CN105924333A

CN105924333A - Synthesizing method for diphenhydramine pharmaceutical intermediate diphenyl carbinol

Info

Publication number: CN105924333A
Application number: CN201610292957.7A
Authority: CN
Inventors: 廖如佴
Original assignee: Chengdu Ka Di Fu Technology Co Ltd
Current assignee: Chengdu Ka Di Fu Technology Co Ltd
Priority date: 2016-05-05
Filing date: 2016-05-05
Publication date: 2016-09-07

Abstract

The invention provides a synthesizing method for the diphenhydramine pharmaceutical intermediate diphenyl carbinol. Benzophenone and nickel powder are added into a mixed solution of trichloro ethylene and 2-bromine-5-fluoronitrobenzene, and the temperature is slowly increased and maintained for 2-3 h; filtering and washing are carried out 3-5 times, 3 L of a potassium bromide solution is introduced, an oxalic acid solution is added, suction filtration, dehydration with a dehydrating agent and recrystallization are carried out, and diphenyl carbinol crystals are obtained. By means of the synthesizing method, the reaction yield is greatly increased. Meanwhile, the invention provides a novel synthesizing path which lays a good foundation for further increasing the reaction yield.

Description

A kind of synthetic method of diphenhydramine pharmaceutical intermediate benzohydrol

Technical field

The present invention relates to the preparation method of a kind of medicine intermediate, belong to organic synthesis field, particularly relate to one Plant the synthetic method of diphenhydramine pharmaceutical intermediate benzohydrol.

Background technology

Diphenhydramine medicine has the effect of antihistaminic H1 receptor, has stronger inhibitory action to nervus centralis, Also has atropine-like effect.It is suitable for Mucocutaneous anaphylactic disease, such as urticaria, pollinosis, anaphylaxis Rhinitis etc..For the derivant of ethanolamine, antihistamine effect is not as good as promethazine, and acting duration is the shortest, Sedation two medicine is consistent.Also there are local anaesthesia, the anti-M-choline-like effect of Tuhe, town.Histamine effect: can be with tissue In H1 receptor on the histamine competitive effect cell that discharges, thus prevent allergy outbreak；Tranquilizing soporific is made With: the mechanism of suppression neural activity is still not clear；Antitussive effect: can be done directly on the cough of oblongata Maincenter, suppresses coughre flex.The anaphylaxis caused by blood transfusion or blood plasma can be alleviated；Usually should before blood transfusion With antihistamine drug's such as diphenhydramine etc., generally give diphenhydramine 40 milligrams of intramuscular injection, note donating blood simultaneously The screening of member, does not use the blood donor of allergies as far as possible.Avoid the blood of the same blood donor of infusion repeatedly, To avoid antigen-antibody reaction, during as there are anti-IgA antibody in donee's body, can be with infusion through washing Erythrocyte after washing, this washing methods can remove the IgA in donor blood, to prevent anaphylactoid Raw.There is the effect of telling of stronger town it can also be used to prevent and treat radiation sickness, Post operation vomiting, drug-induced nauseating Vomiting；For parkinson disease and extrapyramidal symptoms；Calmness, for hypnosis and preoperative administration；Dentistry local anaesthesia, When patient is to conventional local anaesthetics hyperirritability, 1% diphenhydramine liquid can be as dental local anaesthetics；Hexichol Base methanol is as diphenhydramine pharmaceutical intermediate, and its synthetic method is good and bad for improving pharmaceutical synthesis product quality, Reduce by-products content and there is Important Economic meaning.

Zhang Pengfei (Zhang Pengfei, Gu Haining, Ge Haiquan, Li little Ling. the conjunction of α, α-diphenyl-4-piperidine carbinols Become and cleavage of mass spectrum research [J]. Journal of Hangzhou Teachers College (natural science edition), 2006,04:315-318.) Benzophenone is added in dimethylbenzene with 4-cyanopyridine, adds metallic sodium under nitrogen protection, then heat back Stream reaction, cooling decompression filters, washs, dries, and may finally obtain 4-pyridine radicals benzohydrol.Should Hydrogenation reaction uses free radical idol association response, and catalytic hydrogenation etc. is synthesized 4-pyridine radicals benzohydrol, Reaction yield only has 60%, and this synthetic method is unfavorable for the raising of reaction yield, therefore, anti-in order to improve Answer yield, it is necessary to propose a kind of new synthetic method.

Summary of the invention

The technical problem existed based on background technology, the present invention proposes a kind of diphenhydramine pharmaceutical intermediate two The synthetic method of phenyl methanol.

The synthetic method of a kind of diphenhydramine pharmaceutical intermediate benzohydrol, comprises the steps:

A, in the reaction vessel being provided with agitator, reflux condenser, thermometer, add benzophenone (change Formula 2) 0.32mol, trichloro ethylene solution 800-900ml, 2-bromo-5-fluoronitrobenzene solution 1.38mol, nikel powder 0.81mol, controls mixing speed 110-150rpm, and slowly rising solution temperature is to 80 DEG C, and temperature-rise period controls At 90-110min, maintain 2-3h；

B, filtration, filter cake propionitrile solution washs 3-5 time, and merging filtrate and cleaning mixture import 3L potassium bromide In solution, adding oxalic acid solution 500-600ml, separate out solid, sucking filtration, dehydrant is dehydrated, at nitromethane Recrystallization in solution, obtains crystal benzohydrol (chemical formula 1).

Preferably, described trichloro ethylene liquid quality fraction is 30-42%.

Preferably, described 2-bromo-5-fluoronitrobenzene liquid quality fraction is 20-35%.

Preferably, described propionitrile liquid quality fraction is 33-48%.

Preferably, described potassium bromide solution mass fraction is 10-18%.

Preferably, described oxalic acid solution mass fraction is 23-36%.

Preferably, described dehydrant is any one in sodium sulfate, calcium oxide.

Preferably, described nitromethane solution mass fraction is 55-63%.

Whole course of reaction can represent with following reaction equation:

Compared to synthetic method disclosed in background technology, the diphenhydramine pharmaceutical intermediate hexichol that the present invention provides The synthetic method of base methanol, reaction yield is greatly improved, and the invention provides a kind of new synthetic route simultaneously, Lay a good foundation for promoting reaction yield further.

Accompanying drawing explanation

Fig. 1 is the mass fraction of the trichloro ethylene solution normal distribution on the impact of reaction yield.Wherein, Abscissa is the mass fraction of trichloro ethylene solution；Vertical coordinate is reaction yield；

Fig. 2 is the mass fraction of the 2-bromo-5-fluoronitrobenzene solution normal distribution on the impact of reaction yield. Wherein, abscissa is the mass fraction of 2-bromo-5-fluoronitrobenzene solution；Vertical coordinate is reaction yield；

Fig. 3 is the mass fraction of the propionitrile solution normal distribution on the impact of reaction yield.Wherein, horizontal seat It is designated as the mass fraction of propionitrile solution；Vertical coordinate is reaction yield；

Fig. 4 is the mass fraction of the potassium bromide solution normal distribution on the impact of reaction yield.Wherein, horizontal Coordinate is the mass fraction of potassium bromide solution；Vertical coordinate is reaction yield.

Detailed description of the invention

Embodiment 1:

The synthetic method of a kind of diphenhydramine pharmaceutical intermediate benzohydrol, follows the steps below:

In the reaction vessel being provided with agitator, reflux condenser, thermometer, add benzophenone 0.32mol, Mass fraction is the trichloro ethylene solution 900ml of 38%, mass fraction be 30% 2-bromo-5-fluoronitrobenzene molten Liquid 1.38mol, nikel powder 0.81mol, control mixing speed 150rpm, and slowly rising solution temperature is to 80 DEG C, rises Temperature process control, at 110min, maintains 3h, filters, and filter cake mass fraction is that 40% propionitrile solution washs 5 times, Merging filtrate and cleaning mixture, import in the potassium bromide solution that 3L mass fraction is 15%, adds mass fraction and is The oxalic acid solution 600ml of 30%, separates out solid, sucking filtration, and sodium sulfate agent is dehydrated, is 59% at mass fraction Nitromethane solution in recrystallization, obtain crystal benzohydrol 51.23g, yield 87%.

Embodiment 2:

In the reaction vessel being provided with agitator, reflux condenser, thermometer, add benzophenone 0.32mol, Mass fraction is the trichloro ethylene solution 850ml of 38%, mass fraction be 27% 2-bromo-5-fluoronitrobenzene molten Liquid 1.38mol, nikel powder 0.81mol, control mixing speed 130rpm, and slowly rising solution temperature is to 80 DEG C, rises Temperature process control, at 100min, maintains 2h, filters, and filter cake mass fraction is the propionitrile solution washing 4 of 39% Secondary, merging filtrate and cleaning mixture, import in the potassium bromide solution that 3L mass fraction is 15%, add quality and divide Number is the oxalic acid solution 550ml of 27%, separates out solid, sucking filtration, and calcium oxide dehydrant is dehydrated, at mass fraction It is recrystallization in the nitromethane solution of 58%, obtains crystal benzohydrol 48.87g, yield 83%.

Embodiment 3:

In the reaction vessel being provided with agitator, reflux condenser, thermometer, add benzophenone 0.32mol, Mass fraction is the trichloro ethylene solution 800ml of 30%, mass fraction be 20% 2-bromo-5-fluoronitrobenzene molten Liquid 1.38mol, nikel powder 0.81mol, control mixing speed 110rpm, and slowly rising solution temperature is to 80 DEG C, rises Temperature process control, at 90min, maintains 2h, filters, and filter cake mass fraction is the propionitrile solution washing 3 of 33% Secondary, merging filtrate and cleaning mixture, import in the potassium bromide solution that 3L mass fraction is 10%, add quality and divide Number is the oxalic acid solution 500ml of 23%, separates out solid, sucking filtration, and sodium sulfate agent is dehydrated, at mass fraction It is recrystallization in the nitromethane solution of 55%, obtains crystal benzohydrol 47.69g, yield 81%.

The yield of embodiment 1-3 is above 80%, therefore synthetic method ratio provided by the present invention is in background technology Synthetic method, reaction yield is greatly improved.

Below embodiment 4-9 is contrasted with embodiment 1, the percent mass comparison of each solution in research reaction The impact of yield.

Embodiment 4:

Being adjusted by the mass fraction of the trichloro ethylene solution in embodiment 1, remaining preparation condition is joined with raw material Ratio is same as in Example 1, obtains reaction yield as follows:

Table one: the mass fraction of the trichloro ethylene solution impact on reaction yield

From embodiment 4, the mass fraction of trichloro ethylene solution is too high or too low all can affect reaction yield, It becomes normal distribution (Fig. 1) with reaction yield, and it is 30-42% that peak value occurs in mass fraction.

Embodiment 5:

The mass fraction of bromo-for the 2-in embodiment 1 5-fluoronitrobenzene solution is adjusted, remaining preparation condition Same as in Example 1 with proportioning raw materials, obtain reaction yield as follows:

The impact on reaction yield of the mass fraction of table two: 2-bromo-5-fluoronitrobenzene solution

From embodiment 5, the mass fraction of 2-bromo-5-fluoronitrobenzene solution is too high or too low all can be affected instead Answering yield, it becomes normal distribution (Fig. 2) with reaction yield, and it is 20-35% that peak value occurs in mass fraction.

Embodiment 6:

The mass fraction of the propionitrile solution in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials with Embodiment 1 is identical, obtains reaction yield as follows:

Table three: the mass fraction of the propionitrile solution impact on reaction yield

Propionitrile liquid quality fraction %	20	25	28	33	40	48	51	56	60
										Reaction yield %	67	69	74	81	86	84	78	72	68

From embodiment 6, the mass fraction of propionitrile solution is too high or too low all can affect reaction yield, its with Reaction yield becomes normal distribution (Fig. 3), and it is 33-48% that peak value occurs in mass fraction.

Embodiment 7:

The mass fraction of the potassium bromide solution in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials Same as in Example 1, obtain reaction yield as follows:

Table four: the mass fraction of the potassium bromide solution impact on reaction yield

Potassium bromide solution mass fraction %	3	5	8	10	14	18	20	24	28
										Reaction yield %	70	72	74	82	87	85	79	76	73

From embodiment 7, the mass fraction of potassium bromide solution is too high or too low all can affect reaction yield, its Become normal distribution (Fig. 4) with reaction yield, it is 10-18% that peak value occurs in mass fraction.

Embodiment 8:

The mass fraction of the oxalic acid solution in embodiment 1 is adjusted, remaining preparation condition and proportioning raw materials with Embodiment 1 is identical, obtains reaction yield as follows:

Table five: the mass fraction of the oxalic acid solution impact on reaction yield

Oxalic acid solution mass fraction %	13	15	18	23	29	36	41	45	50
										Reaction yield %	70	75	77	84	86	86	86	87	87

From embodiment 8, reaction yield can raise along with the raising of the mass fraction of oxalic acid solution, but matter After amount mark is higher than 23%, promoting speed and substantially slow down, therefore consider cost, preferred mass fraction is 23-36%.

Embodiment 9:

Being adjusted by the mass fraction of the nitromethane solution in embodiment 1, remaining preparation condition is joined with raw material Ratio is same as in Example 1, obtains reaction yield as follows:

Table six: the mass fraction of nitromethane solution is on reaction yield and the impact of recrystallization time

From embodiment 9, reaction yield is had little to no effect by the mass fraction of nitromethane solution, but It is bigger to the time effects of recrystallization, it is considered to cost, and preferred mass fraction is 55-63%.

Described in above example, the only present invention preferably detailed description of the invention, but protection scope of the present invention Be not limited thereto, any those familiar with the art in the technical scope that the invention discloses, According to technical scheme and inventive concept equivalent or change in addition thereof, all should contain in the present invention Protection domain within.

Claims

1. the synthetic method of a diphenhydramine pharmaceutical intermediate benzohydrol, it is characterised in that include as Lower step:

A, in the reaction vessel being provided with agitator, reflux condenser, thermometer, add benzophenone 0.32mol, Trichloro ethylene solution 800-900ml, 2-bromo-5-fluoronitrobenzene solution 1.38mol, nikel powder 0.81mol, control to stir Mixing speed is 110-150rpm, and slowly rising solution temperature is to 80 DEG C, and temperature-rise period controls at 90-110min, Maintain 2-3h；

B, filtration, filter cake propionitrile solution washs 3-5 time, and merging filtrate and cleaning mixture import 3L potassium bromide In solution, adding oxalic acid solution 500-600ml, separate out solid, sucking filtration, dehydrant is dehydrated, at nitromethane Recrystallization in solution, obtains crystal benzohydrol.

2. the synthetic method of diphenhydramine pharmaceutical intermediate benzohydrol as claimed in claim 1, its feature Being, described trichloro ethylene liquid quality fraction is 30-42%.

3. the synthetic method of diphenhydramine pharmaceutical intermediate benzohydrol as claimed in claim 1, its feature Being, described 2-bromo-5-fluoronitrobenzene liquid quality fraction is 20-35%.

4. the synthetic method of diphenhydramine pharmaceutical intermediate benzohydrol as claimed in claim 1, its feature Being, described propionitrile liquid quality fraction is 33-48%.

5. the synthetic method of diphenhydramine pharmaceutical intermediate benzohydrol as claimed in claim 1, its feature Being, described potassium bromide solution mass fraction is 10-18%.

6. the synthetic method of diphenhydramine pharmaceutical intermediate benzohydrol as claimed in claim 1, its feature Being, described oxalic acid solution mass fraction is 23-36%.

7. the synthetic method of diphenhydramine pharmaceutical intermediate benzohydrol as claimed in claim 1, its feature Being, described dehydrant is any one in sodium sulfate, calcium oxide.

8. the synthetic method of diphenhydramine pharmaceutical intermediate benzohydrol as claimed in claim 1, its feature Being, described nitromethane solution mass fraction is 55-63%.