CN110845462B - Industrial production method for controlling isomer ratio of bromadiolone liquid mother drug - Google Patents
Industrial production method for controlling isomer ratio of bromadiolone liquid mother drug Download PDFInfo
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- CN110845462B CN110845462B CN201911246553.4A CN201911246553A CN110845462B CN 110845462 B CN110845462 B CN 110845462B CN 201911246553 A CN201911246553 A CN 201911246553A CN 110845462 B CN110845462 B CN 110845462B
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
- A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
An industrial production method for controlling the isomer ratio of a bromadiolone liquid mother medicine comprises the following steps: preparing a bromadiolone liquid mother medicament, and preparing a solvent: compounding the mixed solution of water and ethanol into a reaction solvent for later use as a reaction solvent; reduction of bromadiolone precursor ketone to prepare bromadiolone: adding a bromadiolone precursor ketone into the prepared ethanol-water mixed solution, continuously heating and stirring, keeping the temperature of a reaction system at 50 ℃, adding potassium borohydride, keeping the temperature and stirring, keeping the reaction for 7 hours, cooling and filtering solid residues to obtain the orange-yellow bromadiolone liquid mother medicine. The invention provides an industrial production method capable of controlling bromadiolone isomers on the premise of not influencing reaction yield, realizes the control of the isomer ratio of a bromadiolone liquid parent drug in the industrial production process, uses water to replace part of organic solvent, has good repeatability, and is applied to the technical field of the control of rodent drugs.
Description
Technical Field
The invention relates to an industrial production method for controlling the isomer ratio of a bromadiolone liquid mother medicament in the technical field of rodent drug control.
Background
At present, the effective component of the bromadiolone liquid mother medicine is bromadiolone, 3- [3,4 '-bromo (1,1' -biphenyl) -4-yl ] -3-hydroxy-1-phenylpropyl-4-hydroxy-2H-1-benzopyran-2-one, and the liquid mother medicine is light yellow liquid. The bromadiolone is a broad-spectrum high-efficiency second-generation anticoagulant rodenticide, is a good drug for killing rats once poisoned, and has low dosage and excellent effect compared with other anticoagulant rodenticides. At present, products synthesized by bromadiolone are racemes mixed with cis-trans diastereoisomers, the modern science proves that the physiological and toxicological effects of different isomers are greatly different, wherein the trans isomer has great secondary damage to non-target organisms (owl, snake and other organisms predating poison mice), and the current standard of China also stipulates that the proportion of the diastereoisomers in the bromadiolone is not more than 0.30. Therefore, the development of an industrial production method for controlling the isomer ratio of the bromadiolone liquid parent drug is a new problem to be solved.
Disclosure of Invention
The invention aims to provide an industrial production method for controlling the isomer ratio of a bromadiolone liquid mother medicine, which provides an industrial production method for controlling the isomer of the bromadiolone on the premise of not influencing the reaction yield, the influence of a solvation effect is increased by adding a water compound solvent for reaction, the synthesized diastereoisomer of chlordiazepoxide is subjected to carbonyl reduction in a last step of bromadiolone precursor ketone, because of the unique molecular structure of the bromadiolone, a nucleophilic reagent is influenced by steric hindrance in the reduction reaction process to generate selectivity, the selectivity of the carbonyl reduction can be enhanced by increasing the polarity of the solvent, thereby realizing the control of the isomer ratio in the bromadiolone liquid mother medicine under the condition of unchanged yield, reducing the ratio of a component A of the bromadiolone to have important influence on the application of the bromadiolone in the natural environment and reducing the harm to non-target animals, and the realization is environment-friendly.
The purpose of the invention is realized as follows: an industrial production method for controlling the isomer ratio of a bromadiolone liquid mother medicine comprises the following steps:
(1) preparing a bromadiolone liquid mother medicine, and preparing a solvent: compounding the mixed solution of water and ethanol into a reaction solvent for later use as a reaction solvent;
(2) reduction of bromadiolone precursor ketone to prepare bromadiolone: adding a bromadiolone precursor ketone into the prepared ethanol-water mixed solution, continuously heating and stirring, keeping the temperature of a reaction system at 50 ℃, adding potassium borohydride, keeping the temperature and stirring, keeping the reaction for 7 hours, cooling and filtering solid residues to obtain an orange-yellow bromadiolone liquid mother medicine;
(3) the proportion of the compound solvent in the step (1) is ethanol: water = 60: 40;
(4) the ratio of the dosage of the bromadiolone in the step (2) to the mass of the solvent is 1: 10;
(5) the ratio of the amount of the potassium borohydride to the bromadiolone in the step (2) is 3: 10;
the action mechanism of the industrial production method for controlling the isomer ratio of the bromadiolone liquid mother medicine is that the industrial production method for controlling the isomer of the bromadiolone can control the industrial production of the isomer under the premise of not influencing the reaction yieldThe method comprises adding water to compound solvent for reaction, changing polarity of the solvent, increasing influence of solvation effect, and increasing dielectric constant ε of the solvent<At 10-15, free ions, ε, are not present in the solution>At 40 deg.C, there is no ionic association in the solution, and the conventional process uses ethanol solvent, εEthanol(= 24.5) and epsilonWater (W)=78.5, using bromadiolone precursor ketone and potassium borohydride as initial raw materials, using water and ethanol to compound into mixed solvent, increasing the polarity of the solvent, leading KBH to be4Increased degree of dissociation; on the other hand, the synthesis diastereoisomer of the bromadiolone is generated in the last step of carbonyl reduction in the bromadiolone precursor ketone, because of the unique molecular structure of the bromadiolone, the nucleophilic reagent is influenced by steric hindrance in the reduction reaction process to generate selectivity, the nucleophilic reagent is easier to attack carbonyl from the side with small steric hindrance, and the solvation effect increases the tendency, and as a result of the two factors, the selectivity of carbonyl reduction can be enhanced in a way of increasing the polarity of a solvent, so that the proportion of the isomer in the bromadiolone liquid mother medicine can be controlled under the condition of unchanged yield, the bromadiolone precursor ketone is reduced by potassium borohydride, and the bromadiolone liquid mother medicine is obtained after filtration treatment; the diastereoisomer ratio in the bromadiolone liquid mother medicine product is controlled to be below 0.30 in national standard, the product adopts a mixed solution of water and ethanol, compared with the traditional process which only uses ethanol as a solvent, the polarity of the solvent is improved, the proportion of the two components A, B of the bromadiolone is changed on the premise of keeping the yield unchanged, and the isomer ratio in the bromadiolone product is adjusted.
The key points of the invention lie in that the invention controls the isomer ratio of the bromadiolone liquid mother medicine, the industrial production method and the action mechanism.
Compared with the prior art, the industrial production method for controlling the isomer ratio of the bromadiolone liquid mother medicine has the advantages that the industrial production method for controlling the isomer ratio of the bromadiolone is provided on the premise of not influencing the reaction yield, the control of the isomer ratio of the bromadiolone liquid mother medicine in the industrial production process is realized, part of organic solvent is replaced by water, the cost is saved, the isomer ratio of the produced product is controlled below 0.30 of the domestic standard, the operation is simple, the cost is reduced, the repeatability is good, the safety and the effectiveness are realized, the isomer ratio index of the produced bromadiolone product meets the domestic and foreign standards, and the like, and the method can be widely applied to the technical field of the control of the rodent drugs.
Detailed Description
An industrial production method for controlling the isomer ratio of a bromadiolone liquid mother medicine comprises the following steps:
(1) preparing a bromadiolone liquid mother medicine, and preparing a solvent: compounding the mixed solution of water and ethanol into a reaction solvent for later use as a reaction solvent;
(2) reduction of bromadiolone precursor ketone to prepare bromadiolone: adding a bromadiolone precursor ketone into the prepared ethanol-water mixed solution, continuously heating and stirring, keeping the temperature of a reaction system at 50 ℃, adding potassium borohydride, keeping the temperature and stirring, keeping the reaction for 7 hours, cooling and filtering solid residues to obtain an orange-yellow bromadiolone liquid mother medicine;
(3) the proportion of the compound solvent in the step (1) is ethanol: water = 60: 40;
(4) the ratio of the dosage of the bromadiolone in the step (2) to the mass of the solvent is 1: 10;
(5) the ratio of the amount of the potassium borohydride to the bromadiolone in the step (2) is 3: 10.
the action mechanism of the industrial production method for controlling the ratio of the isomer of the bromadiolone liquid mother medicine is that the industrial production method for controlling the isomer of the bromadiolone is provided by the invention on the premise of not influencing the reaction yield, the polarity of the solvent is changed and the influence of the solvation effect is increased by adding the water compound solvent for reaction, and the dielectric constant epsilon of the solvent<At 10-15, free ions, ε, are not present in the solution>At 40 deg.C, there is no ionic association in the solution, and the conventional process uses ethanol solvent, εEthanol(= 24.5) and epsilonWater (W)=78.5, using bromadiolone precursor ketone and potassium borohydride as initial raw materials, using water and ethanol to compound into mixed solvent, increasing the polarity of the solvent, leading KBH to be4Increased degree of dissociation; synthetic diastereoisomeric production of bromadiolone on the other handCarbonyl reduction is carried out in the last step of bromadiolone precursor ketone, because of the unique molecular structure of bromadiolone, in the reduction reaction process, the nucleophilic reagent is influenced by steric hindrance to generate selectivity, the nucleophilic reagent can attack carbonyl from the side with small steric hindrance more easily, and the solvation effect increases the tendency, and as a result of the two factors, the selectivity of carbonyl reduction can be enhanced by increasing the polarity of the solvent, so that the proportion of isomers in the bromadiolone liquid mother medicine can be controlled under the condition of unchanged yield, the bromadiolone precursor ketone is reduced by potassium borohydride, and the bromadiolone liquid mother medicine is obtained after filtration treatment; the diastereoisomer ratio in the bromadiolone liquid mother medicine product is controlled to be below 0.30 in national standard, the product adopts a mixed solution of water and ethanol, compared with the traditional process which only uses ethanol as a solvent, the polarity of the solvent is improved, the proportion of the two components A, B of the bromadiolone is changed on the premise of keeping the yield unchanged, and the isomer ratio in the bromadiolone product is adjusted.
Example one
Preparing a bromadiolone liquid mother medicine in a laboratory:
the industrial production method for controlling the isomer ratio of the bromadiolone liquid parent drug comprises the following steps,
(1) preparing a bromadiolone liquid mother medicine, and preparing a solvent: compounding a mixed solution of 40 g of water and 60 g of ethanol into a reaction solvent for later use as a reaction solvent;
(2) reduction of bromadiolone precursor ketone to prepare bromadiolone: adding 10 g of bromadiolone precursor ketone into the prepared ethanol-water mixed solution, continuously heating and stirring, keeping the temperature of a reaction system at 50 ℃, adding 3 g of potassium borohydride, keeping the temperature and stirring, keeping the reaction for 7 hours, cooling and filtering solid residues to obtain an orange-yellow bromadiolone liquid mother medicine; HPLC detection shows that the content is 8.73%, the isomer ratio is 0.22, and the yield is 89.9%.
Example two
Preparing bromadiolone liquid mother medicine in a workshop:
the industrial production method for controlling the isomer ratio of the bromadiolone liquid parent drug comprises the following steps,
(1) preparing a bromadiolone liquid mother medicine, and preparing a solvent: mixing 120 kg of water and 180 kg of ethanol to obtain a reaction solvent, and using the reaction solvent as a reaction solvent;
(2) reduction of bromadiolone precursor ketone to prepare bromadiolone: adding 30 kg of bromadiolone precursor ketone into the prepared ethanol-water mixed solution, continuously heating and stirring, keeping the temperature of a reaction system at 50 ℃, adding 12 kg of potassium borohydride, keeping the temperature and stirring, keeping the reaction for 7 hours, cooling and filtering solid residues to obtain an orange-yellow bromadiolone liquid mother medicine; HPLC detection shows that the content is 8.64%, the isomer ratio is 0.19, and the yield is 89.5%.
Claims (2)
1. An industrial production method for controlling the isomer ratio of a bromadiolone liquid parent drug is characterized by comprising the following steps: the industrial production method for controlling the isomer ratio of the bromadiolone liquid mother medicament comprises the following steps of:
(1) preparing a bromadiolone liquid mother medicine, and preparing a solvent: compounding the mixed solution of water and ethanol into a reaction solvent for later use as a reaction solvent;
(2) reduction of bromadiolone precursor ketone to prepare bromadiolone: adding a bromadiolone precursor ketone into the prepared ethanol-water mixed solution, continuously heating and stirring, keeping the temperature of a reaction system at 50 ℃, adding potassium borohydride, keeping the temperature and stirring, keeping the reaction for 7 hours, cooling and filtering solid residues to obtain an orange-yellow bromadiolone liquid mother medicine;
(3) the mass ratio of the compound solvent ethanol to the water in the step (1) is 60: 40;
(4) the ratio of the consumption of the bromadiolone precursor ketone in the step (2) to the mass of the solvent is 1: 10;
(5) the ratio of the dosage of the potassium borohydride to the bromadiolone precursor ketone in the step (2) is 3: 10.
2. the industrial production method for controlling the isomer ratio of the bromadiolone liquid mother medicine according to the claim 1, which is characterized in that: the action mechanism of the industrial production method for controlling the ratio of the bromadiolone liquid mother medicine isomers is that on the premise of not influencing the reaction yield, the industrial production method for controlling the bromadiolone liquid mother medicine isomers changes the polarity of a solvent and increases the influence of a solvation effect by adding a water compound solvent for reaction, when the dielectric constant epsilon of the solvent is less than 10-15, free ions do not exist in the solution, and when the epsilon is more than 40, ion association does not exist in the solution; on the other hand, the synthesis diastereoisomer of the bromadiolone precursor ketone is generated in the last step of carbonyl reduction in the bromadiolone precursor ketone, because of the unique molecular structure of the bromadiolone precursor ketone, a nucleophilic reagent is influenced by steric hindrance in the reduction reaction process to generate selectivity, the nucleophilic reagent is easier to attack carbonyl from one side with small steric hindrance, the solvation effect increases the tendency, and the results of the two factors enhance the selectivity of carbonyl reduction by increasing the polarity of a solvent so as to realize the control of the proportion of the isomer in the bromadiolone liquid mother medicine under the condition of unchanged yield, the bromadiolone precursor ketone is reduced by potassium borohydride, and the bromadiolone liquid mother medicine is obtained after filtration treatment; on the premise of keeping the yield unchanged, the proportion of the two components A, B of the bromadiolone precursor ketone is changed, and the proportion of isomers in the bromadiolone precursor ketone product is adjusted.
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| CN113636997A (en) * | 2021-09-07 | 2021-11-12 | 江苏莱科化学有限公司 | Diphenyl ether new compound containing 4-hydroxy-2H-1-benzopyran-2-one fragment and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3574234A (en) * | 1966-12-13 | 1971-04-06 | Lipha | Derivatives of 4-hydroxy coumarine |
| IN181367B (en) * | 1995-02-28 | 1998-05-30 | Rallis India Ltd | |
| GB0211018D0 (en) * | 2002-05-14 | 2002-06-26 | Syngenta Ltd | Novel compounds |
| CN103109796A (en) * | 2013-03-14 | 2013-05-22 | 商丘市大卫化工厂 | Bromadiolone mother liquid preparation method |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3574234A (en) * | 1966-12-13 | 1971-04-06 | Lipha | Derivatives of 4-hydroxy coumarine |
| IN181367B (en) * | 1995-02-28 | 1998-05-30 | Rallis India Ltd | |
| GB0211018D0 (en) * | 2002-05-14 | 2002-06-26 | Syngenta Ltd | Novel compounds |
| CN103109796A (en) * | 2013-03-14 | 2013-05-22 | 商丘市大卫化工厂 | Bromadiolone mother liquid preparation method |
Non-Patent Citations (2)
| Title |
|---|
| Long-Distance Control in Stereoselective Reduction of 3-[3-(4*-Bromo[1,1*-Biphenyl]-4-yl)-3-Keto-1-Phenylpropyl]-4-Hydroxy-2H-1-Benzopyran-2-One:Relative Configuration of Prevailing Diastereomer and Absolute Configuration of Its Enantiomers;AMIR AVDAGIC et al.;《CHIRALITY》;19981207;第9卷;第512-522页 * |
| Synthesis and Insecticidal Activity of New 4-Hydroxy-2H-1-benzopyran-2-one Derivatives;Meijing Wang et al.;《Appl Biochem Biotechnol》;20090509;第159卷;第768-777页 * |
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