CN102924484A - Industrial production method of isothipendyl technical material - Google Patents
Industrial production method of isothipendyl technical material Download PDFInfo
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- CN102924484A CN102924484A CN2012104519032A CN201210451903A CN102924484A CN 102924484 A CN102924484 A CN 102924484A CN 2012104519032 A CN2012104519032 A CN 2012104519032A CN 201210451903 A CN201210451903 A CN 201210451903A CN 102924484 A CN102924484 A CN 102924484A
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- adanton
- isothipendyl
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- acetonitrile
- thiodiphenylamine
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Abstract
The invention provides an industrial production method of an isothipendyl technical material, and belongs to the technical field of anti-anaphylaxis medicines. The preparation method is carried out according to the following steps: feeding 1-azaphenothiazine, sodium hydride and anhydrous acetonitrile in a reaction kettle according to a certain ratio under the protection of nitrogen, reacting for 1h at 30 DEG C, opening a steam valve, introducing steam in a jacket of the reaction kettle, reflowing and reacting for 2h; feeding 1-para-toluene sulfonyl-2-N and N-dimethyl propylamine according to a certain ratio, keeping on reflowing and reacting for 3h, cooling reaction mass to be normal temperature, filtering un-dissolved material away, pumping dry hydrogen chloride in collected acetonitrile solution to obtain isothipendyl hydrochloride white crystals, refining, and finally obtaining the isothipendyl, wherein the purity is higher than 99% and the yield is higher than 70%. According to the invention, the continuous reaction is used, an intermediate product does not need to be separated; the preparation method has the following advantages of simple process, low equipment investment, and the like; the purity of the produced isothipendyl is over 99% and the yield is over 70%, so that the preparation method is beneficial for industrial production.
Description
Technical field
The invention belongs to antianaphylaxis medicine technical field, be specifically related to the production technique of the former medicine of a kind of adanton.
Background technology
Adanton belongs to a kind of novel antihistaminic in the antianaphylaxis medicine, belongs to H1 receptor antagonist, and its structural formula is:
Adanton is mainly used in treating the diseases such as urticaria, asthma, allergic rhinitis, allergic dermatitis, skin pruritus, flu, and is also effective in cure to skin burn and scald.Adanton is because having photobiochemistry character, can keep out ultraviolet B radiation and is applied in the sunblock lotion as opalizer.At present, be showed no related production technique report both at home and abroad.
Summary of the invention
The object of the present invention is to provide the production method of the adanton that a kind of technique is simple, yield is high.
The present invention adopts following technical scheme:
With the assorted nitrogen thiodiphenylamine of 1-and 1-p-toluenesulfonyl-2-N, the N-dimethyl propylamine reacts in the acetonitrile solvent in the presence of the sodium hydride, gets adanton.
The industrialized preparing process of the former medicine of adanton, carry out according to following step:
Under the nitrogen protection, the assorted nitrogen thiodiphenylamine of 1-, sodium hydride, anhydrous acetonitrile are dropped into reactor according to a certain percentage, 30 ℃ of reaction 1h open steam valve, pass into steam, back flow reaction 2h in reacting kettle jacketing; Drop into a certain proportion of 1-p-toluenesulfonyl-2-N, the N-dimethyl propylamine is behind the continuation back flow reaction 3h; reaction mass is cooled to room temperature, crosses the elimination insolubles, blast dry hydrogen chloride in the acetonitrile solution of collection; obtain adanton hydrochloride white crystals, again through making with extra care to get adanton.Its moderate purity〉99%, yield〉70%
Wherein reactant feeds intake and is the assorted nitrogen thiodiphenylamine of n(1-): the n(sodium hydride): n(1-p-toluenesulfonyl-2-N, N-dimethyl propylamine)=1:1.0 ~ 1.1:1.1 ~ 1.3.
Wherein reactant feeds intake and is the assorted nitrogen thiodiphenylamine of n(1-): anhydrous acetonitrile=1:5 ~ 10.
Wherein, in the method for the invention, the adanton hydrochloride when refining adanton, is made the aqueous solution with the above-mentioned centrifugal adanton hydrochloride white crystals that obtains again, 30wt% NaOH solution is regulated pH to 8, and centrifugal, vacuum-drying gets the adanton sterling.
Beneficial effect of the present invention
The present invention adopts continuous reaction, and intermediate product need not to separate, and has the advantages such as technique is simple, facility investment is few, the adanton purity of production〉99%, yield〉70%, be conducive to suitability for industrialized production.
Embodiment
Embodiment 1
Under the nitrogen protection, the 100kg anhydrous acetonitrile is squeezed into the 300L reactor by the acetonitrile storage tank through volume pump, adds the assorted nitrogen thiodiphenylamine 20kg of 1-, sodium hydride 2.4kg through charging opening.Material is in 30
oBehind the C reaction 1h, open steam valve, in reacting kettle jacketing, pass into steam, back flow reaction 2h; Add 26.5kg 1-p-toluenesulfonyl-2-N, N-dimethyl propylamine, back flow reaction 3h through charging opening again.Treat that material is cooled to 30
oC, system after filtration, the filtering insolubles, the acetonitrile mother liquor is returned in the reactor again by storage tank again.Hydrogenchloride blasts in the above-mentioned acetonitrile mother liquor through vaporizer, surge tank, under meter, and system is separated out white crystals, and HPLC tracks to adanton disappearance in the mother liquor, stopped reaction.Above-mentioned material is through centrifugation, and the frozen ethanol bubble is washed, recentrifuge, the dry adanton hydrochloride 24.1kg that gets.Discharging after raffinate is processed in the centrifuge mother liquor Distillation recovery acetonitrile, still.
70 kg water are squeezed into the 300L reactor through volume pump, drop into above-mentioned adanton hydrochloride from charging opening, mechanical stirring is to fully dissolving, and 30wt% NaOH solution injects reactor by header tank through under meter, regulation system pH value to 8, stopped reaction behind the continuation stirring 0.5h.Material gets adanton 20.2 kg, purity 99.2%(HPLC through centrifugal, vacuum-drying), yield 71%.
Embodiment 2
Under the nitrogen protection, the 140kg anhydrous acetonitrile is squeezed into the 300L reactor by the acetonitrile storage tank through volume pump, adds the assorted nitrogen thiodiphenylamine 20kg of 1-, sodium hydride 2.5kg through charging opening.Material is in 30
oBehind the C reaction 1h, open steam valve, in reacting kettle jacketing, pass into steam, back flow reaction 2h; Add 28.9 kg 1-p-toluenesulfonyl-2-N, N-dimethyl propylamine, back flow reaction 3h through charging opening again.Treat that material is cooled to 30
oC, system after filtration, the filtering insolubles, the acetonitrile mother liquor is returned in the reactor again by storage tank again.Hydrogenchloride blasts in the above-mentioned acetonitrile mother liquor through vaporizer, surge tank, under meter, and system is separated out white crystals, and HPLC tracks to adanton disappearance in the mother liquor, stopped reaction.Above-mentioned material is through centrifugation, and the frozen ethanol bubble is washed, recentrifuge, the dry adanton hydrochloride 26.3kg that gets.Discharging after raffinate is processed in the centrifuge mother liquor Distillation recovery acetonitrile, still.
70kg water is squeezed into the 300L reactor through volume pump, drop into above-mentioned adanton hydrochloride from charging opening, mechanical stirring is to fully dissolving, and 30wt% NaOH solution injects reactor by header tank through under meter, regulation system pH value to 8, stopped reaction behind the continuation stirring 0.5h.Material gets adanton 22.8 kg, purity 99.5%(HPLC through centrifugal, vacuum-drying), yield 80%.
Embodiment 3
Under the nitrogen protection, the 200kg anhydrous acetonitrile is squeezed into the 300L reactor by the acetonitrile storage tank through volume pump, adds the assorted nitrogen thiodiphenylamine 20kg of 1-, sodium hydride 2.7kg through charging opening.Material is in 30
oBehind the C reaction 1h, open steam valve, in reacting kettle jacketing, pass into steam, back flow reaction 2h; Add 31.3kg 1-p-toluenesulfonyl-2-N, N-dimethyl propylamine, back flow reaction 3h through charging opening again.Treat that material is cooled to 30
oC, system after filtration, the filtering insolubles, the acetonitrile mother liquor is returned in the reactor again by storage tank again.Hydrogenchloride blasts in the above-mentioned acetonitrile mother liquor through vaporizer, surge tank, under meter, and system is separated out white crystals, and HPLC tracks to adanton disappearance in the mother liquor, stopped reaction.Above-mentioned material is through centrifugation, and the frozen ethanol bubble is washed, recentrifuge, the dry adanton hydrochloride 24.7kg that gets.Discharging after raffinate is processed in the centrifuge mother liquor Distillation recovery acetonitrile, still.
70kg water is squeezed into the 300L reactor through volume pump, drop into above-mentioned adanton hydrochloride from charging opening, mechanical stirring is to fully dissolving, and 30wt% NaOH solution injects reactor by header tank through under meter, regulation system pH value to 8, stopped reaction behind the continuation stirring 0.5h.Material gets adanton 21.4kg, purity 99.7%(HPLC through centrifugal, vacuum-drying), yield 75%.
Claims (4)
1. the industrialized preparing process of the former medicine of adanton is characterized in that carrying out according to following step:
Under the nitrogen protection, the assorted nitrogen thiodiphenylamine of 1-, sodium hydride, anhydrous acetonitrile are dropped into reactor according to a certain percentage, 30 ℃ of reaction 1h open steam valve, pass into steam, back flow reaction 2h in reacting kettle jacketing; Drop into a certain proportion of 1-p-toluenesulfonyl-2-N, the N-dimethyl propylamine is behind the continuation back flow reaction 3h; reaction mass is cooled to room temperature, crosses the elimination insolubles, blast dry hydrogen chloride in the acetonitrile solution of collection; obtain adanton hydrochloride white crystals, again through making with extra care to get adanton.
2. the industrialized preparing process of the former medicine of adanton according to claim 1; it is characterized in that wherein the reactant assorted nitrogen thiodiphenylamine take molar ratio computing as 1-that feeds intake: sodium hydride: 1-p-toluenesulfonyl-2-N, N-dimethyl propylamine=1:1.0 ~ 1.1:1.1 ~ 1.3.
3. the industrialized preparing process of the former medicine of adanton according to claim 1 is characterized in that wherein reactant assorted nitrogen thiodiphenylamine: anhydrous acetonitrile=1:5 ~ 10 take molar ratio computing as 1-that feed intake.
4. the industrialized preparing process of the former medicine of adanton according to claim 1, it is characterized in that the adanton hydrochloride is again when refining adanton, the above-mentioned centrifugal adanton hydrochloride white crystals that obtains is made the aqueous solution, 30wt% NaOH solution is regulated pH to 8, and centrifugal, vacuum-drying gets the adanton sterling.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104519032A CN102924484A (en) | 2012-11-13 | 2012-11-13 | Industrial production method of isothipendyl technical material |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012104519032A CN102924484A (en) | 2012-11-13 | 2012-11-13 | Industrial production method of isothipendyl technical material |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610194A (en) * | 2014-10-30 | 2015-05-13 | 江苏宝众宝达药业有限公司 | Method for recovering promethazine oxalate from mother solution of hydrochloric acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1173134A (en) * | 1955-11-03 | 1959-02-20 | Rhone Poulenc Sa | New derivatives of 4 aza-phenothiazine and their preparation |
| US5539107A (en) * | 1993-02-19 | 1996-07-23 | Asta Medica Aktiengesellschaft | Method for the production of azaphenothiazines |
| CN102617608A (en) * | 2012-03-09 | 2012-08-01 | 常州大学 | Methods for synthesizing and separating isothipendyl serving as antihistamine medicine |
-
2012
- 2012-11-13 CN CN2012104519032A patent/CN102924484A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1173134A (en) * | 1955-11-03 | 1959-02-20 | Rhone Poulenc Sa | New derivatives of 4 aza-phenothiazine and their preparation |
| US5539107A (en) * | 1993-02-19 | 1996-07-23 | Asta Medica Aktiengesellschaft | Method for the production of azaphenothiazines |
| CN102617608A (en) * | 2012-03-09 | 2012-08-01 | 常州大学 | Methods for synthesizing and separating isothipendyl serving as antihistamine medicine |
Non-Patent Citations (1)
| Title |
|---|
| 施仁信，等: "抗组胺药及异丙嗪的合成", 《杭州化工》, vol. 35, no. 4, 15 December 2005 (2005-12-15), pages 12 - 4 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610194A (en) * | 2014-10-30 | 2015-05-13 | 江苏宝众宝达药业有限公司 | Method for recovering promethazine oxalate from mother solution of hydrochloric acid |
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Application publication date: 20130213 |