CN1219751C - Industrial production of benzofloxamide - Google Patents
Industrial production of benzofloxamide Download PDFInfo
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- CN1219751C CN1219751C CN 02146253 CN02146253A CN1219751C CN 1219751 C CN1219751 C CN 1219751C CN 02146253 CN02146253 CN 02146253 CN 02146253 A CN02146253 A CN 02146253A CN 1219751 C CN1219751 C CN 1219751C
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- benzyl
- lidocaine
- solvent
- ether
- denatonium benzoate
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Abstract
The present invention relates to an industrial production method for benzofloxamide, which uses lignocaine, benzyl halogen, metal hydroxides and benzoic acid as raw materials for synthesizing the benzofloxamide. The present invention is characterized in that in the first technological step, low-grade ether, low-grade ester and mixtures thereof are used as solvents, and intermediate products of phenyl lidocaine solid powder are obtained by filtration after a reaction is completed. Filter liquor containing unreacted lidocaine and the benzyl halogenis circulated into a reactor and is continuously used as solvents for producing the intermediate products of phenyl lidocaine ammonium halide, which makes generated intermediate products of phenyl lidocaine ammonium halide easily separated. Unreacted materials can be circulated and continuously utilized, and accordingly, the benzofloxamide can be used for industrial continuous production.
Description
The present invention relates to a kind of industrial process of denatonium benzoate, with the benefit cacaine, benzyl halogen, metal hydroxides, phenylformic acid is the synthetic denatonium benzoate of raw material, it is characterized in that in the first step technology, adopt ethers, ester class and their mixture are solvent, after reaction finishes, filtration obtains intermediate product benzyl lidocaine halogenated amine pressed powder, filtrate cycle, continue to serve as the reaction solvent of the first step, the intermediate product benzyl lidocaine halogenated amine that reaction is generated is easy to separate, unreacted raw material can circulate and continue to utilize, and makes denatonium benzoate can be used in industrial continuous production.
The sixties Britain, U. S. application the application patent of denatonium benzoate (J.E.Hag GB955309), relate to the synthetic method of this compound in the patent, promptly use excessive benzyl chlorine and lignocaine under 110 ℃, reaction 36h, intermediate product benzyl lignocaine is behind secondary recrystallization, with methyl alcohol Ke Xingjia alkali reaction, filtering-depositing, with benzoic acid, obtain fusing point and be 155～157 ℃ the thick product of denatonium benzoate (solid).We were by the experimental study of serial experiment chamber in 98 years, above-mentioned out-of-date methods have been carried out a series of improvement (Chinese invention patent number: 98100785.6), comprising: 1. the purification process that improves the post-treating method of reaction and intermediate product, product, save re-crystallization step, directly obtain pure product and improve product yield; 2. improvement proportioning raw materials reduces production costs, reduces impurity in the product and to the pollution of environment; 3. reduction temperature of reaction reduces reaction times and side reaction, improves product purity, reduces energy consumption; 4. change reaction and finishing sequence, simplify synthesis technique.Through improvement, improved quality product and yield, reduce production costs, simplify synthesis technique, reduce pollution to environment.But, in the research process that carries out the denatonium benzoate suitability for industrialized production, if we feel that the synthetic technology in early stage is not further improved, to be difficult to suitability for industrialized production, because after the first step reaction finishes, all be to generate almost transparent solid intermediate product benzyl lidocaine halogenated amine, this solid is one to occupy the solid firm integral body of entire reaction spatial in reactor.Test as the laboratory lab scale, be easy to slowly smash to pieces the solid firm solid intermediate product benzyl lidocaine halogenated amine of 20～30 grams with the steel spoon, be for further processing then and react, but for commercial production scale, as have a daily output of denatonium benzoate more than 100 kilograms, smashing solid firm solid intermediate product benzyl lidocaine halogenated amine to pieces, will be very difficult thing, unfavorable and industrial continuous production.In this external the first step reaction, lignocaine and the reaction of benzyl halogen generate the intermediate product benzyl lidocaine halogenated amine, this reaction is the same with other any organic chemical reactionses, all can not reach 100% productive rate, if carry out recrystallization (GB 955309) or (application for a patent for invention number: 98100785.6) directly carry out next step reaction according to the new method according to out-of-date methods, the capital loses unreacted lignocaine and benzyl halogen, and this will be unfavorable for the throwing receipts ratio of denatonium benzoate suitability for industrialized production and be unfavorable for realizing free of contamination requirement in the suitability for industrialized production.
The object of the invention is to overcome above-mentioned laboratory synthetic technology and is used for the shortcoming that suitability for industrialized production exists, a kind of denatonium benzoate industrialization continuous production that helps is provided, helps improving the industrial production novel method of throwing the denatonium benzoate of receiving ratio in the suitability for industrialized production.
Have now found that in the first step technology, employing has can dissolving raw material lignocaine and benzyl halogen, can not dissolve the solvent of intermediate product benzyl lidocaine halogenated amine performance, the intermediate product benzyl lidocaine halogenated amine that generates in the first step reaction is precipitated out from reaction soln with the form of fine powder, unreacted lignocaine and benzyl halogen are still stayed in the reaction soln, in industry, can pass through simple filtering like this, make the intermediate product benzyl lidocaine halogenated amine of generation be easy to separate with unreacted raw material with higher purity, the filtrate cycle that contains unreacted lignocaine and benzyl halogen continues as the solvent of producing the intermediate product benzyl lidocaine halogenated amine in reactor.Discover ethers with following structural formula:
CH
3(CH
2)
nO(CH
2)
mCH
3
N in the structural formula and m are respectively 0～10 integer, have following structural formula ester class:
HCOOCH
3And CH
3(CH
2)
nCOO (CH
2)
mCH
3
N in the structural formula and m are respectively 0～10 integer, and the mixture of above-mentioned solvent and b propanol, acetone, benzene, toluene equal solvent all have can dissolving raw material lignocaine and benzyl halogen, can not dissolve the performance of intermediate product benzyl lidocaine halogenated amine, and can be well as the solvent of producing the intermediate product benzyl lidocaine halogenated amine.The factor of aspect such as pollution-free and environmental friendliness requirement in utilizability, economy and the current industrial production of the above-mentioned solvent of considering in industry, need to adopt ether, ethyl acetate, methyl acetate and sherwood oil aborning, wherein sherwood oil need be 30～120 ° cut.
The industrial production novel method of denatonium benzoate provided by the invention is compared with original laboratory method, not only removed in original method, after finishing, the first step reaction needs to smash to pieces the process procedure of solid firm solid intermediate product benzyl lidocaine halogenated amine, allow to carry out industrial continuous production, this industrial production novel method can also be by the circulation of reaction solution, make full use of unreacted raw material lignocaine and benzyl halogen, reduced production cost, improved productivity effect, reduced the pollution of unreacted raw material lignocaine and benzyl halogen environment.
Embodiment provided by the invention is as follows:
Embodiment 1. is stirring and respectively 1.266 kilograms benzyl chlorine and 2.343 kilograms lignocaine is being joined in the reactor that 5.0 liters of ether are housed.When making the heating fluid temperature rise to 50 ℃, reaction solution boiling this moment keeps boiling after about 50 hours, and reaction solution is cooled to 5 ℃, the benzyl lignocaine chloride precipitation of adularescent generation gradually in the reaction solution, filtering-depositing.Use 0.2 liter ether washing precipitation then, dry under the room temperature, obtaining weight is the benzyl lignocaine ammonium chloride powder of 3.02 kilograms of whites, productive rate 83.7%.
The circulation first time of synthesize benzyl lignocaine ammonium chloride: filtrate that merging obtains above and washings, use second
Table 1: the synthesis condition of intermediate product benzyl lidocaine halogenated amine when ether, sherwood oil, ethyl acetate and methyl acetate are made circulating solvent
| Embodiment, solvent | Heating temperature (℃) | Reaction times (hour) | Output (kilogram) | Productive rate (%) |
| 1, ether 2, for the first time circulate 3, for the second time circulate 4,5, the four circulations for the third time circulate | ?50 ?50 ?50 ?50 ?50 | ?50 ?50 ?50 ?50 ?50 | ?3.02 ?3.32 ?3.35 ?3.44 ?3.45 | ?83.7 ?92.0 ?92.8 ?95.3 ?95.6 |
| 6, sherwood oil, 30～60 7, for the first time circulate 8, for the second time circulate 9, the 4th circulation for the third time circulates | ?60 ?60 ?60 ?60 ?60 | ?47 ?47 ?47 ?47 ?47 | ?3.10 ?3.25 ?3.45 ?3.31 ?3.32 | ?85.9 ?90.0 ?95.5 ?91.7 ?92.0 |
| Sherwood oil, 60～90 ℃ of the 4th circulations that circulate for the third time that circulate for the second time that circulate for the first time | ?70 ?70 ?70 ?70 ?70 | ?45 ?45 ?45 ?45 ?45 | ?3.00 ?3.15 ?3.41 ?3.38 ?3.35 | ?81.3 ?87.3 ?94.5 ?93.6 ?92.8 |
| Sherwood oil, 90～120 ℃ of the 4th circulations that circulate for the third time that circulate for the second time that circulate for the first time | ?70 ?70 ?70 ?70 ?70 | ?45 ?45 ?45 ?45 ?45 | ?2.96 ?3.13 ?3.31 ?3.35 ?3.35 | ?82.0 ?86.7 ?91.7 ?92.8 ?92.8 |
| Ethyl acetate the 4th circulation that circulate for the third time of circulation for the second time that circulate for the first time | ?60 ?60 ?60 ?60 ?60 | ?47 ?47 ?47 ?47 ?47 | ?3.09 ?3.18 ?3.40 ?3.39 ?3.42 | ?85.6 ?88.1 ?94.2 ?93.9 ?94.7 |
| Methyl acetate the 4th circulation that circulate for the third time of circulation for the second time that circulate for the first time | ?70 ?70 ?70 ?70 ?70 | ?45 ?45 ?45 ?45 ?45 | ?2.98 ?3.19 ?3.31 ?3.35 ?3.38 | ?85.6 ?88.1 ?94.2 ?93.9 ?94.7 |
Ether is supplemented to 5.0 liters, under agitation adds 1.266 kilograms benzyl chlorine and 2.343 kilograms lignocaine then respectively.When making the heating fluid temperature rise to 50 ℃, the reaction solution boiling keeps boiling after about 50 hours, and reaction solution is cooled to 5 ℃, the benzyl lignocaine chloride precipitation of adularescent generation gradually in the reaction solution, filtering-depositing.Use 0.2 liter ether washing precipitation then, dry under the room temperature, obtaining weight is the benzyl lignocaine ammonium chloride powder of 3.32 kilograms of whites, productive rate 92.0%.
The circulation second time of synthesize benzyl lignocaine ammonium chloride: merge filtrate and washings that circulation for the first time obtains, carry out the cyclical operation second time of synthesize benzyl lignocaine ammonium chloride, the same in its method and later for the third time cyclical operation method and the circulation for the first time.The circulation of carrying out intermediate product benzyl lignocaine ammonium chloride with other rudimentary ethers, lower member ester kind solvent is synthetic also just the same with top working method, reaction Heating temperature wherein, and reaction times, output and productive rate see Table 1 respectively.
Embodiment 2. is equipped with 5.0 liters of ether and cut is the mixed solvent (volume/volume: 1/1) in the reactor of 30～60 ℃ of sherwood oils stirring and respectively the lignocaine of 1.716 kilograms benzyl bromine and 2.343 kilograms is joined.When making the heating fluid temperature rise to 50 ℃, the reaction solution boiling keeps boiling after about 50 hours, and reaction solution is cooled to 5 ℃, has flaxen benzyl lignocaine brometo de amonio precipitation to generate filtering-depositing in the reaction solution gradually.Use 0.2 liter mixing solutions washing precipitation then, dry under the room temperature, obtaining weight is 3.12 kilograms of flaxen benzyl lignocaine brometo de amonio powder, productive rate 76.8%.
The circulation first time of synthesize benzyl lignocaine brometo de amonio: merge filtrate and washings above the example, with ether and cut is the mixed solvent (volume/volume: 1/1) be supplemented to 5.0 liters, under agitation add 1.716 kilograms benzyl bromine and 2.343 kilograms lignocaine then respectively of 30～60 ℃ of sherwood oils.When making the heating fluid temperature rise to 50 ℃, the reaction solution boiling keeps boiling after about 50 hours, and reaction solution is cooled to 5 ℃, has flaxen benzyl lignocaine brometo de amonio precipitation to generate filtering-depositing in the reaction solution gradually.Use 0.2 liter mixing solutions washing precipitation then, dry under the room temperature, obtaining weight is 3.70 kilograms of flaxen benzyl lignocaine brometo de amonio powder, productive rate 91.1%.
Circulation second time of synthesize benzyl lignocaine brometo de amonio: merge filtrate and washings in the circulation for the first time, carry out the cyclical operation second time of synthesize benzyl lignocaine brometo de amonio, its method and later for the third time cyclical operation method are with top the same.The circulation of carrying out intermediate product benzyl lignocaine brometo de amonio with the mixed solvent of other rudimentary ethers, lower member ester kind solvent is synthetic the same substantially with top working method.Because in process of the test, lower boiling solvent volatilizees easily, the filtrate and the washings that need to go up this collection merge, and are supplemented to 5.0 liters.The solvent that is used for replenishing is called supplementing solvent at table 2.Differ less solvent for each component boiling point in the mixed solvent, when carrying out the circulation of filtrate and washings and utilize, replenish the mixed solvent the same with reaction solvent as solvent.Differ bigger solvent for each component boiling point in the mixed solvent, when carrying out the circulation of filtrate and washings and utilize as solvent, the main lower boiling solvent that replenishes wherein.Concrete test conditions and the results are shown in Table 2:
Table 2: the synthesis condition of intermediate product benzyl lidocaine halogenated amine when mixing solutions is made circulating solvent
| Solvent | Supplementing solvent | Heating temperature (℃) | Reaction times (hour) | Output (kilogram) | Productive rate (%) |
| Ether/ethyl acetate: the 4th circulation that circulate for the third time that circulate for the second time circulates for 1/1 first time | Ether ether ether ether | ?50 ?50 ?50 ?50 ?50 | ?50 ?50 ?50 ?50 ?50 | ?3.12 ?3.32 ?3.33 ?3.40 ?3.41 | ?76.8 ?91.1 ?82.0 ?83.7 ?84.0 |
| Ether/sherwood oil, 30～60 ℃: the 4th circulation that circulate for the third time that circulate for the second time circulates for 1/1 first time | With mixed solvent with mixed solvent with the same mixed solvent of mixed solvent | ?50 ?50 ?50 ?50 ?50 | ?50 ?50 ?50 ?50 ?50 | ?3.21 ?3.35 ?3.40 ?3.41 ?3.42 | ?79.1 ?81.2 ?83.7 ?84.0 ?84.2 |
| Ether/sherwood oil, 60～90 ℃: the 4th circulation that circulate for the third time that circulate for the second time circulates for 1/1 first time | Ether ether ether ether | ?50 ?50 ?50 ?50 ?50 | ?50 ?50 ?50 ?50 ?50 | ?3.22 ?3.35 ?3.47 ?3.48 ?3.65 | ?79.3 ?81.2 ?85.5 ?85.7 ?90.0 |
| Ether/sherwood oil, 90～120 ℃: the 4th circulation that circulate for the third time that circulate for the second time circulates for 1/1 first time | Ether ether ether ether | ?50 ?50 ?50 ?50 ?50 | ?50 ?50 ?50 ?50 ?50 | ?3.46 ?3.53 ?3.65 ?3.72 ?3.67 | ?85.2 ?86.9 ?90.0 ?91.6 ?90.4 |
| Ethyl acetate/petroleum ether, 30～60 ℃: the 4th circulation that circulate for the third time that circulate for the second time circulates for 1/1 first time | Sherwood oil, 30～60 ℃ of sherwood oils, 30～60 ℃ of sherwood oils, 30～60 ℃ of sherwood oils, 30～60 ℃ | ?50 ?50 ?50 ?50 ?50 | ?50 ?50 ?50 ?50 ?50 | ?3.25 ?3.38 ?3.45 ?3.49 ?3.57 | ?80.0 ?83.2 ?85.0 ?86.0 ?87.9 |
| Ethyl acetate/petroleum ether, 60～90 ℃: the 4th circulation that circulate for the third time that circulate for the second time circulates for 1/1 first time | Sherwood oil, 60～90 ℃ of sherwood oils, 60～90 ℃ of sherwood oils, 60～90 ℃ of sherwood oils, 60～90 ℃ | ?70 ?70 ?70 ?70 ?70 | ?45 ?45 ?45 ?45 ?45 | ?3.44 ?3.69 ?3.55 ?3.79 ?3.68 | ?84.7 ?90.9 ?87.4 ?91.9 ?90.6 |
Embodiment 3. gets and obtains among the embodiment 1 under agitation adding 0.561 kilogram potassium hydroxide then in the methyl alcohol that 3.61 kilograms in benzyl lignocaine ammonium chloride powder is dissolved in 2.0 liters, adds 1.221 kilograms phenylformic acid then.Filter, after methanol wash, mother liquor concentrates, and uses the absolute ethanol washing solids, gets 4.095 kilograms of denatonium benzoates, productive rate 91.7%.
Embodiment 4. gets and obtains among the embodiment 2 under agitation adding 0.40 kilogram sodium hydroxide then in the methyl alcohol that 4.06 kilograms in benzyl lignocaine brometo de amonio powder is dissolved in 2.0 liters, adds 1.221 kilograms phenylformic acid then.Filter, after methanol wash, mother liquor concentrates, and uses the absolute ethanol washing solids, gets 3.998 kilograms of denatonium benzoates, productive rate 89.5%.
Claims (4)
1. the industrial process of a denatonium benzoate, with the benefit cacaine, benzyl halogen, metal hydroxides, phenylformic acid is the synthetic denatonium benzoate of raw material, it is characterized in that in the first step technology, adopt ethers, ester class and their mixture are solvent, after reaction finishes, filtration obtains intermediate product benzyl lidocaine halogenated amine pressed powder, filtrate cycle, continue to serve as the reaction solvent of the first step, the intermediate product benzyl lidocaine halogenated amine that reaction is generated is easy to separate, unreacted raw material can circulate and continue to utilize, and makes denatonium benzoate can be used in industrial continuous production.
2. the industrial process of denatonium benzoate according to claim 1 is characterized in that described ethers has following structural formula:
CH
3(CH
2)
nO(CH
2)
mCH
3
N in the structural formula and m are respectively 0～10 integer, and ethers comprises that ether and cut are 30～120 ° sherwood oil.
3. the industrial production process of denatonium benzoate according to claim 1 is characterized in that described ester class has following structural formula:
HCOOCH
3And CH
3(CH
2)
nCOO (CH
2)
mCH
3
N in the structural formula and m are respectively 0～10 integer; The ester class comprises ethyl acetate and methyl acetate.
4. the industrial production process of denatonium benzoate according to claim 1, the admixture solvent that it is characterized in that described ethers, ester class, the mixed solvent that comprises ether and sherwood oil, ether and ethyl acetate, methyl acetate and sherwood oil, the ratio between them are volume ratio 1: 0.9～9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02146253 CN1219751C (en) | 2002-10-17 | 2002-10-17 | Industrial production of benzofloxamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02146253 CN1219751C (en) | 2002-10-17 | 2002-10-17 | Industrial production of benzofloxamide |
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| Publication Number | Publication Date |
|---|---|
| CN1490307A CN1490307A (en) | 2004-04-21 |
| CN1219751C true CN1219751C (en) | 2005-09-21 |
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ID=34148626
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02146253 Expired - Fee Related CN1219751C (en) | 2002-10-17 | 2002-10-17 | Industrial production of benzofloxamide |
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|---|---|
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2002
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