CN104232696B - The method that asymmetric reduction prochiral carbonyl compounds produce chiral alcohol - Google Patents
The method that asymmetric reduction prochiral carbonyl compounds produce chiral alcohol Download PDFInfo
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- CN104232696B CN104232696B CN201410292443.2A CN201410292443A CN104232696B CN 104232696 B CN104232696 B CN 104232696B CN 201410292443 A CN201410292443 A CN 201410292443A CN 104232696 B CN104232696 B CN 104232696B
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Abstract
The invention discloses a kind of method of asymmetric reduction prochiral carbonyl compounds production chiral alcohol, solves existing for existing method the problem of catalytic is low, narrow to substrate spectrum, space-time yield is low and stereoselectivity is not high.The preservation of catalysis bacterial strain is entitled：Microbacterium (Microbacterium sp.long2), is preserved in China typical culture collection center (CCTCC), and deposit number is：CCTCC No:M2011449, the production method of the chiral alcohol is the microbacterium described in fermentation large-scale culture, obtains active resting cell thalline；Then bacteria suspension is made, adds substrate and carries out catalytic reaction, catalytic reaction terminates rear extractive reaction product, recycling design, obtains product.The inventive method technique is simple, reaction condition and time are gentle, with short production cycle, stereoselectivity is high, and reaction conversion ratio is high, has good prospects for commercial application.
Description
Technical field
The present invention relates to a kind of method for producing chiral alcohol, specifically a kind of asymmetric reduction prochirality carbonyl compound
The method that thing produces chiral alcohol.
Background technology
Chiral drug refers to the single enantiomer of the chemicals containing chiral factor.Meeting after these isomers enter in vivo
Significant difference is produced in pharmacological activity, metabolic process and metabolite, caused toxic side effect etc..Enantiomter
Bioactivity can often differ greatly, so that antipodal pharmacological action or toxicity is presented.Chiral drug has accounted at present
More than the 60% of world's medical market, it has also become the focus of new drug research in the world.The inner principles of this development trend come
From huge in single enantiomer chiral drug and still in the ever-increasing market demand.Chiral drug, chiral intermediate and its
The developmental research of technology has become one of important directions of current international new drug research.
Chiral alcohol is the crucial chiral building block of multiclass chiral drug synthesis, is the key technology of chiral drug synthesis.Catalysis
Corresponding prochiral carbonyl compounds asymmetric reduction is the important method for synthesizing the chiral alcohol.In asymmetric reduction prochirality carbonyl
Synthesize in single enantiomer chiral alcohol catalytic reaction, living things catalysis has efficient three-dimensional, region and chemo-selective, peace because of it
The full advantage such as property and Environmental compatibility, has important application prospect in the synthetic technology of chiral alcohol.But because biology is urged
Change still low there is catalytic, narrow to substrate spectrum, space-time yield is low and that reacts in some cases three-dimensional selects
Property it is not high the problems such as, therefore example in the industrial production can be applied also few.Filter out to more high catalytic activity
Microbial strains, extensive catalytic reaction process is developed, by urging the continuous research and development of reacted condition to optimize, acquired high single
Enantiomeric purity, high conversion and production efficiency, it is the target that those skilled in the art it is expected to reach.
The content of the invention
The invention aims to solve above-mentioned technical problem, there is provided a kind of technique is simple, control is easy, can obtain
Asymmetric reduction prochiral carbonyl compounds to high single enantiomer purity, high conversion and production efficiency produce chiral alcohol side
Method.Above-mentioned bacterial strains be the method use as catalyst.
The preservation of bacterial strain of the present invention is entitled：Microbacterium (Microbacterium sp.long2), is preserved in Chinese Typical Representative
Culture collection (CCTCC), address：Wuhan, China Wuhan University, deposit number are：CCTCC No:M 2011449.Should
The specific features of bacterial strain are as follows：Bacterium colony is circle, and to be faint yellow, wherein mycelia is in fine and close radial.Micro- Microscopic observation mycelia
There is tabula, conidiophore is short, and conidium is cylindrical.Its physio-biochemical characteristics is：Bacterial strain can not make gelatin liquefaction, can not
Make Starch Hydrolysis, milk solidification but do not peptonize, it is impossible to utilize tyrosine chromogenesis, it is impossible to which it is nitrite to reduce nitrate.
Bacterial strain of the present invention is a kind of bacterial strain for belonging to bacterium class, and the bacterial strain separates from soil, former chiral carbonyl chemical combination
The chloro- ethyl acetoacetate of thing methyl-n-butyl ketone, 4- with 4 '-chloro- acetophenone obtains for carbon source method of enrichment isolation from pedotheque.
The inventive method is carried out according to the following steps：
(1) ferment large-scale culture microbacterium, and it is thin that the active tranquillization of wet thallus acquisition is collected by centrifugation in the exponential phase later stage
Born of the same parents' thalline, freezing；
(2) resting cell thalline is suspended from pH buffer solutions and bacteria suspension is made, added substrate and carry out catalytic reaction, generation is single
One chiral chiral alcohol, the substrate is prochiral carbonyl compounds；
(3) nonpolar easy volatile solvent extractive reaction product is utilized after catalytic reaction terminates, is evaporated back using being evaporated under reduced pressure
Extractant is received, obtains product.
In the step (2), it is grape to add cosubstrate and surfactant, the cosubstrate into bacteria suspension
One kind in sugar, sucrose, isopropanol or glycerine；The surfactant is biocompatible surfactants, can include and tell
Temperature 80, single Tryfac 5573, Coconut Fatty Acid Monoethanolamide etc., addition accounts for the 0.01%- of catalystic converter system cumulative volume
0.1%)
In the step (2), the addition (addition in catalystic converter system) of the cosubstrate is 1~20g/
L。
In the step (1), the method for the microbacterium described in large-scale culture claim 1 of fermenting is：
A. bacterial strain described in well-grown claim 1 on inclined-plane is inoculated in seed culture medium a little with transfer needle picking
In the 10% of conical flask volume (culture volume be), 30~37 DEG C, conduct after 150~300r/min shaking table cultures, 24~48h
Seed；
B. mass propgation cell in fermentation medium is inoculated into 1%~5% inoculum concentration again, condition of culture is：It is sterile
0.5~1vvm of air-1Ventilation rate, 150~350r/min, cultivate 24~48h.Centrifuge and collect wet thallus, obtain resting cell；
Wherein, seed culture medium proportion of composing is：Glucose 10g, yeast extract 5g, peptone 5g, MgSO4·7H2O
0.5g, distilled water 1000mL, pH 7.0；
Fermentation medium ratio is：Glucose 10-20g, yeast extract 1-10g, peptone 1-10g, isopropanol 5-
100mg, prochiral carbonyl compounds 5-500mg, FeSO as reaction substrate40.1g, MgSO4·7H2O 0.5g, (NH4)2SO42g, water 1000mL, pH7.0.30~37 DEG C.
In step (2), the cell concentration of resting cell thalline is 0.1-1g/mL in the bacteria suspension, and pH buffer solutions used are
PH 6.0~8.0.
In step (2), the prochiral carbonyl compounds are 20~1000mmol/L as the concentration of substrate.
In step (2), the catalytic reaction temperature is 30~37 DEG C, and the reaction time is 2~24h.
In step (2), the prochiral carbonyl compounds are aromatic ketone, carbonyl ester or aliphatic ketone or ring type ketone.
The solvent extractant can be selected from petroleum ether, ethyl acetate or n-hexane etc..
On the basis of microbacterium (Microbacterium sp.long 2) is obtained, inventor is using the bacterial strain as urging
Agent, using prochiral carbonyl compounds as substrate, catalytic asymmetric reduction reaction.In order to ensure effectively entering for catalytic reaction
OK, reaction conversion ratio and the rate of recovery are improved, it is necessary to carry out strict control to the process conditions being related in catalytic reaction process.
Wherein, in step (1), a small amount of reaction substrate (prochiral carbonyl compounds) is added in fermentation medium, its
Purpose is the carbonyl reductase needed for for the microbial cell great expression subsequent catalyst reaction of inducing catalysis, to subsequent catalyst
Reaction has obvious action.
Step (2) into bacteria suspension except adding substrate, be also specifically added cosubstrate, be glucose, sucrose, different
One kind in propyl alcohol or glycerine, these cosubstrates are auxiliary by being consumed during catalysis of carbonyl reduction reaction by cell metabolism
(carbonyl reduction catalytic process needs to consume reduced coenzyme NAD (P) H and is converted into oxidized coenzyme NAD (P) enzyme NAD (P) H+)
The purpose that reproducibility H electronics reaches reduced coenzyme NAD (P) H in-situ regenerations, preferably isopropanol or glycerine are provided, are more highly preferred to
Glycerine, such alcohol (particularly glycerine) of the cell metabolisms of Microbacterium sp.long 2 is to coenzyme NAD (P) H revival
Rate highest, thus the catalysis to asymmetric reduction reaction is most favourable；The cosubstrate in catalystic converter system (including hang by bacterium
Liquid, substrate, the reaction system of cosubstrate and surfactant) addition be 1~20g/L, it is too high to produce other metabolism
Metabolic by-product can suppress the catalytic efficiency of cell to process increase cell metabolism burden simultaneously, too low to make regenerating coenzyme metabolism not
Enough influence catalytic efficiency；The cell concentration for controlling resting cell thalline in bacteria suspension is 0.1-1g/mL, to ensure enough catalysis energy
Power；PH buffer solutions used are pH 6.0~8.0, and the too high or too low metabolic activity that can influence cell of pH value and intracellular carbonyl are also
The activity of protoenzyme；
Further, the prochiral carbonyl compounds are 20~1000mmol/L as the concentration of substrate, and the substrate is dense
Degree is that the catalysis characteristics of inventor's research bacterial strain is strictly screened, more preferably 30-500mmol/L, excessive concentration meeting
Metabolism and the catalytic activity of toxicity inhibition cell, the too low catalytic efficiency that can influence cell are produced to cell.
Further, the time of catalytic reaction and temperature also have substantial connection with catalytic effect and yield, when described in use
Bacterial strain is as catalyst prochiral carbonyl compounds, it is necessary to strictly control catalysis when asymmetric reduction synthesizes the chiral alcohol
Reaction temperature is 30~37 DEG C (preferably 35), and the reaction time is 2~24h, beyond above-mentioned reaction condition then can not catalytic reaction obtain
To target product.
The prochiral carbonyl compounds are aromatic ketone, carbonyl ester, aliphatic ketone or ring type ketone.The aromatic ketone can be enumerated
Go out acetophenone containing halogen etc., the carbonyl ester can include methyl acetoacetate, 4- chloroacetyl acetacetic esters etc., the fat
Ketone can include 2 heptanone, methyln-hexyl ketone etc., and the ring type ketone can include band halogen cyclohexanone etc.
Bacterial strain of the present invention can have highly-solid selectively, high catalysis effect as the catalyst in chiral alcohol catalytic reaction
The advantages of rate.The method technique of asymmetric reduction prochiral carbonyl compounds of the present invention production chiral alcohol is simple, reaction condition and
Time is gentle, with short production cycle, stereoselectivity is high, and reaction conversion ratio is high, has good prospects for commercial application.Yield is reachable
95%, reaction time most short need 2 hours, single enantiomer excessive value (e.e.) brings up to 99%, and production efficiency is high.
Embodiment
The screening of bacterial strain：
The preservation of bacterial strain of the present invention is entitled：Microbacterium (Microbacterium sp.long2), is preserved in Chinese Typical Representative
Culture collection (CCTCC), address：Wuhan, China Wuhan University, deposit number are：CCTCC No:M 2011449, protect
Hide the date be：On December 8th, 2011.
The microbacterium (Microbacterium sp.long 2) of the present invention is a kind of bacterial strain for belonging to bacterium class, the bacterial strain
Separated from soil, by using prochiral carbonyl compounds methyl-n-butyl ketone, chloro- ethyl acetoacetates of 4- and 4 '-chloro- acetophenone as carbon
Source method of enrichment isolation from pedotheque obtains.
The method for screening efficient asymmetric reduction aromatic ketone bacterial strain is：
5g pedotheques are weighed, add 10mL sterile distilled waters, shaken well is in suspension.Stand standby to supernatant clarification
With；
The soil supernatant stood is taken, is aseptically inoculated in enriched medium (glucose 10g, yeast extraction
Thing 5g, peptone 5g, beef extract 5g, NaCl 5g, water 1000mL) 24~48h of middle culture；
Enrichment culture liquid is taken to be added in first generation culture medium (glucose 5g, yeast extract 5g, beef extract 5g, albumen
Peptone 5g, the NaCl chloro- ethyl acetoacetate of 5g, methyl-n-butyl ketone, 4- and 4 '-chloro- each 10mmol/L of acetophenone, water 1000mL), 30
~37 DEG C, 24~48h is cultivated in 175r/m constant-temperature table.Passage every 24h once, continuous passage culture three generations later.
The bacterium solution dilution of the third generation is taken to be coated on ((NH on inorganic salts plating medium4)2SO44g, KH2PO42g, NaCl
1g, MgSO4·7H2The chloro- ethyl acetoacetate of O 0.2g, agar 2g, methyl-n-butyl ketone, 4- and 4 '-chloro- each 10mmol/L of acetophenone, steams
Distilled water 1000mL), at the same will be equipped with (the chloro- ethyl acetoacetate of methyl-n-butyl ketone, 4- with 4 '-chloro- each 5mL of acetophenone) conical flask and
Scribble bacterium solution flat board wrap sealing with freshness protection package after, be put into 30~37 DEG C of constant incubators and cultivate 2~4 days；
The bacterium colony grown on flat board is provoked and is inoculated on slant medium, 24~48h is cultivated in insulating box；
Thalline in slant medium is inoculated in fermentation medium after incubated 24~48h, added in nutrient solution
Enter the chloro- ethyl acetoacetate of methyl-n-butyl ketone, 4- and 4 '-chloro- each 10mmol/L of acetophenone, continue to be put into carried out on shaking table reaction 24~
48h.After the completion of reaction, extracted.Utilize the catalytic efficiency and stereoselectivity of Chiral gas chromatography measure reaction.Screen
To catalytic efficiency and the preferable bacterial strain of stereoselectivity.
The composition of involved culture medium is as follows：
Enriched medium：Glucose 5g, yeast extract 5g, beef extract 5g, peptone 5g, NaCl 5g, methyl-n-butyl ketone, 4-
Chloro- ethyl acetoacetate and 4 '-chloro- each 10mmol/L of acetophenone, 7.0,121 DEG C of sterilizing 30min of water 1000mL, pH；
Minimal medium：(NH4)2SO44g, KH2PO42g, NaCl 1g, MgSO4·7H2O0.2g, agar 2g, 2- oneself
The chloro- ethyl acetoacetate of ketone, 4- and 4 '-chloro- each 10mmol/L of acetophenone, 7.0,121 DEG C of sterilizing 30min of water 1000mL, pH；
Slant medium：Glucose 10g/L, yeast extract 5g/L, peptone 5g/L, KH2PO42g/L, pH 7.0,121
DEG C sterilizing 30min.
The culture of bacterial strain
From inclined-plane, picking strain Microbacterium sp.long2 are inoculated in conical flask (the seed training of liquid amount 10%
Support base), it is placed in shaking table and vibrates (30-37 DEG C, 150-300r/min) culture 24-48h as seed；
Seed bacterium solution is inoculated into fermentation tank with 1-5% (v/v) inoculum concentration, at 35 DEG C, 150-350r/min, air
Throughput 0.5-1vvm-1Condition of culture under cultivate 24-36h after put tank.Centrifugation, collect thalline and obtain resting cell.
The composition of involved culture medium is as follows：
Seed culture medium：Glucose 10g, yeast extract 5g, peptone 5g, MgSO4·7H2O0.5g, water 1000mL, pH
7.0,121 DEG C of sterilizing 30min；
Fermentation medium ratio is：Glucose 10-20g, yeast extract 1-10g, peptone 1-10g, isopropanol 5-
100mg, thing reaction substrate (prochirality carbonyl compound) 5-500mg, FeSO40.1g, MgSO4·7H2O 0.5g, (NH4)2SO42g,
1000mL, pH7.0,121 DEG C of sterilizing 30min of water.
Chiral alcohol production：
Resting cell (the preparation ratio of bacteria suspension is 0.1-1 (g/mL)) is added in pH 5.0~8.0 pH fliud flushings, added
Enter prochiral carbonyl compounds as substrate, concentration of substrate is 20~1000mmol/L, and reaction system adds the auxiliary of 1~50g/L
Helping substrate (glucose, sucrose, isopropanol or glycerine) and surfactant, reaction temperature is 30~37 DEG C, the reaction time is 2~
24h, through asymmetric reduction reaction, generate single enantiomer chiral alcohol.Reaction extracts after terminating, and is extracted using recovery is evaporated under reduced pressure
Solvent obtains chiral alcohol product, and embodiment 1-20 specific reaction condition, product and experimental result is referring to table 1 and table 2.
Comparative example 1-5：
Reaction temperature is different in comparative example 1,3, ratio compared with 2 in concentration of substrate it is different, auxiliary bottom is not contained in comparative example 4-5
Thing, remaining process conditions is identical with the present invention, and concrete technology condition is referring to table 3 and table 4.
Table 1
Table 2
Table 3
Table 4
Claims (5)
- A kind of 1. method of asymmetric reduction prochiral carbonyl compounds production chiral alcohol, it is characterised in that enter according to the following steps OK：(1) ferment large-scale culture microbacterium, and wet thallus is collected by centrifugation in the exponential phase later stage and obtains active resting cell bacterium Body, freezing；It is described fermentation large-scale culture microbacterium method be：A. well-grown bacterial strain on inclined-plane is inoculated in seed culture medium a little with transfer needle picking, 30~37 DEG C, Seed is used as after 150~300r/min shaking table cultures, 24~48h；B. mass propgation cell in fermentation medium is inoculated into 1%~5% inoculum concentration again, condition of culture is：Filtrated air 0.5~1vvm-1Ventilation rate, 150~350r/min, 24~48h is cultivated, centrifuges and collects wet thallus, obtain resting cell；Wherein, seed culture medium proportion of composing is：Glucose 10g, yeast extract 5g, peptone 5g, MgSO4 .7H2O 0.5g, Distilled water 1000mL, pH 7.0；Fermentation medium ratio is：Glucose 10-20g, yeast extract 1-10g, peptone 1-10g, isopropanol 5-100mg, Prochiral carbonyl compounds 5-500mg, FeSO as reaction substrate40.1g, MgSO4 .7H2O 0.5g, (NH4)2SO42g, 7.0,30~37 DEG C of water 1000mL, pH；(2) resting cell thalline is suspended from pH buffer solutions and bacteria suspension is made, added substrate, cosubstrate and surfactant and enter Row catalytic reaction, the chiral alcohol of single chiral is generated, the substrate is prochiral carbonyl compounds, and the cosubstrate is sweet Oil, addition are 1~20g/L；The surfactant is biocompatible surfactants, and addition accounts for catalystic converter system The 0.01%-0.1% of cumulative volume；(3) nonpolar easy volatile solvent extractive reaction product is utilized after catalytic reaction terminates, extractant is reclaimed using being evaporated under reduced pressure, Obtain product；The microbacterium is a kind of bacterial strain for being capable of efficient asymmetric reduction prochirality aromatic ketone, and preservation is entitled：Microbacterium (Microbacterium sp.long2), is preserved in China typical culture collection center (CCTCC), and deposit number is： CCTCC No:M2011449。
- 2. according to the method for claim 1, it is characterised in that in step (2), resting cell thalline in the bacteria suspension Cell concentration is 0.1-1g/mL, and pH buffer solutions used are pH6.0~8.0.
- 3. according to the method for claim 1, it is characterised in that in step (2), the prochiral carbonyl compounds are the bottom of as The concentration of thing is 20~1000mmol/L.
- 4. according to the method for claim 1, it is characterised in that in step (2), the catalytic reaction temperature is 30~37 DEG C, the reaction time is 2~24h.
- 5. according to the method for claim 1, it is characterised in that：In step (2), the prochiral carbonyl compounds are fragrance Ketone, carbonyl ester or aliphatic ketone or ring type ketone.
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| CN105018439B (en) * | 2015-05-19 | 2019-01-15 | 上海弈柯莱生物医药科技有限公司 | A kind of carbonyl reductase and its application in synthesis of chiral hydroxy compounds |
| CN106497996B (en) * | 2016-10-11 | 2021-01-12 | 凯莱英医药集团（天津）股份有限公司 | Enzymatic preparation method of chiral alcohol |
| CN109943597B (en) * | 2019-03-06 | 2022-08-09 | 江苏惠利生物科技有限公司 | Method for preparing ethyl s-4-chloro-3-hydroxybutyrate by coupling extraction of enzyme membrane reactor |
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| CN101016526A (en) * | 2006-12-26 | 2007-08-15 | 华东理工大学 | Oxidization microbacterium and method of preparing optical pure chiral aryl secondary alcohol by the same |
| CN102382780A (en) * | 2010-09-03 | 2012-03-21 | 中国科学院成都生物研究所 | Microbacterium oxydans and method for preparing chiral bis(trifluoromethyl) phenyl ethanol by using same |
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|---|---|---|---|---|
| CN101016526A (en) * | 2006-12-26 | 2007-08-15 | 华东理工大学 | Oxidization microbacterium and method of preparing optical pure chiral aryl secondary alcohol by the same |
| CN102382780A (en) * | 2010-09-03 | 2012-03-21 | 中国科学院成都生物研究所 | Microbacterium oxydans and method for preparing chiral bis(trifluoromethyl) phenyl ethanol by using same |
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Effective date of registration: 20181205 Address after: 430081 No. 743 Peace Avenue, Qingshan District, Wuhan City, Hubei Province Patentee after: Wuhan University of Science and Technology Asset Management Co., Ltd. Address before: 430081 Qingshan Peace Avenue 947, Wuhan City, Hubei Province Patentee before: Wuhan University of Science and Technology |