CN104388516A - Preparation of (R)-(+)-3-chloro-1-phenylpropan-1-ol - Google Patents
Preparation of (R)-(+)-3-chloro-1-phenylpropan-1-ol Download PDFInfo
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- CN104388516A CN104388516A CN201410523821.3A CN201410523821A CN104388516A CN 104388516 A CN104388516 A CN 104388516A CN 201410523821 A CN201410523821 A CN 201410523821A CN 104388516 A CN104388516 A CN 104388516A
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Abstract
A preparation method of (R)-(+)-3-chloro-1-phenylpropan-1-ol comprises: taking 3-chloro-1-phenylpropan-1-ol as a raw material, a lipase CALB as a biological resolution catalyst, acidic resin as a racemic catalyst and a 4-chlorophenol ester as an acyl donor to perform dynamic kinetic resolution to obtain a (R)-(+)-3-chloro-1-phenylpropan-1-ol ester, and then using LiOH to perform hydrolysis to obtain (R)-(+)-3-chloro-1-phenylpropan-1-ol. The preparation method has the advantages of mild conditions, environment friendliness, good product yield, high selectivity, cheap and easily available employed racemic catalyst, and the like, and thus the technology has extremely high application value in industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of optical homochiral alcohol, especially the Dynamic Kinetic Resolution preparation method of the chloro-1-phenylpropyl alcohol of (R)-(+)-3-.
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.(R)-(+) main raw material of-3-chloro-1-phenylpropyl alcohol not only a kind of efficient phytoalexin, or for the synthesis of attention deficit with many dynamic treating dysfunction medicine tomoxetine hydrochloride (tomoxetine hydrochloride).
The chloro-1-phenylpropyl alcohol of (R)-(+)-3-of current report is prepared synthetic method and mainly can be divided into chemical method and biological process.Chemical method is mainly by by CBS(chiral 1,2,3-oxzaborolidines) asymmetric reduction (J Org Chem. 1991,56 (2): 751-762; J Am Chem Soc, 1987,109 (25): 7925-7926) or rare-earth metal catalyst ruthenium, rhodium, iridium catalytic asymmetric reduction (Agrochemicals, 2012,51 (2); 97-99) obtain the chloro-1-phenylpropyl alcohol of (R)-(+)-3-.Although this method obtains good yield and product ee value, all there is the higher problem of catalyzer price.Biological process can be subdivided into method of asymmetrically reducing and Kinetic Resolution again, biological asymmetric reduction mainly utilizes free yeast (J Org Chem, 1991,56 (21): 6019-6023) or as Anionio etc. enzyme catalytic asymmetric reduction (Tetrahedron:Asymmetry is utilized, 2002,13 (15): 1681-1686) the chloro-1-phenylpropyl alcohol of (R)-(+)-3-is obtained.Asymmetric fractionation utilizes immobilized lipase CRL(Chinese Journal of Pharmaceuticals, 2007,38 (11): 758-759) etc.The chloro-1-phenylpropyl alcohol of this several Biological preparation (R)-(+)-3-, catalytic asymmetric reduction products obtained therefrom ee value is several reaches 100%, but substrate trial is low, cost is high, yield is low.Immobilized lipase CRL fractionation ee value also machine can reach 100%, but there is the not high problem of product yield equally.
Summary of the invention
The present invention, on the basis being lipase kinetic resolution, introduces acidic resins as racemization catalyst, carries out the chloro-1-phenylpropyl alcohol of Dynamic Kinetic Resolution 3-chloro-1-phenylpropyl alcohol preparation (R)-(+)-3-.In the process splitting the chloro-1-phenylpropyl alcohol of preparation (R)-(+)-3-, 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, 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, add the para-chlorophenol ester after the chloro-1-phenylpropyl alcohol of 3-and purifying in the ratio of 1:1-1.5, then add the acidic resins after lipase CALB and process in the ratio of 3-chloro-1-phenylpropyl alcohol massfraction 5%-20%.System is put in the shaking table of 35-70 DEG C and reacts.After reaction certain hour, the completely dissolve of 3-chloro-1-phenylpropyl alcohol can be detected, be converted into R (R)-(+)-3-chloro-1-phenylpropyl alcohol alcohol 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)-(+)-3-chloro-1-phenylpropyl alcohol alcohol ester.3) in step 2, pure (R)-(+) of gained-3-chloro-1-phenylpropyl alcohol alcohol 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)-(+)-3-chloro-1-phenylpropyl alcohol alcohol ester can be detected, be converted into the chloro-1-phenylpropyl alcohol of (R)-(+)-3-.Final system methylene dichloride repeatedly extracts, after separatory, combined dichloromethane, carry out drying, concentrated after, the chloro-1-phenylpropyl alcohol of (R)-(+)-3-.
Use the present invention's preparation (R)-(+)-3-chloro-1-phenylpropyl alcohol 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 156.9g, yield 92.3%.
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 preparation (R)-(+)-3-chloro-1-phenylpropyl alcohol alcohol ester
In the triangular flask of 500ml, add 250ml toluene, then add the chloro-1-phenylpropyl alcohol of 85g (0.5mol) 3-successively, 93.5g (1.1mol) para-chlorophenol acetic ester, 3g CALB, 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 (R)-(+)-3-chloro-1-phenylpropyl alcohol is converted into (R)-(+)-3-chloro-1-phenylpropyl alcohol acetic ester completely, and detecting its ee value is 99.8%.After end, solution is filtered, concentrated, cross post pure (R)-(+)-3-chloro-1-phenylpropyl alcohol acetic ester 101.0g, yield 95.3%.
Other are with para-chlorophenol propionic ester, para-chlorophenol butanic acid ester, and the positive valerate of para-chlorophenol etc. are prepared (R)-(+)-3-chloro-1-phenylpropyl alcohol alcohol ester for acry radical donor and can example be carried out according to this.
3) the chloro-1-phenylpropyl alcohol of (R)-(+)-3-chloro-1-phenylpropyl alcohol Ester hydrolysis preparation (R)-(+)-3-
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 106g (R)-(+)-3-chloro-1-phenylpropyl alcohol acetic ester reflux and react.Point plate detects the completely dissolve of (R)-(+)-3-chloro-1-phenylpropyl alcohol alcohol 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)-(+)-3-chloro-1-phenylpropyl alcohol 97.6g, yield 92.1%, and ee value is 99.5%.
Other hydrolysis (R)-(+)-3-chloro-1-phenylpropyl alcohol propionic ester, (R)-(+)-3-chloro-1-phenylpropyl alcohol butanic acid ester, the chloro-1-phenylpropyl alcohol of preparation (R)-(+)-3-such as the positive valerate of the chloro-1-phenylpropyl alcohol of (R)-(+)-3-can example carry out according to this.
Claims (4)
1. the preparation method of the chloro-1-phenylpropyl alcohol of (R)-(+)-3-, 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 the chloro-1-phenylpropyl alcohol of 3-and purifying in the ratio of 1:1-1.5, then add the acidic resins after lipase CALB and process in the ratio of 3-chloro-1-phenylpropyl alcohol massfraction 5%-20%; System is put in the shaking table of 35-70 DEG C and reacts; After reaction certain hour, the completely dissolve of 3-chloro-1-phenylpropyl alcohol can be detected, be converted into (R)-(+)-3-chloro-1-phenylpropyl alcohol alcohol 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)-(+)-3-chloro-1-phenylpropyl alcohol alcohol ester; 3) in step 2, pure (R)-(+) of gained-3-chloro-1-phenylpropyl alcohol alcohol 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)-(+)-3-chloro-1-phenylpropyl alcohol alcohol ester can be detected, be converted into the chloro-1-phenylpropyl alcohol of (R)-(+)-3-; Final system methylene dichloride repeatedly extracts, after separatory, combined dichloromethane, carry out drying, concentrated after, the chloro-1-phenylpropyl alcohol of (R)-(+)-3-.
2. according to claim 1, the preparation method of the chloro-1-phenylpropyl alcohol of optical purity (R)-(+)-3-, it is characterized in that the acid described in step 1) can be acetic acid, propionic acid, butanic acid, positive valeric acid etc., corresponding para-chlorophenol ester is para-chlorophenol acetic ester, para-chlorophenol propionic ester, para-chlorophenol butanic acid ester, the positive valerate of para-chlorophenol etc.
3. according to claim 1, the preparation method of the chloro-1-phenylpropyl alcohol of optical purity (R)-(+)-3-, it is characterized in that step 2) described in biological resolution catalyzer have lipase CALB, racemization catalyst is acidic resins CD550 or CD8604.
4. according to claim 1, the preparation method of the chloro-1-phenylpropyl alcohol of optical purity (R)-(+)-3-, is characterized in that hydrolysis R-1-phenylglycollic ester used in step 3) alkali used is LiOH solution.
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Citations (4)
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| CN101205548A (en) * | 2007-12-14 | 2008-06-25 | 浙江工业大学 | Use of saccharomyces cerevisiae in preparation of (S)-(-)-3-chlorine-1-phenylpropanol |
| CN101503729A (en) * | 2008-12-08 | 2009-08-12 | 浙江大学 | Enzymatic resolution method of dl 1-phenylethanol compounds |
| US20090280558A1 (en) * | 2006-04-21 | 2009-11-12 | Jason Micklefield | Process For Dynamic Kinetic Resolution (DKR) Of Racemic Compounds In (Hydro) Fluorocarbon Solvents |
| CN101693906A (en) * | 2009-10-20 | 2010-04-14 | 中国药科大学 | Method for producing optical active alcohol by transformation of resting cells in cloud point system |
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2014
- 2014-10-08 CN CN201410523821.3A patent/CN104388516A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090280558A1 (en) * | 2006-04-21 | 2009-11-12 | Jason Micklefield | Process For Dynamic Kinetic Resolution (DKR) Of Racemic Compounds In (Hydro) Fluorocarbon Solvents |
| CN101205548A (en) * | 2007-12-14 | 2008-06-25 | 浙江工业大学 | Use of saccharomyces cerevisiae in preparation of (S)-(-)-3-chlorine-1-phenylpropanol |
| CN101503729A (en) * | 2008-12-08 | 2009-08-12 | 浙江大学 | Enzymatic resolution method of dl 1-phenylethanol compounds |
| CN101693906A (en) * | 2009-10-20 | 2010-04-14 | 中国药科大学 | Method for producing optical active alcohol by transformation of resting cells in cloud point system |
Non-Patent Citations (4)
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| 丁奎岭 等: "《不对称催化新概念与新方法》", 28 February 2009, 化学工业出版社 * |
| 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》 * |
| 陈骿声主编: "《酶制剂生产技术》", 31 January 1994, 化学工业出版社 * |
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