CN103102343A - Preparation method of rupatadine fumarate - Google Patents
Preparation method of rupatadine fumarate Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of rupatadine fumarate. The preparation method comprises the following steps of: adding 235-237g of 3-chloromethyl-5-pyridine hydrochloride and 465-475ml of tertiary butanol in a reaction container; stirring and heating to 55-65 DEG C; dropping 235-245ml of concentration sulfuric acid, controlling the temperature of the reaction liquid to be 55-65 DEG C and reacting for 8-10 hours; cooling to room temperature, diluting with 234-245ml of water, then adding 345-355ml of methylbenzene, and adjusting pH value of the liquor by stronger ammonia water to 7.8-8.2 to separate out an organic phase; and after water layer extraction, combining the organic phases, washing the organic phase, drying and evaporating to remove the solvent to obtain an oily liquid product. The preparation method of rupatadine fumarate is simple and quick in preparation process, so that the preparation method is suitable for industrialized production. The yield is higher, and the reaction time is effectively shortened. Meanwhile, the refining process is simpler and the product purity is higher.
Description
Technical field
The present invention relates to technical field of medicine synthesis, be specifically related to a kind of preparation method of Rupatadine fumarate.
Background technology
Rupatadine fumarate is by novel, the potent anti-allergy agent of Spain Uriach drugmaker development, has antihistamine and antagonism platelet activation factor (PAF) dual function.
The preparation technology of Rupatadine fumarate of the prior art, synthetic route is more, has that yield is lower, a defective such as severe reaction conditions, product purity are lower more.
Summary of the invention
The present invention is intended to overcome the technical problem that exists in above-mentioned prior art, proposes a kind of yield high, is convenient to the preparation method of the Rupatadine fumarate of suitability for industrialized production.
The technical solution used in the present invention is as follows:
The preparation method of Rupatadine fumarate is characterized in that, comprises the steps:
1., the preparation of N-(1,1-dimethyl ethyl)-3-methyl-2-picolinamide
In reaction vessel, add the 3-chloromethyl of 235～237g-5-pyridine hydrochloride and 465～475ml trimethyl carbinol, stir and be warming up to 55～65 ℃, drip 235～245ml vitriol oil, control reacting liquid temperature at 55～65 ℃, reacted 8～10 hours;
Be down to room temperature, with the dilution of 235～245ml water, then add 345～355ml toluene, transfer pH to 7.8～8.2 with strong aqua, tell organic phase;
Merge organic phase after water layer extraction, the organic phase washing, dry, boil off solvent, obtain the oily liquids product, be designated as M2;
2., 3-[2-(3-chloro-phenyl-) ethyl]-preparation of N-(1,1-dimethyl ethyl)-2-picolinamide
Add 31～32g M2 and 595～605ml tetrahydrofuran (THF) to reaction vessel, be cooled to-65～-60 ℃, drip the hexane solution of the n-Butyl Lithium of 95～105ml 2.2mol/L, dropping process temperature control-55～-50 ℃, solution gradually becomes red-purple;
Dropwise, 1.58～1.62g Sodium Bromide is added in reaction solution, then drip the tetrahydrofuran solution that 123～127ml is dissolved with chlorobenzyl chloride between 26～27g, dropping process temperature control-45～-40 ℃, stirring reaction 3～5 hours, then drip water in reaction solution, until solution colour disappears;
Use the ethyl acetate extraction reaction solution, separatory merges organic phase after water layer extraction, the organic phase washing, dry, boil off solvent, obtain the oily liquids product, be designated as M3;
3., 3-[2-(3-chloro-phenyl-) ethyl]-preparation of 2-pyridine nitrile
In reaction vessel, add 378～382g M3 and 1720～1730g phosphorus oxychloride, stirring heating removed unreacted phosphorus oxychloride under reduced pressure after refluxing 3 hours, added entry and Virahol termination reaction;
Transfer the pH value to 6 of reaction solution～8,40～50 ℃ of control solution temperatures with 50% aqueous sodium hydroxide solution; There is solid to separate out, filters, obtain thick product, washing;
Thick product is dissolved in the Virahol of heat, then is cooled to 10～15 ℃, have solid to separate out;
Suction filtration, filter cake washing, drying obtain the white solid product, are designated as M4;
4., the preparation of 1-(methyl-4-piperidines) [3-(2-(3-chloro-phenyl-) ethyl)-2-pyridine] ketone hydrochloride
(1) preparation of the tetrahydrofuran solution of N-methyl piperidine magnesium chloride
Add 718～722g magnesium chips and 195～205ml dry tetrahydrofuran in reaction vessel, stir and pass into nitrogen protection, then drip 39.5～40.5g1-methyl-4-Chloperastine, drip post-heating and refluxed 1～1.5 hour, obtain the tetrahydrofuran solution of N-methyl piperidine magnesium chloride;
(2) preparation of 1-(methyl-4-piperidines) [3-(2-(3-chloro-phenyl-) ethyl)-2-pyridine] ketone hydrochloride adds 10.5～10.7g M4 and 595～605ml heavily to steam tetrahydrofuran (THF) in reaction vessel, be warming up to 40～50 ℃, drip the tetrahydrofuran solution of freshly prepd 195～200ml N-methyl piperidine magnesium chloride in the reaction solution, time for adding is 15～20 minutes, dropwise 20～30 ℃ of holding temperatures, stirring reaction 30～40 minutes;
Transfer reacting liquid pH value to 2 with 2N hydrochloric acid, 23～27 ℃ of temperature controls reacted 1～1.5 hour;
Remove tetrahydrofuran solvent under reduced pressure, transfer reacting liquid pH value to 3.5 with aqueous sodium hydroxide solution, be cooled to 0～5 ℃, filter and obtain crystalline salt hydrochlorate solid, washing, drying obtain the white solid product, are designated as M5;
5., 8-chloro-11-(1-methyl-4-piperidylidene)-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
Add 375～380g M5 and 1628～1629g trifluoromethanesulfonic acid in reaction vessel, stir and nitrogen protection, be warming up to 50～55 ℃, reacted 5～6 hours;
Be down to room temperature, add the frozen water termination reaction in reaction solution, with aqueous sodium carbonate conditioned reaction liquid pH value to 6;
When extracting, being concentrated into residue 1.5～2.2L, washing, decolouring;
Transfer reacting liquid pH value to 10 with 50% aqueous sodium hydroxide solution again, organic phase is told in extraction;
Remove solvent under reduced pressure, residual solution is dissolved in the normal hexane of heat, filter, concentrate, obtain the beige powder, be designated as M6;
6., 8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
Add 97～98g M6 and 630～650ml toluene in reaction vessel, stir and be warming up to 95～100 ℃, slowly drip 91～92g Vinyl chloroformate;
Dropwise, 75～80 ℃ of temperature controls reacted 1～1.5 hour, then added 3.8～4.2g diisopropyl ethyl amine and 9～9.5g Vinyl chloroformate, 75～80 ℃ of temperature controls, stirring reaction 3～4 hours;
Reaction solution is down to room temperature, washes with water, the organic phase concentrating under reduced pressure with the hot acetonitrile dissolving of 630～650ml, adds 2.5～3g activated carbon decolorizing with residual solution;
Suction filtration, decompression remove portion solvent is cooled to 0～5 ℃ with residual solution, has solid to separate out, suction filtration, filter cake washing, drying obtain the white solid product, are designated as M7;
7., 8-chloro-11-(4-piperidylidene)-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
Add 76～77g M7,95～105g potassium hydroxide, 605～615ml ethanol and 535～545ml water in reaction vessel, pass into nitrogen protection, reflux 60～70 hours removes part ethanol under reduced pressure, add the salt solution dilution in residual solution, with ethyl acetate extraction three times, tell organic phase, organic phase is dry, suction filtration, remove solvent under reduced pressure, obtain solid crude product, recrystallization obtains the white plates crystal, is designated as M8;
8., 8-chloro-11-[1-[(5-methyl-3-pyridine) methyl] piperidines-4-subunit]-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
Add 16.5～17.5ml 3 in reaction vessel, 5-lutidine and 995～1005ml dithiocarbonic anhydride stir, pass into nitrogen protection, then add 25.5～26.5g N-bromo-succinimide, reflux 8～10 hours, with the reaction solution cooling, there is solid to separate out, filter;
Add 23.5～24.5g M8 and 0.15～0.25g 4-(dimethylamino) pyridine, stirring at room 18～20 hours in filtrate;
Add again 16.5～17ml triethylamine, with 980～1020ml methylene dichloride dilute reaction solution, first wash with the 0.5N sodium hydrogen carbonate solution, then wash with water, tell organic phase, use anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 55～60g residual solution, cross silicagel column, drip washing, obtain white solid, be designated as M9;
9., 8-chloro-11-[1-[(5-methyl-3-pyridine) methyl] piperidines-4-subunit]-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine (E)-(E)-butenedioic acid salt
39～41gM9 and 195～205ml ethyl acetate are joined reaction vessel, stir, drip the methanol solution that 85～95ml is dissolved with 12～13g fumaric acid again in reaction solution, dropwise, reaction solution was placed in refrigerator and cooled but 12～16 hours, the adularescent crystal is separated out, and obtains the white solid powder after drying, i.e. the Rupatadine fumarate crude product.
Further, the process for purification of described Rupatadine fumarate crude product is: with the mixing solutions of 9.5～10.5g Rupatadine fumarate crude product, 85～95ml ethyl acetate and methyl alcohol, join in container, reflux 10～15 hours, after being chilled to room temperature, change but crystallization of refrigerator and cooled over to, suction filtration, drying after 1～2 day get the Rupatadine fumarate highly finished product.
The preparation method of Rupatadine fumarate of the present invention, preparation technology is simple and direct, is suitable for suitability for industrialized production, and yield is higher, effectively Reaction time shorten.Simultaneously, process for refining is comparatively simple and direct, and product purity is higher.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.
1., the preparation of N-(1,1-dimethyl ethyl)-3-methyl-2-picolinamide
In the 2000ml there-necked flask, add the 3-chloromethyl of 236g (2.0mol)-5-pyridine hydrochloride and 470ml trimethyl carbinol, stir, be warming up to 60 ℃, drip the 240ml vitriol oil to reaction mixture, time for adding is 30 minutes.Control reacting liquid temperature at 65 ℃, stirring reaction 8 hours.
Reacting liquid temperature is down to room temperature, with the dilution of 240ml water, then adds 350ml toluene, transfer pH to 8 with strong aqua, tell organic phase; Extract again 2 times with toluene, merge organic phase, wash with saturated common salt.Tell organic phase, use anhydrous magnesium sulfate drying, suction filtration removes solvent toluene under reduced pressure, obtains 357.2g oily liquids product, is designated as M2, and yield is 93%.
2., 3-[2-(3-chloro-phenyl-) ethyl]-preparation of N-(1,1-dimethyl ethyl)-2-picolinamide
In the 1000ml there-necked flask, add 31.5g (0.164mol) M2 and 600ml tetrahydrofuran (THF), liquid nitrogen acetone system is cooled to-60 ℃, drip the hexane solution of 100ml (2.2mol/L) n-Butyl Lithium to reaction solution, in the dropping process, reacting liquid temperature is controlled at-50 ℃, solution gradually becomes red-purple.Dropwise, the 1.6g Sodium Bromide is added in reaction solution, then drip the tetrahydrofuran solution that 125ml is dissolved with chlorobenzyl chloride between 26.5g (174mmol), in the dropping process, control reacting liquid temperature-40 ℃, stirring reaction 4 hours, then drip water in reaction solution, until solution colour disappears.Use the ethyl acetate extraction reaction solution, tell organic phase, wash with water.The organic phase anhydrous magnesium sulfate drying, suction filtration removes solvent under reduced pressure, obtains 48.8g oily liquids product, is designated as M3, and yield is 92.3%.
3., 3-[2-(3-chloro-phenyl-) ethyl]-preparation of 2-pyridine nitrile
In the 2000ml there-necked flask, add the phosphorus oxychloride of M3 and the 1726g (11.26mol) of 380g (1.20mol), stir reflux 3 hours.Remove unreacted phosphorus oxychloride under reduced pressure, add entry and Virahol termination reaction.Transfer the pH value to 6 of reaction solution～8 with 50% aqueous sodium hydroxide solution, the control solution temperature is below 50 ℃.There is solid to separate out, filters, obtain thick product, washing.Thick product is dissolved in the Virahol of heat, then is cooled to 10～15 ℃, have solid to separate out.Suction filtration washs solid with normal hexane, and is dry under 50 ℃ of conditions, obtains 236g white solid product, is designated as M4, and yield is 89.4%, fusing point: 72～73 ℃.
4., the preparation of 1-(methyl-4-piperidines) [3-(2-(3-chloro-phenyl-) ethyl)-2-pyridine] ketone hydrochloride
(1) tetrahydrofuran solution of N-methyl piperidine magnesium chloride
In the 500ml there-necked flask; add 720g (0.30mol) magnesium chips and 200ml dry tetrahydrofuran; mechanical stirring; and pass into nitrogen protection; then drip 40.0g (0.30mol) 1-methyl-4-Chloperastine in reaction flask; complete, reflux 1 hour obtains the tetrahydrofuran solution (standby) of N-methyl piperidine magnesium chloride.
(2) preparation of 1-(methyl-4-piperidines) [3-(2-(3-chloro-phenyl-) ethyl)-2-pyridine] ketone hydrochloride
In the 1000ml there-necked flask, add 10.6g (0.25mol) M4 and 600ml heavily to steam tetrahydrofuran (THF), be warming up to 45 ℃, drip new system for the tetrahydrofuran solution of 198ml (0.30mol) N-methyl piperidine magnesium chloride in reaction solution, time for adding is 15 minutes, dropwise 20～30 ℃ of holding temperatures, stirring reaction 30 minutes.Transfer reacting liquid pH value to 2 with 2N hydrochloric acid, 25 ℃ of temperature controls reacted 1 hour, removed tetrahydrofuran solvent under reduced pressure.Transfer reacting liquid pH value to 3.5 with aqueous sodium hydroxide solution, be cooled to 0～5 ℃, filter and obtain the crystalline salt hydrochlorate, wash solid with frozen water, be dried to constant weight under 60 ℃ of conditions, obtain 83.2g white solid product, be designated as M5, yield is 87.8%, fusing point: 183～185 ℃.
5., 8-chloro-11-(1-methyl-4-piperidylidene)-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
In the 2000ml there-necked flask, add 379g (1.0mol) M5 and 1628.2g (10.62mol) trifluoromethanesulfonic acid, mechanical stirring also passes into nitrogen protection, is warming up to 50～55 ℃, reacts 5 hours.Be down to room temperature, add the frozen water termination reaction in reaction solution, with aqueous sodium carbonate conditioned reaction liquid pH value to 6.Use dichloromethane extraction, the concentrating under reduced pressure reaction solution washes with water during residue 2L, then uses the 1N hcl as extraction agent, adds the 60g decolorizing with activated carbon, uses diatomite filtration.Transfer reacting liquid pH value to 10 with 50% aqueous sodium hydroxide solution again, use dichloromethane extraction, tell organic phase, remove solvent under reduced pressure, residual solution is dissolved in the normal hexane of heat, filter out insolubles, concentrate and obtain 237.5g beige powder, be designated as M6, yield is 73.2%.
6., 8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
In the 1000ml there-necked flask, add 97.4g (0.30mol) M6 and 640ml toluene, stir, be warming up to 100 ℃, slowly drip 91.8g (0.846mol) Vinyl chloroformate in reaction solution.Dropwise, 80 ℃ of temperature controls reacted 1 hour, then added 4g (0.032mol) diisopropyl ethyl amine and 9.4g (0.086mol) Vinyl chloroformate, 80 ℃ of temperature controls, stirring reaction 3 hours.Reaction solution is down to room temperature, washes with water, the organic phase concentrating under reduced pressure with the hot acetonitrile dissolving of 640ml, adds the 3g activated carbon decolorizing with residual solution.Suction filtration, decompression remove portion solvent is cooled to 0～5 ℃ with residual solution, has solid to separate out, and suction filtration is dry below 70 ℃ with cold acetonitrile washing solid, obtains 94.4g white solid product, is designated as M7, and yield is 82.3%.
7., 8-chloro-11-(4-piperidylidene)-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
In the 2000ml there-necked flask, add 76.5g (0.20mol) M7,100g potassium hydroxide, 610ml ethanol and 540ml water, pass into nitrogen protection; reflux 64 hours removes the part alcohol solvent under reduced pressure, adds the salt solution dilution in residual solution; with ethyl acetate extraction three times, tell organic phase, use anhydrous sodium sulfate drying; suction filtration removes solvent under reduced pressure, obtains solid crude product; use the toluene recrystallization, obtain 45.8g white plates crystal, be designated as M8; yield is 77%, fusing point: 154～155 ℃.
8., 8-chloro-11-[1-[(5-methyl-3-pyridine) methyl] piperidines-4-subunit]-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
In the 2000ml there-necked flask; add 17ml (150mmol) 3,5-lutidine and 1000ml dithiocarbonic anhydride stir; pass into nitrogen protection; add 26g (150mmol) N-bromo-succinimide again in reaction flask, reflux 8 hours is lowered the temperature reaction solution; there is solid to separate out; filter, add 24g (75mmol) M8 and 0.2g4-(dimethylamino) pyridine, stirring at room 18 hours in filtrate.Add the 16.8ml triethylamine, with 1000ml methylene dichloride dilute reaction solution, first wash with the 0.5N sodium hydrogen carbonate solution, wash with water again, tell organic phase, use anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain the 57g residual solution, cross silicagel column, eluent is chloroform: methyl alcohol: ammoniacal liquor=60:2:0.2, obtain the 12.2g white solid, be designated as M9, yield is 38.0%, fusing point: 58～61 ℃.
9., 8-chloro-11-[1-[(5-methyl-3-pyridine) methyl] piperidines-4-subunit]-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine (E)-(E)-butenedioic acid salt
M9 and the 200ml ethyl acetate of 40g (72mmol) are joined in the 500ml there-necked flask, mechanical stirring, drip the methanol solution that 90ml is dissolved with 12.5g (108.0mmol) fumaric acid again in reaction solution, dropwise, reaction solution was placed in refrigerator and cooled but 12 hours, the adularescent crystal is separated out, obtain 41.6g white solid powder after drying, be the Rupatadine fumarate crude product, yield is 81.2%, fusing point: 198～204 ℃.
10., the Rupatadine fumarate crude product is refining
Mixing solutions (ethyl acetate: methyl alcohol=2:1) join in the 250ml round-bottomed flask with 10.0g Rupatadine fumarate crude product, 90ml ethyl acetate and methyl alcohol, reflux 10 hours, after being chilled to room temperature, change but crystallization of refrigerator and cooled over to, 1-2 suction filtration after day, 60 ℃ of dryings get highly finished product 9.2g, refining yield 92.0%.Product characteristics: white solid powder, fusing point: 199～203 ℃.
Above content is only that the present invention is conceived example and explanation; affiliated those skilled in the art make various modifications to described specific embodiment or replenish or adopt similar mode to substitute; only otherwise depart from the design of invention or surmount this scope as defined in the claims, all should belong to protection scope of the present invention.
Claims (2)
1. the preparation method of Rupatadine fumarate, is characterized in that, comprises the steps:
1., the preparation of N-(1,1-dimethyl ethyl)-3-methyl-2-picolinamide
In reaction vessel, add the 3-chloromethyl of 235～237g-5-pyridine hydrochloride and 465～475ml trimethyl carbinol, stir and be warming up to 55～65 ℃, drip 235～245ml vitriol oil, control reacting liquid temperature at 55～65 ℃, reacted 8～10 hours;
Be down to room temperature, with the dilution of 235～245ml water, then add 345～355ml toluene, transfer pH to 7.8～8.2 with strong aqua, tell organic phase;
Merge organic phase after water layer extraction, the organic phase washing, dry, boil off solvent, obtain the oily liquids product, be designated as M2;
2., 3-[2-(3-chloro-phenyl-) ethyl]-preparation of N-(1,1-dimethyl ethyl)-2-picolinamide
Add 31～32g M2 and 595～605ml tetrahydrofuran (THF) to reaction vessel, be cooled to-65～-60 ℃, drip the hexane solution of the n-Butyl Lithium of 95～105ml 2.2mol/L, dropping process temperature control-55～-50 ℃, solution gradually becomes red-purple;
Dropwise, 1.58～1.62g Sodium Bromide is added in reaction solution, then drip the tetrahydrofuran solution that 123～127ml is dissolved with chlorobenzyl chloride between 26～27g, dropping process temperature control-45～-40 ℃, stirring reaction 3～5 hours, then drip water in reaction solution, until solution colour disappears;
Use the ethyl acetate extraction reaction solution, separatory merges organic phase after water layer extraction, the organic phase washing, dry, boil off solvent, obtain the oily liquids product, be designated as M3;
3., 3-[2-(3-chloro-phenyl-) ethyl]-preparation of 2-pyridine nitrile
In reaction vessel, add 378～382g M3 and 1720～1730g phosphorus oxychloride, stirring heating removed unreacted phosphorus oxychloride under reduced pressure after refluxing 3 hours, added entry and Virahol termination reaction;
Transfer the pH value to 6 of reaction solution～8,40～50 ℃ of control solution temperatures with 50% aqueous sodium hydroxide solution; There is solid to separate out, filters, obtain thick product, washing;
Thick product is dissolved in the Virahol of heat, then is cooled to 10～15 ℃, have solid to separate out;
Suction filtration, filter cake washing, drying obtain the white solid product, are designated as M4;
4., the preparation of 1-(methyl-4-piperidines) [3-(2-(3-chloro-phenyl-) ethyl)-2-pyridine] ketone hydrochloride
(1) preparation of the tetrahydrofuran solution of N-methyl piperidine magnesium chloride
Add 718～722g magnesium chips and 195～205ml dry tetrahydrofuran in reaction vessel, stir and pass into nitrogen protection, then drip 39.5～40.5g1-methyl-4-Chloperastine, drip post-heating and refluxed 1～1.5 hour, obtain the tetrahydrofuran solution of N-methyl piperidine magnesium chloride;
(2) preparation of 1-(methyl-4-piperidines) [3-(2-(3-chloro-phenyl-) ethyl)-2-pyridine] ketone hydrochloride
Add 10.5～10.7g M4 and 595～605ml heavily to steam tetrahydrofuran (THF) in reaction vessel, be warming up to 40～50 ℃, drip the tetrahydrofuran solution of freshly prepd 195～200ml N-methyl piperidine magnesium chloride in the reaction solution, time for adding is 15～20 minutes, dropwise 20～30 ℃ of holding temperatures, stirring reaction 30～40 minutes;
Transfer reacting liquid pH value to 2 with 2N hydrochloric acid, 23～27 ℃ of temperature controls reacted 1～1.5 hour;
Remove tetrahydrofuran solvent under reduced pressure, transfer reacting liquid pH value to 3.5 with aqueous sodium hydroxide solution, be cooled to 0～5 ℃, filter and obtain crystalline salt hydrochlorate solid, washing, drying obtain the white solid product, are designated as M5;
5., 8-chloro-11-(1-methyl-4-piperidylidene)-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
Add 375～380g M5 and 1628～1629g trifluoromethanesulfonic acid in reaction vessel, stir and nitrogen protection, be warming up to 50～55 ℃, reacted 5～6 hours;
Be down to room temperature, add the frozen water termination reaction in reaction solution, with aqueous sodium carbonate conditioned reaction liquid pH value to 6;
When extracting, being concentrated into residue 1.5～2.2L, washing, decolouring;
Transfer reacting liquid pH value to 10 with 50% aqueous sodium hydroxide solution again, organic phase is told in extraction;
Remove solvent under reduced pressure, residual solution is dissolved in the normal hexane of heat, filter, concentrate, obtain the beige powder, be designated as M6;
6., 8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
Add 97～98g M6 and 630～650ml toluene in reaction vessel, stir and be warming up to 95～100 ℃, slowly drip 91～92g Vinyl chloroformate;
Dropwise, 75～80 ℃ of temperature controls reacted 1～1.5 hour, then added 3.8～4.2g diisopropyl ethyl amine and 9～9.5g Vinyl chloroformate, 75～80 ℃ of temperature controls, stirring reaction 3～4 hours;
Reaction solution is down to room temperature, washes with water, the organic phase concentrating under reduced pressure with the hot acetonitrile dissolving of 630～650ml, adds 2.5～3g activated carbon decolorizing with residual solution;
Suction filtration, decompression remove portion solvent is cooled to 0～5 ℃ with residual solution, has solid to separate out, suction filtration, filter cake washing, drying obtain the white solid product, are designated as M7;
7., 8-chloro-11-(4-piperidylidene)-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
Add 76～77g M7,95～105g potassium hydroxide, 605～615ml ethanol and 535～545ml water in reaction vessel, pass into nitrogen protection, reflux 60～70 hours removes part ethanol under reduced pressure, add the salt solution dilution in residual solution, with ethyl acetate extraction three times, tell organic phase, organic phase is dry, suction filtration, remove solvent under reduced pressure, obtain solid crude product, recrystallization obtains the white plates crystal, is designated as M8;
8., 8-chloro-11-[1-[(5-methyl-3-pyridine) methyl] piperidines-4-subunit]-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine
Add 16.5～17.5ml 3 in reaction vessel, 5-lutidine and 995～1005ml dithiocarbonic anhydride stir, pass into nitrogen protection, then add 25.5～26.5g N-bromo-succinimide, reflux 8～10 hours, with the reaction solution cooling, there is solid to separate out, filter;
Add 23.5～24.5g M8 and 0.15～0.25g 4-(dimethylamino) pyridine, stirring at room 18～20 hours in filtrate;
Add again 16.5～17ml triethylamine, with 980～1020ml methylene dichloride dilute reaction solution, first wash with the 0.5N sodium hydrogen carbonate solution, then wash with water, tell organic phase, use anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 55～60g residual solution, cross silicagel column, drip washing, obtain white solid, be designated as M9;
9., 8-chloro-11-[1-[(5-methyl-3-pyridine) methyl] piperidines-4-subunit]-6, the preparation of 11-dihydro-5H-benzo [5,6] heptane [1,2-b] pyridine (E)-(E)-butenedioic acid salt
39～41gM9 and 195～205ml ethyl acetate are joined reaction vessel, stir, drip the methanol solution that 85～95ml is dissolved with 12～13g fumaric acid again in reaction solution, dropwise, reaction solution was placed in refrigerator and cooled but 12～16 hours, the adularescent crystal is separated out, and obtains the white solid powder after drying, i.e. the Rupatadine fumarate crude product.
2. the preparation method of Rupatadine fumarate according to claim 1, it is characterized in that, the process for purification of described Rupatadine fumarate crude product is: with the mixing solutions of 9.5～10.5g Rupatadine fumarate crude product, 85～95ml ethyl acetate and methyl alcohol, join in container, reflux 10～15 hours after being chilled to room temperature, changes but crystallization of refrigerator and cooled over to, suction filtration, drying after 1～2 day get the Rupatadine fumarate highly finished product.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304542A (en) * | 2013-06-21 | 2013-09-18 | 四川海思科制药有限公司 | Rupatadine fumarate compound |
| CN103755682A (en) * | 2013-12-30 | 2014-04-30 | 山东达因海洋生物制药股份有限公司 | Novel crystal form for desloratadine and preparation method thereof |
| CN103804357A (en) * | 2014-01-02 | 2014-05-21 | 珠海金鸿药业股份有限公司 | Rupatadine fumarate compound as well as synthesis method and pharmaceutical composition thereof |
| CN112341433A (en) * | 2020-11-16 | 2021-02-09 | 成都大学 | Preparation method of loratadine |
| CN113004245A (en) * | 2019-12-20 | 2021-06-22 | 南京亿华药业有限公司 | Preparation method of desloratadine |
| CN113135897A (en) * | 2021-03-24 | 2021-07-20 | 北京嘉林药业股份有限公司 | Rupatadine fumarate B crystal form and preparation method thereof |
| CN116496259A (en) * | 2023-04-24 | 2023-07-28 | 黑龙江珍宝岛药业股份有限公司 | Preparation method of rupatadine fumarate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103304542A (en) * | 2013-06-21 | 2013-09-18 | 四川海思科制药有限公司 | Rupatadine fumarate compound |
| CN103304542B (en) * | 2013-06-21 | 2014-07-23 | 四川海思科制药有限公司 | Rupatadine fumarate compound |
| CN103755682A (en) * | 2013-12-30 | 2014-04-30 | 山东达因海洋生物制药股份有限公司 | Novel crystal form for desloratadine and preparation method thereof |
| CN103804357A (en) * | 2014-01-02 | 2014-05-21 | 珠海金鸿药业股份有限公司 | Rupatadine fumarate compound as well as synthesis method and pharmaceutical composition thereof |
| CN103804357B (en) * | 2014-01-02 | 2016-03-23 | 珠海金鸿药业股份有限公司 | A kind of Rupatadine fumarate compound, its synthetic method and pharmaceutical composition thereof |
| CN113004245A (en) * | 2019-12-20 | 2021-06-22 | 南京亿华药业有限公司 | Preparation method of desloratadine |
| CN113004245B (en) * | 2019-12-20 | 2022-04-15 | 南京亿华药业有限公司 | Preparation method of desloratadine |
| CN112341433A (en) * | 2020-11-16 | 2021-02-09 | 成都大学 | Preparation method of loratadine |
| CN113135897A (en) * | 2021-03-24 | 2021-07-20 | 北京嘉林药业股份有限公司 | Rupatadine fumarate B crystal form and preparation method thereof |
| CN113135897B (en) * | 2021-03-24 | 2022-03-22 | 北京嘉林药业股份有限公司 | Rupatadine fumarate B crystal form and preparation method thereof |
| CN116496259A (en) * | 2023-04-24 | 2023-07-28 | 黑龙江珍宝岛药业股份有限公司 | Preparation method of rupatadine fumarate |
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