CN106496219B - The method of high-purity technical metaplasia production Tizanidine - Google Patents
The method of high-purity technical metaplasia production Tizanidine Download PDFInfo
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Abstract
The invention discloses a kind of methods that high-purity technical metaplasia produces Tizanidine, with 4- amino -5- chloro- 2,1,3- diazosulfide and 2- imidazolidinone are starting material, it reacts and Tizanidine is made with chlorine phosphate in the ionic liquid of quaternary ammonium type, salt-forming reaction obtains Tizanidine in 95% alcoholic solvent.Present invention process route is novel, process conditions are mild, easy to operate, it is operated without repeated recrystallize, only need the qualified products that can once obtain purity >=99.5%, solves Tizanidine contaminant problem, the bulk pharmaceutical chemicals requirement of United States Pharmacopeia and European Pharmacopoeia standard is complied fully with, there are preferable practical value and economic results in society.
Description
Technical field
The present invention relates to a kind of methods of maincenter skeletal muscle relaxant for producing imdazole derivatives, relate in particular to one kind
The method that high-purity technical metaplasia produces Tizanidine, belongs to technical field of medicine synthesis.
Background technique
Tizanidine is imdazole derivatives, optionally inhibits and the overstretched related more cynapse machines of muscle
System reduces intrerneuron and discharges excitatory amino acid.This product does not influence the transmitting of nerves and muscles, and tolerance is good, and
The resistance of passive movement can be reduced, spasm and clonic spasm are mitigated, enhances voltuntary movement intensity.To acute painful muscle spasmus and it is derived from
The chronic spasticity of spinal cord and brain is effective.This product can also increase the anti-inflammatory effect of non-steroidal anti-inflammatory drugs (NSAID), and can
The Gastric mucosal lesion for preventing NSAID from inducing.This product can reduce gastric acid secretion and reverse caused by aspirin in animal experiments
Stomach lining glycoprotein is reduced.This product is similar to Baclofen effect, invalid to Baclofen or be not resistant to person this product can be used.This product
With diazepam when treating the spasticity of hemiplegia and paravertebral muscle spasm patient, effect is similar, but the flesh by treatment backbone
When meat spasm, this product works faster.
Tizanidine is the maincenter skeletal muscle relaxant developed by Novartis company, Switzerland, head in 1988 earliest
It is secondary to be listed in Denmark and Switzerland, treatment is clinically used for because of brain and trauma of spinal cord, cerebral hemorrhage, encephalitis and multiple sclerosis etc.
The diseases such as caused bone hypermyotonia, muscle spasmus and myotonia.This product therapeutic dose does not generate psychologic dependence, is tolerance
Property and the preferable central muscle relaxant of curative effect.
Tizanidine (Tizanidine Hydrochloride), Chinese chemical name are the chloro- N- of 5- (4,5- bis-
Hydrogen -1H- imidazoles -2- base) -2,1,3- diazosulfide -4- amine hydrochlorate, the entitled 5-Chloro-N- (4,5- of English language Chemical
Dihydro-1H-imidazol-2-yl) -2,1,3-benzothiadiazole-4-amine monohydrochloride changes
It is as follows to learn structural formula:
In Tizanidine industrialized production, due to production technology difference, it is related to several crucial known impurities in product
It is middle to exist and be difficult to completely remove, seriously affect the quality of product.They are: impurity A, impurity B and impurity C, knot
Structure formula is as follows:
Synthetic technology document disclosed in existing Tizanidine, can be mainly divided into following several method:
Method one, CN102140095 are disclosed using 4- chloro-2-nitroaniline as raw material, by catalytic hydrogenating reduction, ring
Conjunction, condensation, obtains at six step of salt hydrochloric acid for Buddhist nun is pricked at nitrification, catalytic hydrogenating reduction, though this method reduces pollution, product is deposited
In two impurity, the Control of Impurities limit that can meet ICH need to be repeatedly refined just hereinafter, the process route is as follows:
Process route disclosed in method two, Indian Pat, 2008MU01713 is as follows:
This method synthetic route is long, seriously polluted, and yield is extremely low, though impurity A, impurity B and impurity C have been effectively removed,
Be not suitable for industrialized production.
Method three, Chinese Journal of Pharmaceuticals, 36 (10), 593~595, process route disclosed in 2005 is as follows:
The benefits of this method and method one play the same tune on different musical instruments, the disadvantage is that impurity A, impurity B and impurity C have residual, and impurity B
It is difficult to effectively remove.
Method four, Chinese Journal of New Drugs, 15 (8), 621~623, process route disclosed in 2006 is as follows:
The benefits of this method and method one and method three equally play the same tune on different musical instruments, it is residual to be all that impurity A, impurity B and impurity C have
It stays, and impurity B is difficult to effectively remove.
Process route disclosed in method five, Czech Rep., 286717,14 Jun 2000 is as follows:
This method uses phosphorus oxychloride, seriously polluted, and post-reaction treatment is difficult, while it is small not to generate two Polarity comparisions
Know impurity, the requirement of the United States Pharmacopeia limit of impurities need to can be just met by repeated recrystallize, is not suitable for industrialized production.
Process route disclosed in method six, Jp Pat. 07258251 and Eur. Pat. 644192 is as follows:
This method improves to some extent compared with method six, but same residual impurity A, impurity B and impurity C, and impurity B is difficult effectively to go
It removes.
Process route disclosed in method seven, Ger. Pat. 246764 is as follows:
Though this method free from admixture B and impurity C reacts wordy, yield is low, is unfavorable for industrialized production.
Summary of the invention
It is an object of the present invention to which the shortcomings that overcoming the prior art and deficiency, provide a kind of high-purity technical metaplasia production salt
The method of sour Tizanidine.It has obtained Tizanidine with high yield high-purity, and wherein impurity A, impurity B and impurity C are equal
Without detection, it can be used as industrial method and be mass produced.
Technical solution process provided by the invention is as follows:
With 4- amino -5- chloro- 2,1,3- diazosulfide and 2- imidazolidinone are starting material, in the ionic liquid of quaternary ammonium type
It reacts and Tizanidine is made with chlorine phosphate in body, salt-forming reaction obtains Tizanidine in 95% alcoholic solvent, specific to walk
Suddenly are as follows:
A, II preparation:
The chloro- 2,1,3- diazosulfide of 4- amino -5-, 2- imidazolidinone are in the ionic liquid of quaternary ammonium type and chlorine phosphate
Reaction, end of reaction filter to get intermediate II；
B, I preparation:
Intermediate II is dissolved in alcohols solvent, is heated to certain temperature, slightly cold with 6N salt acid for adjusting pH, is added 6 ‰~2%
Injection stage active carbon stirs 20~30min, filters decarburization, and filtrate is cooling, and filtering is washed up to Tizanidine (I).
In addition, the present invention also proposes following attached technical scheme:
Wherein, the ionic liquid of the quaternary ammonium type in step a is 50% aqueous solution of methacryl hydroxypropyltrimonium chloride
Or 4-butyl ammonium fluoride trihydrate；Chlorine phosphate is chlorine dimethyl phosphate or diethyl chloro-phosphate；Reaction temperature is 15~25
℃；The alcohols solvent of step b is 95% methanol or 95% ethyl alcohol；Reaction temperature is 65~75 DEG C；The pH range of adjusting be 2.5~
3.5。
Compared with prior art, the present invention having the advantages that significant:
1. using 4- amino -5- chloro- 2,1,3- diazosulfide and 2- imidazolidinone are starting material, so in the process not
Impurity B and impurity C are generated, meanwhile, 2- imidazolidinone is Water-solubility Material, is extremely easy to remove, noresidue；
2. starting material 4- amino -5- chloro- 2,1,3- diazosulfide, that is, impurity A, due to having used dissolubility fabulous
Ionic liquid causes impurity A without any residual；
3. step a yield is high, and >=95%, and post-reaction treatment is simple, and product can be obtained by simple filtration；
4. ionic liquid may be reused 8~10 times by simple extraction, low in cost, pollution-free；
5. product purity is high, it is only necessary to which primary purification can reach >=99.5%；
6. step b, at salt, is not necessarily to hydrogen chloride gas using 6N hydrochloric acid, simple to operate.
Specific embodiment
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Embodiment one:
A, the preparation of intermediate II:
2- imidazolidinone 310g(3.6mol), 50% aqueous solution 930ml of methacryl hydroxypropyltrimonium chloride, in
Stirred at 15~25 DEG C, chlorine dimethyl phosphate 520g(3.6mol be added thereto), insulated and stirred reacts 3h, and 4- ammonia is then added
Base -5- chloro- 2,1,3- diazosulfide 278g(1.5mol), maintain the temperature to be stirred to react, (the expansion of thin layer identification terminal
Agent: methylene chloride-methanol-triethylamine=1:1:0.1), end of reaction, filtering, solid is washed with a small amount, then uses proper amount of methanol
Washing, 50~55 DEG C of vacuum dry 6h obtain 369g(1.454mol) pale yellow powder shape solid intermediate II (Tizanidine) receipts
Rate 97.0%, mp:221~222 DEG C, HPLC content 99.1%.
B, the preparation of chemical compounds I (Tizanidine):
Intermediate II 360g(1.42mol), 95% ethyl alcohol 2160ml, 65~75 DEG C, under stirring are heated to, with 6N hydrochloric acid tune
PH to 2.5~3.5 is saved, is added 21.6g injection active carbon after slightly cold, room temperature to 65~75 DEG C of 20~30min of stirring, mistake while hot
Decarburization is filtered, filtrate is first cooled to room temperature, and then at 0~5 DEG C of placement 3h, filtering, solid is washed with ethanol in proper amount, and 70~75 DEG C of vacuum
Dry 8h, obtains 404g off-white color crystalline solid Tizanidine, yield 98.1%, mp:289~290 DEG C (decomposition), HPLC
Content 99.8%, without detection, detection method is as follows by impurity A, impurity B and impurity C:
Impurity A, impurity B and impurity C are purchased from United States Pharmacopeia reference substance, and the solution of 0.1mg/ml is each formulated into methanol
It is used as comparison liquid；
Standard solution: Tizanidine standard items use mobility dilution to be configured to the solution of 0.046mg/ml as marking
Quasi- solution；
System suitability solution: taking 23mg acid hydrochloride salt Tizanidine reference substance, set in 100ml volumetric flask, and 20ml is added
Methanol after dissolution, is separately added into above-mentioned impurity A solution, impurity B solution and each 10ml of impurity C solution and uses first after mixing
Alcohol is settled to 100ml；
Inspection method: HPLC method (CP2015 general rule 0512)；Chromatographic condition: chromatographic column: C18(25cm × 4.6mm, 5 μm)；
Detector: UV detector (254nm, changes into 318nm later in 3min)；Column temperature: 25 DEG C；Mobile phase A: water-formic acid (200:
1), adjusting pH with 28% ammonium hydroxide is 8.5, Mobile phase B: acetonitrile-mobile phase A (4:1)；Sampling volume: 20 μ l；Flow velocity: 1.0ml/
min；Gradient condition see the table below:
Embodiment two:
The methacryl propyl in one step a of embodiment is replaced with 40% aqueous solution of 4-butyl ammonium fluoride trihydrate
50% aqueous solution of trimethyl ammonium chloride, remaining step is identical, and Tizanidine 407g, total recovery 95.5%, mp:289 is made
~290 DEG C (decomposition), HPLC content 99.9%, impurity A, impurity B and impurity C are without detection.
Embodiment three:
The chlorine dimethyl phosphate in one step a of embodiment is replaced with diethyl chloro-phosphate, remaining step is identical, and hydrochloric acid is made
Tizanidine 405g, total recovery 95.3%, mp:289~290 DEG C (decomposition), HPLC content 99.8%, impurity A, impurity B and impurity C
Without detection.
Specific embodiment described in the present invention only illustrate the spirit of the present invention by way of example.The neck of technology belonging to the present invention
The technical staff in domain can make various modifications or additions to the described embodiments or replace by a similar method
In generation, however, it does not deviate from the spirit of the invention or beyond the scope of the appended claims.
It is skilled to this field although present invention has been described in detail and some specific embodiments have been cited
For technical staff, as long as it is obvious for can making various changes or correct without departing from the spirit and scope of the present invention.
Claims (7)
1. a kind of method that high-purity technical metaplasia produces Tizanidine (I), it the following steps are included:
A, II preparation:
The chloro- 2,1,3- diazosulfide of 4- amino -5-, 2- imidazolidinone are in the ionic liquid of quaternary ammonium type and chlorine phosphate is anti-
It answers, end of reaction, filters to get intermediate II；
B, I preparation:
Intermediate II is dissolved in alcohols solvent, is heated to certain temperature, slightly cold with 6N salt acid for adjusting pH, and 6 ‰~2% note is added
A grade active carbon is penetrated, 20~30min is stirred, filters decarburization, filtrate is cooling, and filtering is washed up to Tizanidine (I).
2. the method that a kind of high-purity technical metaplasia according to claim 1 produces Tizanidine, it is characterised in that step
The ionic liquid of quaternary ammonium type in rapid a is 50% aqueous solution, the tetrabutyl ammonium fluoride of methacryl hydroxypropyltrimonium chloride
Trihydrate.
3. the method that a kind of high-purity technical metaplasia according to claim 1 produces Tizanidine, it is characterised in that step
Chlorine phosphate in rapid a is chlorine dimethyl phosphate, diethyl chloro-phosphate.
4. the method that a kind of high-purity technical metaplasia according to claim 1 produces Tizanidine, it is characterised in that step
The reaction temperature of rapid a is 15~25 DEG C.
5. the method that a kind of high-purity technical metaplasia according to claim 1 produces Tizanidine, it is characterised in that step
The alcohols solvent of rapid b is 95% methanol, 95% ethyl alcohol.
6. the method that a kind of high-purity technical metaplasia according to claim 1 produces Tizanidine, it is characterised in that step
The reaction temperature of rapid b is 65~75 DEG C.
7. the method that a kind of high-purity technical metaplasia according to claim 1 produces Tizanidine, it is characterised in that step
The pH range that rapid b is adjusted is 2.5~3.5.
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| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0644192A1 (en) * | 1993-09-09 | 1995-03-22 | Permachem Asia, Ltd. | A process for making a benzothiadiazole derivative |
| RU2253653C2 (en) * | 2003-02-28 | 2005-06-10 | Российская Федерация в лице Федерального государственного унитарного предпрятия "Центр по химии лекарственных средств" (ФГУП ЦХЛС-ВНИХФИ) | Method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride |
| CN102140095A (en) * | 2010-12-30 | 2011-08-03 | 常州亚邦制药有限公司 | Green new process for preparing tizanidine hydrochloride |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08176150A (en) * | 1994-12-19 | 1996-07-09 | Y I C:Kk | Production of 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole or its salt |
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2016
- 2016-11-01 CN CN201610935014.1A patent/CN106496219B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0644192A1 (en) * | 1993-09-09 | 1995-03-22 | Permachem Asia, Ltd. | A process for making a benzothiadiazole derivative |
| RU2253653C2 (en) * | 2003-02-28 | 2005-06-10 | Российская Федерация в лице Федерального государственного унитарного предпрятия "Центр по химии лекарственных средств" (ФГУП ЦХЛС-ВНИХФИ) | Method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride |
| CN102140095A (en) * | 2010-12-30 | 2011-08-03 | 常州亚邦制药有限公司 | Green new process for preparing tizanidine hydrochloride |
Non-Patent Citations (4)
| Title |
|---|
| "Identification and characterization of potential impurities of tizanidine hydrochloride";Ghanta Mahesh Reddy，et al.;《ACAIJ》;20080831;第7卷(第8期);586-590 |
| "Validated liquid chromatography method for assay of tizanidine in drug substance and formulated products";Mei-Ling Qi，et al.;《Analytica Chimica Acta》;20031231;第478卷;171–177 |
| "盐酸替扎尼定的合成";徐加，等;《中国医药工业杂志》;20051231;第36卷(第10期);593-595 |
| "盐酸替扎尼定的合成改进";吴贝，等;《中国新药杂志》;20061231;第15卷(第8期);621-623 |
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