CN111455013B - Method for auxiliary resolution of pantolactone by weak base salt - Google Patents
Method for auxiliary resolution of pantolactone by weak base salt Download PDFInfo
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- CN111455013B CN111455013B CN202010405713.1A CN202010405713A CN111455013B CN 111455013 B CN111455013 B CN 111455013B CN 202010405713 A CN202010405713 A CN 202010405713A CN 111455013 B CN111455013 B CN 111455013B
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- acid lactone
- pantoic acid
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/001—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by metabolizing one of the enantiomers
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
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- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
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- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
- C12P7/42—Hydroxy-carboxylic acids
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Abstract
The invention relates to a method for separating pantoic acid lactone by using weak base salt to assist biological enzyme. The method prepares the pantoic acid lactone into an aqueous solution with the content of 16-26 percent, adds 5-15 percent of biological enzyme by the mass of the aqueous solution, and puts the ammonium bicarbonate with the same molar weight of the D-pantoic acid lactone contained in the aqueous solution into the aqueous solution by times or at one time at the temperature of 23-30 ℃. The pH was maintained at 6.5-7.8 and the reaction was continued until the hydrolysis of the D-ester was complete. The method solves the problem of passive chemical hydrolysis of partial L-pantoic acid lactone caused by congenital difficulty that ammonia is difficult to rapidly and uniformly distribute in large-capacity reaction equipment when ammonia is added dropwise to assist biological enzyme to split the pantoic acid lactone.
Description
Technical Field
The invention relates to a method for splitting pantoic acid lactone, in particular to a method for splitting pantoic acid lactone by using weak base salt to assist biological enzyme.
Background
The D-pantoic acid lactone is generated by splitting the pantoic acid lactone aqueous solution through biological enzyme so as to synthesize products such as D-calcium pantothenate, D-panthenol and the like, which is a general industrial production route for the products such as the D-calcium pantothenate, the D-panthenol and the like;
the process of the separation of the pantoic acid lactone by the biological enzyme comprises the following steps: d-pantoic acid lactone in the pantoic acid lactone aqueous solution is hydrolyzed into D-pantoic acid by biological enzyme, and then is converted into D-pantoic acid ammonium under the assistance of dropwise adding ammonia water (the PH value of the system is required to be kept in the range of 6.5-7.8), then the L-pantoic acid lactone and the D-pantoic acid ammonium are separated by adopting an extraction process, and when the ammonia water is dropwise added to assist the biological enzyme to split the pantoic acid lactone, the ammonia water is difficult to be rapidly and uniformly distributed in large-capacity reaction equipment, so that part of the L-pantoic acid lactone is passively and chemically hydrolyzed due to congenital difficulty.
Disclosure of Invention
The invention adopts weak alkali salt represented by ammonium bicarbonate to replace ammonia water to complete resolution reaction;
preparing 16-26% of pantoic acid lactone into aqueous solution, adding 5-15% of biological enzyme by mass of the aqueous solution, stirring uniformly, adding ammonium bicarbonate with the molar quantity not higher than 1.1 times of that of D-pantoic acid lactone contained in the aqueous solution for several times or once at 23-30 ℃, and reacting until D-ester is hydrolyzed completely (sampling and filtering out clear liquid, wherein the clear liquid takes that the specific optical rotation converted by the L-pantoic acid lactone is more than or equal to 50 degrees as an end point).
The technical scheme adopted for realizing the above purpose of the invention is as follows: a method for separating pantolactone by using weak base salt to assist biological enzyme comprises the following steps:
(1) preparing a splitting system: 10000 kilograms of tap water 6000 and 2600 kilograms of pantolactone are added into the 15m ethanol cultivation reaction kettle to prepare 16-26 percent of pantolactone aqueous solution, 5-15 percent of biological enzyme by mass of the aqueous solution is added, and the mixture is stirred for 0.5-2 hours at 23-30 ℃ for standby,
(2) adding ammonium bicarbonate: adding ammonium hydrogen carbonate with the mole number not higher than 1.1 times of that of D-pantoic acid lactone contained in (1) into the whole resolution reaction time period for 1-15 times under the stirring state at 23-30 ℃, sampling after 3 hours and filtering to obtain clear liquid, wherein the specific optical rotation converted by L-pantoic acid lactone at 23-30 ℃ is more than or equal to 50 ℃ in the clear liquid as the reaction end point.
In the step (1), a pantolactone aqueous solution with the content of 16-26% is prepared.
In the step (1), 5-15% of biological enzyme by mass of the aqueous solution is added at 23-30 ℃.
In the step (1), biological enzyme is added at the temperature of 23-30 ℃.
In the step (2), ammonium bicarbonate is added for 1 to 15 times.
In the step (2), the resolution reaction temperature is 23-30 ℃.
In the step (2), the molar number of ammonium hydrogencarbonate is not more than 1.1 times that of D-pantoic acid lactone contained in (1), and for a divalent ionic substance, the molar number is required to be not more than 0.55 times that of D-pantoic acid lactone contained in (1).
In the step (2), the reaction end point is that the specific optical rotation converted by L-pantoic acid lactone at 23-30 ℃ is greater than or equal to 50 ℃ in clear liquid.
In the step (2), ammonium bicarbonate can be partially replaced by ammonia water.
In the step (2), the ammonium bicarbonate can be an element or a mixture capable of forming a weak base salt property, such as ammonium bicarbonate and/or calcium acetate and/or calcium citrate and/or ammonium citrate and/or calcium carbonate and/or urea.
Therefore, compared with the prior art, the invention has the following advantages:
1. the invention can ensure the uniformity and stability of the alkalinity of the reaction system in the large reaction device;
2. the hydrolysis reaction of the enzyme can be ensured not to cause ineffective extension of the resolution time because of untimely alkaline supply;
3. the resolution efficiency can be close to 100% (only 80-90% by using dropwise ammonia water to assist resolution).
The invention is further illustrated with reference to the following examples (the scope of protection includes, but is not limited to, the following examples).
Example 1
(1) Preparing a splitting system: 10000 kilograms of tap water is added into a 15m ethanol production kettle, 2600 kilograms (20 kilomoles) of pantolactone is added to prepare 20.63 percent of pantolactone aqueous solution, 1000 kilograms of biological enzyme is added, and the mixture is stirred for 0.5 hour at the temperature of 23-30 ℃ for standby application;
(2) adding ammonium bicarbonate: adding 790 kg (10 kmol) ammonium bicarbonate into the mixture for three times at the temperature of 23-30 ℃ under stirring for 0 hour, 5 hours and 10 hours, sampling after 16 hours, and filtering to obtain clear liquid, wherein the specific optical rotation of the clear liquid at 23 ℃ converted by L-pantoic acid lactone is equal to 50 degrees.
Example 2
(1) Preparing a splitting system: 8000 kg of tap water is added into a 15m ethanol-producing kettle, 2300 kg (17.692 kmol) of pantolactone is added to prepare a pantolactone aqueous solution with the content of 22.33 percent, 900 kg of biological enzyme is added, and the mixture is stirred for 1.5 hours at the temperature of 23-30 ℃ for standby application;
(2) adding ammonium bicarbonate: 698.8 kg (8.846 kmol) of ammonium bicarbonate was added in one portion at 23-30 ℃ with stirring, and after 15 hours sampling and filtration were started to obtain a clear solution in which the specific optical rotation at 25 ℃ converted from L-pantolactone was 51 °.
Example 3
(1) Preparing a splitting system: 9000 kg of tap water is added into a 15m ethanol-producing reaction kettle, 2600 kg (20 kmol) of pantolactone is added to prepare a pantolactone aqueous solution with the content of 22.41 percent, 1000 kg of biological enzyme is added, and the mixture is stirred for 1 hour at the temperature of 23-30 ℃ for later use;
(2) adding calcium bicarbonate water emulsion: adding 1810 kg (5 kmole) of calcium bicarbonate emulsion into the mixture for five times at the temperature of between 23 and 30 ℃ under stirring for 0 hour, 3 hours, 6 hours, 8 hours and 10 hours, sampling after 16 hours, and filtering to obtain clear liquid, wherein the specific optical rotation of the clear liquid at 23 ℃ converted by L-pantoic acid lactone is 53 degrees.
Claims (2)
1. A method for resolving pantoic acid lactone with the assistance of weak base salt comprises the following steps:
(1) preparing a splitting system: 10000 kilograms of tap water 6000 and 2600 kilograms of pantolactone are added into the 15m ethanol cultivation reaction kettle to prepare 16-26 percent of pantolactone aqueous solution, 5-15 percent of biological enzyme by mass of the aqueous solution is added, and the mixture is stirred for 0.5-2 hours at 23-30 ℃ for standby,
(2) adding ammonium bicarbonate: adding ammonium hydrogen carbonate with the mole number not more than 1.1 times of that of D-pantoic acid lactone contained in (1) into the whole resolution reaction time period for 1-15 times under the stirring state at 23-30 ℃, sampling after 3 hours and filtering to obtain clear liquid, wherein the specific optical rotation converted by L-pantoic acid lactone in the clear liquid is more than or equal to 50 ℃ at 23-30 ℃ as the reaction end point.
2. The method for the auxiliary resolution of pantolactone with weak base salt according to claim 1, characterized in that: in the step (2), the ammonium bicarbonate is replaced by a simple substance or a mixture of ammonium bicarbonate and/or calcium acetate and/or ammonium citrate and/or urea.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010405713.1A CN111455013B (en) | 2020-05-14 | 2020-05-14 | Method for auxiliary resolution of pantolactone by weak base salt |
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| CN202010405713.1A CN111455013B (en) | 2020-05-14 | 2020-05-14 | Method for auxiliary resolution of pantolactone by weak base salt |
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| CN111455013B true CN111455013B (en) | 2022-06-07 |
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Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2844354B2 (en) * | 1989-08-03 | 1999-01-06 | 富士薬品工業株式会社 | Method for producing D-pantolactone |
| CN1199961C (en) * | 2002-10-23 | 2005-05-04 | 浙江新和成股份有限公司 | Spliting method for DL-pantoyl internal ester |
| CN1293194C (en) * | 2004-08-03 | 2007-01-03 | 江南大学 | D-Pantothe internal ester hydrolase c DNA and its clone expression and application |
| CN101392278B (en) * | 2008-06-11 | 2011-07-20 | 济南大华广济畜牧发展有限公司 | Method for preparing D-pantolactone by microbe mixed fermentation method |
| CN107523559B (en) * | 2017-10-16 | 2020-10-16 | 宁夏金维制药股份有限公司 | Culture medium for producing D-pantolactone hydrolase by fermentation of fusarium oxysporum |
| CN108102926B (en) * | 2017-11-27 | 2021-04-13 | 苏州百福安酶技术有限公司 | Aspergillus niger strain BFA010-7 for high-yield levorotatory lactone hydrolase and application thereof in preparation of D-pantolactone |
| CN207918811U (en) * | 2018-01-25 | 2018-09-28 | 江苏凌云药业股份有限公司 | One kind being used for the continuous detachment device of mixed pantoic acid lactone |
| CN108559767A (en) * | 2018-01-25 | 2018-09-21 | 江苏凌云药业股份有限公司 | A kind of method that mixed pantoic acid lactone is continuously split and its device |
| CN108456701B (en) * | 2018-03-23 | 2020-10-16 | 精晶药业股份有限公司 | Preparation method of D-pantoic acid lactone |
| CN108624513B (en) * | 2018-06-15 | 2020-11-03 | 成都本则生科技有限公司 | Method for high-density culture of D-pantolactone hydrolase producing strain and application |
| CN110257464A (en) * | 2019-07-12 | 2019-09-20 | 抚顺顺特化工有限公司 | A kind of preparation method of D-VB5 calcium |
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Effective date of registration: 20201119 Address after: 233700 Economic Development Zone, Guzhen County, Bengbu City, Anhui Province Applicant after: Anhui tiger Biotechnology Co.,Ltd. Address before: 430070 Room 602, Unit 2, Building 7, No. 938 Xiongchu Avenue, Hongshan District, Wuhan City, Hubei Province Applicant before: Wu Jiang |
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