CN108251491A - A kind of method of enzymatic method synthesis ursodesoxycholic acid - Google Patents
A kind of method of enzymatic method synthesis ursodesoxycholic acid Download PDFInfo
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Abstract
The invention discloses a kind of method of enzymatic method synthesis ursodesoxycholic acid, the method that ursodesoxycholic acid is synthesized using chenodeoxycholic acid as starting material.This method is dissolved in the phosphate buffer of 50mM using chenodeoxycholic acid as substrate first in NAD, NOX2 and in the case of being passed through oxygen, and 7 keto lithcholic acids are obtained using 7 α steroid dehydrogenase enzymatic oxidation chenodeoxycholic acids；Then in the presence of NAD, L malic acid and malic dehydrogenase, 7 keto lithcholic acids is restored using 7 β steroid dehydrogenases enzymatics and obtain ursodesoxycholic acid.This method is not using organic solvent, and easy to operate, reaction condition is mildly easily-controllable, and raw material availability is high, and high conversion rate is up to more than 99%.
Description
Technical field
The present invention provides a kind of method of enzymatic method catalysis chenodeoxycholic acid synthesis ursodesoxycholic acid.The invention belongs to biologies
Field of engineering technology.
Background technology
Ursodesoxycholic acid chemical name is：3 α, 7-5 β of beta-dihydroxy-cholanic acid, it is identical with the molecular formula of chenodeoxycholic acid,
Stereochemical structure is different, and the structural relation of both compounds is chemically become isomer.Ursodesoxycholic acid is white knot
Crystalline flour end, odorless, bitter.It is soluble in ethyl alcohol, chloroform, glacial acetic acid, sig water, is slightly soluble in ether, be insoluble in water and dilute ore deposit acid, melt
203 DEG C of point.Ursodesoxycholic acid UDCA is a kind of hydrophilic cholic acid of nontoxicity, can competitively inhibit toxic endogenous cholic acid in ileum
Absorption, by the signal network that calcium ion, protein kinase C is activated to form, and increased by activating mitotic activity albumen base enzyme
Add the effect of cholestasis.Ursodesoxycholic acid can also competitively replace the toxicity cholic acid molecules on cell break-in organelle, prevent
Only liver cell and bile duct cell are damaged by more toxicity cholic acid.Clinically, ursodesoxycholic acid be mainly used for dissolve courage consolidate
Alcohol type gall stone, primary biliary cirrhosis PBC, chronic hepatitis C, while alcoholic liver disease is additionally operable to, non-alcoholic fatty
Liver, benign recurrent intrahepatic cholestasis disease, congenital interior Choledochal cysts.
At present mainly ursodeoxycholic is prepared by multi-step chemical reaction using cholic acid and chenodeoxycholic acid for raw material both at home and abroad
Acid, it is more serious to the damage ratio of environment using a large amount of solvent, Oxidizing and Reducing Agents in reaction process；And chenodeoxycholic acid
Conversion ratio is relatively low, and post processing is complicated.
Invention content
The purpose of the invention is to overcome shortcoming of the prior art, a kind of simple for process, synthetic route is provided
Short, high conversion rate, post processing is easier, more environment-friendly ursodesoxycholic acid preparation method.
In order to achieve the above object, the present invention uses following scheme：
A kind of method of enzymatic method synthesis ursodesoxycholic acid, feature include the following steps：
A, chenodeoxycholic acid is put into reaction vessel, adds in phosphate buffer and dissolve, adjusting solution ph, addition NAD,
NOX2,7- α steroid dehydrogenases are passed through oxygen, controlling reaction temperature and pH value in reaction, react 5 hours, react until goose deoxygenates
The residual quantity of cholic acid in the solution is less than 1%, and heating stirring, is then cooled to room temperature after the completion of reaction；
B, add in L MALIC ACID sodium, malic dehydrogenase, 7- β steroid dehydrogenases in reaction solution, controlling reaction temperature and
PH value in reaction is reacted 3 hours, is reacted and is less than 0.1%, after the completion of reaction until 7- Ketocholic acid remains, and adds alkali heating stirring,
Then room temperature is cooled to, the solid content being filtered to remove in solution, filtrate acid adding crystallizes to obtain UDCA.
A kind of method of enzymatic method synthesis ursodesoxycholic acid as described above, it is characterised in that the phosphoric acid described in step A
Buffer concentration is 50-100mM.
A kind of method of enzymatic method synthesis ursodesoxycholic acid as described above, it is characterised in that the solution described in step A
PH value is 7.5-8.5.
The method of a kind of enzymatic method synthesis ursodesoxycholic acid as described above, it is characterised in that the NAD described in step A is used
Measure the 0.10-0.30% for chenodeoxycholic acid weight；The NOX2 dosages are the 1.0-3.0% of chenodeoxycholic acid weight；Institute
The 7- α steroid dehydrogenases enzyme dosage stated is the 0.30-0.50% of chenodeoxycholic acid weight.
A kind of method of enzymatic method synthesis ursodesoxycholic acid as described above, it is characterised in that the flow velocity of oxygen in step A
For 20-100ml/L/min, reaction temperature is room temperature, pH value in reaction 7.5-8.0.
A kind of method of enzymatic method synthesis ursodesoxycholic acid as described above, it is characterised in that the reaction described in step A
Temperature rise is to 40-80 DEG C afterwards；Mixing time was controlled at 20-60 minutes.
A kind of method of enzymatic method synthesis ursodesoxycholic acid as described above, it is characterised in that the L- apples described in step B
Tartaric acid sodium dosage is the 40-70% of chenodeoxycholic acid weight；The malate dehydrogenase enzyme dosage is chenodeoxycholic acid weight
1.0-3.0%；The 7- β steroid dehydrogenases enzyme dosage is the 0.1-0.3% of chenodeoxycholic acid weight.
The method of a kind of enzymatic method synthesis ursodesoxycholic acid as described above, it is characterised in that reaction temperature is in step B
25-30 DEG C, reaction pH is 7.0-7.5.
The method of a kind of enzymatic method synthesis ursodesoxycholic acid as described above, it is characterised in that heat up after being reacted in step B
To 60-80 DEG C, mixing time was controlled at 1-3 hours.
A kind of method of enzymatic method synthesis ursodesoxycholic acid as described above, it is characterised in that the crystallization described in step B
Acid used is inorganic acid, and crystallization pH is 2-3.
In conclusion beneficial effects of the present invention：
First, enzymatic reaction condition is mild in the present invention, various solvents, oxidant, the reducing agent used without using chemical method,
Industrial amplification production is easy to control and safety.The waste water of generation is easily processed, environmental-friendly.
2nd, enzymatic reaction high selectivity in the present invention, by-product is few compared with chemical method, is extracted after product and refined simpler
It is single.
Specific embodiment
The present invention is described further With reference to embodiment：
Embodiment 1
Chenodeoxycholic acid 10g, 50mMPH9.0 phosphate buffer 100ml is added in reaction bulb, is slowly added to 10% hydrogen-oxygen
Between changing sodium adjusting solution PH 7.5-8.0, chenodeoxycholic acid is completely dissolved.Add in NAD10mg, NOX0.15g, 7- α steroids take off
Hydrogen enzyme 30mg is passed through oxygen, and control oxygen gas flow rate is 5ml/min, is reacted at room temperature to CDCA residuals less than 1.0%.It has reacted
Quan Hou, stopping are passed through oxygen, are warming up to 50-55 degree and temperature is maintained to stir 20 minutes.
Material is cooled to room temperature, adding in L MALIC ACID sodium 4.5g, malic dehydrogenase 0.18g, 7- β classes in reaction solution consolidates
It is reacted between control PH7.0-7.5 under alcohol dehydrogenase 15mg, 25-30 degree, until 7- Ketocholic acid residual is less than 0.1%.Instead
It after the completion of answering, adds in 10% sodium hydroxide solution and adjusts more than 8.0 solution PH, be warming up to 70-75 degree and maintain temperature stirring 2 small
When, room temperature is then cooled to, the solid content being filtered to remove in solution adds in 1 in filtrate:1 hydrochloric acid conditioning solution PH2-3, filtering,
Massive laundering washs filter cake to wash water PH neutrality, and drying obtains ursodesoxycholic acid 9.8g.
Embodiment 2
Chenodeoxycholic acid 10g, 50mMPH9.0 phosphate buffer 100ml is added in reaction bulb, is slowly added to 10% hydrogen-oxygen
Between changing sodium adjusting solution PH 7.5-8.0, chenodeoxycholic acid is completely dissolved.Add in NAD15mg, NOX0.20g, 7- α steroids take off
Hydrogen enzyme 33mg is passed through oxygen, and control oxygen gas flow rate is 5.5ml/min, is reacted at room temperature to CDCA residuals less than 1.0%.Reaction
After completely, stopping is passed through oxygen, is warming up to 50-55 degree and temperature is maintained to stir 30 minutes.
Material is cooled to room temperature, adding in L MALIC ACID sodium 5.0g, malic dehydrogenase 0.18g, 7- β classes in reaction solution consolidates
It is reacted between control PH7.0-7.5 under alcohol dehydrogenase 20mg, 25-30 degree, until 7- Ketocholic acid residual is less than 0.1%.Instead
It after the completion of answering, adds in 10% sodium hydroxide solution and adjusts more than 8.0 solution PH, be warming up to 70-75 degree and maintain temperature stirring 2 small
When, room temperature is then cooled to, the solid content being filtered to remove in solution adds in 1 in filtrate:1 hydrochloric acid conditioning solution PH2-3, filtering,
Massive laundering washs filter cake to wash water PH neutrality, and drying obtains ursodesoxycholic acid 9.9g.
Embodiment 3
Chenodeoxycholic acid 10g, 50mMPH9.0 phosphate buffer 100ml is added in reaction bulb, is slowly added to 10% hydrogen-oxygen
Between changing sodium adjusting solution PH 7.5-8.0, chenodeoxycholic acid is completely dissolved.Add in NAD18mg, NOX0.25g, 7- α steroids take off
Hydrogen enzyme 35mg is passed through oxygen, and control oxygen gas flow rate is 6.0ml/min, is reacted at room temperature to CDCA residuals less than 1.0%.Reaction
After completely, stopping is passed through oxygen, is warming up to 50-55 degree and temperature is maintained to stir 25 minutes.
Material is cooled to room temperature, adding in L MALIC ACID sodium 5.5g, malic dehydrogenase 0.25g, 7- β classes in reaction solution consolidates
It is reacted between control PH7.0-7.5 under alcohol dehydrogenase 25mg, 25-30 degree, until 7- Ketocholic acid residual is less than 0.1%.Instead
It after the completion of answering, adds in 10% sodium hydroxide solution and adjusts more than 8.0 solution PH, be warming up to 70-75 degree and maintain temperature stirring 2 small
When, room temperature is then cooled to, the solid content being filtered to remove in solution adds in 1 in filtrate:1 hydrochloric acid conditioning solution PH2-3, filtering,
Massive laundering washs filter cake to wash water PH neutrality, and drying obtains ursodesoxycholic acid 9.9g.
Embodiment 4
A kind of method of enzymatic method synthesis ursodesoxycholic acid, includes the following steps：
A, chenodeoxycholic acid is put into reaction vessel, adds in phosphate buffer and dissolve, adjusting solution ph, addition NAD,
NOX2,7- α steroid dehydrogenases, are passed through oxygen, controlling reaction temperature and pH value in reaction, react until chenodeoxycholic acid is in solution
In residual quantity less than 1%, heating stirring, is then cooled to room temperature after the completion of reaction；
B, add in L MALIC ACID sodium, malic dehydrogenase, 7- β steroid dehydrogenases in reaction solution, controlling reaction temperature and
PH value in reaction reacts and is less than 0.1%, after the completion of reaction until 7- Ketocholic acid remains, and adds alkali heating stirring, is then cooled to
Room temperature, the solid content being filtered to remove in solution, filtrate acid adding crystallize to obtain UDCA.
Phosphate buffer density described in step A is 50M.
Solution ph described in step A is 7.5.
NAD dosages described in step A are the 0.10% of chenodeoxycholic acid weight；The NOX2 dosages are chenodeoxycholic
The 1.0% of sour weight；The 7- α steroid dehydrogenases enzyme dosage is the 0.30% of chenodeoxycholic acid weight.
The flow velocity of oxygen is 20-ml/L/min in step A, and reaction temperature is room temperature, pH value in reaction 7.5.
Temperature rise is to 40 DEG C after reaction described in step A；Mixing time was controlled at 20 minutes.
L MALIC ACID sodium dosage described in step B is the 40% of chenodeoxycholic acid weight；The malic dehydrogenase
Dosage is the 1.0% of chenodeoxycholic acid weight；The 7- β steroid dehydrogenases enzyme dosage is the 0.1% of chenodeoxycholic acid weight.
Reaction temperature is 25 DEG C in step B, and reaction pH is 7.0.
60 DEG C are warming up to after being reacted in step B, mixing time was controlled at 1 hour.
The acid used in crystallization described in step B is inorganic acid, and crystallization pH is 2.
Embodiment 5
A kind of method of enzymatic method synthesis ursodesoxycholic acid, includes the following steps：
A, chenodeoxycholic acid is put into reaction vessel, adds in phosphate buffer and dissolve, adjusting solution ph, addition NAD,
NOX2,7- α steroid dehydrogenases, are passed through oxygen, controlling reaction temperature and pH value in reaction, react until chenodeoxycholic acid is in solution
In residual quantity less than 1%, heating stirring, is then cooled to room temperature after the completion of reaction；
B, add in L MALIC ACID sodium, malic dehydrogenase, 7- β steroid dehydrogenases in reaction solution, controlling reaction temperature and
PH value in reaction reacts and is less than 0.1%, after the completion of reaction until 7- Ketocholic acid remains, and adds alkali heating stirring, is then cooled to
Room temperature, the solid content being filtered to remove in solution, filtrate acid adding crystallize to obtain UDCA.
Phosphate buffer density described in step A is 100mM.
Solution ph described in step A is 8.5.
NAD dosages described in step A are the 0.30% of chenodeoxycholic acid weight；The NOX2 dosages are chenodeoxycholic
The 3.0% of sour weight；The 7- α steroid dehydrogenases enzyme dosage is the 0.50% of chenodeoxycholic acid weight.
The flow velocity of oxygen is 20-100ml/L/min in step A, and reaction temperature is room temperature, pH value in reaction 8.0.
Temperature rise is to 80 DEG C after reaction described in step A；Mixing time was controlled at 60 minutes.
L MALIC ACID sodium dosage described in step B is the 70% of chenodeoxycholic acid weight；The malic dehydrogenase
Dosage is the 3.0% of chenodeoxycholic acid weight；The 7- β steroid dehydrogenases enzyme dosage is the 0.3% of chenodeoxycholic acid weight.
Reaction temperature is 30 DEG C in step B, and reaction pH is 7.5.
80 DEG C are warming up to after being reacted in step B, mixing time was controlled at 3 hours.
The acid used in crystallization described in step B is inorganic acid, and crystallization pH is 3.
Embodiment 6
A kind of method of enzymatic method synthesis ursodesoxycholic acid, includes the following steps：
A, chenodeoxycholic acid is put into reaction vessel, adds in phosphate buffer and dissolve, adjusting solution ph, addition NAD,
NOX2,7- α steroid dehydrogenases, are passed through oxygen, controlling reaction temperature and pH value in reaction, react until chenodeoxycholic acid is in solution
In residual quantity less than 1%, heating stirring, is then cooled to room temperature after the completion of reaction；
B, add in L MALIC ACID sodium, malic dehydrogenase, 7- β steroid dehydrogenases in reaction solution, controlling reaction temperature and
PH value in reaction reacts and is less than 0.1%, after the completion of reaction until 7- Ketocholic acid remains, and adds alkali heating stirring, is then cooled to
Room temperature, the solid content being filtered to remove in solution, filtrate acid adding crystallize to obtain UDCA.
Phosphate buffer density described in step A is 80mM.
Solution ph described in step A is 8.
NAD dosages described in step A are the 0.20% of chenodeoxycholic acid weight；The NOX2 dosages are chenodeoxycholic
The 2.0% of sour weight；The 7- α steroid dehydrogenases enzyme dosage is the 0.40% of chenodeoxycholic acid weight.
The flow velocity of oxygen is 50ml/L/min in step A, and reaction temperature is room temperature, pH value in reaction 7.8.
Temperature rise is to 60 DEG C after reaction described in step A；Mixing time was controlled at 40 minutes.
L MALIC ACID sodium dosage described in step B is the 60% of chenodeoxycholic acid weight；The malic dehydrogenase
Dosage is the 2.0% of chenodeoxycholic acid weight；The 7- β steroid dehydrogenases enzyme dosage is the 0.2% of chenodeoxycholic acid weight.
Reaction temperature is 28 DEG C in step B, and reaction pH is 7.3.
70 DEG C are warming up to after being reacted in step B, mixing time was controlled at 2 hours.
The acid used in crystallization described in step B is inorganic acid, and crystallization pH is 2.5.
Although the invention has been described by way of example and in terms of the preferred embodiments, but it is not for limiting the present invention, any this field
Technical staff without departing from the spirit and scope of the present invention, may be by the methods and technical content of the disclosure above to this hair
Bright technical solution makes possible variation and modification, therefore, every content without departing from technical solution of the present invention, and according to the present invention
Technical spirit any simple modifications, equivalents, and modifications made to the above embodiment, belong to technical solution of the present invention
Protection domain.
Claims (10)
- A kind of 1. method of enzymatic method synthesis ursodesoxycholic acid, it is characterised in that include the following steps：A, chenodeoxycholic acid is put into reaction vessel, adds in phosphate buffer and dissolve, adjusting solution ph, addition NAD, NOX2,7- α steroid dehydrogenases, are passed through oxygen, controlling reaction temperature and pH value in reaction, react until chenodeoxycholic acid is in solution In residual quantity less than 1%, heating stirring, is then cooled to room temperature after the completion of reaction；B, L MALIC ACID sodium, malic dehydrogenase, 7- β steroid dehydrogenases, controlling reaction temperature and reaction are added in reaction solution PH value reacts and is less than 0.1%, after the completion of reaction until 7- Ketocholic acid remains, and adds alkali heating stirring, is then cooled to often Temperature, the solid content being filtered to remove in solution, filtrate acid adding crystallize to obtain UDCA.
- 2. the method for a kind of enzymatic method synthesis ursodesoxycholic acid according to claim 1, it is characterised in that described in step A Phosphate buffer density be 50-100mM.
- 3. the method for a kind of enzymatic method synthesis ursodesoxycholic acid according to claim 1, it is characterised in that described in step A Solution ph be 7.5-8.5.
- 4. the method for a kind of enzymatic method synthesis ursodesoxycholic acid according to claim 1, it is characterised in that described in step A NAD dosages be chenodeoxycholic acid weight 0.10-0.30%；The NOX2 dosages are the 1.0- of chenodeoxycholic acid weight 3.0%；The 7- α steroid dehydrogenases enzyme dosage is the 0.30-0.50% of chenodeoxycholic acid weight.
- A kind of 5. method of enzymatic method synthesis ursodesoxycholic acid according to claim 1, it is characterised in that oxygen in step A Flow velocity for 20-100ml/L/min, reaction temperature is room temperature, pH value in reaction 7.5-8.0.
- 6. the method for a kind of enzymatic method synthesis ursodesoxycholic acid according to claim 1, it is characterised in that described in step A Reaction after temperature rise to 40-80 DEG C；Mixing time was controlled at 20-60 minutes.
- 7. the method for a kind of enzymatic method synthesis ursodesoxycholic acid according to claim 1, it is characterised in that described in step B L MALIC ACID sodium dosage be chenodeoxycholic acid weight 40-70%；The malate dehydrogenase enzyme dosage is chenodeoxycholic acid The 1.0-3.0% of weight；The 7- β steroid dehydrogenases enzyme dosage is the 0.1-0.3% of chenodeoxycholic acid weight.
- 8. the method for a kind of enzymatic method synthesis ursodesoxycholic acid according to claim 1, it is characterised in that reacted in step B Temperature is 25-30 DEG C, and reaction pH is 7.0-7.5.
- 9. the method for a kind of enzymatic method synthesis ursodesoxycholic acid according to claim 1, it is characterised in that reacted in step B After be warming up to 60-80 DEG C, mixing time was controlled at 1-3 hours.
- A kind of 10. method of enzymatic method synthesis ursodesoxycholic acid according to claim 1, it is characterised in that institute in step B The acid used in crystallization stated is inorganic acid, and crystallization pH is 2-3.
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| CN109055473A (en) * | 2018-08-21 | 2018-12-21 | 湖南宝利士生物技术有限公司 | A method of ursodesoxycholic acid and high chiral purity D- amino acid are synthesized based on enzyme process coupling technology |
| CN109929896A (en) * | 2019-04-23 | 2019-06-25 | 南京久安源环保科技有限公司 | A kind of production technology of ursodesoxycholic acid |
| CN112759623A (en) * | 2021-03-12 | 2021-05-07 | 中山百灵生物技术股份有限公司 | Synthetic method of deoxycholic acid |
| CN112813128A (en) * | 2021-01-12 | 2021-05-18 | 中山百灵生物技术股份有限公司 | Synthetic method of alloursodeoxycholic acid |
| CN114276401A (en) * | 2021-12-27 | 2022-04-05 | 中山百灵生物技术股份有限公司 | Method for synthesizing 24-norursodeoxycholic acid |
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| CN109055473A (en) * | 2018-08-21 | 2018-12-21 | 湖南宝利士生物技术有限公司 | A method of ursodesoxycholic acid and high chiral purity D- amino acid are synthesized based on enzyme process coupling technology |
| CN109929896A (en) * | 2019-04-23 | 2019-06-25 | 南京久安源环保科技有限公司 | A kind of production technology of ursodesoxycholic acid |
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| CN112759623A (en) * | 2021-03-12 | 2021-05-07 | 中山百灵生物技术股份有限公司 | Synthetic method of deoxycholic acid |
| CN114276401A (en) * | 2021-12-27 | 2022-04-05 | 中山百灵生物技术股份有限公司 | Method for synthesizing 24-norursodeoxycholic acid |
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Application publication date: 20180706 |