CN109295119A - A kind of Biocatalysis method producing statins drug midbody - Google Patents
A kind of Biocatalysis method producing statins drug midbody Download PDFInfo
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Abstract
This application provides a kind of Biocatalysis methods for producing statins drug midbody A7, comprising the following steps: with chloro- 3, the 5- dihydroxy hecanoic acid t-butyl ester, that is, D3 of (3R, 5S) 6- for substrate, the substrate D3 disposably feeds intake 20-150g/L；Using halohydrin dehalogenase as catalyst；Substrate NaCN aqueous solution does not stop according to reaction solution pH to be added, and the control method of reaction solution pH is staged raising, is improved from initial pH7.0 to pH9.0；Chaotropic agent and hydrolysis inhibitor of the final concentration 0.2-1.5v/v% tert-butyl alcohol as D3 and A7 are added, under the conditions of 25-45 DEG C, reacts 1.5-4h, it is final to obtain product Stains pharmaceutical intermediate A7.The present invention provides effective solution for the hydrolysis problem of A7 biocatalysis process, to improve the productivity and A7 yield of catalytic process.
Description
Technical field
The present invention relates to field of medicine preparing technology, more particularly, to a kind of production statins drug midbody (3R, 5R)
The Biocatalysis method of 6- itrile group -3,5- dihydroxy hecanoic acid t-butyl ester (A7).
Background technique
Cardiovascular and cerebrovascular disease is that one kind seriously threatens the mankind, has the characteristics that high illness rate, high disability rate and high mortality,
The number that cardiovascular and cerebrovascular disease is died of in the whole world every year is up to 15,000,000 people, and it is the first to occupy the various causes of the death.Domestic Adjust-blood lipid in 2015
Class drug overall market more than 20,000,000,000 yuans, come out top by statins, domestic statins terminal retail price city
Field has reached 151.43 hundred million yuan of scale, accounts for entire reducing blood lipid medication market nearly 80%.Wherein, statins list nearly 20 years
It is clinical prove, drug safety is high, adverse reaction is small, better than other statins in terms of reducing LDL cholesterol treatment.
2015, Chinese statins overall market reached 83.19 hundred million yuan, and year-on-year upper one year increases 7.97%, and still presents
The trend to go up year by year.
With increasingly sharpening for market competition and implementing for corporate social responsibility, the production technology of atorvastatin is needed
It improves and innovates, on the one hand need to reduce industrial production to the destruction of environmental resource and the waste of the energy, on the other hand can reduce enterprise
Industry cost and patient medication cost, to promote the economic benefit and social benefit of entire industry.Upgraded using biocatalysis technology
Statins key intermediate of medicament synthetic technology can establish energy conservation, green, efficient new production process.Halohydrin is de-
Halogen enzyme has the chemical synthesis step of one step conversion substitution high energy consumption and high solvent dosage, has the characteristic of efficient catalytic, fits
For establishing the statins side chain new technique for synthesizing of low energy consumption, low cost and environmental protection.
The key difficult point of A7 biocatalysis first is that the hydrolysis of product and substrate in aqueous solution, Chinese patent application
CN105567655A discloses a kind of halide alcohol dehalogenase and its application in synthesis statins drug midbody, although this document
By being recombinated to halide alcohol dehalogenase, yield is improved to a certain extent, but does not have patent disclosure to solve A7 and D3
In the hydrolysis problem of biocatalysis process.In some disclosed patents, the time of Biocatalytic Conversion is greater than 10 hours, this phase
Between the hydrolysis of A7 and D3 be difficult to effectively to avoid, how to effectively reduce the reaction time, catalytic conversion efficiency and A7 biology be provided
The key of catalysis.The present invention be directed to A7 biocatalysis the two critical issues, i.e., the hydrolysis problem of product and bottom and how fastly
Speed completes catalysis reaction, discloses corresponding solution.
Summary of the invention
In view of the above-mentioned problems existing in the prior art, this application provides a kind of biologies for producing statins drug midbody
Catalysis process.The present invention provides effective solution for the hydrolysis problem of A7 biocatalysis process, is catalyzed to improve
The productivity and A7 yield of journey.
Technical scheme is as follows:
A kind of Biocatalysis method producing statins drug midbody A7, the A7 are (3R, 5R) 6- itrile group -3,5- bis-
The hydroxycaproic acid tert-butyl ester, comprising the following steps:
With chloro- 3, the 5- dihydroxy hecanoic acid t-butyl ester, that is, D3 of (3R, 5S) 6- for substrate, the substrate D3 disposably feeds intake 20-
150g/L；Using halohydrin dehalogenase as catalyst；Substrate NaCN aqueous solution carries out stream according to reaction solution pH and adds, the control of reaction solution pH
Method processed is staged raising, is improved from initial pH7.0 to pH9.0；Add final concentration 0.2-1.5v/v% tert-butyl alcohol conduct
The chaotropic agent and hydrolysis inhibitor of D3 and A7 reacts 1.5-4h under the conditions of 25-45 DEG C, final to obtain product Atorvastatin
Class pharmaceutical intermediate A7.
The control method of the reaction solution pH improves 0.2-0.5 pH every 10-30min by reacting initial pH7.0
Value, i.e. staged improve pH value in reaction；The reacting liquid pH value that improves is realized by stream plus the NaCN aqueous solution of alkalinity.
Preferably, the mass concentration of the NaCN aqueous solution is 5-30%.
The chaotropic agent and the hydrolysis inhibitor tert-butyl alcohol of A7 and D3 are added in the catalysis reaction solution, addition manner is reaction
The tert-butyl alcohol is added at one time when beginning.
The halohydrin dehalogenase be with catalysis substrate D3 synthesize A7 halohydrin dehalogenase, be commercial enzyme preparation or
The fermentation liquid of enzyme；Its inventory are as follows: dosage is not less than 500U halohydrin dehalogenase preparation in every kilogram of substrate D3, and first in reaction
Phase disposably feeds intake.
Above-mentioned catalysis reaction obtains product A7, and residual rate of the catalysis yield not less than 95%, D3 of the A7 is not more than
3%.
Further, the addition final concentration of the substrate D3 is with the preferred 80-100g/L of reaction solution volume；The NaCN preferably with
The form of mass concentration 10-30%NaCN aqueous solution is added.
Further, the catalyst is halohydrin dehalogenase, has the bioactivity of catalysis D3 conversion A7, including business
Change halohydrin dehalogenase enzyme preparation or the halogen according to made from the patent (application No. is CN 201810133923.2) of published application
For alcohol dehalogenase fermentation liquid.
Further, the staged improves reacting liquid pH value, i.e. the reaction of catalysis D3 conversion A7 generates hydrochloric acid, reduces pH,
As shown in Figure 1, automatically controlling pH by stream plus alkalinity NaCN aqueous solution.The control of initial reaction liquid pH value is 7.0, and reaction starts
Afterwards, every 10-30min, the pH value control point of 0.2-0.5, the i.e. pH value of staged raising reaction solution are improved.
Further, the addition chaotropic agent and the hydrolysis inhibitor tert-butyl alcohol, final concentration are preferred in terms of reaction solution volume
0.5% (v/v).
Further, the reaction temperature is 25-45 DEG C (preferably 35-40 DEG C).
The present invention is beneficial to be had the technical effect that
During the biocatalysis for producing statins drug midbody A7, substrate, intermediate product and product are easy to hydrolyze,
Catalysis reaction yield is reduced, this is the production problem of the efficient production catalysis of puzzlement, before and has no relevant effective workaround.
The present invention with chloro- 3, the 5- dihydroxy hecanoic acid t-butyl ester (D3) of (3R, 5S) 6- be substrate, to be commercialized halohydrin dehalogenase enzyme preparation
Or the fermentation liquid of enzyme is catalyst, the method for preparing A7 using biocatalysis technology, the hydrolysis for A7 biocatalysis process asks
Topic provides effective solution, to improve the productivity and A7 yield of catalytic process.
Main innovation point of the present invention is embodied in two aspects:
1. producing acid according to catalysis reaction pilot process, the low feature of stability, invention are set in aqueous solution with substrate D3 and A7
The control method that staged improves reaction solution pH is counted；I.e. by stream plus alkaline substrate NaCN aqueous solution, make reacting liquid pH value rank
Ladder type rises, and accelerates rate of catalysis reaction, substantially reduces the reaction time, reduces the hydrolysis of substrate and product, effectively improves A7's
Catalyzed conversion yield；
2. according to the structure feature of substrate and product and water-soluble low feature, addition have promote substrate D3 dissolution and
Inhibit the difunctional tert-butyl alcohol of D3 and A7 hydrolysis, effectively acceleration reaction rate, inhibits product and substrate hydrolysis.
By the process modification of both new methods, the reaction rate of D3 Biocatalytic Conversion A7 improves 20% or more,
The yield of product A7 improves 15% or more.The biocatalysis yield of A7 improves 10-25%, and the biocatalysis for significantly improving A7 is raw
Produce efficiency.
Detailed description of the invention
Fig. 1 is the reaction process that halohydrin dehalogenase catalysis substrate D3 generates A7.
Fig. 2 be substrate D3, intermediate product epoxy material, product A7 gas chromatographic analysis figure and its catalysis initial reaction stage and
React the data analysis chart in later period.
Fig. 3 is the influence of different pH dominating pair of vertices D3 catalyzed conversion A3 rates and conversion ratio.
Fig. 4 is that single-point pH is controlled compared with gradient promotes the catalysis process of pH control.
Fig. 5 is the influence adding various concentration chaotropic agent and the hydrolysis inhibitor tert-butyl alcohol and generating to A7.
Specific embodiment
With reference to the accompanying drawings and examples, the present invention is specifically described, but protection scope of the present invention and not only limited
In this.
Embodiment 1: the biocatalytic reaction of A7 is carried out using different pH value control points
The preparation of halohydrin dehalogenase fermentation liquid: according to patent (the application number CN of published application
201810133923.2) halohydrin dehalogenase fermentation liquid, cell density 100g/L, are prepared, the enzyme activity of dehalogenase is 160U/
ML (enzyme activity definition and enzyme activity determination method, see the patent of application number CN 201810133923.2).
10ml halohydrin dehalogenase fermentation liquid is taken, distilled water 30ml is added, high-pressure homogenization obtains fresh halohydrin dehalogenation
Enzyme enzyme solution is placed in 40 DEG C of water-baths.Agitating device and pH automatic control device are installed.4g substrate D3 is added, i.e. inventory is
100g/L.Automatic Titration reaction solution pH is carried out using 10wt%NaCN aqueous solution.Set the different control points pH, including pH7.0,
PH7.5, pH8.0, pH8.5 and pH9.0.
Sampling analysis in reaction process.Sample treatment is as follows: taking 100 μ L of sample, is added to the ethyl acetate of 1.0mL
In；After fulling shake, 10000 × g is centrifuged 1min；100 μ L of supernatant is taken, is added in the ethyl acetate of 900 μ L；By diluted sample
Product are used for gas chromatographic analysis.
Gas chromatography analysis method is as follows: capillary chromatographic column: 30m × 0.53mm × 1.5 μm DB1701；Column temperature: 100
DEG C 200 DEG C are warming up to 20 DEG C/min, keep the temperature 5min；Injector temperature: 140 DEG C；Detector temperature: 260 DEG C；Carrier gas (N2):
5ml/min；Split ratio: 20: 1；Sample volume: 1 μ l；Blank solution: ethyl acetate.In reaction process, D3, the color for being cyclized object and A7
Spectral peak, as shown in Figure 2.
Catalytic reaction process automatically controls point using different pH, generates yield to rate of catalysis reaction and A and causes significantly
It influences, D3 and A7 are as shown in Figure 3 in the comparison of reaction process dynamic change.
When controlling reaction solution pH7.0, reaction speed is slower, reacts 10 hours, D3 still remains 72.3%, and A7 is only generated
13.6%.But, according to D3+A7+ be cyclized object total concentration, decline it is slower, show its in pH7.0, these compound phases
To relatively stable.
It when controlling reaction solution pH7.5, is significantly increased, reacts 10 hours when reaction rate is compared with pH7.0, D3 residual
45.1%, and A7 generates 44.6%.And total concentration is declined.
It when controlling reaction solution pH8.0, is significantly increased, reacts 10 hours when reaction rate is compared with pH7.5, D3 residual
9.8%, and A7 generates 80.6%.And total concentration decline is obvious.
When controlling reaction solution pH8.5, reaction rate is fast, reacts 6 hours, D3 residual 5%, and A7 generates 90.7%, table
Bright higher pH is remarkably improved catalytic rate.But total concentration decline is obvious, when reacting 3.5h, declines when total concentration is compared with 0.5h
24%.
When controlling reaction solution pH9.0, reaction rate quickly, is reacted 3.5 hours, D3 residual 3.2%, and A7 is generated
92.2%, show that higher pH is remarkably improved catalytic rate, but total concentration decline is obvious, it is aobvious to show that hydrolysis occurs for substrate and product
It writes.
So using halohydrin dehalogenase, the reaction of catalysis D3 conversion A7 improves reaction solution pH and is remarkably improved reaction speed
Rate, but increase the hydrolysis rate of substrate and product simultaneously, pass through the single control point pH, it is difficult to reach higher A7 yield.
Embodiment 2: the biocatalytic reaction that reaction solution pH carries out A7 is improved using procedural staged
The halohydrin dehalogenase fermentation enzyme solution that 10mi is above-mentioned is taken, distilled water 30ml is added, high-pressure homogenization obtains fresh halogen
For alcohol dehalogenase enzyme solution, it is placed in 40 DEG C of water-baths.Agitating device and pH automatic control device are installed.4g substrate D3 is added, that is, throws
Doses is 100g/L.Automatic Titration reaction solution pH is carried out using 10wt%NaCN aqueous solution.
Procedural raising pH:pH7.0,10min are set；PH7.5,10min；PH8.0,20min；PH8.25,30min；
PH8.5,30min；PH8.8,20min；PH9.0,10min.And using the single control method of pH8.85 as control.Catalytic process takes
The variation of the rate of change and concentration of sample analysis, D3 and A7 is as shown in Figure 4.
When single high ph-values, which control, reacts, i.e. pH8.85, reaction rate is very fast, reacts 3.5 hours, D3 residual concentration accounts for
Than being 5%, and the concentration accounting that A7 is generated is 91.8%, realizes quick catalysis.But total concentration decline is obvious, when reacting 3.5h,
Total concentration decrease speed is accelerated.After reaction 2 hours, A7 generates rate and slows down, and concentration reduces instead, illustrates that hydrolysis rate is accelerated.
To the catalysis reaction solution of single pH point control, A7 yield analysis is carried out: using the ethyl acetate of 3 times of volumes to reaction
Liquid carries out extraction 2 times；The acetic acid ethyl acetate extract for merging 2 times, is settled to 250mL；Extract liquor is taken, using ethyl acetate dilution 30
After times, it to be used for gas chromatographic analysis.The result shows that the amount for generating A7 is 2.74g, the remaining amount of D3 is 0.17g.And the theory of A7
Yield is 3.84g, so A7 net yield are as follows: 71.2%.
And when staged being used to promote the control method of pH, such as Fig. 4, reaction rate is also very fast, after reaction in 3.5 hours, D3
It remains 5.9%, A7 and generates 89.6%.The rapid decrease of total concentration is effectively controlled, and shows that the hydrolysis rate of product and substrate is bright
It is aobvious to weaken.In addition, A7 concentration keeps sustainable growth in entire reaction process, show that A7 is persistently generated, and inhibit its too fast hydrolysis.
The catalysis reaction solution of pH control is promoted to gradient, carries out A7 yield analysis: using the ethyl acetate of 3 times of volumes to anti-
Liquid is answered to carry out extraction 2 times；The acetic acid ethyl acetate extract for merging 2 times, is settled to 250mL；Extract liquor is taken, is diluted using ethyl acetate
After 20 times, it to be used for gas chromatographic analysis.The result shows that the amount for generating A7 is 3.55g, the remaining amount of D3 is 0.2g.And the reason of A7
It is 3.84g by yield, so A7 net yield are as follows: 92.4%.
Embodiment 3: the biocatalytic reaction of addition chaotropic agent and hydrolysis inhibitor tert-butyl alcohol progress A7
The halohydrin dehalogenase fermentation enzyme solution that 10ml is above-mentioned is taken, distilled water 30ml is added, high-pressure homogenization obtains fresh halogen
For alcohol dehalogenase enzyme solution, it is placed in 40 DEG C of water-baths.Agitating device and pH automatic control device are installed.4g substrate D3 is added, that is, throws
Doses is 100g/L.
Add the different amounts of tert-butyl alcohol (in terms of volumetric concentration): 0%, 0.2%, 0.5%, 1.0%, 1.5%.
Automatic Titration reaction solution pH is carried out using 10wt%NaCN aqueous solution, it is as follows that pH increases program: pH7.0,
10min；PH7.5,10min；PH8.0,20min；PH8.25,30min；PH8.5,30min；PH8.8,20min；PH9.0,
10min。
Different tert-butyl alcohol additive amounts, the generation of A7 are more as shown in Figure 5.The result shows that the addition of the tert-butyl alcohol effectively increases
The throughput rate of A7.When add volumetric concentration be respectively 0%, 0.2%, 0.5%, 1.0% and 1.5% when the tert-butyl alcohol when, urge
Change reaction 3.5h, the concentration of A7 is 76.3g/L, 82.4g/L, 91.8g/L, 89.2g/L and 87.7g/L respectively；And D3's is residual
Staying rate is respectively: 4.2%, 2.5%, 1.1%, 0.9% and 0.8%.So adding the tert-butyl alcohol of 0.2%-1.5%, can be improved
The yield of A7 is 8%-20.3%, and the residual rate that the rate of catalysis reaction of D3 improves 15% or more, D3 significantly reduces.
Embodiment 4: addition chaotropic agent and the hydrolysis inhibitor tert-butyl alcohol carry out generating A7 to the D3 catalyzed conversion of 20g/L
The halohydrin dehalogenase fermentation enzyme solution that 10ml is above-mentioned is taken, distilled water 30ml is added, high-pressure homogenization obtains fresh halogen
For alcohol dehalogenase enzyme solution, it is placed in 40 DEG C of water-baths.Agitating device and pH automatic control device are installed.0.8g substrate D3 is added, i.e.,
Inventory is 20g/L.It adds the tert-butyl alcohol (in terms of volumetric concentration): 0.5%.Automatic Titration is carried out using 20wt%NaCN aqueous solution
Reaction solution pH, it is as follows that pH increases program: pH7.0,5min；PH7.5,10min；PH8.0,10min；PH8.25,10min；
PH8.5,10min；PH8.8,5min.Terminate catalysis reaction in 50min.
Reaction terminates, and carries out sample treatment and analysis.Sample treatment is as follows: in the ethyl acetate using 3 times of volumes
It is extracted twice；By extract liquor ethyl acetate constant volume 250ml；The sampling liquid of constant volume ethyl acetate is diluted 5 times, is used for gas phase
Chromatography.
Analysis the result shows that, the yield of A7 is 0.73g, and the residual quantity of D3 is 0.0065g, the i.e. yield of A7 are as follows: 95%, D3
Residual rate are as follows: 0.8%.
Embodiment 5: addition chaotropic agent and the hydrolysis inhibitor tert-butyl alcohol carry out generating A7 to the D3 catalyzed conversion of 150g/L
The halohydrin dehalogenase fermentation enzyme solution that 10ml is above-mentioned is taken, distilled water 30ml is added, high-pressure homogenization obtains fresh halogen
For alcohol dehalogenase enzyme solution, it is placed in 40 DEG C of water-baths.Agitating device and pH automatic control device are installed.6g substrate D3 is added, that is, throws
Doses is 150g/L.It adds the tert-butyl alcohol (in terms of volumetric concentration): 0.5%.Automatic Titration is carried out using 30wt%NaCN aqueous solution
Reaction solution pH, it is as follows that pH increases program: pH7.0,10min；PH7.5,20min；PH8.0,30min；PH8.25,60min；
PH8.6,60min；PH8.8,30min；PH9.0,30min.Terminate catalysis reaction in 4h.
Reaction terminates, and carries out sample treatment and analysis.Sample treatment is as follows: in the ethyl acetate using 3 times of volumes
It is extracted twice；By extract liquor ethyl acetate constant volume 250ml；The sampling liquid of constant volume ethyl acetate is diluted 50 times, is used for gas
Analysis of hplc.
Analysis the result shows that, the residual quantity that the yield of A7 is 5.08, D3 is 0.12g, i.e. the yield of A7 are as follows: 88%, D3's
Residual rate are as follows: 2.0%.
Claims (6)
1. a kind of Biocatalysis method for producing statins drug midbody A7, the A7 is (3R, 5R) 6- itrile group -3,5- dihydroxy
Base hecanoic acid t-butyl ester, it is characterised in that the following steps are included:
With chloro- 3, the 5- dihydroxy hecanoic acid t-butyl ester, that is, D3 of (3R, 5S) 6- for substrate, the substrate D3 disposably feeds intake 20-150g/
L；Using halohydrin dehalogenase as catalyst；Substrate NaCN aqueous solution carries out stream according to reaction solution pH and adds, the controlling party of reaction solution pH
Method is staged raising, is improved from initial pH7.0 to pH9.0；Add the final concentration 0.2-1.5v/v% tert-butyl alcohol as D3 with
The chaotropic agent and hydrolysis inhibitor of A7 reacts 1.5-4h under the conditions of 25-45 DEG C, final to obtain product Stains medicine
Object intermediate A 7.
2. according to the method described in claim 1, it is characterized in that the control method of the reaction solution pH, by reacting initial
PH7.0 improves 0.2-0.5 pH value every 10-30min, i.e. staged improves pH value in reaction；The raising reacting liquid pH value is
It is realized by stream plus the NaCN aqueous solution of alkalinity.
3. method according to claims 1 and 2, it is characterised in that the mass concentration of the NaCN aqueous solution is 5-30%.
4. according to the method described in claim 1, it is characterized in that chaotropic agent and the hydrolysis of A7 and D3 is added in the reaction solution
The inhibitor tert-butyl alcohol, addition manner are that reaction is added at one time the tert-butyl alcohol when starting.
5. according to the method described in claim 1, it is characterized in that the halohydrin dehalogenase is to synthesize with catalysis substrate D3
The halohydrin dehalogenase of A7 is the fermentation liquid of commercial enzyme preparation or enzyme；Its inventory are as follows: dosage is not small in every kilogram of substrate D3
It disposably feeds intake in 500U halohydrin dehalogenase preparation, and in initial reaction stage.
6. according to the method described in claim 1, the A7's is catalyzed it is characterized in that catalysis reaction obtains product A7
Residual rate of the rate not less than 95%, D3 is not more than 3%.
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