CN110698424A - Preparation method of probenazole - Google Patents
Preparation method of probenazole Download PDFInfo
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- CN110698424A CN110698424A CN201911068412.8A CN201911068412A CN110698424A CN 110698424 A CN110698424 A CN 110698424A CN 201911068412 A CN201911068412 A CN 201911068412A CN 110698424 A CN110698424 A CN 110698424A
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- probenazole
- saccharin
- allyl alcohol
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- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
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Abstract
The invention provides a preparation method of probenazole, which takes saccharin as an initial raw material, uses thionyl chloride to chlorinate in 1, 4-dioxane to obtain chloride, adds a high-boiling point solvent to remove the solvent dioxane and excessive thionyl chloride, directly carries out substitution reaction with sodium salt or potassium salt of allyl alcohol, and directly obtains high-purity probenazole through centrifugal desalination, cooling and recrystallization; the method solves the problem of difficult kettle transfer caused by chloride solidification in the prior art, avoids the generation of allyl chloride during etherification by allyl alcohol, and reduces the water washing procedure in the traditional method. Compared with the traditional method, the preparation method has the advantages of simple and convenient operation, high yield, less three wastes, high purity of the obtained product, great saving of production cost and environmental protection cost, and easy realization of industrialization.
Description
Technical Field
The invention relates to the field of probenazole production, in particular to a preparation method of probenazole.
Background
Probenazole, whose chemical name is 3- (prop-2-ene)Oxy) -1, 1-dioxobenzo [ d [ -D ]]Isothiazole, CAS registry number [27605-76-1]Molecular formula is C10H9NO3S, the structural formula is as follows:
the probenazole does not have direct bactericidal activity per se, but can stimulate the potential of plants, so the probenazole is called as a disease-resistant activator. It is used as inducer to induce the plant to produce defense effect on rice blast and some bacterial diseases, so as to inhibit the generation and development of diseases. Probenazole as low-toxicity pesticide, acute oral administration LD for male mice502750mg/kg, 3000mg/kg of female mice, is low-toxic and safe to nonpathogenic microorganisms and warm-blooded animals, and belongs to an environment-friendly pesticide. The synthetic route is divided into two steps of chlorination and allyl alcohol substitution. In the chlorination step, inorganic acyl chloride is mainly used as a chlorinating agent, such as PCl5Chlorination yield 60% at 220 degrees [ Journal of Chemical evolution, 2016,93(10), 1781-; a chlorination yield of 63% at 180 [ [ Journal of Molecular Catalysis A: Chemical,2016,425, 283-; journal of Organic Chemistry 2015,80(1),392- "400; 2015, when the temperature is reduced to 130 ℃ reaction, the yield can be increased to 91% [ PCT int.appl.,2004007518 ], using POCl3Chlorination yield at 180 ℃ of 63% [ Chemistry-A European Journal,2018,24(13), 3251-; adopts SOCl2Refluxing in 1, 4-dioxane for 12-24 h with 74-75% yield [ CN107417682, PCT int.appl.,2017064277 ], if DMF is added as catalyst, the yield is increased to 85-99 [ Organic Reactions (Hoboken, NJ, United States),2007,69, 347-; office, 102010043497. Wherein SOCl is used2In 1, 4-dioxane, DMF as catalyst is added to result in high yield and excessive SOCl2Easy recovery has been industrialized. In the second step, allyl alcohol is adopted for direct substitution, and excessive allyl alcohol or toluene, dichloromethane and dimethyl sulfoxide can be used as solvents [ JPn7014301 ]; JPn 7524272, respectively; journal of chemists 2001, (8), 18; journal of Applicable Chemistry,2012,1(4): 467-477; US 5985903; US6589974 in which dichloro is usedMethane is the best solvent and has been adopted industrially. The dichloromethane used as the solvent has the advantages of good solubility and low boiling point, so that the byproduct HCl can be discharged in time, the allyl chloride and water generated by the reaction of the HCl and allyl alcohol are avoided, the yield is greatly reduced due to the reaction of the water and the chloride, and the current industrialized synthetic route is as follows:
the existing process has the problems that (1) excessive thionyl chloride needs to be completely distilled off after chlorination is finished, otherwise, residual thionyl chloride can react with allyl alcohol to generate allyl chloride during the second step of substitution, 1, 4-dioxane needs to be evaporated to dryness in order to remove the thionyl chloride completely, and the chlorinated product is suddenly solidified to damage stirring slurry or block a pipeline in a kettle transferring process due to high melting point of the chlorinated product when the chlorinated product is distilled to the later stage, which is a problem difficult to overcome in production. (2) Although dichloromethane is good to chloride solubility, does benefit to going on of reaction, and the dichloromethane boiling point is low simultaneously, can leave the reaction system with most HCl gas that produces during the alcoholysis and time, and furthest has avoided the formation of allyl chloride:
the water produced in the above reaction can also be used for continuously hydrolyzing chloride to convert the chloride into saccharin:
if a high boiling point solvent such as toluene is used, HCl gas generated in the substitution reaction cannot be timely removed from the reaction system, and the side reaction is more serious, so that most of chloride is converted into saccharin.
Although the use of methylene chloride as solvent can largely avoid the above side reactions, the product probenazole has very good solubility in methylene chloride, which must be removed to obtain the final product. Generally, water is supplemented after the reaction is finished, dichloromethane is completely distilled out, a large amount of wastewater is generated, the temperature at the later stage of a dichloromethane removing process is also high, and the probenazole is subjected to Claisen rearrangement to generate N-allyl saccharin:
if the methylene dichloride is removed under reduced pressure, the cost of condensation or the loss of the methylene dichloride is increased.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of probenazole.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a preparation method of probenazole, regard saccharin as raw materials, chloridize with thionyl chloride in 1, 4-dioxane to get chloride, add high boiling point hydrocarbon or chlorinated aromatic hydrocarbon solvent after chloridizing, then atmospheric distillation reclaims excessive thionyl chloride and 1, 4-dioxane, chloride has very good solubility in high boiling point hydrocarbon or chlorinated aromatic hydrocarbon solvent, will not separate out suddenly, and the boiling point of the postaddition solvent is high, can reclaim thionyl chloride totally; and then directly adding an allyl alcohol solution of sodium (potassium) allyl alcohol, controlling the reaction at room temperature, distilling to remove excessive allyl alcohol after the reaction is finished, filtering to remove salt, cooling, and crystallizing and separating out the probenazole, so that the probenazole with high purity and high yield can be obtained, and the whole process does not use water and does not discharge waste water.
Preferably, in the above method for producing probenazole, the high-boiling-point hydrocarbon solvent is xylene, and the chlorinated aromatic hydrocarbon solvent is chlorobenzene.
Preferably, the preparation method of probenazole comprises the following steps:
(1) chlorination: taking dried saccharin as a raw material, 1, 4-dioxane accounting for 2-3 times of the mass of saccharin as a solvent, and thionyl chloride accounting for 1-2 times of the mass of saccharin as a chlorinating agent, and slowly refluxing at 70-105 ℃ for 5-20 hours;
(2) recovering 1, 4-dioxane and excess thionyl chloride: supplementing aromatic hydrocarbon or chlorohydrocarbon solvent with high boiling point and 2 times of saccharin, and recovering excessive thionyl chloride and 1, 4-dioxane as a solvent by virtue of Weishi column rectification;
(3) and (3) substitution reaction: adding allyl alcohol solution of sodium allyl alcohol or potassium allyl alcohol with the mass of saccharin and the like, reacting for 2-4 hours at room temperature, distilling and recovering allyl alcohol, filtering to remove sodium chloride while hot, cooling the filtrate to 0 ℃, and performing suction filtration or centrifugal drying to obtain pure probenazole.
Preferably, in the above method for preparing probenazole, the high-boiling aromatic hydrocarbon or chlorinated hydrocarbon solvent is toluene, ethylbenzene, xylene, chlorobenzene or trichloroethane.
Preferably, in the preparation method of probenazole, sodium allyl alcohol or potassium allyl alcohol is directly used for nucleophilic substitution reaction, the dosage of the substitution reaction is 0.9-1.1 times of the mass of saccharin, and the optimal reaction temperature is 0-30 ℃.
The invention has the beneficial effects that:
compared with the prior art, the preparation method of the probenazole has the following advantages: (1) the probenazole obtained by the method is high in purity and has good price advantage; (2) the method has the advantages of simple process, short route and easy operation; (3) the method has the advantages of no waste water, less other three wastes, low production cost and environmental protection cost, is convenient for realizing industrial production, reduces the production energy consumption and improves the product yield and quality.
Drawings
FIG. 1 shows the preparation of probenazole obtained in example 11H NMR spectrum.
FIG. 2 is a high performance liquid chromatography of probenazole obtained in example 1.
FIG. 3 shows the preparation of probenazole obtained in example 21H NMR spectrum.
FIG. 4 is a high performance liquid chromatography of probenazole obtained in example 2.
Detailed Description
The technical solution of the present invention is further described with reference to the following specific examples.
Example 1
A preparation method of probenazole comprises the following specific steps:
1. chloride preparation:
(1) 500g of thoroughly dried saccharin [ FW183, 2.73mol ] was added to a 3L four-necked flask, and the mixture was not thoroughly dried and consumed SOCl2Increase, 1335g of 1, 4-dioxane, 552g of SOCl2[ FW119, 4.64mol ] 22g DMF. CaCl is linked to the upper end of the reflux condenser tube in sequence2A drying column, a buffer bottle, a 464mL water hydrogen chloride absorption bottle, a buffer bottle, a solution of 110g NaOH and 300mL water (for producing sodium bisulfite or freezing below-10 ℃ to a liquid state for saccharin production).
(2) Slowly heating to reflux until no gas is discharged, and supplementing 1000g of dry xylene;
(3) heating to evaporate unreacted thionyl chloride and 1, 4-dioxane, and stopping heating when the temperature in the kettle rises to 140 ℃ to obtain a xylene solution of chloride.
2. Preparation of sodium allyl alcohol:
300g of allyl alcohol is added into a 500mL three-neck flask, the mixture is cooled in a water bath, 63g of Na (2.73 mol) which is cut into small blocks is added in 6 times, and the reaction is stirred until the metallic sodium disappears. To obtain the allyl alcohol solution of sodium allyl alcohol.
3. Preparation of probenazole:
and adding an allyl alcohol solution of sodium allyl alcohol into a xylene solution of the chloride, and controlling the temperature to be 20-30 ℃ to react for 2 hours. The sodium chloride is removed by filtration and the excess allyl alcohol is distilled off at a temperature of not more than 100 ℃. The residue was cooled to 0 ℃ to give 580g of probenazole in 95% yield, melting point: 136 ℃ and 137 ℃ and the HPLC purity of 98.14 percent, and the nuclear magnetic resonance hydrogen spectrum is shown in figure 1, and the HPLC spectrum [ detection wavelength is 220nm, VMethanol：VWater (W)See figure 2 for 60: 40.
Example 2
A preparation method of probenazole comprises the following specific steps:
1. chloride preparation:
(1) 500g of thoroughly dried saccharin [ FW183, 2.73mol ] was added to a 3L four-necked bottle without dryingComplete and consume SOCl2Increase, 1335g of 1, 4-dioxane, 552g of SOCl2[ FW119, 4.64mol ] 22g DMF. CaCl is linked to the upper end of the reflux condenser tube in sequence2A drying column, a buffer bottle, a 464mL water hydrogen chloride absorption bottle, a buffer bottle, a solution of 110g NaOH and 300mL water (for producing sodium bisulfite or freezing below-10 ℃ to a liquid state for saccharin production).
(2) Slowly heating to reflux until no gas is discharged, and supplementing 1000g of dry chlorobenzene;
(3) heating to evaporate unreacted thionyl chloride and 1, 4-dioxane, and stopping heating when the temperature in the kettle rises to 135 ℃ to obtain a chlorobenzene solution of chloride.
2. Preparation of potassium allyl alcohol:
160g of powdered KOH (1 eq), 100mL of cyclohexane and 300g of allyl alcohol (1.5 eq) are added into a 1000mL three-neck flask, heated under reflux for dehydration until 50g of water is removed, and the cyclohexane as a water-carrying agent is distilled out. To obtain the allyl alcohol solution of potassium allyl alcohol.
3. Substitution preparation of probenazole:
dropwise adding the allyl alcohol solution of the potassium allyl alcohol into a chlorobenzene solution of chloride, and controlling the temperature to be 20-30 ℃ for reacting for 2 hours. The potassium chloride is removed by filtration and the excess allyl alcohol is distilled off at a temperature of not more than 100 ℃. The residue was cooled to 0 ℃ to give 585g of probenazole in 96% yield, melting point: 136 ℃ and 137 ℃ and has HPLC purity of 99.06 percent. The hydrogen spectrum of NMR is shown in FIG. 3, and the HPLC spectrum is shown in FIG. 4.
The above detailed description of the process for the preparation of probenazole with reference to the examples is illustrative and not restrictive, and several examples may be cited within the limits specified, whereby changes and modifications which do not depart from the general concept of the present invention are intended to be within the scope of the present invention.
Claims (5)
1. A preparation method of probenazole is characterized in that: taking saccharin as a raw material, chlorinating with thionyl chloride in 1, 4-dioxane to obtain chloride, adding a high-boiling-point hydrocarbon or chlorinated aromatic hydrocarbon solvent to remove the solvent 1, 4-dioxane and excessive thionyl chloride, then carrying out substitution reaction with sodium (potassium) allyl propanol, and carrying out centrifugal desalination and cooling recrystallization to obtain the high-purity probenazole.
2. The process for preparing probenazole according to claim 1, wherein: the high boiling point hydrocarbon solvent is dimethylbenzene, and the chlorinated aromatic hydrocarbon solvent is chlorobenzene.
3. The process for preparing probenazole according to claim 1, wherein: the method comprises the following specific steps:
(1) chlorination: taking dried saccharin as a raw material, 1, 4-dioxane accounting for 2-3 times of the mass of saccharin as a solvent, and thionyl chloride accounting for 1-2 times of the mass of saccharin as a chlorinating agent, and slowly refluxing at 70-105 ℃ for 5-20 hours;
(2) recovering 1, 4-dioxane and excess thionyl chloride: supplementing aromatic hydrocarbon or chlorohydrocarbon solvent with high boiling point and 2 times of saccharin, and recovering excessive thionyl chloride and 1, 4-dioxane as a solvent by virtue of Weishi column rectification;
(3) and (3) substitution reaction: adding allyl alcohol solution of sodium allyl alcohol or potassium allyl alcohol with the mass of saccharin and the like, reacting for 2-4 hours at room temperature, distilling and recovering allyl alcohol, filtering to remove sodium chloride while hot, cooling the filtrate to 0 ℃, and performing suction filtration or centrifugal drying to obtain pure probenazole.
4. The process for preparing probenazole according to claim 3, wherein: the high boiling point aromatic hydrocarbon or chlorinated hydrocarbon solvent is toluene, ethylbenzene, xylene, chlorobenzene or trichloroethane, and the quantity of the supplemented solvent is 1-3 times of the mass of saccharin.
5. The process for preparing probenazole according to claim 3, wherein: the substitution reaction directly uses sodium allyl alcohol or potassium allyl alcohol to carry out nucleophilic substitution reaction, the dosage is 0.9-1.1 times of the saccharin quality, and the reaction temperature is 0-30 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000095769A (en) * | 1998-09-22 | 2000-04-04 | Kankyo Meneki Gijutsu Kenkyusho:Kk | Hapten compound of probenazole, antibody and assay |
| CN101456847A (en) * | 2008-11-25 | 2009-06-17 | 天津市鑫卫化工有限责任公司 | Probenazole and preparation method thereof |
| CN106518801A (en) * | 2016-10-08 | 2017-03-22 | 盐城联合伟业化工有限公司 | Method for recovering insoluble saccharin from probenazole produced wastewater |
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2019
- 2019-11-05 CN CN201911068412.8A patent/CN110698424A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000095769A (en) * | 1998-09-22 | 2000-04-04 | Kankyo Meneki Gijutsu Kenkyusho:Kk | Hapten compound of probenazole, antibody and assay |
| CN101456847A (en) * | 2008-11-25 | 2009-06-17 | 天津市鑫卫化工有限责任公司 | Probenazole and preparation method thereof |
| CN106518801A (en) * | 2016-10-08 | 2017-03-22 | 盐城联合伟业化工有限公司 | Method for recovering insoluble saccharin from probenazole produced wastewater |
Non-Patent Citations (2)
| Title |
|---|
| 王晓军等: ""烯丙异噻唑的合成研究"", 《化工时刊》 * |
| 阿丰索等: "《绿色分离过程—基础与应用》", 31 May 2008, 华东理工大学出版社 * |
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Inventor after: Liu Hongjun Inventor after: Li Shengbin Inventor after: Liu Yongsheng Inventor after: Cao Shijia Inventor after: Chang Hong Inventor after: Wang Yue Inventor before: Li Shengbin Inventor before: Liu Hongjun Inventor before: Liu Yongsheng Inventor before: Cao Shijia Inventor before: Chang Hong Inventor before: Wang Yue |
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Application publication date: 20200117 |