CN101624609A - Method for preparing (S)-3-substituent glutaric acid monoester class compound by enzyme catalysis - Google Patents
Method for preparing (S)-3-substituent glutaric acid monoester class compound by enzyme catalysis Download PDFInfo
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Abstract
The invention relates to a method for preparing a chiral compound based on biologic enzyme catalysis, in particular to a method for preparing a (S)-3-substituent glutaric acid monoester class compound by enzyme catalysis. The method comprises the following steps: taking a 3-substituent glutaric acid class compound and organic alcohol as raw materials to react in an organic solvent under the action of biologic enzymes at the temperature of 15-60 DEG C and prepare the (S)-3-substituent glutaric acid monoester class compound. The preparation method provided by the invention has mild reaction conditions, simple post-treatment, higher atom utilization rate, yield greater than 92% and ee value greater than 99% and conforms to the requirement of green chemistry. By applying the method, the cost can be greatly lowered, and the demand of the society to the (S)-3-substituent glutaric acid single alkyl ester class compound is met.
Description
Technical field
The present invention relates to a kind ofly prepare the method for chipal compounds, refer in particular to a kind of method of enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound based on biological enzyme.
Background technology
Chiral monomer (S)-3-substituent glutaric acid mono alkyl ester compounds (I) is a kind of important intermediate of Ta Ting and analogue thereof.
The new era for the treatment of hyperlipidemia has been opened up in the discovery of statins.Such medicine with safety, effectively, better tolerance, the effect advantage such as long of holding time, become the choice drug in the lipid lowerers.And preventing and treating the obvious benefit that is obtained aspect the cardiovascular disorder, and the report in succession of the clinical new application outside the effect for reducing fat, the interest and the concern of the world of medicine caused.A large amount of experimentation on animalies and clinical study prove, statins has the effect of remarkable reduction plasma cholesterol (CH) and low density lipoprotein cholesterol (LDL-C), synthetic statins drug midbody (S)-3-substituent glutaric acid mono alkyl ester compounds I receives increasing concern in recent years, this compounds of part correlation and derivative synthetic thereof report is also arranged both at home and abroad, as:
L6pez-Garc í a et al (Tetrahedron:Asymmetry 14 (2003) 603-609.) PLE (pork liver enzyme) hydrolysis 3-substituent glutaric acid dialkyl, obtain (S)-pentanedioic acid mono alkyl ester compounds (I), the ee value is up to 99%, but yield less than 40% and this method pentanedioic acid two ester compounds that the 3-position need be replaced be dissolved in the damping fluid, because of its solubleness less, and then make aftertreatment more numerous, be not suitable for large-scale industrial production.Chen, Ching Shih et al (Journal of the American Chemical Society (1982), 104 (25), 7294-9.) utilize the alcoholysis under the enzyme effect of 3-substituted ring penta acid anhydride to prepare (S)-3-substituent glutaric acid mono alkyl ester compounds, yield is about 87%, but the ee value is not high, is not suitable for medicinal requirements.Ozegowski, (Liebigs Annalen der Chemie (1993), (7) 805-8.) utilize alcoholysis 3-substituted ring penta acid anhydride to prepare chirality (S)-3-substituent glutaric acid mono alkyl ester compounds to Ruediger et al, it is same because ee＜86% does not meet medicinal requirements.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method who prepares chiral monomer (S)-3-substituent glutaric acid mono alkyl ester compounds with biological enzyme as the low use pentanedioic acid of catalyzer, gentleness, yield height, environmental friendliness, cost and 3-substituent glutaric acid compounds and organic pure esterification.
The technical solution used in the present invention is as follows:
A kind of method of enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound, described method is for being raw material suc as formula the 3-substituent glutaric acid compounds shown in (II) and organic alcohol, under the effect of biological enzyme, in organic solvent in 15-60 ℃ of following prepared in reaction suc as formula (the S)-3-substituent glutaric acid monoester class compound shown in (I), its reaction equation is:
Wherein, R
1Be hydroxyl, tertiary butyl disiloxane, the fat chain of C1-C8, aromatic ring, phenyl ring,
The chloro of C1-C5, fluoro or bromo alkyl; R
2Be the alkyl group of C1-C8, the fluoro of C1-C5, chloro or bromo alkyl; Described biological enzyme is Lipase from Thermomyces lanuginosus, LipaseB from Candida antarctica, Lipase from Candide Rugosa, Lipase PS " Amano " SD, Lipase AS " Amano ", Lipase AK " Amano ", any among the Lipase AYS " Amano ".
Further, described 3-substituent glutaric acid compounds is 1: 1～20 with the ratio of the amount of substance of organic alcohol; Described 3-substituent glutaric acid compounds is 1: 0.005～0.1 with the ratio of the quality of biological enzyme.
Further, described organic solvent is organic alcohol, hexanaphthene, normal hexane, octane-iso, propane, ether, a kind of or several mixing arbitrarily in methyl tertiary butyl ether and the isopropyl ether; And the amount of substance of described organic solvent is 5～30 times of amount of substance of 3-substituent glutaric acid compounds.
Further, use anhydrous cupric sulfate in the described reaction process, molecular sieve, polymeric membrane or water removal device are removed the water that generates in the dereaction.
Further, the reaction times of described reaction is 5～72 hours.
Further, this reaction is that developping agent is that ethyl acetate and sherwood oil volume ratio are 1～2: 1 mix reagent with the reaction of TLC platelet tracking monitor; Used colouring reagents is the ethanolic soln of tetrabromo-mcresolsulfonphthalein, judges reaction end by the concentration and the concentration of the point that is left of the new point that produces in the monitoring reaction.
Further, this reacts with gas phase monitoring reaction progress, judges reaction end by the formation at (S)-3-substituent glutaric acid monoester class compound peak and the disappearance of pentanedioic acid class material in the monitoring liquid chromatography.
Further, reaction is to carry out according to following steps:
A. according to 3-substituent glutaric acid compounds: the ratio of the amount that feeds intake of organic alcohol is 1: 1～1: 3, described 3-substituent glutaric acid compounds: the ratio of biological enzyme quality is 1: 0.005～1: 0.1, the amount of substance of described organic solvent is 5～10 times of amount of substance of 3-substituent glutaric acid compounds, with 3-substituent glutaric acid compounds, organic alcohol, immobilization biological enzyme and solvent are put in the reactor successively;
B. controlled temperature reacts in 15～60 ℃, during carry out tracking monitor with TLC silica-gel plate or liquid chromatography, substantially no longer carry out until reaction;
C. filtering reacting liquid is removed biological enzyme, removes organic solvent and the organic alcohol of unreacted, can obtain rough (S)-3-substituent glutaric acid monoester class compound.
Further, employed biological enzyme is recyclable is reused.
Preparation method's reaction conditions gentleness provided by the invention, yield＞92%, ee value＞99%, and aftertreatment is simple, and the atom availability meets the requirement of Green Chemistry than higher.Using this method can reduce cost greatly, satisfies the demand of society to (S)-3-substituent glutaric acid mono alkyl ester compounds.
Embodiment
Following specific examples illustrates technical scheme of the present invention, but the scope of protection is not limited in this.
The involved biological enzyme of this patent is all purchased in amano enzyme goods company (Amano Enzyme Inc.), wherein be called after the Lipase from Thermomyces lanuginosus immobilization: Lipozyme TLIM, be called after the Lipase B from Candida antarctica immobilization: Novozym 435, and Lipase fromCandide Rugosa is called for short CRL.Remaining reaction thing and reagent are market and buy gained.
Embodiment 1
Thermometer will be housed, in three mouthfuls of the 50ml of drying tube and magnetic agitation or the two mouthfuls of flasks, add 3-tertiary butyl disiloxane pentanedioic acid 5.25g, ethanol 10g, biological enzyme CRL0.03g, adding finishes, and temperature is fixed on 35 ℃, magnetic agitation, reacted 24 hours, TLC platelet monitoring during this time or liquid chromatography monitoring, after reaction finishes, aftertreatment, remove organic solvent and unreacted ethanol, purification process obtains clear crystal (S)-3-tertiary butyl disiloxane pentanedioic acid mono ethyl ester.
(S)-and 3-tertiary butyl disiloxane pentanedioic acid mono ethyl ester, yield 54%, purity＞97%, ee value 96%.
Embodiment 2
With 3-tertiary butyl disiloxane pentanedioic acid 5.25g, n-propyl alcohol 8g, biological enzyme 0.025g joins in the reactor, adding finishes, and temperature is fixed on 37 ℃, magnetic agitation was reacted 48 hours, during TLC platelet monitoring or liquid chromatography monitoring, the enzyme that uses is CRL.
Other operations are as embodiment 1, and purification process obtains clear crystal (S)-3-tertiary butyl disiloxane pentanedioic acid list n-propyl.
(S)-and 3-tertiary butyl disiloxane pentanedioic acid list n-propyl, yield 97%, purity＞98%, ee value＞99%.
Embodiment 3
With 3-tertiary butyl disiloxane pentanedioic acid 5.25g, Virahol 15g, biological enzyme 0.25g join in the Erlenmeyer flask of 50ml, and employed enzyme is Lipase B from Candida antarctica.Adding finishes, and Erlenmeyer flask is placed in the shaking table.Fixed temperature is at 35 ℃, rotating speed 200r/ branch.Reacted 10 hours, and added the 0.5g biological enzyme then, continue reaction 14 hours, during monitoring of TLC platelet or liquid chromatography monitoring.
Reaction finishes, and organic solvent and unreacted Virahol are removed in aftertreatment, and purification process obtains clear crystal (S)-3-tertiary butyl disiloxane pentanedioic acid list isopropyl ester.
(S)-and 3-tertiary butyl disiloxane pentanedioic acid list isopropyl ester, yield 93%, purity 98%, ee value 99%.
Embodiment 4
With 3-tertiary butyl disiloxane pentanedioic acid 5.25g, trimethyl carbinol 7g, biological enzyme 0.13g join in the Erlenmeyer flask of 50ml, and employed enzyme is Lipase AS " Amano ".Adding finishes, and Erlenmeyer flask is placed in the shaking table.Fixed temperature reacted 15 hours at 45 ℃, added the 0.3g biological enzyme then, continued reaction 15 hours, during monitoring of TLC platelet or liquid chromatography monitoring.
Other operations obtain clear crystal (S)-3-tertiary butyl disiloxane pentanedioic acid list tert-butyl ester as embodiment 3 purification process.
(S)-and the 3-tertiary butyl disiloxane pentanedioic acid list tert-butyl ester, yield 83%, purity 99%, ee value 99%.
Embodiment 5
With 3-tertbutyl ether pentanedioic acid 4.1g, trimethyl carbinol 7g, biological enzyme 0.03g join in the Erlenmeyer flask of 50ml, and employed enzyme is Lipase AK " Amano ".Adding finishes, and Erlenmeyer flask is placed in the shaking table.Fixed temperature is at 45 ℃, and rotating speed 200r/ branch reacted 25 hours, during TLC platelet monitoring or liquid chromatography monitoring.
Other operations obtain clear crystal (S)-3-tertbutyl ether pentanedioic acid list tert-butyl ester as embodiment 3 purification process.
(S)-and the 3-tertbutyl ether pentanedioic acid list tert-butyl ester, yield 65%, purity＞97%, ee value＞95%.
Embodiment 6
With 3-tertbutyl ether pentanedioic acid 4.1g, n-propyl alcohol 11g, biological enzyme 0.1g join in the Erlenmeyer flask of 50ml, and employed enzyme is Lipase AK " Amano ".
Adding finishes, and Erlenmeyer flask is placed in the shaking table.Fixed temperature is at 45 ℃, and rotating speed 200r/ branch reacted 25 hours, during TLC platelet monitoring or liquid chromatography monitoring.
Other operations obtain clear crystal (S)-uncle's 3-butyl ether pentanedioic acid list n-propyl as embodiment 3 purification process.
(S)-and uncle's 3-butyl ether pentanedioic acid list n-propyl, yield 92%, purity 98%, ee value 99%.
Embodiment 7
With 3-tertbutyl ether pentanedioic acid 4.1g, trimethyl carbinol 15g, biological enzyme 0.25g join in the Erlenmeyer flask of 50ml, and employed enzyme is CRL.
Adding finishes, and Erlenmeyer flask is placed in the shaking table.Fixed temperature reacted 48 hours at 45 ℃, during TLC platelet monitoring or liquid chromatography monitoring.
Other operations obtain clear crystal (S)-uncle's 3-butyl ether pentanedioic acid list tert-butyl ester as embodiment 3 purification process.
(S)-and uncle's 3-butyl ether pentanedioic acid list tert-butyl ester, yield 72%, purity＞98%, ee value＞97%.
Embodiment 8
With 3-tertbutyl ether pentanedioic acid 4.1g, trimethyl carbinol 15g, biological enzyme 0.15g join in the Erlenmeyer flask of 50ml, and employed enzyme is Lipase AYS " Amano ".Adding finishes, and Erlenmeyer flask is placed in the shaking table.Fixed temperature reacted 36 hours at 45 ℃, during TLC platelet monitoring or liquid chromatography monitoring.
Other operations obtain clear crystal (S)-uncle's 3-butyl ether pentanedioic acid list tert-butyl ester as embodiment 3 purification process.
(S)-and uncle's 3-butyl ether pentanedioic acid list tert-butyl ester, yield 70%, purity＞98%, ee value＞94%.
Embodiment 9
With 3-hydroxy ethers pentanedioic acid 3.0g, Virahol 10g, biological enzyme 0.08g joins in the Erlenmeyer flask of 50ml, and adding finishes, and employed enzyme is Novozyme 435.Erlenmeyer flask is placed in the shaking table.Fixed temperature is at 37 ℃, and rotating speed 200r/ branch reacted 48 hours, during TLC platelet monitoring or liquid chromatography monitoring.
Other operations obtain clear crystal (S)-3-hydroxyl pentanedioic acid list isopropyl ester as embodiment 3 purification process.
(S)-and 3-hydroxyl pentanedioic acid list isopropyl ester, yield 79%, purity 98%, ee value 97%.
Embodiment 10
With 3-methyl ether pentanedioic acid 3.64g, ethanol 10g, biological enzyme 0.4g joins in the reactor, and the enzyme that uses is Lipase PS " Amano " SD.Adding finishes, and temperature is fixed on 40 ℃, and rotating speed 200r/ branch reacted 36 hours, during TLC platelet monitoring or liquid chromatography monitoring.
Other operations are as embodiment 1, and purification process obtains clear crystal (S)-3-methyl ether pentanedioic acid mono ethyl ester.
(S)-and 3-methyl ether pentanedioic acid mono ethyl ester, yield 90%, purity＞98%, ee value＞96%.
Embodiment 11
With 3-sec.-propyl pentanedioic acid 3.5g, n-propyl alcohol 11g, biological enzyme 0.8g joins in the reactor, and the enzyme that uses is Lipase B from Candida antarctica.Adding finishes, and temperature is fixed on 40 ℃, and rotating speed 200r/ branch reacts and adds 0.5g biological enzyme (Lipase B from Candida antarctica) after 20 hours again, continues reaction 16 hours.TLC platelet monitoring during this time or liquid chromatography monitoring.
Other operations are as embodiment 3, and purification process obtains clear crystal (S)-3-sec.-propyl pentanedioic acid list n-propyl.
(S)-and 3-sec.-propyl pentanedioic acid list n-propyl, yield 79%, purity＞98%, ee value＞98%.
Embodiment 12
With 3-sec.-propyl pentanedioic acid 3.5g, n-propyl alcohol 11g, biological enzyme 0.2g joins in the reactor, and the enzyme that uses is Lipase from Thermomyces lanuginosus.Adding finishes, and temperature is fixed on 30 ℃, and rotating speed 140r/ branch reacts and adds 0.6g biological enzyme (Lipase from Thermomyceslanuginosus) after 15 hours again, continues reaction 15 hours.TLC platelet monitoring during this time or liquid chromatography monitoring.
Other operations are as embodiment 3, and purification process obtains clear crystal (S)-3-sec.-propyl pentanedioic acid list n-propyl.
(S)-and 3-sec.-propyl pentanedioic acid list n-propyl, yield 90%, purity＞98%, ee value＞99%.
Claims (9)
1. the method for enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound, it is characterized in that: described method is for being raw material suc as formula the 3-substituent glutaric acid compounds shown in (II) and organic alcohol, under the effect of biological enzyme, in organic solvent in 15-60 ℃ of following prepared in reaction suc as formula (the S)-3-substituent glutaric acid monoester class compound shown in (I), its reaction equation is:
Wherein, R
1Be hydroxyl, tertiary butyl disiloxane, the fat chain of C1-C8, aromatic ring, phenyl ring,
The chloro of C1-C5, fluoro or bromo alkyl; R
2Be the alkyl group of C1-C8, the fluoro of C1-C5, chloro or bromo alkyl; Described biological enzyme is Lipase from Thermomyces lanuginosus, Lipase B from Candida antarctica, Lipase from Candide Rugosa, Lipase PS " Amano " SD, Lipase AS " Amano ", Lipase AK " Amano ", any among the Lipase AYS " Amano ".
2. the method for enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound as claimed in claim 1, it is characterized in that: described 3-substituent glutaric acid compounds is 1: 1～20 with the ratio of the amount of substance of organic alcohol; Described 3-substituent glutaric acid compounds is 1: 0.005～0.1 with the ratio of the quality of biological enzyme.
3. the method for enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound as claimed in claim 1, it is characterized in that: described organic solvent is organic alcohol, hexanaphthene, normal hexane, octane-iso, propane, ether, a kind of or several mixing arbitrarily in methyl tertiary butyl ether and the isopropyl ether; And the amount of substance of described organic solvent is 5～30 times of amount of substance of 3-substituent glutaric acid compounds.
4. the method for enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound according to claim 1 is characterized in that: use anhydrous cupric sulfate in the described reaction process, and molecular sieve, polymeric membrane or water removal device are removed the water that generates in the dereaction.
5. the method for enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound according to claim 1, it is characterized in that: the reaction times of described reaction is 5～72 hours.
6. the method for enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound according to claim 1, it is characterized in that: this reaction is that developping agent is that ethyl acetate and sherwood oil volume ratio are 1～2: 1 mix reagent with the reaction of TLC platelet tracking monitor; Used colouring reagents is the ethanolic soln of tetrabromo-mcresolsulfonphthalein, judges reaction end by the concentration and the concentration of the point that is left of the new point that produces in the monitoring reaction.
7. the method for enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound according to claim 1, it is characterized in that: this reaction is judged reaction end with gas phase monitoring reaction progress by the formation at (S)-3-substituent glutaric acid monoester class compound peak and the disappearance of pentanedioic acid class material in the monitoring liquid chromatography.
8. the method for enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound according to claim 1 is characterized in that: reaction be to carry out according to following steps:
A. according to 3-substituent glutaric acid compounds: the ratio of the amount that feeds intake of organic alcohol is 1: 1～1: 3, described 3-substituent glutaric acid compounds: the ratio of biological enzyme quality is 1: 0.005～1: 0.1, the amount of substance of described organic solvent is 5～10 times of amount of substance of 3-substituent glutaric acid compounds, with 3-substituent glutaric acid compounds, organic alcohol, immobilization biological enzyme and solvent are put in the reactor successively;
B. controlled temperature reacts in 15～60 ℃, during carry out tracking monitor with TLC silica-gel plate or liquid chromatography, substantially no longer carry out until reaction;
C. filtering reacting liquid is removed biological enzyme, removes organic solvent and the organic alcohol of unreacted, can obtain rough (S)-3-substituent glutaric acid monoester class compound.
9. the method for enzyme catalysis preparation (S)-3-substituent glutaric acid monoester class compound according to claim 1, it is characterized in that: employed biological enzyme is recyclable to be reused.
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| CN115595340A (en) * | 2022-11-28 | 2023-01-13 | 凯莱英生命科学技术（天津）有限公司（Cn） | Method for synthesizing alkylene diacid monoester |
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| CN115595340A (en) * | 2022-11-28 | 2023-01-13 | 凯莱英生命科学技术（天津）有限公司（Cn） | Method for synthesizing alkylene diacid monoester |
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