CN101130805A - Method for enzymatically splitting and preparing chiral 1-aryl-3-chlorine-1, 2-propylene glycol - Google Patents
Method for enzymatically splitting and preparing chiral 1-aryl-3-chlorine-1, 2-propylene glycol Download PDFInfo
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- CN101130805A CN101130805A CNA2007100702381A CN200710070238A CN101130805A CN 101130805 A CN101130805 A CN 101130805A CN A2007100702381 A CNA2007100702381 A CN A2007100702381A CN 200710070238 A CN200710070238 A CN 200710070238A CN 101130805 A CN101130805 A CN 101130805A
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Abstract
The present invention discloses a method capable of utilizing enzymatic resolution process to prepare chiral 1-aryl-3-chloro-1,2-propylene glycol. Said method includes the following steps: (1), dissolving racemic 1-aryl-3-chloro-1,2-propylene glycol in an organic reaction solvent, then adding ester, the molen ratio of added 1-aryl-3-chloro-1,2-propylene glycol and ester is 1:0.5-1:20, fully mixing them; (2), in the above-mentioned reaction system adding enzyme to catalyze esterification reaction of 1-aryl-3-chloro-1,2-propylene glycol, its reaction temperature is 10deg.C-60deg.C, the dose ratio of 1-aryl-3-chloro-1,2-propylene glycol and enzyme is 0.1-1000 mol of 1-aryl-3-chloro-1,2-propylene glycol and 1g of enzyme; and (3), filtering reaction liquor and recovering enzyme so as to obtain (S)-1-aryl-3-chloro-1,2-propylene glycol acetate and (R)-1-aryl-3-chloro-1,2-propylene glycol with higher optical activity.
Description
Technical field
The present invention relates to a kind of enzymatically splitting and preparing chiral 1-aryl-3-chloro-1, the method for 2-propylene glycol.
Background technology
1-aryl-3-chloro-1,2-propylene glycol are the important chiral intermediates of a class, and cl radical is easy to be converted into nitrile, and nitrile compound further is converted into chiral materials such as gamma-amino alcohol, beta-hydroxy acid, beta-hydroxy acid ketone, beta-amino acids.Chiral hydroxyl group can be preparation chirality 1 as chiral source, the 3-glycol, and 1, the 3-amino alcohol provides effective synthetic method.Aromatic ring be can also slough and chirality 3-chloro-1,2-propylene glycol obtained.Chirality 3-chloro-1,2-propylene glycol are important chiral source, thereby have broad application prospects in fields such as medicine, agricultural chemicals, fine chemistry industries.
Chirality 1-aryl-3-chloro-1,2-propylene glycol are also to can be used for synthetic HMG-CoA reductase inhibitor (Statins hypolipemic preparation).In recent years HMG-CoA reductase inhibitor (statins) be studies show that this class drug selectivity suppresses rate-limiting enzyme---the HMG-CoA reductase enzyme that cholesterol generates in the liver, make liver that blood plasma cholesterol level is descended.Therefore synthetic 1-aryl-3-chloro-1,2-propylene glycol are the research topics of an awfully hot door.
At present, prepare chirality 1-aryl-3-chloro-1 about the lipase transesterificationization, the report of 2-propylene glycol also seldom, document [Kamal, A.; Khanna, G.B.R.Tetrahedron:Asymmetry 12 (2001) 405-410] a kind of 1-aryl-3-chloro-1 for preparing similar structures of description, the lipase Split Method of 2-propylene glycol.Document [(a) Partali, V. are arranged; Waagen, V.; Alivik, T.; Anthonsen T.Tetrahedron:Asymmetry 1993,4,961-968; (b) Hansen, T.V.; Waagen, V.; Partali, V.; Anthonsen, H.W.Anthonsen, T.Tetrahedron:Asymmetry 1993,6,499-504.] and reported that enzyme process prepares chirality 1-aryl-3-chloro-1, the 2-propylene glycol, but all be the catalytic hydrolysis effect that utilizes lipase.
Summary of the invention
The purpose of this invention is to provide a kind of enzymatically splitting and preparing chiral 1-aryl-3-chloro-1, the method for 2-propylene glycol.
The step of method is as follows:
1) with racemization 1-aryl-3-chloro-1, the 2-propylene glycol is dissolved in the organic solvent, adds ester then, thorough mixing, and 1-aryl-3-chloro-1, the mol ratio of 2-propylene glycol and ester is 1: 0.5-1: 20;
2) add enzyme, with 1-aryl-3-chloro-1, the 2-propylene glycol carries out the catalysis transesterification, and temperature of reaction is 10 ℃-60 ℃, and the reaction times is 0.5-300 hour, every gram enzyme catalysis 1-aryl-3-chloro-1, and the amount of 2-propylene glycol is 0.1-1000mol;
3) with reacting liquid filtering, reclaim enzyme, make chirality 1-aryl-3-chloro-1, the 2-propylene glycol.
2. a kind of enzymatically splitting and preparing chiral 1-aryl according to claim 1-3-chloro-1, the method for 2-propylene glycol is characterized in that, described chirality 1-aryl-3-chloro-1, the molecular structural formula of 2-propylene glycol is:
Wherein: R
1Be the substituting group on the phenyl ring, substituting group is alkyl, halogen or alkoxyl group; The position of substitution is in the 2-6 position; The substituting group number is 1-5; R
2Be alkyl.
Described ester is vinyl-acetic ester, methylvinyl acetate or ethyl acetate.Organic solvent is normal hexane, hexanaphthene, normal heptane, octane-iso, toluene, benzene, methyl tertiary butyl ether, isopropyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform or acetonitrile.The water that contains 0.01%～1% weight in the organic solvent.Temperature of reaction is preferably 10 ℃-50 ℃.
The present invention is by with 1-aryl-3-chloro-1,2-propylene glycol and ester are dissolved in the organic solvent, add enzyme then, under the katalysis of enzyme, 1-aryl-3-chloro-1, asymmetric transesterification takes place in 2-propylene glycol and ester, obtains to have higher optically active 1-aryl-3-chloro-1, the 2-propylene glycol, good reaction selectivity, transformation efficiency height, the product 1-aryl-3-chloro-1 of acquisition, 2-propylene glycol optical purity height, the reaction broad application temperature range can be carried out the reaction conditions gentleness at normal temperatures, easy to operate, equipment is simple.By high purity 1-aryl-3-chloro-1 that the enzyme catalysis transesterification obtains, the 2-propylene glycol can directly apply to the subsequent reactions step.This technology is to realize in organic solvent, and enzyme activity is stable, does not run off, and can recycle repeatedly, thereby have bigger prospects for commercial application.
Embodiment
Used ester among the present invention is a vinyl-acetic ester, methylvinyl acetate, and ethyl acetate, the ester of other structures of methyl acetate also can be used as reaction substrate, enumerates no longer one by one at this.Described organic solvent can be common solvent such as ether, aromatic hydrocarbons, substituted arene, alkane, haloalkane or nitrile, comprise the mixed solvent that the mutual mixing of above-mentioned solvent obtains, reflect as normal hexane, hexanaphthene, normal heptane, octane-iso, toluene, benzene, methyl tertiary butyl ether, isopropyl ether, ether, tetrahydrochysene mutter, dioxane, methylene dichloride, chloroform or acetonitrile etc.
In the described substrate 1: R
1Being the substituting group on the phenyl ring, can be alkyl, halogenic substituent, alkoxyl group; The position of substitution can be in the 2-6 position; The substituting group number can be 1-5; R
2Can be alkyl, halogenic substituent, alkoxyl group.R
1, R
2Be other substituent 1-aryl-3-chloro-1, the 2-propylene glycol also can be used as reaction substrate.
Described enzyme can be by after the microorganism culturing, through the thick enzyme of initial gross separation purifying acquisition; Also can be commercial enzyme, such as from Sigma, Fluka, Meitosangy.And company such as Biochemical pure enzyme or the immobilized enzyme that obtain with highly selective catalytic capability.The water that can contain 0%-2% weight in the above-mentioned organic solvent, the organic solvent that contains the greater concn water yield also can react, but may influence the optical purity and the transformation efficiency of product, recommends to contain in the organic solvent water of 0-1% weight.Minor amount of water in the organic solvent of the present invention can be just to contain originally in the organic solvent, also can manually add in anhydrous organic solvent.Usually also contain a spot of water in the middle of the enzyme.
Adopt the present invention to produce optically active 1-aryl-3-chloro-1, during the 2-propylene glycol, it is the height enantio-selectivity that utilizes enzyme, catalysis 1-aryl-3-chloro-1 in little water organic solvent, asymmetric transesterification takes place in 2-propylene glycol and ester, and with the 1-aryl-3-chloro-1 of racemization, the asymmetric transesterification of 2-propylene glycol turns to (S)-1-aryl-3-chloro-1 accordingly, 2-propylene glycol and (R)-1-aryl-3-chloro-1, the ester of 2-propylene glycol.Its chemical equation is as follows:
Racemization 1-aryl-3-chloro-1,2-propylene glycol (I) (S)-1-aryl-3-chloro-1, in the 2-glycol (II) (R)-ester (III)
The reaction implementation process is as follows: R
1Being the substituting group on the phenyl ring, can be alkyl, halogenic substituent, alkoxyl group; The position of substitution can be in the 2-6 position; The substituting group number can be 1-5; R
2Can be alkyl, halogenic substituent, alkoxyl group.
The reaction before with all reagent, comprise 1-aryl-3-chloro-1,2-propylene glycol, Fatty Alcohol(C12-C14 and C12-C18) and organic solvent carry out pre-treatment, to remove the moisture that wherein exists, in anhydrous solvent, add a certain amount of water according to concrete reaction conditions then, reach predetermined water-content.In order to prevent the volatilization of solvent and reactant, be reflected in the reactor of sealing and carry out.During reaction with racemization 1-aryl-3-chloro-1,2-propylene glycol, ester and organic solvent and enzyme successively join in the reactor, as previously mentioned, used ester is for being vinyl-acetic ester, methylvinyl acetate, the ester of other structures of ethyl acetate also can be used as reaction substrate, and the fatty ester of other structures also can be used as reaction substrate, enumerates no longer one by one at this.Used organic solvent can be common solvent such as ether, aromatic hydrocarbons, substituted arene, alkane, haloalkane or nitrile, the mixed solvent that comprises the mutual mixing acquisition of above-mentioned solvent, as long as used organic solvent is an inert for reaction, as normal hexane, hexanaphthene, normal heptane, octane-iso, toluene, benzene, methyl tertiary butyl ether, isopropyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform or acetonitrile etc.
Temperature of reaction is to the almost not influence of selectivity of enzymic catalytic reaction, higher temperature of reaction can improve speed of reaction, therefore, under higher temperature, react, can finish reaction in the short period of time, but higher temperature can influence the stability of product, cause the aggravation of product degree of decomposition, both reduce the yield of product, and also can reduce the enantiomeric purity of product.The transformation efficiency and the enantiomeric purity of product are measured with chiral high performance liquid chromatography.
Enzyme is: commercial enzyme is such as deriving from Candida rugoso, Candida cylindracea, pseudomonascepacia, Pseudomonas SP. (sigma company), Rhizopus delemar, Chromobacteriumviscosum, Rhizopus niveus, Arthrobacter sp.Aspergillus niger, Aspergillusoryzae, Candida Antarctica, Candida lipolytica, Candida utilis, Mucor javanicus, Rhizopus miehei (Fluka company), Alcaligenes sp., Pseduomonas stutzeri (meito sangyo company) and Phizopus arrhizus (Roche Mol.Biochemical company) etc. has the pure enzyme or the immobilized enzyme of highly selective catalytic capability.
Embodiment 1: enzymatically splitting and preparing chiral 1-phenmethyl-3-chloro-1,2-propylene glycol
Under 10 ℃ with 0.01mol (2.0g) racemization 1-aryl-3-chloro-1, the 2-propylene glycol, 0.01mol vinyl-acetic ester (0.84g) and 250ml analytical pure normal hexane join in the 500ml reaction flask, add 500mgCandida Antarctica enzyme then, stirring reaction 0.5 hour.After reaction finishes, reacting liquid filtering is reclaimed Candida Antarctica enzyme reusing, (the R)-1-phenmethyl-3-chloro-1 in the solution, 2-propylene glycol and (S)-1-phenmethyl-3-chloro-1, after the acetic ester of 2-propylene glycol is crossed post, the content efficient liquid phase chromatographic analysis.(R)-and 1-phenmethyl-3-chloro-1,2-propylene glycol productive rate is 46.0%, the e.e. value is 98%.(S)-and 1-phenmethyl-3-chloro-1, the acetic ester productive rate of 2-propylene glycol is 45.0%, the e.e. value is 97%.The Candida Antarctica enzyme that reclaims joined in the fresh reaction solution reuse, catalytic capability does not descend.(R)-and 1-phenmethyl-3-chloro-1, the hydrogen spectrum of 2-propylene glycol is:
1H NMR (400Hz, CDCl
3): δ 7.30～7.38 (m, 5H), 4.56 (s, 2H), 3.97～4.02 (m, 1H), 3.58～3.67 (m, 2H), 3.59 (d, J=4.0Hz, 2H), 2.59 (br s, 1H).(S)-and 1-phenmethyl-3-chloro-1, the hydrogen spectrum of the acetic ester of 2-propylene glycol is:
1H NMR (400Hz, CDCl
3): δ 7.29～7.37 (m, 5H), 5.15～5.17 (m, 1H), 4.56 (d, J=4.8Hz, 2H), 3.67～3.78 (m, 2H), 3.64～3.66 (m, 2H), 2.10 (s, 3H).
Embodiment 2: enzyme process splits preparation (R)-1-phenmethyl-3-chloro-1,2-propylene glycol
Under 60 ℃, with 0.02mol (4.0g) racemization 1-aryl-3-chloro-1, the 2-propylene glycol, 0.4mol methylvinyl acetate (4.0g) and 500ml analytical pure normal heptane join in the 1000ml reaction flask, add 5mgCandida Antarctica enzyme then, stirring reaction 300 hours.After reaction finishes, reacting liquid filtering is reclaimed Candida Antarctica enzyme reusing, (the R)-1-phenmethyl-3-chloro-1 in the solution, 2-propylene glycol and (S)-1-phenmethyl-3-chloro-1, after the acetic ester of 2-propylene glycol is crossed post, the content efficient liquid phase chromatographic analysis.(R)-and 1-phenmethyl-3-chloro-1,2-propylene glycol productive rate is 40.0%, the e.e. value is 95%.The Candida Antarctica enzyme that reclaims joined in the fresh reaction solution reuse, catalytic capability does not obviously descend.
Embodiment 3: enzyme process splits preparation (R)-1-phenmethyl-3-chloro-1,2-propylene glycol
Under 30 ℃ with 0.01mol (2.0g) racemization 1-aryl-3-chloro-1, the 2-propylene glycol, 0.1mol moisture 0～1% acetonitrile of ethyl acetate (8.8g) and 250ml joins in the 500ml reaction flask, adds 300mgArthrobacter sp. enzyme then, stirring reaction 200 hours.After reaction finishes, reacting liquid filtering is reclaimed Arthrobacter sp. enzyme reusing, (the R)-1-phenmethyl-3-chloro-1 in the solution, 2-propylene glycol and (S)-1-phenmethyl-3-chloro-1, after the acetic ester of glycol is crossed post in the 2-, the content efficient liquid phase chromatographic analysis.(R)-and 1-phenmethyl-3-chloro-1,2-propylene glycol productive rate is 35.0%, the e.e. value is 90%.The Arthrobacter sp. enzyme that reclaims joined in the fresh reaction solution reuse, catalytic capability does not obviously descend.
Embodiment 4: enzyme process splits preparation (R)-1-phenmethyl-3-chloro-1,2-propylene glycol
Under 40 ℃ with 0.01mol (2.0g) racemization 1-phenmethyl-3-chloro-1, the 2-propylene glycol, 0.05mol moisture 0～1% acetonitrile of vinyl-acetic ester (4.3g) and 250ml and normal hexane (volume ratio 1: 1) join in the 500ml reaction flask, add 300mg Pseudomonas sp. enzyme then, stirring reaction 50 hours.After reaction finishes, reacting liquid filtering is reclaimed, Pseudomonas sp. enzyme to be reusing, (the R)-1-phenmethyl-3-chloro-1 in the solution, 2-propylene glycol and (S)-1-phenmethyl-3-chloro-1, the acetic ester of 2-propylene glycol, content efficient liquid phase chromatographic analysis.Mixture obtains (R)-1-phenmethyl-3-chloro-1 after crossing post, 2-propylene glycol productive rate is 45.0%, and the e.e. value is 98%.The Arthrobacter sp. enzyme that reclaims joined in the fresh reaction solution reuse, catalytic capability does not obviously descend.
Embodiment 5: enzymatically splitting and preparing chiral 1-(4-methyl-benzyl)-3-chloro-1,2-propylene glycol
Under 30 ℃ with 0.01mol (2.1g) racemization 1-(4-methyl-benzyl)-3-chloro-1, the 2-propylene glycol, 0.05mol moisture 0～0.1% isopropyl ether of vinyl-acetic ester (4.3g) and 250ml joins in the 500ml reaction flask, add 300mg Candida Antarctica enzyme then, stirring reaction 80 hours.After reaction finishes, reacting liquid filtering is reclaimed Candida Antarctica enzyme, (R)-1-in the solution (4-methyl-benzyl)-3-chloro-1,2-propylene glycol and (S)-1-(4-methyl-benzyl)-3-chloro-1, the acetic ester of 2-propylene glycol, content efficient liquid phase chromatographic analysis, cross post and obtain (R)-1-(4-methyl-benzyl)-3-chloro-1, the 2-propylene glycol is 48.0%, and the e.e. value is 99.0%, and the hydrogen spectrum is:
1HNMR (400Hz, CDCl
3): δ 7.23 (d, J=8.0Hz, 2H), 7.17 (d, J=7.6Hz, 2H), 4.52 (s, 2H), 3.96～4.01 (m, 1H), 3.58～3.67 (m, 2H), 3.58 (d, J=4.4Hz, 2H), 2.35 (s, 3H).(S)-and 1-(4-methyl-benzyl)-3-chloro-1, the acetic ester productive rate of 2-propylene glycol is 49.0%, and the e.e. value is 98.0%, and the hydrogen spectrum is:
1H NMR (400Hz, CDCl
3): δ 7.23 (d, J=8.0Hz, 2H), 7.17 (d, J=8.0Hz, 2H), 5.15～5.58 (m, 1H), 4.52 (d, J=5.2Hz, 2H), 3.66～3.77 (m, 2H), 3.62～3.65 (m, 2H), 2.35 (s, 3H), 2.10 (s, 3H).
Embodiment 6: enzymatically splitting and preparing chiral 1-(4-benzyl chloride base)-3-chloro-1,2-propylene glycol
Under 40 ℃ with 0.01mol (2.3g) racemization 3-hydroxyl-4-to chlorine benzyloxy butyronitrile, 0.05mol moisture 0～0.01% toluene of vinyl-acetic ester (4.3g) and 250ml joins in the 500ml reaction flask, add Pseudomonas sp. enzyme then, stirring reaction 80 hours.After reaction finishes, reacting liquid filtering is reclaimed Pseudomonas sp. enzyme to reuse.(R)-1-in the solution (4-benzyl chloride base)-3-chloro-1,2-propylene glycol and (S)-1-(4-benzyl chloride base)-3-chloro-1, the acetic ester of 2-propylene glycol, the content efficient liquid phase chromatographic analysis, cross post and obtain (R)-1-(4-benzyl chloride base)-3-chloro-1,2-propylene glycol productive rate is 46.0%, and the e.e. value is 98.0%, and the hydrogen spectrum is:
1HNMR (400Hz, CDCl
3): δ 7.33 (d, J=8.8Hz, 2H), 7.26 (d, J=8.4Hz, 2H), 4.52 (s, 2H), 3.98～4.01 (m, 1H), 3.59～3.67 (m, 2H), 3.58 (d, J=4.8Hz, 2H), 2.57 (brs, 1H).(S)-and 1-(4-benzyl chloride base)-3-chloro-1, the acetic ester productive rate of 2-propylene glycol is 48.0%, the e.e. value is 97.0%,
1HNMR (400Hz, CDCl
3): δ 7.33 (d, J=8.8Hz, 2H), 7.26 (d, J=8.4Hz, 2H), 5.14～5.17 (m, 1H), 4.52 (d, J=5.2Hz, 2H), 3.67～3.77 (m, 2H), 3.63～3.66 (m, 2H), 2.10 (s, 3H).
Embodiment 7: enzymatically splitting and preparing chiral 1-(4-mehtoxybenzyl)-3-chloro-1,2-propylene glycol
Under 50 ℃ with 0.01mol (2.3g) racemization 3-hydroxyl-4-to methoxyl group benzyloxy base butyronitrile, 0.05mol moisture 0～1% methyl tertiary butyl ether of vinyl-acetic ester (4.3g) and 250ml joins in the 500ml reaction flask, add 300mg pseudomonas cepacia enzyme then, stirring reaction 88 hours.After reaction finishes, reacting liquid filtering is reclaimed enzyme to reuse, (R)-1-in the solution (4-mehtoxybenzyl)-3-chloro-1,2-propylene glycol and (S)-1-(4-mehtoxybenzyl)-3-chloro-1, the acetic ester of 2-propylene glycol, content efficient liquid phase chromatographic analysis, cross post and obtain (R)-1-(4-mehtoxybenzyl)-3-chloro-1,2-propylene glycol productive rate is 45.0%, and the e.e. value is 97.0%, and the hydrogen spectrum is:
1H NMR (400Hz, CDCl
3): δ 7.25 (d, J=7.2Hz, 2H), 6.89 (d, J=8.4Hz, 2H), 4.49 (s, 2H), 3.96～3.99 (m, 1H), 3.57～3.65 (m, 2H), 3.55 (d, J=5.2Hz, 2H), 3.00 (s, 3H), 2.56 (br s, 1H).(S)-and 1-(4-mehtoxybenzyl)-3-chloro-1, the acetic ester productive rate of 2-propylene glycol is 48.0%, and the e.e. value is 99.0%, and the hydrogen spectrum is:
1H NMR (400Hz, CDCl
3): δ 7.25 (d, J=8.0Hz, 2H), 6.89 (d, J=8.8Hz, 2H), 5.13～5.15 (m, 1H), 4.48 (d, J=6.4Hz, 2H), 3.80 (s, 3H), 3.64～3.76 (m, 2H), 3.60～3.62 (m, 2H), 2.09 (s, 3H).
Embodiment 9: enzymatically splitting and preparing chiral 1-(4-fluorobenzene methyl)-3-chloro-1,2-propylene glycol
Under 30 ℃ with 0.01mol (2.2g) racemization 1-(4-fluorobenzene methyl)-3-chloro-1, the 2-propylene glycol, 0.05mol moisture 0～1% acetonitrile of vinyl-acetic ester (4.3g) and 250ml joins in the 500ml reaction flask, adds 300mg Pseduomonas stutzeri enzyme then, stirring reaction 80 hours.After reaction finishes, reacting liquid filtering is reclaimed Pseduomonas stutzeri enzyme to reuse, (R)-1-in the solution (4-fluorobenzene methyl)-3-chloro-1,2-propylene glycol and (S)-1-(4-fluorobenzene methyl)-3-chloro-1, the acetic ester of 2-propylene glycol, content efficient liquid phase chromatographic analysis, cross post and obtain (R)-1-(4-fluorobenzene methyl)-3-chloro-1,2-propylene glycol productive rate is 46.0%, and the e.e. value is 97.0%, and the hydrogen spectrum is:
1H NMR (400Hz, CDCl
3): δ 7.27～7.31 (m, 2H), 7.02～7.06 (m, 2H), 4.52 (s, 2H), 3.99～4.01 (m, 1H), 3.58～3.67 (m, 2H), 3.59 (d, J=5.2Hz, 2H), 2.51 (br s, 1H).(S)-and 1-(4-fluorobenzene methyl)-3-chloro-1,2-propylene glycol acetic ester productive rate is 48.0%, and the e.e. value is 98.0%, and the hydrogen spectrum is:
1H NMR (400Hz, CDCl
3): δ 7.27～7.30 (m, 2H), 7.01～7.05 (m, 2H), 5.14～5.17 (m, 1H), 4.52 (d, J=5.6Hz, 2H), 3.66～3.76 (m, 2H), 3.63～3.65 (m, 2H), 2.10 (s, 3H).
Embodiment 10: enzyme process splits preparation (R)-1-(1-styroyl oxygen base)-3-chloro-1,2-propylene glycol
Under 35 ℃ with 0.1mol (21.4g) 1-(1-styroyl oxygen base)-3-chloro-1, the 2-propylene glycol, 0.05mol moisture 0～1% acetonitrile of vinyl-acetic ester (4.3g) and 350ml joins in the 1000ml reaction flask, adds 20mg Pseduomonas stutzeri enzyme then, stirring reaction 100 hours.After reaction finishes, reacting liquid filtering is reclaimed Pseduomonas stutzeri enzyme to reuse, (R)-1-in the solution (1-styroyl oxygen base)-3-chloro-1,2-propylene glycol and (S)-1-(1-styroyl oxygen base)-3-chloro-1,2-content of propylene glycol efficient liquid phase chromatographic analysis (R)-1-(1-styroyl oxygen base)-3-chloro-1,2-propylene glycol productive rate is 48%, and the e.e. value is 95.2%.
Embodiment 11: enzymatically splitting and preparing chiral 1-(2, the 4-dimethyl benzyl)-3-chloro-1,2-propylene glycol
Under 35 ℃ with 0.02mol (4.6g) racemization 1-(2, the 4-dimethyl benzyl)-and 3-chloro-1, the 2-propylene glycol, 0.1mol vinyl-acetic ester (8.6g) and 100ml analytical pure dioxane alkane join in the 500ml reaction flask, add 100mg Candida utilis enzyme then, stirring reaction 50 hours.After reaction finishes, reacting liquid filtering is reclaimed 100mg Candida utilis enzyme to reuse, with (the R)-1-(2 in the chromatography column separation solution, the 4-dimethyl benzyl)-3-chloro-1,2-propylene glycol and (S)-1-(2, the 4-dimethyl benzyl)-3-chloro-1, the acetic ester of 2-propylene glycol.Obtain (R)-1-(2, the 4-dimethyl benzyl)-3-chloro-1,2-propylene glycol productive rate 45%, the e.e. value is 98%.
Embodiment 12: enzymatically splitting and preparing chiral 1-(2,4 dichloro benzene methyl)-3-chloro-1,2-propylene glycol
Under 50 ℃ with 0.02mol (5.3g) racemization 1-(2,4-dichlorobenzene methyl)-and 3-chloro-1, the 2-propylene glycol, 0.02mol methylvinyl acetate (2g) and 100ml analyze tetrahydrofuran (THF) and join in the 200ml reaction flask, add 5mg Candida utilis enzyme then, stirring reaction 50 hours.After reaction finishes, reacting liquid filtering is reclaimed Candida utilis enzyme to reuse, with (the R)-1-(2 in the chromatography column separation solution, 4-dichlorobenzene methyl)-3-chloro-1,2-propylene glycol and (S)-1-(2,4 dichloro benzene methyl)-3-chloro-1, the acetic ester of 2-propylene glycol.Obtain (R)-1-(2,4 dichloro benzene methyl)-3-chloro-1, the productive rate of 2-propylene glycol is 43%, and the e.e. value is 95.0%, and the hydrogen spectrum is:
1H NMR (400Hz, CDCl
3): δ 7.27～7.36 (m, 3H), 4.61 (s, 2H), 4.01～4.05 (m, 1H), 3.60～3.70 (m, 4H), 2.51 (d, J=5.6Hz, 1H).(S)-and 1-(2,4 dichloro benzene methyl)-3-chloro-1, the productive rate of the acetic ester of 2-propylene glycol is 47%, and the e.e. value is 90.0%, and the hydrogen spectrum is:
1H NMR (400Hz, CDCl
3): δ 7.26～7.38 (m, 3H), 5.16～5.21 (m, 1H), 4.60 (d, J=4.0Hz, 2H), 3.67～3.8 (m, 4H), 2.11 (s, 3H).
Claims (7)
1. enzymatically splitting and preparing chiral 1-aryl-3-chloro-1, the method for 2-propylene glycol is characterized in that, the step of method is as follows:
1) with racemization 1-aryl-3-chloro-1, the 2-propylene glycol is dissolved in the organic solvent, adds ester then, thorough mixing, and 1-aryl-3-chloro-1, the mol ratio of 2-propylene glycol and ester is 1: 0.5-1: 20;
2) add enzyme, with 1-aryl-3-chloro-1, the 2-propylene glycol carries out the catalysis transesterification, and temperature of reaction is 10 ℃-60 ℃, and the reaction times is 0.5-300 hour, every gram enzyme catalysis 1-aryl-3-chloro-1, and the amount of 2-propylene glycol is 0.1-1000mol;
3) with reacting liquid filtering, reclaim enzyme, make chirality 1-aryl-3-chloro-1, the 2-propylene glycol.
2. a kind of enzymatically splitting and preparing chiral 1-aryl according to claim 1-3-chloro-1, the method for 2-propylene glycol is characterized in that, described chirality 1-aryl-3-chloro-1, the molecular structural formula of 2-propylene glycol is:
Wherein: R
1Be the substituting group on the phenyl ring, substituting group is alkyl, halogen or alkoxyl group; The position of substitution is in the 2-6 position; The substituting group number is 1-5; R
2Be alkyl.
3. a kind of enzymatically splitting and preparing chiral 1-aryl according to claim 1-3-chloro-1, the method for 2-propylene glycol is characterized in that, described ester is vinyl-acetic ester, methylvinyl acetate or ethyl acetate.
4. a kind of enzymatically splitting and preparing chiral 1-aryl according to claim 1-3-chloro-1, the method of 2-propylene glycol, it is characterized in that described organic solvent is normal hexane, hexanaphthene, normal heptane, octane-iso, toluene, benzene, methyl tertiary butyl ether, isopropyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform or acetonitrile.
5. a kind of enzymatically splitting and preparing chiral 1-aryl according to claim 1-3-chloro-1, the method for 2-propylene glycol is characterized in that, contains the water of 0.01%～1% weight in the described organic solvent.
6. a kind of enzymatically splitting and preparing chiral 1-aryl according to claim 1-3-chloro-1, the method for 2-propylene glycol is characterized in that, described temperature of reaction is 10 ℃-50 ℃.
7. a kind of enzymatically splitting and preparing chiral 1-aryl according to claim 1-3-chloro-1, the method for 2-propylene glycol is characterized in that, the described reaction times is 0.5-250 hour.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100702381A CN101130805A (en) | 2007-07-27 | 2007-07-27 | Method for enzymatically splitting and preparing chiral 1-aryl-3-chlorine-1, 2-propylene glycol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100702381A CN101130805A (en) | 2007-07-27 | 2007-07-27 | Method for enzymatically splitting and preparing chiral 1-aryl-3-chlorine-1, 2-propylene glycol |
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| Publication Number | Publication Date |
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| CN101130805A true CN101130805A (en) | 2008-02-27 |
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| CNA2007100702381A Pending CN101130805A (en) | 2007-07-27 | 2007-07-27 | Method for enzymatically splitting and preparing chiral 1-aryl-3-chlorine-1, 2-propylene glycol |
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| CN (1) | CN101130805A (en) |
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