CN106883167A - A kind of new chlorphenamine maleate synthetic method - Google Patents
A kind of new chlorphenamine maleate synthetic method Download PDFInfo
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- CN106883167A CN106883167A CN201510968588.4A CN201510968588A CN106883167A CN 106883167 A CN106883167 A CN 106883167A CN 201510968588 A CN201510968588 A CN 201510968588A CN 106883167 A CN106883167 A CN 106883167A
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- chlorphenamine
- chlorobenzyl
- pyridine
- added
- chlorphenamine maleate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to medicinal chemistry arts, and in particular to a kind of synthetic method of chlorphenamine maleate.The inventive method is included following steps in sequence：(1) chlorine cyanobenzene is reacted under the catalysis of catalyst cobaltocene with acetylene gas, generates p-chlorobenzyl pyridine；(2) p-chlorobenzyl pyridine reacts under the catalysis of Sodamide with N, N- dimethyl chloride ethane, generates chlorphenamine, then with maleic acid neutralization reaction, generates chlorphenamine maleate.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of synthetic method of chlorphenamine maleate.
Background technology
Chlorphenamine maleate, English name：Chlorphenamine maleate, chemical name：2- [p- chloro- a- [2- (dimethylamino) ethyl] phenyl] pyridine maleate molecular formula：C16H19ClN2.C4H4O4, molecular weight：390.87, No. CAS：113-92-8.
This product has antihistamine effect, can alleviate cold symptoms.Indication is used to catch a cold and mucocutaneous anaphylactia, indication nettle rash, eczema, dermatitis, drug rash, cutaneous pruritus, neurodermatitis, insect bite disease, solar dermatitis, can also be used for allergic dermatitis, vasomotor rhinitis, medicine and food hypersenstivity etc..
The content of the invention
The inventive method is included following steps in sequence：
1. the preparation of p-chlorobenzyl pyridine
Added in autoclave to chlorine cyanobenzene and catalyst cobaltocene, vacuumize, 150 DEG C are warming up to, are passed through through the acetylene gas of dried process, temperature rises, temperature maintains 150~170 DEG C and is passed through acetylene gas, after ventilation terminates, in 150~170 DEG C of reaction under high pressure 4h, after reaction terminates, distillation, obtains p-chlorobenzyl pyridine
It is a feature of the present invention that being reacted under the catalysis of catalyst cobaltocene chlorine cyanobenzene and acetylene gas, p-chlorobenzyl pyridine is generated.
2. the preparation of chlorphenamine maleate
In tetrahydrofuran solvent, p-chlorobenzyl pyridine, Sodamide are added, temperature is reacted 1 hour at 20~25 DEG C, and N, the toluene solution of N- dimethyl chloride ethane is then added dropwise, temperature control after completion of dropping, is reacted 2 hours at 30~40 DEG C at 40~45 DEG C, after reaction terminates, normal temperature is down to, then adds water and wash organic phase to neutrality, recycling design, chlorphenamine concentrate is obtained, concentrate obtains chlorphenamine through vacuum distillation.Maleic acid is added in absolute ethyl alcohol, after stirring and dissolving, chlorphenamine is added, after adding, stirred 30 minutes, be cooled to 0~-2 DEG C and be incubated 2 hours, suction filtration obtains chlorphenamine maleate crude product and is refining to obtain chlorphenamine maleate fine work with 1.5 times of absolute ethyl alcohol.
It is a feature of the present invention that in tetrahydrofuran solution, p-chlorobenzyl pyridine is under the catalysis of Sodamide, and the reaction of N, N- dimethyl chloride ethane, generates chlorphenamine.
Specific implementation method
With reference to specific experiment example, the present invention is described in further detail.
Embodiment 1：The preparation of chlorphenamine maleate
(1) preparation of p-chlorobenzyl pyridine
Added in 500ml autoclaves to chlorine cyanobenzene 200g and catalyst cobaltocene 10g, vacuumize, 150 DEG C are warming up to, are passed through through the acetylene gas of dried process, temperature rises, temperature maintains 150~170 DEG C and is passed through acetylene gas 100g, after ventilation terminates, in 150~170 DEG C of reaction under high pressure 4h, after reaction terminates, distillation, obtains p-chlorobenzyl pyridine 260g.
(2) preparation of chlorphenamine maleate
In tetrahydrofuran solvent, p-chlorobenzyl pyridine 260g, Sodamide 95g are added, temperature is reacted 1 hour at 20~25 DEG C, and N, the toluene solution of N- dimethyl chloride ethane is then added dropwise, temperature control after completion of dropping, is reacted 2 hours at 30~40 DEG C at 40~45 DEG C, after reaction terminates, normal temperature is down to, then adds water and wash organic phase to neutrality, recycling design, chlorphenamine concentrate is obtained, concentrate obtains chlorphenamine 270g through vacuum distillation.130g maleic acids are added in 500g absolute ethyl alcohols, after stirring and dissolving, chlorphenamine is added, after adding, stirring 30 minutes, is cooled to 0~-2 DEG C and is incubated 2 hours, and suction filtration obtains chlorphenamine maleate crude product 390g. 350 grams refined of chlorphenamine maleate fine work of 1.5 times of absolute ethyl alcohol.
Embodiment 2：The preparation of chlorphenamine maleate
(1) preparation of p-chlorobenzyl pyridine
Added in 500ml autoclaves to chlorine cyanobenzene 200g and catalyst cobaltocene 8g, vacuumize, 140 DEG C are warming up to, are passed through through the acetylene gas of dried process, temperature rises, temperature maintains 140~160 DEG C and is passed through acetylene gas 100g, after ventilation terminates, in 150~160 DEG C of reaction under high pressure 4.5h, after reaction terminates, distillation, obtains p-chlorobenzyl pyridine 270g.
(2) preparation of chlorphenamine maleate
In tetrahydrofuran solvent, p-chlorobenzyl pyridine 270g, Sodamide 100g are added, temperature is reacted 1 hour at 20~25 DEG C, and N, the toluene solution 282g (content 60%) of N- dimethyl chloride ethane is then added dropwise, temperature control after completion of dropping, is reacted 2 hours at 30~40 DEG C at 40~45 DEG C, after reaction terminates, normal temperature is down to, then adds water and wash organic phase to neutrality, recycling design, chlorphenamine concentrate is obtained, concentrate obtains chlorphenamine 276g through vacuum distillation.130g maleic acids are added in 500g absolute ethyl alcohols, after stirring and dissolving, chlorphenamine is added, after adding, stirring 30 minutes, is cooled to 0~-2 DEG C and is incubated 2 hours, and suction filtration obtains chlorphenamine maleate crude product 360g. 335 grams refined of chlorphenamine maleate fine work of 1.5 times of absolute ethyl alcohol.
Claims (3)
1. a kind of new chlorphenamine maleate synthetic method, it is characterised in that including following steps in sequence：
(1) preparation of p-chlorobenzyl pyridine
Added in autoclave to chlorine cyanobenzene and cobaltocene solution, vacuumize, 150 DEG C are warming up to, are passed through through the acetylene gas of dried process, temperature rises, temperature maintains 150~170 DEG C and is passed through acetylene gas, after ventilation terminates, in 150~170 DEG C of reaction under high pressure 4h, after reaction terminates, distillation, obtains p-chlorobenzyl pyridine
(2) preparation of chlorphenamine maleate
In tetrahydrofuran solvent, p-chlorobenzyl pyridine, Sodamide are added, temperature is reacted 1 hour at 20~25 DEG C, and N, the toluene solution of N- dimethyl chloride ethane is then added dropwise, temperature control after completion of dropping, is reacted 2 hours at 30~40 DEG C at 40~45 DEG C, after reaction terminates, normal temperature is down to, then adds water and wash organic phase to neutrality, recycling design, chlorphenamine concentrate is obtained, concentrate obtains chlorphenamine through vacuum distillation.Maleic acid is added in absolute ethyl alcohol, after stirring and dissolving, chlorphenamine is added, after adding, stirred 30 minutes, be cooled to 0~-2 DEG C and be incubated 2 hours, suction filtration obtains chlorphenamine maleate crude product and is refining to obtain chlorphenamine maleate fine work with 1.5 times of absolute ethyl alcohol.
2. according to claim 1, in step (1), the invention is characterised in that, chlorine cyanobenzene is reacted under the catalysis of catalyst cobaltocene with acetylene gas, generate p-chlorobenzyl pyridine.
3. according to claim 1, in step (2), the invention is characterised in that, p-chlorobenzyl pyridine reacts under the catalysis of Sodamide in tetrahydrofuran solution with N, N- dimethyl chloride ethane, generates chlorphenamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510968588.4A CN106883167A (en) | 2015-12-16 | 2015-12-16 | A kind of new chlorphenamine maleate synthetic method |
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| CN201510968588.4A CN106883167A (en) | 2015-12-16 | 2015-12-16 | A kind of new chlorphenamine maleate synthetic method |
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| CN106883167A true CN106883167A (en) | 2017-06-23 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372578A (en) * | 2019-05-31 | 2019-10-25 | 嘉实（湖南）医药科技有限公司 | A kind of new chlorphenamine maleate synthetic method |
| CN110963962A (en) * | 2019-12-20 | 2020-04-07 | 嘉实（湖南）医药科技有限公司 | Novel chlorpheniramine maleate crystal and preparation method thereof |
| CN111393357A (en) * | 2020-04-26 | 2020-07-10 | 上海新华联制药有限公司 | Refining method of chlorpheniramine maleate |
| CN111499567A (en) * | 2020-04-26 | 2020-08-07 | 上海新华联制药有限公司 | Chlorpheniramine maleate, preparation method and application thereof |
| CN111533686A (en) * | 2020-04-26 | 2020-08-14 | 上海新华联制药有限公司 | Chlorpheniramine maleate salt former, and synthesis method and application thereof |
| CN111747887A (en) * | 2019-03-29 | 2020-10-09 | 四川迪菲特药业有限公司 | Preparation method of chlorpheniramine maleate |
| CN114835637A (en) * | 2022-06-20 | 2022-08-02 | 南京联智医药科技有限公司 | Preparation method of chlorpheniramine maleate |
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| US4079061A (en) * | 1976-06-21 | 1978-03-14 | Smithkline Corporation | Process using alkali fusion for decyanation of tert.-nitriles |
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2015
- 2015-12-16 CN CN201510968588.4A patent/CN106883167A/en active Pending
Patent Citations (3)
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| US4079061A (en) * | 1976-06-21 | 1978-03-14 | Smithkline Corporation | Process using alkali fusion for decyanation of tert.-nitriles |
| CN101108821A (en) * | 2007-08-15 | 2008-01-23 | 新乡市恒基化工有限公司 | Method of manufacturing 2-picoline |
| CN101967120A (en) * | 2010-01-08 | 2011-02-09 | 广西大学 | Preparation method of 2-p-chlorobenzyl pyridine |
Non-Patent Citations (2)
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| CARLO BOTTEGHI ET AL.: ""New Synthetic Route to Pheniramines via Hydroformylation of Functionalyzed Olefins"", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111747887A (en) * | 2019-03-29 | 2020-10-09 | 四川迪菲特药业有限公司 | Preparation method of chlorpheniramine maleate |
| CN111747887B (en) * | 2019-03-29 | 2023-04-07 | 四川迪菲特药业有限公司 | Preparation method of chlorpheniramine maleate |
| CN110372578A (en) * | 2019-05-31 | 2019-10-25 | 嘉实（湖南）医药科技有限公司 | A kind of new chlorphenamine maleate synthetic method |
| CN110963962A (en) * | 2019-12-20 | 2020-04-07 | 嘉实（湖南）医药科技有限公司 | Novel chlorpheniramine maleate crystal and preparation method thereof |
| CN111393357A (en) * | 2020-04-26 | 2020-07-10 | 上海新华联制药有限公司 | Refining method of chlorpheniramine maleate |
| CN111499567A (en) * | 2020-04-26 | 2020-08-07 | 上海新华联制药有限公司 | Chlorpheniramine maleate, preparation method and application thereof |
| CN111533686A (en) * | 2020-04-26 | 2020-08-14 | 上海新华联制药有限公司 | Chlorpheniramine maleate salt former, and synthesis method and application thereof |
| CN114835637A (en) * | 2022-06-20 | 2022-08-02 | 南京联智医药科技有限公司 | Preparation method of chlorpheniramine maleate |
| CN114835637B (en) * | 2022-06-20 | 2023-12-26 | 南京联智医药科技有限公司 | Preparation method of chlorpheniramine maleate |
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