CN102108059A

CN102108059A - Method for synthesizing doxylamine succinate

Info

Publication number: CN102108059A
Application number: CN 201010275180
Authority: CN
Inventors: 许华建; 齐洪侠; 王珏玉; 郑法银; 曹明成; 晏飞; 冯乙巳
Original assignee: HEFEI CHUANGXIN MEDICAL TECHNOLOGY Co Ltd; Hefei University of Technology
Current assignee: HEFEI CHUANGXIN MEDICAL TECHNOLOGY Co Ltd; Hefei University of Technology
Priority date: 2010-09-03
Filing date: 2010-09-03
Publication date: 2011-06-29
Anticipated expiration: 2030-09-03
Also published as: CN102108059B

Abstract

The invention discloses a method for synthesizing doxylamine succinate. 2-acetylpyridine is taken as an initiative material, and the method comprises the following steps of: reacting the 2-acetylpyridine with a Grignard reagent prepared from bromobenzene and magnesium to obtain 2-pyridyl phenyl methyl carbinol; reacting the 2-pyridyl phenyl methyl carbinol with sodium amide and 2-dimethylaminoethyl chloride in turn to obtain doxylamine; and performing salt-forming reaction on the doxylamine and succinic acid to obtain the doxylamine succinate. The synthesis route is orientation reaction without byproduct. The doxylamine succinate is an ethanol antihistamine, and has antihistaminic and cholinolytic effects and obvious tranquillizing effect.

Description

A kind of synthetic method of doxylamine succinate

One, technical field

The present invention relates to a kind of synthetic method of ethanol class antihistaminic, specifically a kind of doxylamine succinate synthetic method.

Two, background technology

Doxylamine succinate is an ethanol class antihistaminic, has antihistamine effect, cholinolytic effect and significant sedative effect, is applicable to multiple anaphylaxis dermatosis, spring fever, allergic rhinitis, asthmatic bronchitis etc.; Also the short that can be used to have a sleepless night as soporific produces sleepiness by suppressing central nervous system.

The doxylamine 25mg tablet listing of in October, 1978 FDA approval CHATTEM company is used for helping to alleviate difficulty falling asleep.Became OTC (nonprescription drugs) in 1979.In September, 1996 approval, in August, 2004, LNK company was as the imitation medicine official listing.Doxylamine is as the OTC antihistamine drug of assisting therapy sleep, and its clinical safety is effective, general reaction rate height, better tolerance.At present, the synthesis technique of doxylamine succinate does not still have bibliographical information both at home and abroad.

The doxylamine succinate structural formula is as follows:

Doxylamine succinate

Chemical name: doxylamine succinate

English name: Doxylamine succinate

CAS number: 562-10-7

Molecular formula: C ₂₁H ₂₈N ₂O ₅

Molecular weight: 388.46

Three, summary of the invention

The present invention aims to provide a kind of as ethanol class antihistaminic doxylamine succinate, and technical problem to be solved is to select new simple synthetic method.

The operational path of this ambroid acid doxylamine is:

This synthetic method is starting raw material with the 2-acetopyridine, comprise the synthetic and salt-forming reaction of doxylamine and separation, each unit process of purifying, the synthetic Grignard reagent react generation 2-pyridyl phenylmethylcarbinol that at first generates that it is characterized in that described doxylamine by 2-acetopyridine and bromobenzene and magnesium, 2-pyridyl phenylmethylcarbinol generates doxylamine with sodium amide and the reaction of 2-dimethylamino monochloroethane successively then, and last doxylamine and succsinic acid salify obtain the target product doxylamine succinate.

Detailed process is at first to prepare Grignard reagent, magnesium chips is added in ether or the tetrahydrofuran solvent under agitation dripping bromine phenyl ethyl ether solution or bromobenzene tetrahydrofuran solution then, back flow reaction 1.5～2.5 hours.

Under agitation slowly drop to 2-acetopyridine diethyl ether solution or tetrahydrofuran solution in the mentioned reagent liquid, stirring reaction is no less than 15 hours, then with ammonium chloride frozen water solution quencher reaction, stir the back standing separation, get organic phase, aqueous phase extracted obtains 2-pyridyl phenylmethylcarbinol behind the merging organic phase precipitation.

Also can be further purified 2-pyridyl phenylmethylcarbinol.129～134 ℃ of cuts are collected in underpressure distillation under gauge pressure 0.5mmHg post, just can obtain 32～34 ℃ of comparatively purified 2-pyridyl phenylmethylcarbinols of fusing point.

In xylene solvent, add sodium amide, stir the xylene solution that slowly drips 2-pyridyl phenylmethylcarbinol down, back flow reaction 4～6 hours; Continue slowly to drip 2-dimethylamino monochloroethane xylene solution then, back flow reaction is no less than 18 hours and generates doxylamine, adds frozen water quencher reaction at last, stir the back standing separation, get organic phase, aqueous phase extracted, merge organic phase, obtain the crude product doxylamine behind the precipitation.

The crude product doxylamine carries out purifying with silica gel column chromatography, with volume ratio is that 2: 1 sherwood oil and ethyl acetate miscible agent carries out wash-out, main wash-out is the not 2-pyridyl phenylmethylcarbinol of complete reaction and recovery as yet, doxylamine is present in the filler silica gel, use the diethylamine extraction separation, obtain pure doxylamine after sloughing diethylamine.

The synthetic of target product is an organic amine and organic acid salt-forming reaction, the extremely dissolving of heated and stirred in organic solvent with doxylamine and succsinic acid, and freezing and crystallizing separates, again recrystallization purifying.

The concrete operations step is as follows:

1,2-pyridyl phenylmethylcarbinol is synthetic

This route is to generate Grignard reagent by bromobenzene and magnesium, solvent can be ether or tetrahydrofuran (THF) etc., then 2-acetopyridine is added drop-wise in the Grignard reagent of preparation, react after 20 hours with aqueous ammonium chloride solution cancellation reaction, standing separation, keep organic phase, aqueous phase extracted merges organic phase; Underpressure distillation obtains 2-pyridyl phenylmethylcarbinol.

2, doxylamine is synthetic

With 2-pyridyl phenylmethylcarbinol and sodium amide reaction, generate 2-pyridyl phenylmethylcarbinol sodium, solvent can be dimethylbenzene, after reaction refluxed 5 hours, 2-dimethylamino monochloroethane is added drop-wise in the reaction solution, continued back flow reaction 20 hours, water cancellation reaction.The mixture that obtains separates 2-pyridyl phenylmethylcarbinol by the column chromatography wash-out with doxylamine, elutriant is the V sherwood oil: V ethyl acetate=2: 1.

3, doxylamine succinate is synthetic

With doxylamine and succsinic acid salify, solvent can be acetone, Virahol and ethyl acetate mixed solvent etc.

The advantage of this synthetic route: synthetic route is an orientation response, and without any by product, the productive rate of the first step Synthetic 2-pyridyl phenylmethylcarbinol is higher.

Four, description of drawings

Figure 12-pyridyl phenylmethylcarbinol ¹The HNMR collection of illustrative plates

Fig. 2 doxylamine ¹The HNMR collection of illustrative plates

Fig. 3 doxylamine succinate ¹The HNMR collection of illustrative plates

Five, embodiment

1,2-pyridyl phenylmethylcarbinol is synthetic

Get 3.12g (0.13mol) magnesium chips and put into the 250ml there-necked flask, add the 50ml anhydrous diethyl ether, stir, get 17.27g (0.11mol) bromobenzene mixing 50ml anhydrous diethyl ether, slowly drip.Dripped off in about 10 minutes.After reaction caused, ether refluxed in a large number, and reaction solution becomes muddiness and color becomes the metal grey gradually.Kept aether backflow two hours.Get 12.1g (0.1mol) 2-acetopyridine, mix the 30ml anhydrous diethyl ether, slowly drop in the above-mentioned Grignard reagent, rate of addition be controlled at 2 seconds every.Mixed solution splashes into Grignard reagent and becomes white milk immediately, and a large amount of heat release, and anhydrous diethyl ether refluxes.After dropwising, solution becomes clarification, gray dope appears in drag, continues to stir, and solution is swift in response a large amount of heat releases by the clarification look milk sap that bleaches.Continue to stir 20 hours.

After reaction finishes, drip 100ml ammonium chloride frozen water solution in reaction solution, the limit edged stirs.After dropwising, continue to stir half an hour.Mixed solution was left standstill 6 hours.With the mixed solution separatory, keep organic phase then, water with extracted with diethyl ether (4*50ml), is merged organic phase, revolve to steam to remove and desolvate.

The thick product that obtains is carried out underpressure distillation, collect 129-134 ℃/0.5mmHg post component, obtain product 14g, yield 70%.Fusing point 32-34 ℃.

¹HNMR(CDCl ₃)，δ：8.51(1H，m)，7.60-7.61(1H，m)，7.40(2H，m)，7.33-7.17(5H，m)，1.98(3H，s)。

2, doxylamine is synthetic

Add dimethylbenzene 40ml in the 150ml there-necked flask, take by weighing 2.34g (0.06mol) sodium amide and add in the there-necked flask, take by weighing 10g (0.05mol) 2-pyridyl phenylmethylcarbinol and be dissolved in the 20ml dimethylbenzene, slowly drip, stir.After dropwising, 150 ℃ of oil bath heating keep refluxing xylene, back flow reaction 5 hours.The reaction solution color is by the faint yellow Vandyke brown that becomes gradually, and solid dissolves gradually.

Exsiccant 2-dimethylamino monochloroethane mixing 20ml dimethylbenzene is added dropping funnel, slowly in there-necked flask, drip, after dropwising, continue to keep refluxing 20 hours.Variation (the V sherwood oil: V ethyl acetate=5: 1) of TLC monitoring reactant and product in the reaction process.

Behind the stopped reaction, remove oil bath, reaction solution is cooled to room temperature, add ice bath, slowly in reaction solution, drip frozen water 50ml, stir half an hour.With the reaction solution separatory, keep organic phase, water merges organic phase with xylene extraction (3*40ml).Drying, suction filtration revolves to steam and removes removal xylene.

The thick product of gained carries out silica gel mixed sample, and liquid-like and silica gel mass ratio are 1: 2, use acetic acid ethyl dissolution, stirs half an hour, revolves to steam to remove to desolvate.To mix sample silica gel and carry out column chromatography, elutriant is that (the V sherwood oil: V ethyl acetate=2: 1), the elutriant wash-out is collected fully until the component of 2-pyridyl phenylmethylcarbinol, stops wash-out for sherwood oil and ethyl acetate mixed solvent.Collect elutriant, revolve to steam to remove and desolvate, recycle after the 2-pyridyl phenylmethylcarbinol vacuum-drying of recovery.

Silica gel in the chromatography column and residual elutriant are poured in the single port flask, and the diethylamine of quality such as adding and thick product stirs half an hour, and suction filtration revolves steaming except that desolvating and diethylamine with liquid phase, obtains doxylamine 7.3g, yield 54%.Gas phase content is 99%.(250 ℃ of column compartment temperature, 300 ℃ of detected temperatures, 300 ℃ of vaporization temperatures).

¹HNMR(CDCl ₃)，δ：8.51(1H，m)，7.60-7.61(2H，m)，7.40(2H，m)，7.27(2H，m)，7.18(1H，m)，7.09(1H，m)，3.41(2H，m)，2.59(2H，m)，2.27(6H，s)，1.98(3H，s)。

3, doxylamine succinate is synthetic

Doxylamine 1.35g (0.005mol) and succsinic acid 0.59g (0.005mol) add in the 10ml single port flask, add acetone 7ml, and heated and stirred continues to stir half an hour to dissolving, stops heating.Be cooled to room temperature, put into refrigerator-20 then ℃ freezing 24 hours.Suction filtration is put into vacuum drier with solid and is steamed residual solvent, dry 6 hours.Thick product is continued with acetone heating for dissolving recrystallization (1g doxylamine succinate: 2.5mL acetone).Step is the same, and recrystallization obtains doxylamine succinate 1.6g, yield 82%.Fusing point 101-103 ℃.

¹HNMR(CDCl ₃)，δ：8.54(1H，m)，7.69(1H，m)，7.51(1H，m)，7.32(2H，m)，7.30(2H，m)，7.23(1H，m)，7.16(1H，m)，3.63(2H，m)，3.18(2H，m)，2.80(6H，s)，2.54(4H，s)，1.99(3H，s)。

Claims

1. the synthetic method of a doxylamine succinate, comprise the synthetic and salt-forming reaction of doxylamine and separation, each unit process of purifying, it is characterized in that: described doxylamine the synthetic Grignard reagent react generation 2-pyridyl phenylmethylcarbinol that at first to be 2-acetopyridine generate with bromobenzene and magnesium; 2-pyridyl phenylmethylcarbinol generates doxylamine with sodium amide and the reaction of 2-dimethylamino monochloroethane successively.

2. synthetic method according to claim 1, it is characterized in that: in ether or tetrahydrofuran solvent, add magnesium chips, stir dripping bromine benzole soln down, back flow reaction obtained the Grignard reagent solution in 1.5～2.5 hours, then under agitation slowly drip 2-acetopyridine solution, stirring reaction is no less than 15 hours, with ammonium chloride frozen water solution quencher reaction, obtains 2-pyridyl phenylmethylcarbinol behind separation, precipitation at last.

3. synthetic method according to claim 2 is characterized in that: the 2-pyridyl phenylmethylcarbinol behind the precipitation is carried out underpressure distillation, collect 129～134 ℃ cut under the 0.5mmHg post, obtain the 2-pyridyl phenylmethylcarbinol of 32～34 ℃ of fusing points.

4. synthetic method according to claim 1, it is characterized in that: in xylene solvent, add sodium amide, stir and slowly drip 2-pyridyl phenylmethylcarbinol solution down, back flow reaction 4～6 hours, continue slowly to drip 2-dimethylamino monochloroethane solution then, back flow reaction is no less than 18 hours, adds frozen water quencher reaction at last, obtains doxylamine behind separation, precipitation.

5. synthetic method according to claim 4, it is characterized in that: to silica gel column chromatography on the doxylamine behind the precipitation, with 2: 1 sherwood oil of volume ratio and ethyl acetate mixed solvent wash-out, in silica gel, obtain the doxylamine of purifying with the diethylamine extraction separation.