CN104311392A - Synthesis of R-1-(3, 4-dimethylphenyl) ethanol and ester thereof - Google Patents

Synthesis of R-1-(3, 4-dimethylphenyl) ethanol and ester thereof Download PDF

Info

Publication number
CN104311392A
CN104311392A CN201410534055.0A CN201410534055A CN104311392A CN 104311392 A CN104311392 A CN 104311392A CN 201410534055 A CN201410534055 A CN 201410534055A CN 104311392 A CN104311392 A CN 104311392A
Authority
CN
China
Prior art keywords
dimethylphenyl
ethanol
ester
chlorophenol
para
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201410534055.0A
Other languages
Chinese (zh)
Inventor
王同俊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to CN201410534055.0A priority Critical patent/CN104311392A/en
Publication of CN104311392A publication Critical patent/CN104311392A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a synthesis method of R-1-(3, 4-dimethylphenyl) ethanol and ester thereof. According to the synthesis method, 1-(3, 4-dimethylphenyl) 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, 4-dimethylphenyl) ethanol ester is obtained by dynamic kinetic resolution, and R-1-(3, 4-dimethylphenyl) 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, 4-dimethylphenyl) 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

The synthesis of R-1-(3,4-3,5-dimethylphenyl) ethanol and ester thereof
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-(3,4-3,5-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-(3, the 4-3,5-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-(3 is prepared in the fractionation of the Dynamic Kinetic of existing report, 4-3,5-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-(3,4-3,5-dimethylphenyl) ethanol and prepare R-1-(3,4-3,5-dimethylphenyl) ethanol ester.Gained R-1-(3,4-3,5-dimethylphenyl) ethanol ester can obtain R-1-(3,4-3,5-dimethylphenyl) ethanol by hydrolysis again.In the process splitting preparation R-1-(3,4-3,5-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-(3 is added in the ratio of 1:1-1.5,4-3,5-dimethylphenyl) para-chlorophenol ester after ethanol and purifying, then the ratio of pressing 1-(3,4-3,5-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-(3,4-3,5-dimethylphenyl) ethanol completely dissolve can be detected, be converted into R-1-(3,4-3,5-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-(3,4-3,5-dimethylphenyl) ethanol ester.3) in step 2, the pure R-1-of gained (3,4-3,5-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-(3,4-3,5-dimethylphenyl) ethanol ester can be detected, be converted into R-1-(3,4-3,5-dimethylphenyl) ethanol.Final system methylene dichloride repeatedly extracts, after separatory, combined dichloromethane, carry out drying, concentrated after, obtain R-1-(3,4-3,5-dimethylphenyl) ethanol.
The present invention is used to prepare R-1-(3,4-3,5-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, 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-(3,4-3,5-dimethylphenyl) ethanol ester
In the triangular flask of 500ml, add 250ml toluene, then add 68g (0.5mol) 1-(3,4-3,5-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-(3,4-3,5-dimethylphenyl) ethanol is converted into R-1-(3,4-3,5-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-(3,4-3,5-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-(3,4-3,5-dimethylphenyl) ethanol ester for acry radical donor and can example be carried out according to this.
3) R-1-(3,4-3,5-dimethylphenyl) ethanol Ester hydrolysis prepares R-1-(3,4-3,5-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-(3,4-3,5-dimethylphenyl) alcohol, acetic acid ester reflux and react.Point plate detects the completely dissolve of R-1-(3,4-3,5-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-(3,4-3,5-dimethylphenyl) ethanol 70.2g, yield 93.5%, and ee value is 99.6%.
Other are hydrolyzed R-1-(3,4-3,5-dimethylphenyl) ethanol propionic ester, R-1-(3,4-3,5-dimethylphenyl) ethanol butanic acid ester, R-1-(3,4-3,5-dimethylphenyl) preparation such as ethanol positive valerate R-1-(3,4-3,5-dimethylphenyl) ethanol can example carry out according to this.

Claims (3)

1.R-1-(3,4-3,5-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-(3 is added in the ratio of 1:1-1.5,4-3,5-dimethylphenyl) para-chlorophenol ester after ethanol and purifying, then the ratio of pressing 1-(3,4-3,5-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-(3,4-3,5-dimethylphenyl) ethanol and ester thereof can be detected, be converted into R-1-(3,4-3,5-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-(3,4-3,5-dimethylphenyl) ethanol ester; 3) in step 2, the pure R-1-of gained (3,4-3,5-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-(3,4-3,5-dimethylphenyl) ethanol ester can be detected, be converted into R-1-(3,4-3,5-dimethylphenyl) ethanol; Final system methylene dichloride repeatedly extracts, after separatory, combined dichloromethane, carry out drying, concentrated after, obtain R-1-(3,4-3,5-dimethylphenyl) ethanol.
2. according to claim 1, the synthetic method of optical purity R-1-(3,4-3,5-dimethylphenyl) 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-(3,4-3,5-dimethylphenyl) ethanol and ester thereof, is characterized in that hydrolysis R-1-phenylglycollic ester used in step 3) alkali used is LiOH solution.
CN201410534055.0A 2014-10-12 2014-10-12 Synthesis of R-1-(3, 4-dimethylphenyl) ethanol and ester thereof Pending CN104311392A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410534055.0A CN104311392A (en) 2014-10-12 2014-10-12 Synthesis of R-1-(3, 4-dimethylphenyl) ethanol and ester thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410534055.0A CN104311392A (en) 2014-10-12 2014-10-12 Synthesis of R-1-(3, 4-dimethylphenyl) ethanol and ester thereof

Publications (1)

Publication Number Publication Date
CN104311392A true CN104311392A (en) 2015-01-28

Family

ID=52366742

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410534055.0A Pending CN104311392A (en) 2014-10-12 2014-10-12 Synthesis of R-1-(3, 4-dimethylphenyl) ethanol and ester thereof

Country Status (1)

Country Link
CN (1) CN104311392A (en)

Citations (2)

* Cited by examiner, † Cited by third party
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Title
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》 *
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》 *

Similar Documents

Publication Publication Date Title
CN104262093A (en) R-1-(3-methylphenyl)ethanol and synthesis of ester thereof
CN104263797B (en) The preparation of the tetrahydro naphthylamines of R 1
CN104263796B (en) A kind of preparation method of the tetrahydro naphthylamines of R 1
CN104276956B (en) A kind of preparation method of S-1-tetrahydro naphthylamine
CN102659594A (en) Method for preparing ethyl levulinate by using straw-type biomass
CN103804167A (en) Method for extracting levulinic acid from biomass hydrolysate glucose
CN104262096A (en) Synthetic method of R-1-(4-bromophenyl) ethanol and ester of R-1-(4- bromophenyl) ethanol
CN104311392A (en) Synthesis of R-1-(3, 4-dimethylphenyl) ethanol and ester thereof
US8952201B2 (en) Separation method of acetophenone and A-methylbenzyl alcohol
CN104262091A (en) R-1-(2,5-dimethylphenyl)ethanol and synthesis of ester thereof
CN104311393A (en) Preparation method of R-1-(3-chlorphenyl) ethanol and ester thereof
CN104342478A (en) Synthesis of R-1-(2,3-dimethyl phenyl) ethyl alcohol and ester thereof
CN104262095A (en) R-1-(4-fluorophenyl)ethanol and synthesis of ester thereof
CN104292074A (en) R-1-(2,4-dimethyl phenyl) ethanol and synthetic method of R-1-(2,4-dimethyl phenyl) ethanol ester
CN104262092A (en) R-1-(2-methylphenyl)ethanol and synthesis of ester thereof
CN104388518A (en) Preparation method of R-1-(2-chlorophenyl)ethanol and its ester
CN104262094A (en) Synthetic method of R-1-(4-chlorphenyl) ethanol and ester of R-1-(4-chlorphenyl) ethanol
CN104357531A (en) Preparation method for R-ortho-chloromandelic acid and acyl compound thereof
CN104262115A (en) Synthetic method of R-1-(4-methoxyphenyl) ethanol and ester of R-1-(4-methoxyphenyl) ethanol
CN103265429A (en) Technical method for synthesizing methyl acetate
CN104388517A (en) R-mandelic acid and R-mandelic acid acylate compound
CN104961716A (en) Method for separating high-purity lactone type lovastatin from fermentum rubrum powder
CN104262169B (en) The preparation of R-2-tetrahydro naphthylamine
CN104388480A (en) Synthesis and use of R-1-phenylethyl esters
CN104388516A (en) Preparation of (R)-(+)-3-chloro-1-phenylpropan-1-ol

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20150128

WD01 Invention patent application deemed withdrawn after publication