CN105439811A - Synthesis method of trifluperidol drug intermediate m-bromobenzotrifluoride - Google Patents
Synthesis method of trifluperidol drug intermediate m-bromobenzotrifluoride Download PDFInfo
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- CN105439811A CN105439811A CN201510981703.1A CN201510981703A CN105439811A CN 105439811 A CN105439811 A CN 105439811A CN 201510981703 A CN201510981703 A CN 201510981703A CN 105439811 A CN105439811 A CN 105439811A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
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Abstract
The invention relates to a synthesis method of a trifluperidol drug intermediate m-bromobenzotrifluoride, which comprises the following steps: (i) adding 300mL of 50-70 wt% potassium chloride solution into a reaction vessel which is provided with a stirrer, a thermometer and a dropping funnel, control the stirring rate at 300-500 rpm, adding 0.35mol of m-aminobromobenzotrifluoride (2), heating the solution to 60-65 DEG C until the solid is completely dissolved, cooling to 5-8 DEG C, dropwisely adding 0.35-0.39mol of sodium nitrate in 60ml of water to prepare a solution, controlling the reaction temperature at 15-20 DEG C, and determining the end point with potassium iodide test paper to obtain diazonium salt (3); and (ii) adding 0.12 mol of nickel dichloride into 300ml of sodium bromide solution, heating the solution to 85-90 DEG C, adding the diazonium salt (3) solution obtained in the step (i), carrying out steam distillation until no organic matters are distilled out, separating out the organic layer, washing with a solution, washing with a salt solution, washing with a neutralizing solution, dehydrating with a dehydrating agent, distilling under reduced pressure, and collecting the 80-85-DEG C fraction to obtain the m-bromobenzotrifluoride.
Description
Technical field
The present invention relates to the synthetic method of 5 bromine benzotrifluoride between a kind of trifluperidol pharmaceutical intermediate.
Background technology
Trifluperidol belongs to butyrophenones medicine, by blocking Dopamine Receptors effect in brain, suppressing the effect of dopaminergic neuron, and can promote the conversion of Dopamine HCL in brain.In addition, the also neuro alpha-2-adrenoceptor in periphery capable of blocking.Produce corresponding physiological effect.Antipsycholic action is strong soon.During the general dosage of this product, eliminate solitarily indifferent, the dull symptom of shrinking back such as passive, have and optionally rouse oneself active effect; During larger dose, excited restless to control, the psychomotor excitements such as conduct disorder are effective.Between 5 bromine benzotrifluoride as trifluperidol pharmaceutical intermediate, its synthetic method is good and bad for raising pharmaceutical synthesis quality product, reduces by-products content and has Important Economic meaning.
Summary of the invention
The object of the present invention is to provide the synthetic method of 5 bromine benzotrifluoride between a kind of trifluperidol pharmaceutical intermediate, comprise the steps:
I () is being equipped with agitator, thermometer, in the reaction vessel of dropping funnel, add the Klorvess Liquid 300mL that massfraction is 50-70%, control stirring velocity at 300-500rpm, add mamino-trifluoromethyl benzene (2) 0.35mol, solution temperature is made to be increased to 60--65 DEG C, it is made to dissolve completely, then 5--8 DEG C is cooled to, drip Sodium Nitrite 0.35-0.39mol and be dissolved in 60ml water wiring solution-forming, control temperature of reaction at 15--20 DEG C, the time controling of configuration sodium nitrite solution is at 20-30min, terminal is measured with potassium iodide starch paper, obtain diazonium salt (3)
(ii) protochloride nickel 0.12mol is joined in the sodium bromide solution of 300ml, heated solution, to 85--90 DEG C, then adds diazonium salt (3) solution of step (i) gained, maintains duration of the reaction 40-50min, by wet distillation, until distillate without organism, separate organic layer, with solution washing, then successively with brine, neutralization solution washing, dewatering agent dehydration, then underpressure distillation, collects the cut of 80--85 DEG C, 5 bromine benzotrifluoride between obtaining; The strong phosphoric acid of the solution used of the solution washing described in step (ii) to be massfraction be 80%--85%, brine solution used is any one in Sodium Bromide, Potassium Bromide, iron bromide, it is any one in sodium bicarbonate, saleratus that neutralization solution washs solution used, what dewatering agent dewatered dewatering agent used is in calcium sulfate, anhydrous sodium sulphate any one, the pressure residing for pressure distillation is 6.5-7kPa.
Whole reaction process can represent with following reaction formula:
The invention has the advantages that: the middle-chain decreasing reaction, reduce temperature of reaction and reaction times, improve reaction yield.
Embodiment
Below in conjunction with concrete embodiment, the invention will be further described:
The synthetic method of 5 bromine benzotrifluoride between a kind of trifluperidol pharmaceutical intermediate
Example 1:
I () is in the reaction vessel being equipped with agitator, thermometer, dropping funnel, add the Klorvess Liquid 300mL that massfraction is 50%, control stirring velocity at 300rpm, add mamino-trifluoromethyl benzene (2) 0.35mol, solution temperature is made to be increased to 60 DEG C, it is made to dissolve completely, then 5 DEG C are cooled to, drip Sodium Nitrite 0.35mol and be dissolved in 60ml water wiring solution-forming, control temperature of reaction at 15 DEG C, the time controling of configuration sodium nitrite solution, at 20min, measures terminal with potassium iodide starch paper, obtains diazonium salt (3);
(ii) protochloride nickel 0.12mol is joined in the sodium bromide solution of 300ml, heated solution to 85 DEG C, then diazonium salt (3) solution of step (i) gained is added, maintain duration of the reaction 40min, by wet distillation, until distillate without organism, separate organic layer, with the concentrated phosphoric acid washing that massfraction is 80%, then successively with sodium bromide solution washing, sodium hydrogen carbonate solution washing, calcium sulfate dehydration, then 6.5kPa underpressure distillation, collects the cut of 80--85 DEG C, 5 bromine benzotrifluoride 50.40g between obtaining, yield 64%.
Example 2:
I () is in the reaction vessel being equipped with agitator, thermometer, dropping funnel, add the Klorvess Liquid 300mL that massfraction is 60%, control stirring velocity at 400rpm, add mamino-trifluoromethyl benzene (2) 0.35mol, solution temperature is made to be increased to 63 DEG C, it is made to dissolve completely, then 7 DEG C are cooled to, drip Sodium Nitrite 0.37mol and be dissolved in 60ml water wiring solution-forming, control temperature of reaction at 18 DEG C, the time controling of configuration sodium nitrite solution, at 25min, measures terminal with potassium iodide starch paper, obtains diazonium salt (3);
(ii) protochloride nickel 0.12mol is joined in the sodium bromide solution of 300ml, heated solution to 87 DEG C, then diazonium salt (3) solution of step (i) gained is added, maintain duration of the reaction 43min, by wet distillation, until distillate without organism, separate organic layer, with the concentrated phosphoric acid washing that massfraction is 83%, then successively with potassium bromide solution washing, potassium bicarbonate solution washing, anhydrous sodium sulfate dehydration, then 6.8kPa underpressure distillation, collects the cut of 80--85 DEG C, 5 bromine benzotrifluoride 54.34g between obtaining, yield 69%.
Example 3:
I () is in the reaction vessel being equipped with agitator, thermometer, dropping funnel, add the Klorvess Liquid 300mL that massfraction is 70%, control stirring velocity at 500rpm, add mamino-trifluoromethyl benzene (2) 0.35mol, solution temperature is made to be increased to 65 DEG C, it is made to dissolve completely, then 8 DEG C are cooled to, drip Sodium Nitrite 0.39mol and be dissolved in 60ml water wiring solution-forming, control temperature of reaction at 20 DEG C, the time controling of configuration sodium nitrite solution, at 30min, measures terminal with potassium iodide starch paper, obtains diazonium salt (3);
(ii) protochloride nickel 0.12mol is joined in the sodium bromide solution of 300ml, heated solution to 90 DEG C, then diazonium salt (3) solution of step (i) gained is added, maintain duration of the reaction 50min, by wet distillation, until distillate without organism, separate organic layer, with the concentrated phosphoric acid washing that massfraction is 85%, then successively with iron bromide solution washing, sodium hydrogen carbonate solution washing, calcium sulfate dehydration, then 7kPa underpressure distillation, collects the cut of 80--85 DEG C, 5 bromine benzotrifluoride 57.49g between obtaining, yield 73%.
Claims (5)
1. the synthetic method of 5 bromine benzotrifluoride between trifluperidol pharmaceutical intermediate, is characterized in that, comprise the steps:
I () is being equipped with agitator, thermometer, in the reaction vessel of dropping funnel, add the Klorvess Liquid 300mL that massfraction is 50-70%, control stirring velocity at 300-500rpm, add mamino-trifluoromethyl benzene (2) 0.35mol, solution temperature is made to be increased to 60--65 DEG C, it is made to dissolve completely, then 5--8 DEG C is cooled to, drip Sodium Nitrite 0.35-0.39mol and be dissolved in 60ml water wiring solution-forming, control temperature of reaction at 15--20 DEG C, the time controling of configuration sodium nitrite solution is at 20-30min, terminal is measured with potassium iodide starch paper, obtain diazonium salt (3),
(ii) protochloride nickel 0.12mol is joined in the sodium bromide solution of 300ml, heated solution, to 85--90 DEG C, then adds diazonium salt (3) solution of step (i) gained, maintains duration of the reaction 40-50min, by wet distillation, until distillate without organism, separate organic layer, with solution washing, then successively with brine, neutralization solution washing, dewatering agent dehydration, then underpressure distillation, collects the cut of 80--85 DEG C, 5 bromine benzotrifluoride between obtaining; The strong phosphoric acid of the solution used of the solution washing described in step (ii) to be massfraction be 80%--85%.
2. the synthetic method of 5 bromine benzotrifluoride between a kind of trifluperidol pharmaceutical intermediate according to claim 1, is characterized in that, the solution used of the brine described in step (ii) is any one in Sodium Bromide, Potassium Bromide, iron bromide.
3. the synthetic method of 5 bromine benzotrifluoride between a kind of trifluperidol pharmaceutical intermediate according to claim 1, is characterized in that, it is any one in sodium bicarbonate, saleratus that the neutralization solution described in step (ii) washs solution used.
4. the synthetic method of 5 bromine benzotrifluoride between a kind of trifluperidol pharmaceutical intermediate according to claim 1, is characterized in that, what the dewatering agent described in step (ii) dewatered dewatering agent used is in calcium sulfate, anhydrous sodium sulphate any one.
5. the synthetic method of 5 bromine benzotrifluoride between a kind of trifluperidol pharmaceutical intermediate according to claim 1, it is characterized in that, the pressure residing for pressure distillation described in step (ii) is 6.5-7kPa.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510981703.1A CN105439811A (en) | 2015-12-23 | 2015-12-23 | Synthesis method of trifluperidol drug intermediate m-bromobenzotrifluoride |
| CN201610824162.6A CN106397109A (en) | 2015-12-23 | 2016-09-17 | Synthetic method of trifluperidol medicine intermediate 3-bromobenzotrifluoride |
| AU2016102213A AU2016102213A4 (en) | 2015-12-23 | 2016-12-23 | Trifluperidol drug intermediates bromobenzotrifluoride synthesis method |
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| CN201510981703.1A CN105439811A (en) | 2015-12-23 | 2015-12-23 | Synthesis method of trifluperidol drug intermediate m-bromobenzotrifluoride |
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| CN201610824162.6A Pending CN106397109A (en) | 2015-12-23 | 2016-09-17 | Synthetic method of trifluperidol medicine intermediate 3-bromobenzotrifluoride |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105801348A (en) * | 2016-04-20 | 2016-07-27 | 江苏中能化学科技股份有限公司 | 3-bromobenzotrifluoride and preparation method thereof |
| CN106336340A (en) * | 2016-08-22 | 2017-01-18 | 苏州天马精细化学品股份有限公司 | Method for synthesizing 2-Bromobenzotrifluoride |
| CN106905104A (en) * | 2017-01-03 | 2017-06-30 | 浙江巍华化工有限公司 | A kind of synthetic method of the fluoride trifluoro toluene of 2 bromine 5 |
| CN112110790A (en) * | 2020-09-28 | 2020-12-22 | 杭州臻挚生物科技有限公司 | Preparation method of 3, 5-dihalo trifluorotoluene and 3 '-chloro-5' - (trifluoromethyl) phenyl trifluoroacetone |
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2015
- 2015-12-23 CN CN201510981703.1A patent/CN105439811A/en active Pending
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- 2016-09-17 CN CN201610824162.6A patent/CN106397109A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105801348A (en) * | 2016-04-20 | 2016-07-27 | 江苏中能化学科技股份有限公司 | 3-bromobenzotrifluoride and preparation method thereof |
| CN105801348B (en) * | 2016-04-20 | 2018-03-06 | 江苏中能化学科技股份有限公司 | Between 5 bromine benzotrifluoride and preparation method thereof |
| CN106336340A (en) * | 2016-08-22 | 2017-01-18 | 苏州天马精细化学品股份有限公司 | Method for synthesizing 2-Bromobenzotrifluoride |
| CN106336340B (en) * | 2016-08-22 | 2019-12-31 | 苏州天马药业有限公司 | Synthesis method of o-bromobenzotrifluoride |
| CN106905104A (en) * | 2017-01-03 | 2017-06-30 | 浙江巍华化工有限公司 | A kind of synthetic method of the fluoride trifluoro toluene of 2 bromine 5 |
| CN106905104B (en) * | 2017-01-03 | 2019-12-24 | 浙江巍华新材料股份有限公司 | Synthesis method of 2-bromo-5-fluorobenzotrifluoride |
| CN112110790A (en) * | 2020-09-28 | 2020-12-22 | 杭州臻挚生物科技有限公司 | Preparation method of 3, 5-dihalo trifluorotoluene and 3 '-chloro-5' - (trifluoromethyl) phenyl trifluoroacetone |
| CN112110790B (en) * | 2020-09-28 | 2023-06-23 | 台州臻挚生物科技有限公司 | Preparation method of 3, 5-dihalide benzotrifluoride and 3 '-chloro-5' -trifluoromethyl phenyl trifluoro-ethanone |
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| CN106397109A (en) | 2017-02-15 |
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Application publication date: 20160330 |