alcohol, acetic acid ester completely, and detecting its ee value is 99.8%.After end, solution is filtered, concentrated, cross post pure R-1-(2,3-3,5-dimethylphenyl) alcohol, acetic acid ester 90.8g, yield 94.5%.
Other are with para-chlorophenol propionic ester, and para-chlorophenol butanic acid ester, the positive valerate of para-chlorophenol etc. is prepared R-1-(2,3-3,5-dimethylphenyl) ethanol ester for acry radical donor and can example be carried out according to this.
3) R-1-(2,3-3,5-dimethylphenyl) ethanol Ester hydrolysis prepares R-1-(2,3-3,5-dimethylphenyl) 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 96.06gR-1-(2,3-3,5-dimethylphenyl) alcohol, acetic acid ester reflux and react.Point plate detects the completely dissolve of R-1-(2,3-3,5-dimethylphenyl) alcohol, acetic acid ester, then react end.System carries out underpressure distillation removing methyl alcohol, after cooling, adds 200ml methylene dichloride and extracts, after separatory, dichloromethane solution carried out drying, concentrate to obtain R-1-(2,3-3,5-dimethylphenyl) ethanol 70.2g, yield 93.5%, and ee value is 99.6%.
Other are hydrolyzed R-1-(2,3-3,5-dimethylphenyl) ethanol propionic ester, R-1-(2,3-3,5-dimethylphenyl) ethanol butanic acid ester, R-1-(2,3-3,5-dimethylphenyl) preparation such as ethanol positive valerate R-1-(2,3-3,5-dimethylphenyl) ethanol can example carry out according to this.
Claims (3)
1.R-1-(2,3-3,5-dimethylphenyl) synthetic method of 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, after some plate detection reaction terminates, filter, concentrated, crossing post, to obtain pure para-chlorophenol ester stand-by as acry radical donor; 2) in toluene solvant, 1-(2 is added in the ratio of 1:1-1.5,3-3,5-dimethylphenyl) para-chlorophenol ester after ethanol and purifying, then the ratio of pressing 1-(2,3-3,5-dimethylphenyl) ethanol massfraction 5%-20% adds the acidic resins after lipase CRL and process; System is put in the shaking table of 35-70 DEG C and reacts; After reaction certain hour, the synthesis completely dissolve of 1-(2,3-3,5-dimethylphenyl) ethanol and ester thereof can be detected, be converted into R-1-(2,3-3,5-dimethylphenyl) 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-(2,3-3,5-dimethylphenyl) ethanol ester; 3) in step 2, the pure R-1-of gained (2,3-3,5-dimethylphenyl) 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-(2,3-3,5-dimethylphenyl) ethanol ester can be detected, be converted into R-1-(2,3-3,5-dimethylphenyl) ethanol; Final system methylene dichloride repeatedly extracts, after separatory, combined dichloromethane, carry out drying, concentrated after, obtain R-1-(2,3-3,5-dimethylphenyl) ethanol.
2. according to claim 1, optical purity R-1-(2,3-3,5-dimethylphenyl) synthetic method of ethanol and ester thereof, it is characterized in that step 2) described in biological resolution catalyzer have lipase CRL, racemization catalyst is acidic resins CD550 or CD8604.
3. according to claim 1, the synthetic method of optical purity R-1-(2,3-3,5-dimethylphenyl) 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 (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101503729A (en) * | 2008-12-08 | 2009-08-12 | 浙江大学 | Enzymatic resolution method of dl 1-phenylethanol compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101503729A (en) * | 2008-12-08 | 2009-08-12 | 浙江大学 | Enzymatic resolution method of dl 1-phenylethanol compounds |
Non-Patent Citations (1)
| Title |
|---|
| 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（电子期刊）工程科技Ⅰ辑》 * |
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