CN102140095A - Green new process for preparing tizanidine hydrochloride - Google Patents
Green new process for preparing tizanidine hydrochloride Download PDFInfo
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- CN102140095A CN102140095A CN2010106130195A CN201010613019A CN102140095A CN 102140095 A CN102140095 A CN 102140095A CN 2010106130195 A CN2010106130195 A CN 2010106130195A CN 201010613019 A CN201010613019 A CN 201010613019A CN 102140095 A CN102140095 A CN 102140095A
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- NBGDKTHDTLEUQJ-UHFFFAOYSA-N CC(N1C(Nc(c2n[s]nc2cc2)c2Cl)=NCC1)=O Chemical compound CC(N1C(Nc(c2n[s]nc2cc2)c2Cl)=NCC1)=O NBGDKTHDTLEUQJ-UHFFFAOYSA-N 0.000 description 1
- YCVAUCIQIJIQKJ-UHFFFAOYSA-N CNc(c1n[s]nc1cc1)c1Cl Chemical compound CNc(c1n[s]nc1cc1)c1Cl YCVAUCIQIJIQKJ-UHFFFAOYSA-N 0.000 description 1
- 0 CSN=C(C=CC(Cl)=C1)C1=* Chemical compound CSN=C(C=CC(Cl)=C1)C1=* 0.000 description 1
- XFYDIVBRZNQMJC-UHFFFAOYSA-N Clc(ccc1n[s]nc11)c1NC1=NCCN1 Chemical compound Clc(ccc1n[s]nc11)c1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 1
- BXIXXXYDDJVHDL-UHFFFAOYSA-N Nc(c(N)c1)ccc1Cl Chemical compound Nc(c(N)c1)ccc1Cl BXIXXXYDDJVHDL-UHFFFAOYSA-N 0.000 description 1
- PBGKNXWGYQPUJK-UHFFFAOYSA-N Nc(c([N+]([O-])=O)c1)ccc1Cl Chemical compound Nc(c([N+]([O-])=O)c1)ccc1Cl PBGKNXWGYQPUJK-UHFFFAOYSA-N 0.000 description 1
- MSDMEVQEACHYNS-UHFFFAOYSA-N [O-][N+](c(c1n[s]nc1cc1)c1Cl)=O Chemical compound [O-][N+](c(c1n[s]nc1cc1)c1Cl)=O MSDMEVQEACHYNS-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a green new process for preparing a bulk pharmaceutical chemical, namely tizanidine hydrochloride. The green new process comprises the following steps: taking 4-chlorine-2-nitraniline as raw material and carrying out catalytic hydrogenation and reduction, cyclization, nitration, catalytic hydrogenation and reduction, condensation and salification on the raw material so as to obtain the tizanidine hydrochloride. The green new process not only has simple post-processing, is simple to operate, greatly reduces pollution to environment and corrosion on device, reduces production cost and is more suitable for industrial production.
Description
Technical field
The present invention relates to the preparation technology of medical material medicine, be specifically related to a kind of new preparation process of medical material medicine tizanidine hydrochloride, belong to the synthetic field of medicine.
Background technology
Tizanidine hydrochloride is the central skeletal muscular relaxant with imidazoline structure of Switzerland Novartis Co.,Ltd exploitation, is used to reduce because of the diseases such as bone hypermyotonia, myospasm and myotony due to brain and trauma of spinal cord, hematencephalon, encephalitis and the multiple sclerosis disease etc.This product can be alleviated spasticity, but does not cause myasthenia, does not produce psychologic dependence under therapeutic dose, and better tolerance is a clinical evaluation central muscle relaxant preferably.Structural formula is as follows.
The main method of bibliographical information synthetic hydrochloric acid tizanidine and route (Chinese Journal of Pharmaceuticals, 2005,36,593～595 as follows; Chinese Journal of New Drugs, 2006,15,621～623; Chemical reagent, 2003,25,115～116; European patent EP 644192; Japanese Patent JP8176150):
This route is a raw material with 4-chloro-2-N-methyl-p-nitroaniline, reduction nitro through zinc powder or hydrazine hydrate obtains 4-chloro-1, and the 2-phenylenediamine obtains 5-chloro-2 with the sulfur oxychloride cyclization, 1, the 3-diazosulfide, the nitrated again 5-chloro-4-nitro-2,1 that obtains, the 3-diazosulfide, re-use the iron powder reducing nitro and obtain 4-amino-5-chloro-2,1,3-diazosulfide.4-amino-5-chloro-2,1,3-diazosulfide and 1-acetyl imidazole quinoline are done in phosphorus oxychloride under the condition of solvent after the condensation, and the hydrochloric acid deacetylate obtains tizanidine hydrochloride.Wherein, the nitroreductions in two steps have used zinc powder and iron powder, or the very big hydrazine hydrate of toxicity, and operation complexity not only, heat release is violent, dashes material easily, and reaction can produce a large amount of iron mud and zinc mud, handles loaded down with trivial details, and very big to environmental hazard.In addition, at 4-amino-5-chloro-2,1; in the reaction of 3-diazosulfide and the condensation of 1-acetyl imidazole quinoline, use phosphorus oxychloride to make solvent, not only the corrodibility to equipment is strong; and can produce a large amount of acid tail gas in the reaction process, all extremely unfriendly to human body and environment.
Summary of the invention
The object of the present invention is to provide a new green synthesis process of preparation tizanidine hydrochloride, be intended to overcome the shortcoming in the above synthesis technique, the pollution of reductions degree environment, make it to operate easier, safer, be more suitable for suitability for industrialized production.
The present invention is a raw material with 4-chloro-2-N-methyl-p-nitroaniline, obtains tizanidine hydrochloride through catalytic hydrogenating reduction, cyclization, nitrated, catalytic hydrogenating reduction, condensation, six steps of salify.Synthetic route is as follows:
Details are as follows for concrete synthesis step:
(1) catalytic hydrogenating reduction: with 4-chloro-2-N-methyl-p-nitroaniline is raw material, in suitable solvent, adds heterogeneous catalyst, feeds hydrogen to certain pressure, and reaction obtains 4-chloro-1,2-phenylenediamine under proper temperature.Solvent can be selected one or more in water, methyl alcohol, ethanol, ethyl acetate, Virahol, acetic acid, the tetrahydrofuran (THF), wherein particular methanol, ethanol.Catalyzer can be selected palladium carbon, palladium hydroxide, palladium black, platinum oxide, Raney-Ni, Ni-based composite catalyst, lacquer original nickel, wherein preferred palladium carbon, Raney-Ni.Hydrogen pressure 0.2～5Mpa.Temperature of reaction is 25～120 ℃, preferred 40～80 ℃.
(2) cyclization: in toluene solvant, under the ice-water bath, add the DMF of catalytic amount, drip SOCl again
2, temperature rising reflux obtains 5-chloro-2,1, the 3-diazosulfide.
(3) nitrated: 5-chloro-2,1, the nitration mixture that the 3-diazosulfide is formed with the concentrated nitric acid and the vitriol oil carries out nitrated, obtains 5-chloro-4-nitro-2,1, the 3-diazosulfide.
(4) catalytic hydrogenating reduction: 5-chloro-4-nitro-2,1,3-diazosulfide add heterogeneous catalyst in suitable solvent, feed hydrogen to certain pressure, and reaction obtains 4-amino-5-chloro-2,1,3-diazosulfide under proper temperature.Solvent can be selected one or more in water, methyl alcohol, ethanol, ethyl acetate, Virahol, acetic acid, the tetrahydrofuran (THF), wherein particular methanol, ethanol.Catalyzer can be selected palladium carbon, palladium hydroxide, palladium black, platinum oxide, Raney-Ni, Ni-based composite catalyst, lacquer original nickel, wherein preferred palladium carbon, palladium hydroxide and Raney-Ni.Hydrogen pressure 0.2～5Mpa.Temperature of reaction is 25～150 ℃, preferred 50～100 ℃.
(5) condensation: 4-amino-5-chloro-2,1,3-diazosulfide and 1-benzoyl tetrahydroglyoxaline in suitable solvent, add dewatering agent, and after the reacting by heating, alkaline hydrolysis obtains tizanidine.Solvent can be selected toluene, dimethylbenzene, N, one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, methylene dichloride, ethylene dichloride, the trichloroethane, wherein preferred toluene, dimethylbenzene, N, dinethylformamide; Dewatering agent can be selected phosphorus oxychloride, thionyl chloride, oxalyl chloride, Vanadium Pentoxide in FLAKES, polyphosphoric acid, trifluoromethanesulfanhydride anhydride, cyanuryl chloride; The consumption of solvent is 4-amino-5-chloro-2,1, and the 2-10 of 3-diazosulfide charging capacity is (v/w) doubly, and preferred 3-6 is (v/w) doubly; The consumption of dewatering agent is 4-amino-5-chloro-2,1,1～7 times (mol/mol) of 3-diazosulfide charging capacity, preferred 2～5 times (mol/mol); Temperature of reaction is 30～150 ℃, preferred 50～110 ℃.
(6) salify: tizanidine salify in the ethanolic soln of hydrochloric acid obtains tizanidine hydrochloride.
Advantage of the present invention:
(1) adopt nitro in two steps of method reduction of shortening, not only handle simple to operationly, greatly reduced pollution simultaneously, and hydrogenation catalyst can be recycled, reduced production cost, be fit to suitability for industrialized production more environment.
(2) method that has adopted solvent to add dewatering agent has replaced simple phosphorus oxychloride solvent, has not only significantly reduced the consumption of dewatering agent, and very friendly to environment.
Embodiment
Following exemplary embodiments is used for illustrating the present invention, within the technical scheme that those skilled in the art all belong to the present invention to simple replacement that the present invention did or improvement etc. and protected.
Synthesizing of embodiment 1:4-chlorine O-Phenylene Diamine
Add 5L ethanol and 4-chloro-2-N-methyl-p-nitroaniline 2.5Kg in the hydrogenation reaction kettle of 10L, add 5% palladium carbon 125g, logical then hydrogen three times displaces the air in the reactor, is warming up to 65～70 ℃, and keeping the still internal pressure is 2Mpa.After the TLC detection reaction is complete, filtering palladium carbon, twice of washing with alcohol of filter cake.Filtrate and washing lotion merging are evaporated to dried, promptly obtain 4-chlorine O-Phenylene Diamine 1.88Kg, yield 91%.
Synthesizing of embodiment 2:4-chlorine O-Phenylene Diamine
Add 5L ethanol and 4-chloro-2-N-methyl-p-nitroaniline 2.5Kg in the hydrogenation reaction kettle of 10L, add Raney-Ni 250g, logical then hydrogen three times displaces the air in the reactor, is warming up to 65～70 ℃, and keeping the still internal pressure is 2Mpa.After the TLC detection reaction is complete, filtering Raney-Ni, twice of washing with alcohol of filter cake.Filtrate and washing lotion merging are evaporated to dried, promptly obtain 4-chlorine O-Phenylene Diamine 1.96Kg, yield 95%.
Synthesizing of embodiment 3:4-chlorine O-Phenylene Diamine
Add 5L methyl alcohol and 4-chloro-2-N-methyl-p-nitroaniline 2.5Kg in the hydrogenation reaction kettle of 10L, add platinum oxide 125g, logical then hydrogen three times displaces the air in the reactor, is warming up to 60～65 ℃, and keeping the still internal pressure is 3.0Mpa.After the TLC detection reaction is complete, filtering Raney-Ni, twice of washing with alcohol of filter cake.Filtrate and washing lotion merging are evaporated to dried, promptly obtain 4-chlorine O-Phenylene Diamine 1.86Kg, yield 90%.
Embodiment 4:5-chloro-2,1,3-diazosulfide synthetic
Add 4-chloro-O-Phenylene Diamine, the toluene of 5L and the DMF of catalytic amount of 400g in the reaction flask of 10L, ice bath cools off down the slowly SOCl of Dropwise 5 00mL
2After dropwising, be warming up to back flow reaction, TLC detects.After question response is complete, be cooled to room temperature, suction filtration, filtrate decompression concentrates, and gets brown solid 5-chloro-2,1,3-diazosulfide 451g, yield 94%.
Embodiment 5:5-chloro-4-nitro-2,1,3-diazosulfide synthetic
In the reaction flask of 10L, add the 4.5L concentrated nitric acid and the 1.5L vitriol oil, be cooled to 5 ℃, add 5-chloro-2,1 in batches, 3-diazosulfide 450g, the temperature of control reaction solution is no more than 15 ℃.Behind reinforced the finishing, continued stirring reaction 3 hours down in 20～25 ℃.Reaction solution is poured in the frozen water, suction filtration, filter cake washes with water, gets 5-chloro-4-nitro-2,1,3-diazosulfide 483g, yield 85% after the drying.
Embodiment 6:5-chloro-4-amino-2,1,3-diazosulfide synthetic
The ethanol and the 5-chloro-4-nitro-2,1 that add 5L in the hydrogenation reaction kettle of 10L, 3-diazosulfide 2.5kg adds palladium carbon 125g.Logical hydrogen three times displaces the air in the reactor, is warming up to 75～80 ℃, and keeping the still internal pressure is 2.5Mpa.After the TLC detection reaction is complete, filtering palladium carbon, twice of washing with alcohol of filter cake.Be evaporated to driedly after filtrate and washing lotion merge, promptly obtain 5-chloro-4-amino-2,1,3-diazosulfide 1.85Kg, yield 86%.
Embodiment 7:5-chloro-4-amino-2,1,3-diazosulfide synthetic
The ethanol and the 5-chloro-4-nitro-2,1 that add 5L in the hydrogenation reaction kettle of 10L, 3-diazosulfide 2.5kg adds Raney-Ni 250g.Logical hydrogen three times displaces the air in the reactor, is warming up to 75～80 ℃, and keeping the still internal pressure is 3.5Mpa.After the TLC detection reaction is complete, filtering Raney-Ni, twice of washing with alcohol of filter cake.Be evaporated to driedly after filtrate and washing lotion merge, promptly obtain 5-chloro-4-amino-2,1,3-diazosulfide 1.76Kg, yield 82%.
Embodiment 8:5-chloro-4-amino-2,1,3-diazosulfide synthetic
The methyl alcohol and the 5-chloro-4-nitro-2,1 that add 5L in the hydrogenation reaction kettle of 10L, 3-diazosulfide 2.5kg adds platinum oxide 125g.Logical hydrogen three times displaces the air in the reactor, is warming up to 70～75 ℃, and keeping the still internal pressure is 3.5Mpa.After the TLC detection reaction is complete, filtering platinum oxide, twice of washing with alcohol of filter cake.Be evaporated to driedly after filtrate and washing lotion merge, promptly obtain 5-chloro-4-amino-2,1,3-diazosulfide 1.8Kg, yield 84%.
Embodiment 9: tizanidine synthetic
In the 10L reactor, add 730g 5-chloro-4-amino-2,1,3-diazosulfide, the new SOCl that steams of 1-benzoyl-2-imidazolone 500g and 5L
2, be warming up to 65 ℃, reacted 35 hours.After reaction finishes, reaction solution is slowly poured in the frozen water of 7.5Kg, controlled temperature is no more than 30 ℃.Add 30% the NaOH aqueous solution again, regulate pH to 8, stir 20min under the room temperature.Filter, filter cake washes with water.Filter cake is joined in the mixed solvent of the 30%NaOH aqueous solution/methyl alcohol of 15L (v/v=55/45), reflux 5 hours removes solvent then under reduced pressure, cooling, and crystallization filters.Filter cake obtains tizanidine 745g 60 ℃ of following vacuum-dryings, yield 75%.
Embodiment 10: tizanidine synthetic
The POCl that in the 10L reactor, adds 1.5L
3With the toluene of 5L, be heated to 65 ℃ after, add the 5-chloro-4-amino-2,1 of 1Kg, 1-benzoyl-2-imidazolone of 3-diazosulfide and 1.05Kg.Behind reinforced the finishing, be warming up to 90～95 ℃, the TLC detection reaction.After question response is complete, reaction solution is slowly poured in the frozen water of 5.5Kg, controlled temperature is no more than 35 ℃.Add 30% the NaOH aqueous solution again, regulate pH to 8, stir 20min under the room temperature.Filter, filter cake washes with water.Filter cake is joined in the mixed solvent of the 30%NaOH aqueous solution/methyl alcohol of 15L (v/v=50/45), reflux 5 hours removes solvent then under reduced pressure, cooling, and crystallization filters.Filter cake obtains tizanidine 1.06Kg 60 ℃ of following vacuum-dryings, yield 78%.
Embodiment 11: tizanidine hydrochloride synthetic
In the 10L reactor, add the saturated ethanol solution of hydrogen chloride of 6L and the tizanidine of 150g, stirring at room 2 hours, suction filtration, filter cake absolute ethanol washing after drying, ethyl alcohol recrystallization gets faint yellow tizanidine hydrochloride product 162g, yield 94%.
Claims (16)
1. novel environment-friendly process for preparing tizanidine hydrochloride, the molecular formula of tizanidine hydrochloride is as follows:
2. the new preparation process of tizanidine hydrochloride according to claim 1, it is characterized in that with 4-chloro-2-N-methyl-p-nitroaniline be raw material, obtain tizanidine hydrochloride through catalytic hydrogenating reduction, cyclization, nitrated, catalytic hydrogenating reduction, condensation, six steps of salify, reaction formula is as follows:
3. the new preparation process of tizanidine hydrochloride according to claim 2 is characterized in that with 4-chloro-2-N-methyl-p-nitroaniline be raw material, in suitable solvent, add heterogeneous catalyst, feed hydrogen to certain pressure, reaction obtains 4-chloro-1,2-phenylenediamine under proper temperature.
4. the new preparation process of tizanidine hydrochloride according to claim 3 is characterized in that solvent can select one or more in water, methyl alcohol, ethanol, ethyl acetate, Virahol, acetic acid, the tetrahydrofuran (THF), wherein particular methanol, ethanol.
5. the new preparation process of tizanidine hydrochloride according to claim 3 is characterized in that catalyzer can select palladium carbon, palladium hydroxide, palladium black, platinum oxide, Raney-Ni, Ni-based composite catalyst, lacquer original nickel, wherein preferred palladium carbon, Raney-Ni.
6. the new preparation process of tizanidine hydrochloride according to claim 3 is characterized in that hydrogen pressure 0.2～5Mpa, and temperature of reaction is 25～120 ℃, and preferable reaction temperature is 40～80 ℃.
7. the new preparation process of tizanidine hydrochloride according to claim 2, it is characterized in that 5-chloro-4-nitro-2,1, the 3-diazosulfide is in suitable solvent, add heterogeneous catalyst, feed hydrogen to certain pressure, reaction obtains 4-amino-5-chloro-2 under proper temperature, 1, the 3-diazosulfide.
8. the new preparation process of tizanidine hydrochloride according to claim 7 is characterized in that solvent can select one or more in water, methyl alcohol, ethanol, ethyl acetate, Virahol, acetic acid, the tetrahydrofuran (THF), wherein particular methanol, ethanol.
9. the new preparation process of tizanidine hydrochloride according to claim 7, it is characterized in that catalyzer can select palladium carbon, palladium hydroxide, palladium black, platinum oxide, Raney-Ni, Ni-based composite catalyst, lacquer original nickel, wherein preferred palladium carbon, palladium hydroxide and Raney-Ni.
10. the new preparation process of tizanidine hydrochloride according to claim 7 is characterized in that hydrogen pressure 0.2～5Mpa, and temperature of reaction is 25-150 ℃, and preferable reaction temperature is 50～100 ℃.
11. the new preparation process of tizanidine hydrochloride according to claim 2 is characterized in that 4-amino-5-chloro-2,1; 3-diazosulfide and 1-benzoyl tetrahydroglyoxaline in suitable solvent, add dewatering agent; after the reacting by heating, alkaline hydrolysis obtains tizanidine.
12. the new preparation process of tizanidine hydrochloride according to claim 11, it is characterized in that solvent can select toluene, dimethylbenzene, N, dinethylformamide, N, in N-N,N-DIMETHYLACETAMIDE, acetonitrile, methylene dichloride, ethylene dichloride, the trichloroethane one or more, wherein preferred toluene, dimethylbenzene, N, dinethylformamide.
13. the new preparation process of tizanidine hydrochloride according to claim 11 is characterized in that dewatering agent can select phosphorus oxychloride, thionyl chloride, oxalyl chloride, Vanadium Pentoxide in FLAKES, polyphosphoric acid, trifluoromethanesulfanhydride anhydride, cyanuryl chloride.
14. the new preparation process of tizanidine hydrochloride according to claim 11, the consumption that it is characterized in that solvent are 4-amino-5-chloro-2,1,2～10 times (v/w) of 3-diazosulfide charging capacity, preferred 3～6 times (v/w).
15. the new preparation process of tizanidine hydrochloride according to claim 11, the consumption that it is characterized in that dewatering agent are 4-amino-5-chloro-2,1,1～7 times (mol/mol) of 3-diazosulfide charging capacity, preferred 2～5 times (mol/mol).
16. the new preparation process of tizanidine hydrochloride according to claim 11 is characterized in that temperature of reaction is 30～150 ℃, preferred 50～110 ℃.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566314A (en) * | 2014-10-09 | 2016-05-11 | 四川科瑞德制药有限公司 | Tizanidine hydrochloride compound |
| CN106496219A (en) * | 2016-11-01 | 2017-03-15 | 安徽省逸欣铭医药科技有限公司 | The method that high-purity technical metaplasia produces tizanidine hydrochloride |
| CN106946874A (en) * | 2017-04-07 | 2017-07-14 | 四川智强医药科技开发有限公司 | The discoloration method of Tizanidine |
| CN107759582A (en) * | 2016-08-17 | 2018-03-06 | 四川科瑞德制药股份有限公司 | A kind of preparation method of new central skeletal muscle relaxant |
| CN107778307A (en) * | 2016-08-24 | 2018-03-09 | 四川科瑞德制药股份有限公司 | A kind of preparation method of the adrenoceptor agonists of central α 2 |
| CN114957031A (en) * | 2022-05-17 | 2022-08-30 | 河北圣雪大成制药有限责任公司 | Novel method for synthesizing 9-amino minocycline sulfate |
-
2010
- 2010-12-30 CN CN2010106130195A patent/CN102140095A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 徐加等: "盐酸替扎尼定的合成", 《中国医药工业杂志》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566314A (en) * | 2014-10-09 | 2016-05-11 | 四川科瑞德制药有限公司 | Tizanidine hydrochloride compound |
| CN105566314B (en) * | 2014-10-09 | 2019-04-16 | 四川科瑞德制药股份有限公司 | A kind of Tizanidine compound |
| CN107759582A (en) * | 2016-08-17 | 2018-03-06 | 四川科瑞德制药股份有限公司 | A kind of preparation method of new central skeletal muscle relaxant |
| CN107778307A (en) * | 2016-08-24 | 2018-03-09 | 四川科瑞德制药股份有限公司 | A kind of preparation method of the adrenoceptor agonists of central α 2 |
| CN107778307B (en) * | 2016-08-24 | 2021-05-28 | 四川科瑞德制药股份有限公司 | Preparation method of central alpha 2 adrenoreceptor agonist |
| CN106496219A (en) * | 2016-11-01 | 2017-03-15 | 安徽省逸欣铭医药科技有限公司 | The method that high-purity technical metaplasia produces tizanidine hydrochloride |
| CN106496219B (en) * | 2016-11-01 | 2019-09-06 | 安徽恒星制药有限公司 | The method of high-purity technical metaplasia production Tizanidine |
| CN106946874A (en) * | 2017-04-07 | 2017-07-14 | 四川智强医药科技开发有限公司 | The discoloration method of Tizanidine |
| CN114957031A (en) * | 2022-05-17 | 2022-08-30 | 河北圣雪大成制药有限责任公司 | Novel method for synthesizing 9-amino minocycline sulfate |
| CN114957031B (en) * | 2022-05-17 | 2024-05-31 | 河北圣雪大成制药有限责任公司 | Novel method for synthesizing 9-amino minocycline sulfate |
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Application publication date: 20110803 |