CN104630297B - A kind of enzyme process nonaqueous phase catalyzes and synthesizes (R) -3-TBDMSO glutaric acid first monoesters and its derivative - Google Patents
A kind of enzyme process nonaqueous phase catalyzes and synthesizes (R) -3-TBDMSO glutaric acid first monoesters and its derivative Download PDFInfo
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Abstract
Disclosure sets forth a kind of enzyme process nonaqueous phases to catalyze and synthesize (R) 3 TBDMSO glutaric acid first monoesters and its derivative, belongs to technical field of bioengineering.The present invention relates to the preparation of rosuvastain calcium (Rosuvastatin), the especially wherein preparation method of a key intermediate.The present invention discloses a kind of using Novozyme435 enzyme law catalysis synthesis (R) 3 TBDMSO glutaric acid monoesters (R J6) and its derivative method, enzymatic conversion condition is optimized using this method, R J after reaction for 24 hours6Product assay is up to 67.1g/L, the R J after optimization6Yield be 14. times of (optimization before for 4.5g/L) before optimization；Orthogonal experiment finds that the influence factor primary and secondary sequence of enzymatic is：Concentration of substrate ＞ alcohol acid anhydride molar ratio ＞ enzyme concentrations；Optimal enzymatic conversion system is concentration of substrate 250g/L, and enzyme concentration 60g/L, alcohol acid anhydride molar ratio 2: 1, solvent is isooctane, and catalytic temperature is 35 DEG C, after enzymatic conversion for 24 hours, R J in conversion fluid6Content is up to 68.9g/L, production intensity 2.87 (g/Lh).
Description
Technical field
A kind of enzyme process nonaqueous phase catalyzes and synthesizes (R) -3-TBDMSO glutaric acid first monoesters and its derivative, belongs to bioengineering
Field.The present invention relates to the preparations of rosuvastain calcium (Rosuvastatin), the especially wherein preparation of a key intermediate
Method.
Background technology
(R) complete entitled (the R) -3- tertiary butyl dimethyl Sis Ji Wuersuanjia of -3-TBDMSO glutaric acids first monoesters Chinese is mono-
Ester, it is the key intermediate of synthesizing rosuvastatin spit of fland calcium (Rosuvastatin), and chemical structural formula is as follows：
Rosuvastain calcium (Rosuvastatin Calcium) is that a kind of HMG CoA (HMG-COA) is gone back
Reductase inhibitor can reduce the concentration of raised low density cholesterol, T-CHOL, triglycerides and apoB, simultaneously
The concentration of increasing high density cholesterol, available for primary hypercholesterolemia, mixed type dyslipidemia and homozygous family
The complex treatment of race's property hypercholesterolemia；Rosuvastain calcium inhibits the effect of HMG-CoA reductase than existing listing statin
Class drug is stronger, and has many advantages, such as hepatic cell selective, have efficiently, low toxicity, Small side effects, statins it is reported that
Also there is anti AIDS virus (HIV), and the favor for also having other potential application values to receive people, market prospects
Fairly good, the market demand becomes prosperous.But since its preparation has suitable difficulty, the control of content of isomer is extremely stringent, needs
Have and more can ensure that the technique of its optical texture to prepare, synthesized using (R) -3-TBDMSO glutaric acid first monoesters intermediated chemistries method
Rosuvastain calcium technological process is as follows：
Chirality (R) -3- tertiary butyl dimethyl Si base monomethyl glutarate class compounds, mainly passing through are prepared at present
Method synthesis, it common are chiral reagent method and catalyst method.Document (J.Org.Chem.Vol.59, No.25,7849-
7854,1994) it discloses and prepares (R) -3- tertiary butyl dimethyl Si base monomethyl glutarates by raw material of anhydride compound：
But the first step reaction product yield of this method is low, needs the chiral reagent that purchasing price is high, subsequent processing
Complexity, environmental pollution is serious, equally exists the problem of manufacturing cost is higher, addition catalyst method synthesis R-J6Reaction condition is severe
It carves, (such as low temperature) carries out chemical method generally in extreme conditions, needs expensive catalyst, and often contain in catalyst
There is heavy metal, influence the quality of product, production process energy consumption is big, easily generates a large amount of waste water, causes environmental pollution, is unsuitable for work
Industryization mass produces.And people study and find enzymic catalytic reaction with reaction condition is mild, side reaction is few, high selectivity, ring
The advantages that border pollution is small.Biological enzyme is mainly to be obtained using asymmetric reduction or asymmetric hydrolysis.At present, preparation method
In main shortcoming be：3- carbonyls-glutaric acid or the 3- substitutions-solubility of glutaric acid diester (substrate) in aqueous solution are very
Concentration that is small, feeding intake is very low and the obtained yield of product (R) -3- hydroxyl glutaric acid monoesters is extremely low.Therefore one is found newly
Preparation method it is most important to solve shortcoming present in current synthetic method.
Invention content
The technical solution adopted by the present invention is：The object of the present invention is to provide a kind of reaction step is short, cost is relatively low, high yield
The enzyme process nonaqueous phase of amount catalyzes and synthesizes (R) -3-TBDMSO glutaric acid first monoesters (R-J6) and its derivative preparation method.The party
Lipase described in method is one of following：LipozymeTLIM, Novozym435, Trypsin are lipase purchased in market, preferably
Novozyme435 is catalyst, and substrate is 3-TBDMSO glutaric anhydrides or 3-TBDMSO glutaric acids, and auxiliary substrate is methanol or ethyl alcohol
Or propyl alcohol or butanol or benzyl alcohol, simple for process, green pollution-free.In order to solve the above technical problems, it realizes extensive raw
Produce R-J6, key reaction flow of the invention is as follows：
In above formula, R is methyl, ethyl, propyl, butyl or benzyl and other C1-C8Arbitrary substitution alkyl；Substrate is
3-TBDMSO glutaric anhydrides or 3-TBDMSO glutaric acids；
Technical scheme of the present invention：
1st, the foundation of (R) -3-TBDMSO glutaric acid first monoesters and substrate content high performance liquid chromatography
Sample removes enzyme through 5000rpm centrifugations 2min, and organic phase is taken to be placed in electric heating constant-temperature blowing drying box in centrifuge tube
Middle drying removes solvent, sample is dissolved in suitable mobile phase (the appropriate multiple of dilution), with 0.22 μm of organic membrane filter, filter
Liquid detects for liquid-phase inlet.Using (R) -3-TBDMSO glutaric acid first monoesters as standard items, prepare 0.5,1,2,2.7,3.3,
3.8th, 6,8,10,12, the 17, standard solution of 20g/L.Using 3-TBDMSO glutaric anhydrides as standard items, prepare 2,4,6,8,10,
15th, the standard solution of 16g/L.By supernatant and standard solution after 0.22 μm of organic membrane filtration of micropore, high-efficient liquid phase color is used
Spectrometry measures the content of (R) -3-TBDMSO glutaric acid first monoesters and substrate (3-TBDMSO glutaric anhydrides).
Chromatographic condition：
Chromatographic column：DAICEL ChiralPak AD-H 5μm(4.0×250mm)；
Mobile phase：N-hexane (n-Hexane): isopropanol (Iso-propanol)=96: 4 (0.02% trifluoroacetic acid (v/
v))；, with 0.45 μm of membrane filtration；
Column temperature：25℃；Detection wavelength：210nm；
Sample size：10μl；Flow velocity：1.0ml/min；
(R) -3-TBDMSO glutaric acids first monoesters (R-J6) standard specimen appearance time be 7.778min (Fig. 1)；R-J60.5~
Linear relationship is best in 20.0g/L concentration ranges, such as Fig. 2, R-J6Regression equation：(Y represents R-J to Y=126.9X-18.4146's
Peak area；X represents R-J6Standard specimen concentration), coefficient R2=0.99945.
3-TBDMSO glutaric anhydrides (substrate) appearance time is 11.341min (Fig. 3), and 3-TBDMSO glutaric anhydrides are 1.0
Linear relationship is best in~20.0g/L concentration ranges, such as Fig. 4, substrate regression equation：(Y represents peak to Y=121.48X+28.045
Area；X represents the concentration of substrate standard specimen), coefficient R2=0.99907.It it is demonstrated experimentally that can be same using identical testing conditions
When measure target product R-J6Product assay and concentration of substrate.
2nd, a kind of auxiliary substrate of computer-aided screening (alcohol) for producing (R) -3-TBDMSO glutaric acid first monoesters
It is as follows that chemical method prepares rosuvastain calcium final step technological process：
Ester bond in its branch finally can be hydrolyzed, and illustrate the type of alcohol (auxiliary substrate) to end product quality without shadow
It rings.And the space structure of variety classes alcohol is different, it is different that the conformation of enzyme is influenced, i.e., variety classes alcohol influences the enantiomer choosing of enzyme
Selecting property.Different alcohol is selected as ligand, observation R types product and S types product and the ratio of zymoprotein molecular docking free energy
Variation.In addition to benzyl alcohol and benzyl carbinol, supplemented by other alcohol during substrate, esterification can occur, and can detect monoesters
Change product to exist.By comparing, if finding substrate supplemented by selection methanol, ER/ESRatio highest, be 1.072, illustrate it more
Conducive to the product of synthesis R configurations, therefore it is preferred that methanol is as auxiliary substrate.
3rd, a kind of Production by Enzymes (R) -3-TBDMSO glutaric acid first monoesters (R-J6) lipase screening.
The enzyme for separate sources lipase (the immobilized lipase Novozyme435 (N435) of commercialization and
Lipozyme TLIM are respectively provided with higher catalytic activity, the relatively low pancreatin of city's price), screening is conducive to synthesis R-J6Best enzyme, and
It is applied to R-J6Production.High effective liquid chromatography for measuring product assay is used after conversion.The study found that after conversion for 24 hours
Novozyme435 catalyzes and synthesizes the R-J of 29.3g/L6, production intensity reaches 1.22 (g/Lh) thereon at this time, therefore it is preferred that
Novozyme435。
4th, a kind of Production by Enzymes (R) -3-TBDMSO glutaric acid first monoesters (R-J6) reaction condition optimization.
Influence of the condition of optimizing the environment to esterification, when the initial pH of Novozyme435 immobilised enzymes 7.2-8.6 it
Between, R-J6Change of production it is little, be maintained at 0.7-1.4g/L or so, when initial pH be 9.5 when, R-J6Yield reach 4.2g/
L；When the temperature is 35 DEG C, R-J6Yield reach 17.03g/L；The organic solvent is selected from methyl tertiary butyl ether, different
Octane, n-hexane, normal octane, when solvent is isooctane, R-J6Yield reach 21.5g/L or so；Enzymatic conversion condition optimizing
After, measure R-J in conversion fluid with HPLC6Content is 67.1g/L.
Molar ratio (the alcohol acid anhydride mole of 3-TBDMSO glutaric anhydrides concentration (concentration of substrate), methanol (auxiliary substrate) and substrate
Than), immobilised enzymes Novozyme435 concentration (enzyme concentration) Three factors-levels orthogonal experiments find it is as follows：Enzymatic
Influence factor primary and secondary sequence be：Concentration of substrate ＞ alcohol acid anhydride molar ratio ＞ enzyme concentrations；Optimal enzymatic conversion system is concentration of substrate
250g/L, enzyme concentration 60g/L, alcohol acid anhydride molar ratio 2: 1；Solvent is isooctane；Catalytic temperature is 35 DEG C, after enzymatic conversion item, is turned
Change R-J in liquid6Content is up to 68.9g/L, production intensity 2.87 (g/Lh).
Description of the drawings
Fig. 1 is (R) -3-TBDMSO glutaric acid first monoesters (R-J6) (single configuration) standard specimen liquid chromatogram.
Fig. 2 is (R) -3-TBDMSO glutaric acid first monoesters (single configuration) standard curve.
Fig. 3 is 3-TBDMSO glutaric anhydride standard specimen liquid chromatograms.
Fig. 4 is 3-TBDMSO glutaric anhydride linear regression curves.
The initial pH of Fig. 5 are to the influence relational graph of (R) -3-TBDMSO glutaric acid first monoesters enzymatic clarifications.
The influence relational graph that Fig. 6 temperature synthesizes (R) -3-TBDMSO glutaric acid first monoesters.
Fig. 7 different solvents are to the influence relational graph of (R) -3-TBDMSO glutaric acid first monoesters enzymatic clarifications.
The influence relational graph that Fig. 8 methanol synthesizes (R) -3-TBDMSO glutaric acid first monoesters with anhydride molar ratio value.
Fig. 9 Novozyme43 enzyme concentrations are to the influence relational graph of enzymatic clarification (R) -3-TBDMSO glutaric acid first monoesters.
Figure 10 concentration of substrate is to the influence relational graph of (R) -3-TBDMSO glutaric acid first monoesters enzymatic clarifications.
Specific embodiment
It is the embodiment of nonaqueous phase enzyme law catalysis production (R) -3-TBDMSO glutaric acid first monoesters below.
1. optimal auxiliary substrate alcohol Structure Selection
With three-dimensional structure (the structure X differences for the product J that Chem-Office software buildings are synthesized using different types of alcohol
Product J three-dimensional structure), the energy-optimised Charmm field of forces.Different product J is as ligand respectively with being obtained on PDB websites
CALB (1TCA) crystal structure obtained carries out molecular docking, and finally docking energy is compared and (is shown in Table 1).It was found that when
Supplemented by methanol during substrate, ER/ESRatio highest, it is more conducive to synthesize the product of R configurations, therefore it is preferred that methanol is as auxiliary substrate.
The molecular docking energy comparison of the different alcohol of table 1 and CALB enzymes
a.ER/ESFor the docking energy of R isomers and ratio (Kcal/mol) for docking energy of R isomers
B. "+" represents that enzymic catalytic reaction can occur, and can detect that mono-ester product exists in conversion fluid, and "-" represents anti-
It answers and fails to detect that mono-ester product exists in conversion fluid.
2. different lipase enzymatic clarification (R) -3-TBDMSO glutaric acid first monoesters (R-J6) catalytic effect.
3-TBDMSO glutaric anhydrides (substrate) a concentration of 120g/L, final enzyme concentration are 60g/L, auxiliary substrate (methanol) and bottom
The molar ratio of object be 3: 1, solvent be methyl tertiary butyl ether(MTBE) (MTBE), 37 DEG C of reaction temperature, shaking speed 200rpm.Using not
With the immobilized lipase in source, different lipase are investigated to R-J6The influence of yield, is surveyed after conversion with high performance liquid chromatography
Determine product assay, the results are shown in Table 2.The study found that Novozyme435 catalyzes and synthesizes the R-J of 29.3g/L after conversion for 24 hours6, at this time
It is 1.22 (g/Lh) that it, which produces intensity, therefore the preferred Novozyme435 of catalyst.
Table 2. compares to synthesize R-J6Different lipase changing effect
3. initial pH optimizations：
Novozyme435 is catalyst, and 3-TBDMSO glutaric anhydrides (substrate) 30g/L, final enzyme concentration is 0.1g, is reacted
The molar ratio of system 10mL, methanol and substrate is 3: 1；Weigh the Novozyme 435 of equivalent pH be respectively 6.1,6.8,7.2,
8.0th, it is handled in 8.6,9.5 aqueous solutions overnight, freeze-drying removes all water, is converted in MTBE solvents, conversion temperature
It is 35 DEG C, rotating speed 200r/min to spend, and detects R-J6Yield.When initial pH is between 7.2-8.6, R-J6Change of production it is little,
Maintain 0.7-1.4g/L or so；When initial pH is 9.5, R-J6Yield reach 4.2g/L, as shown in Figure 5.
4. temperature optimization：
Novozyme435 is catalyst, ultimate density 80g/L, using isooctane as solvent, to the 3- of 20g/L
In TBDMSO glutaric anhydrides (substrate), reaction system total volume is 10mL, and substrate is 3: 1 with methanol molar ratio；Respectively in temperature
It is 22 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 45 DEG C, is converted under the conditions of 200r/min, detects R-J6Yield.The results are shown in Figure 6, works as temperature
It spends when being 35 DEG C, R-J6Yield reach 18.03g/L.Preferred catalytic temperature is 35 DEG C.
5. solvent optimization：
Novozyme435 is catalyst, and 3-TBDMSO glutaric anhydrides (substrate) concentration 40g/L, final enzyme concentration is 20g/
L, the molar ratio 3: 1 of auxiliary substrate (methanol) and substrate, solvent be respectively methyl tertiary butyl ether(MTBE), n-hexane, normal octane, isooctane,
Isooctane (5% toluene (v/v)), 35 DEG C, shaking speed 200rpm of reaction temperature, conversion is for 24 hours.It is surveyed with high performance liquid chromatography
Fixed (R) -3-TBDMSO glutaric acid first monoesters (R-J6) content.The results are shown in Figure 7, when it is solvent to choose isooctane, R-J6Contain
Amount is up to 21.5g/L, R-J6Yield reaches 35%, and preferably isooctane is reaction dissolvent.
6. methanol optimizes with anhydride molar ratio value (alcohol acid anhydride ratio)：
Novozyme435 is catalyst, using isooctane as solvent, 3-TBDMSO glutaric anhydrides (substrate) 40g/L, and final enzyme
A concentration of 20g/L, reaction system 10mL, methanol and substrate molar ratio are respectively 1,2,3,4,5；35 DEG C of reaction temperature, shaking table turn
Speed is 200rpm, and conversion is for 24 hours.Detect R-J6Yield.The results are shown in Figure 8, when alcohol acid anhydride molar ratio reaches 2: 1, target product
R-J6Yield and yield reach maximum, respectively 9.8g/L and 20% then improves alcohol acid anhydride molar ratio, to R-J6Yield shadow
Ring little, enzymatic clarification R-J6Optimal alcohol acid anhydride molar ratio is 2: 1.
7. enzyme concentration optimizes：
Novozyme435 is catalyst, using isooctane as solvent, auxiliary substrate (methanol) and the molar ratio 2: 1 of substrate, and 3-
TBDMSO glutaric anhydrides (substrate) concentration 60g/L, final enzyme concentration are respectively 10g/L, 20g/L, 50g/L, 60g/L, 90g/L,
Reaction system 10mL, 35 DEG C, shaking speed 200rpm of reaction temperature, conversion is for 24 hours.Detect R-J6Yield.As a result such as Fig. 9 institutes
Show, when enzyme concentration reaches 60g/L, target product R-J6Yield and yield reach maximum, respectively 13.2g/L and
22%；Therefore a concentration of 60g/L of preferred enzyme.
8. concentration of substrate optimizes：
Novozyme435 is catalyst, and isooctane is solvent, and the molar ratio of auxiliary substrate (methanol) and substrate is 2: 1, with
60g/L Novozym 435s are catalysts, and 3-TBDMSO glutaric anhydrides (substrate) concentration is respectively 40g/L, 50g/L, 80g/
L, 100g/L, 160g/L, 200g/L, reaction system 10mL, reaction temperature are 35 DEG C, shaking speed 200rpm, and conversion is for 24 hours.
Detect R-J6Yield.The results are shown in Figure 10, when concentration of substrate reaches 200g/L, R-J6Yield be 33.53%, R-J6's
Yield reaches up to 67.1g/L.Therefore immobilised enzymes synthesis R-J6More excellent concentration of substrate is 200g/L.
9. optimization of orthogonal test：
Orthogonal design table is designed using 8.0 softwares of Design-Expert.Investigate 3-TBDMSO glutaric anhydride concentration
The molar ratio (alcohol acid anhydride molar ratio) of (concentration of substrate), methanol (auxiliary substrate) and substrate, immobilised enzymes Novozyme435 concentration (enzymes
Concentration) to the combined influence situation of esterification.Reaction dissolvent is isooctane, and reaction temperature is 35 DEG C, and shaking speed is
200rpm, conversion is for 24 hours.Detect R-J6Yield.Enzymatic influence factor primary and secondary sequence be：Concentration of substrate ＞ alcohol acid anhydride molar ratios ＞
Enzyme concentration；Optimal enzymatic conversion system be concentration of substrate 250g/L, enzyme concentration 60g/L, alcohol acid anhydride molar ratio 2: 1；Solvent is different pungent
Alkane；Catalytic temperature is 35 DEG C,
3. orthogonal test table of table
Claims (7)
1. a kind of enzyme process nonaqueous phase catalyzes and synthesizes the preparation method of (R) -3-TBDMSO glutaric acid first monoesters and its derivative,
Preparation process is represented with formulas below：
In above formula, R is methyl, ethyl, n-propyl, normal-butyl, isobutyl group, tertiary butyl, just base；Substrate is 3-TBDMSO penta
Dicarboxylic anhydride or 3-TBDMSO glutaric acids；Its cardinal principle is in nonaqueous phase organic solvent, utilizes lipase
Novozyme435 is catalyzed substrate, is allowed to alcoholysis, realizes the mono-esterification of dicarboxylic acids, passes through inorganic base NaHCO3PH value is adjusted, is had
Solvent extracts, and can obtain chipal compounds (R) -3-TBDMSO glutaric acid monoesters；
The organic solvent is selected from isooctane, n-hexane, normal octane；The lipase is one of following：LipozymeTLIM、
Novozym435、Trypsin；The substrate is selected from 3-TBDMSO glutaric anhydrides or 3-TBDMSO glutaric acids.
2. method according to claim 1, which is characterized in that the substrate is 3-TBDMSO glutaric anhydrides.
3. a kind of enzyme process nonaqueous phase according to claim 1 catalyze and synthesize (R) -3-TBDMSO glutaric acid first monoesters and its
The preparation method of derivative, it is characterised in that：The alcohol is selected from methanol, ethyl alcohol, propyl alcohol, n-butanol, isobutanol.
4. method according to claim 3, it is characterised in that the alcohol is methanol.
5. a kind of enzyme process nonaqueous phase according to claim 1 catalyze and synthesize (R) -3-TBDMSO glutaric acid first monoesters and its
The preparation method of derivative, it is characterised in that：Vacuum after the Novozym435 is handled in advance with the buffer solution of different pH
It is dry, make the pH of enzyme institute " memory " between 7.2-9.5, then for the chiral catalysis of enzyme.
6. a kind of enzyme process nonaqueous phase according to claim 1 catalyze and synthesize (R) -3-TBDMSO glutaric acid first monoesters and its
The preparation method of derivative, it is characterised in that：The 3-TBDMSO glutaric anhydrides concentration of substrate is 160-250g/L；Auxiliary substrate first
The molar concentration ratio of alcohol and substrate is 1: 1-5: 1；A concentration of 20-90g/L of addition of enzyme；Enzymatic system temperature maintains
35-50℃；Enzymic catalytic reaction time 6-45h；(R) yield of -3-TBDMSO glutaric acids first monoesters is up to 68.87g/L, and production is by force
It spends for 2.87 g/Lh.
7. a kind of enzyme process nonaqueous phase according to claim 1 catalyze and synthesize (R) -3-TBDMSO glutaric acid first monoesters and its
The preparation method of derivative, it is characterised in that：(the R) -3-TBDMSO and its derivative object detecting method use efficient liquid phase
Detection method, chromatographic column are 5 μm of 4.0 × 250mm of Daicel ChiralPak AD-H, and mobile phase is n-hexane n-Hexane：
Isopropanol Iso-propanol=96: 4,0.02% trifluoroacetic acid v/v, with 0.45 μm of membrane filtration, column temperature is 5-40 DEG C, detection
Wavelength is 210-350nm, and sample size is 5-30 μ l, flow velocity 0.5-1.5ml/min.
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| CN1742000A (en) * | 2002-12-10 | 2006-03-01 | 兰贝克赛实验室有限公司 | Process for the preparation of rosuvastatin |
| CN103361386A (en) * | 2013-06-28 | 2013-10-23 | 苏州汉酶生物技术有限公司 | Method for preparing rosuvastatin intermediate |
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| CN1742000A (en) * | 2002-12-10 | 2006-03-01 | 兰贝克赛实验室有限公司 | Process for the preparation of rosuvastatin |
| CN103361386A (en) * | 2013-06-28 | 2013-10-23 | 苏州汉酶生物技术有限公司 | Method for preparing rosuvastatin intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 固定化脂肪酶合成3-TBDMSO戊二酸甲酯;王霞等;《化学工程》;20140731;第42卷(第7期);第7页右栏第1段，第1.2-1.3节，第8页左栏第2段，右栏第5段，右栏第7段，第9页第1段，第10页左栏第2.3节，图4，右栏第3节 * |
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