CN106946874A - The discoloration method of Tizanidine - Google Patents
The discoloration method of Tizanidine Download PDFInfo
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- CN106946874A CN106946874A CN201710224260.0A CN201710224260A CN106946874A CN 106946874 A CN106946874 A CN 106946874A CN 201710224260 A CN201710224260 A CN 201710224260A CN 106946874 A CN106946874 A CN 106946874A
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention relates to a kind of discoloration method of Tizanidine, belong to medicinal chemistry arts.The problem of present invention is in order to solve Tizanidine and poor Tizanidine solubility, there is provided a kind of discoloration method of brand-new Tizanidine, this method is, by Tizanidine and organic acid reaction, to form corresponding organic salt compound, the dissolubility of compound is improved, is comprised the following steps that：A, Tizanidine add solvent and organic acid, and reaction obtains crude product Tizanidine acylate；B, crude product Tizanidine acylate obtained by step A adds to solvent, organic acid, hydrochloric acid solution, reaction, cool crystallization, is filtrated to get Tizanidine.Discoloration method of the present invention has evaded the problem of Tizanidine and Tizanidine are difficult refined because of autolysis is poor, by changing its acid group form, the preferable material of new dissolubility is formd to be recrystallized, yield and purity all higher Tizanidines are obtained, while solvent load is greatly reduced.
Description
Technical field
The present invention relates to a kind of discoloration method of Tizanidine, belong to medicinal chemistry arts.
Background technology
Tizanidine (Tizanidine Hydrochloride) chemical name：The chloro- 4- of 5- (2- imidazoline -2- ammonia
Base) -2,1,3- benzothiazide hydrochloride, structural formula is as follows：
Tizanidine
Tizanidine is the central skeletal muscle relaxant with imidazoline structure of Novartis Co., Ltd's exploitation, 1988
January is listed in Denmark and Switzerland first with trade name Ternelin, then successively in more than 20 countries such as Europe, the U.S., Japan
Selling license is obtained, for treating because of the skeletal muscle caused by brain and trauma of spinal cord, cerebral hemorrhage, encephalitis and multiple sclerosis etc.
The diseases such as tension force increases, muscle spasmus and myotonia.This product alleviates spasticity, but does not cause myasthenia, under therapeutic dose not
Psychologic dependence is produced, better tolerance is the preferable central muscle relaxant of clinical evaluation.In order to improve Tizanidine
Decolouring purifying in the quality of bulk drug, research building-up process is of great importance to the quality of bulk drug.
The synthetic method comparative maturity of Tizanidine, main synthetic route domestic at present is：
In preparation process, many pigment impurities can be produced and accessory substance is brought into Tizanidine, cause final product
Need by repeatedly purifying and recrystallize, can just obtain qualified Tizanidine.
The solution of Tizanidine or Tizanidine is generally at present：
1st, Tizanidine final product can reach through repeated recrystallize and activated carbon decolorizing and remove relevant material
Effect, but decolorizing effect is poor.
2nd, to Tizanidine precursor, i.e. Tizanidine alkali is refined, and inventor has found in actual mechanical process,
Using the refined difficult bigger of Tizanidine alkali, because its dissolubility is very poor, solubility is smaller in most of organic solvents, causes
Its refined and decolorizing effect is very poor.
And for example, German patent DE 3610407 provides a kind of discoloration method, is that Tizanidine is dissolved in into dimethyl formyl
Activated carbon decolorizing is handled in amine (DMF), adds and the higher Tizanidine of purity is obtained in the relatively low water of dissolubility or ethanol.Should
The drawbacks of method be DMF dissolubilities very well, product be wherein difficult in the product for separating out and separating out DMF be difficult to remove, solvent is residual
Stay larger.
And for example, the Tizanidine for dissolving 1g using methanol as solvent in United States Patent (USP) US384668 at least needs more than 40mL
Methanol, the quantity of solvent of recrystallization is larger, causes product yield extremely low.
Under use above background, the present inventor is intended to provide a kind of discoloration method of brand-new Tizanidine, with
Obtain the Tizanidine of high-purity.
The content of the invention
There is provided a kind of brand-new for the problem of present invention is in order to solve Tizanidine and poor Tizanidine solubility
The discoloration method of Tizanidine, to obtain the Tizanidine of high-purity.
Discoloration method of the present invention is, by Tizanidine and organic acid reaction, to form corresponding organic salt compound, improve
The dissolubility of compound, finally gives the Tizanidine of high-purity, comprises the following steps that：
A, Tizanidine added in solvent, is warming up to backflow, adds organic acid, clarified to Tizanidine solvent soln,
Stop heating, slow cooling is to there is solid precipitation, and insulation reaction is cooled to less than 0 DEG C, crystallization is filtrated to get crude product Tizanidine
Acylate；
It B, crude product Tizanidine acylate will add in solvent obtained by step A, and be warming up to backflow, addition organic acid is to molten
Liquid is clarified, and adds hydrochloric acid solution, stops heating, has been cooled to solid precipitation, insulated and stirred 2 hours, then be cooled to 10 DEG C with
Under, crystallization is filtrated to get Tizanidine.
In above-mentioned technical proposal, solvent described in step A is the lower alcohols such as methanol, ethanol, isopropanol；Or using acetone etc.
Ketones solvent.
In above-mentioned technical proposal, solvent load described in step A is that the mass ratio of Tizanidine and solvent is 1:2-1:10；It is excellent
The mass ratio for selecting Tizanidine and solvent is 1:3-1:6.
In above-mentioned technical proposal, organic acid described in step A is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid；Organic acid
It is preferred that acetic acid.
In above-mentioned technical proposal, organic acid consumption described in step A is that the mol ratio of Tizanidine and organic acid is 1:1-1:
10, the preferably mol ratio of Tizanidine and organic acid is 1:1.5-1:5.
In above-mentioned technical proposal, recrystallization temperature described in step A is -10-30 DEG C, preferably -10-0 DEG C.
In above-mentioned technical proposal, the crystallization time described in step A is 1-10 hours, preferably 3-4 hours.
In above-mentioned technical proposal, insulation reaction described in step A is 1-2 hours, preferably 2 hours.
In above-mentioned technical proposal, the solvent and organic acid that step B is used are consistent with step A.
In above-mentioned technical proposal, step B solvent loads are that the mass ratio of Tizanidine acylate and solvent is 1:2-1:
10, the preferably mass ratio of Tizanidine acylate and solvent is 1:3-1:6.
In above-mentioned technical proposal, step B organic acid consumptions are that the mol ratio of Tizanidine and organic acid is 1:1-1:10；It is excellent
The mol ratio for selecting Tizanidine and organic acid is 1:1.5-1:5.
In above-mentioned technical proposal, hydrochloric acid solution described in step B is concentrated hydrochloric acid.
In above-mentioned technical proposal, hydrochloric acid solution consumption is described in step B：The volume ratio of hydrochloric acid solution and organic acid is 1:2-
1:10；It is preferred that the volume ratio of hydrochloric acid solution and organic acid is 1:3-1:5.
In above-mentioned technical proposal, recrystallization temperature described in step B is -10-30 DEG C；It is preferred that recrystallization temperature is 0-10 DEG C.
In above-mentioned technical proposal, the crystallization time described in step B is 1-10 hours；It is preferred that 3-4 hours crystallization time.
Inventor has found that 5g Tizanidine is added in 25mL methanol solution and is heated to reflux temperature in an experiment, not molten
Solution, then the addition 1mL acetic acid into solution, solid are completely dissolved, and it is acetic acid Tizanidine that pale solid is separated out after cooling, plus
Enter the Tizanidine that hydrochloric acid obtains high-purity.Discoloration method of the present invention compared with Tizanidine recrystallizing methanol discoloration method,
It is an advantage of the present invention that evaded Tizanidine and Tizanidine is difficult refined ask because autolysis is poor
Topic, by changing its acid group form, forms the preferable material of new dissolubility and is recrystallized, obtained yield and purity all
Higher Tizanidine, while solvent load is greatly reduced.
Embodiment
The embodiment of form, remakes further specifically to the above of the invention by the following examples
It is bright, illustrate but do not limit the present invention.
Embodiment 1
Tizanidine 12g is added in 60mL methanol, is heated to backflow, adds formic acid 5.44g, solution clarification, slow cooling
To having solid precipitation, an insulated and stirred 2 hours, then it is cooled to less than 0 DEG C, crystallization 3 hours, filtering is dried to obtain gray solid and replaced
Zha Niding formates crude product 10g, yield is 70.4%, is directly used in next step.
Tizanidine formates crude product 10g, is added in 50mL methanol, is heated to backflow, adds formic acid 5g, and solution is clarified,
Add hydrochloric acid 2mL, slow cooling is to having solid precipitation, an insulation reaction 2 hours, then is cooled to 0-10 DEG C, crystallization 3 hours, filtering,
Faint yellow solid Tizanidine 7.23g is dried to obtain, yield is 74.7%, and purity is 99.7%.
Embodiment 2
Tizanidine 45g is added in 180mL acetone, is heated to backflow, adds acetic acid 21.3g, solution clarification, slow cooling
To having solid precipitation, an insulated and stirred 2 hours, then it is cooled to less than 0 DEG C, crystallization 3 hours, filtering is dried to obtain pale solid
Tizanidine acetate crude product 51.4g, yield is 92.4%, is directly used in next step.
Tizanidine acetate crude product 50g, is added in 200mL acetone, is heated to backflow, adds acetic acid 24g, and solution is clear
Clearly, hydrochloric acid 10mL is added, slow cooling is to having solid precipitation, an insulation reaction 2 hours, then is cooled to 0-10 DEG C, crystallization 3 hours,
Filtering, is dried to obtain white solid Tizanidine 39.7g, yield is 87.8%, and purity is 99.9%.
Embodiment 3
Tizanidine 23g is added in 138mL isopropanols, is heated to backflow, adds propionic acid 14.4g, solution clarification, slow drop
Temperature is to having solid precipitation, an insulated and stirred 2 hours, then is cooled to less than 0 DEG C, and crystallization 3 hours, filtering is dried to obtain off-white color solid
Body Tizanidine propionate crude product 25.2g, yield is 84.8%, is directly used in next step.
Tizanidine propionic acid hydrochlorate crude product 25g, is added in 150mL isopropanols, is heated to backflow, adds propionic acid 13.7g, molten
Liquid is clarified, and adds hydrochloric acid 6mL, and slow cooling is to having solid precipitation, an insulation reaction 2 hours, then is cooled to 0-10 DEG C, and crystallization 3 is small
When, filtering is dried to obtain white solid Tizanidine 19.2g, yield is 86.8%, and purity is 99.9%.
Embodiment 4
Tizanidine 5g is added in 28mL ethanol, is heated to backflow, adds valeric acid 4.63g, and solution is clarified, and slow cooling is extremely
There are solid precipitation, an insulated and stirred 1 hour, then be cooled to less than 0 DEG C, crystallization 3 hours, filtering is dried to obtain pale solid and replaced
Zha Niding valerate crude product 5.5g, yield is 78.4%, is directly used in next step.
Tizanidine valerate crude product 5g, is added in 28mL ethanol, is heated to backflow, adds valeric acid 4.4g, and solution is clarified,
Hydrochloric acid 1.2mL is added, slow cooling is to having solid precipitation, insulation reaction 2 hours, then is cooled to 0-10 DEG C, crystallization 3 hours, mistake
Filter, is dried to obtain off-white powder Tizanidine 3.5g, yield is 85.8%, and purity is 99.6%.
Comparative example 1
Tizanidine 45g is added in 180mL acetone, is heated to backflow, adds acetic acid 21.3g, solution clarification, slow cooling
To there is solid precipitation, insulated and stirred 2 hours keeps 30-35 DEG C of recrystallization temperature, and crystallization 3 hours, filtering is dried to obtain canescence
Solid Tizanidine acetate crude product 45.6g, yield is 81.9%, is directly used in next step.
Tizanidine acetate crude product 45g, is added in 200mL acetone, is heated to backflow, adds acetic acid 24g, and solution is clear
Clearly, hydrochloric acid 10mL is added, slow cooling is to having solid precipitation, an insulation reaction 2 hours, then is cooled to 0-10 DEG C, crystallization 3 hours,
Filtering, is dried to obtain white solid Tizanidine 34.9g, yield is 86.8%, and purity is 97.8%.
It can be seen that comparative example 1 is in addition to recrystallization temperature and embodiment 2 are inconsistent, the equal be the same as Example of remaining method and step
2, but the yield of Tizanidine acetate crude product reduces more than 10 percentage points；Final Tizanidine finished product purity compared with
It is low.
Comparative example 2
Tizanidine 45g is added in 180mL acetone, is heated to backflow, adds acetic acid 21.3g, solution clarification, slow cooling
To having solid precipitation, an insulated and stirred 0.5 hour, then it is cooled to less than 0 DEG C, crystallization 3 hours, filtering is dried to obtain canescence and consolidated
Body Tizanidine acetate crude product 39.8g, yield is 71.5%, is directly used in next step.
It can be seen that comparative example 2 is in addition to insulated and stirred time and embodiment 2 are inconsistent, remaining method and step is with real
Example 2 is applied, but the yield of Tizanidine acetate crude product reduces more than 20 percentage points.
Claims (10)
1. the discoloration method of Tizanidine, it is characterised in that：Comprise the following steps：
A, Tizanidine added in solvent, be warming up to backflow, add organic acid, to the clarification of Tizanidine solvent soln, stopping
Heating, slow cooling is to there is solid precipitation, and insulation reaction is cooled to less than 0 DEG C, it is organic that crystallization is filtrated to get crude product Tizanidine
Hydrochlorate；
B, crude product Tizanidine acylate obtained by step A added in solvent, be warming up to backflow, addition organic acid is clear to solution
Clearly, hydrochloric acid solution is added, stops heating, solid precipitation, insulated and stirred 2 hours has been cooled to, then be cooled to less than 10 DEG C, analysis
Crystalline substance, is filtrated to get Tizanidine.
2. the discoloration method of Tizanidine according to claim 1, it is characterised in that：Solvent described in step A is using rudimentary
Alcohol or ketones solvent.
3. the discoloration method of Tizanidine according to claim 2, it is characterised in that：The lower alcohol be methanol, ethanol,
Isopropanol；The ketones solvent is acetone.
4. the discoloration method of Tizanidine according to claim 1, it is characterised in that：Solvent load described in step A be for
The mass ratio of Zha Niding and solvent is 1:2-1:10；Solvent load described in preferred steps A is the mass ratio of Tizanidine and solvent
For 1:3-1:6.
5. the discoloration method of Tizanidine according to claim 1, it is characterised in that：At least meet following any one：
Organic acid described in step A is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid；It is preferred that, organic acid described in step A is second
Acid；
The solvent and organic acid that step B is used are consistent with step A.
6. the discoloration method of Tizanidine according to claim 1, it is characterised in that：Organic acid consumption is described in step A
The mol ratio of Tizanidine and organic acid is 1:1-1:10；Organic acid consumption described in preferred steps A is Tizanidine and organic acid
Mol ratio be 1:1.5-1:5.
7. the discoloration method of Tizanidine according to claim 1, it is characterised in that：At least meet following any one：
Recrystallization temperature described in step A is -10-30 DEG C；
- 10-0 DEG C of recrystallization temperature described in preferred steps A；
The crystallization time described in step A is 1-10 hours；
The crystallization time described in preferred steps A is 3-4 hours；
Insulation reaction described in step A is 1-2 hours；
Insulation reaction described in preferred steps A is 2 hours.
8. the discoloration method of Tizanidine according to claim 1, it is characterised in that：Step B solvent loads are for bundle Buddhist nun
The mass ratio for determining acylate and solvent is 1:2-1:10；Preferred steps B solvent loads are Tizanidine acylate and solvent
Mass ratio be 1:3-1:6.
9. the discoloration method of Tizanidine according to claim 1, it is characterised in that：Step B organic acids consumption is for bundle
Buddhist nun determines and the mol ratio of organic acid is 1:1-1:10；Preferred steps B organic acids consumption is the mol ratio of Tizanidine and organic acid
For 1:1.5-1:5.
10. the discoloration method of Tizanidine according to claim 1, it is characterised in that：At least meet following any one：
Hydrochloric acid solution described in step B is concentrated hydrochloric acid；
It is preferred that, hydrochloric acid solution consumption is described in step B：The volume ratio of hydrochloric acid solution and organic acid is 1:2-1:10；
It is preferred that, hydrochloric acid solution consumption is described in step B：The volume ratio of hydrochloric acid solution and organic acid is 1:3-1:5；
Recrystallization temperature described in step B is -10-30 DEG C；
It is preferred that, recrystallization temperature described in step B is 0-10 DEG C；
The crystallization time described in step B is 1-10 hours；
The crystallization time described in preferred steps B is 3-4 hours.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109535151A (en) * | 2017-09-22 | 2019-03-29 | 四川科瑞德制药股份有限公司 | P-methyl benzenesulfonic acid Tizanidine crystal form A and its preparation method and application |
| CN109535149A (en) * | 2017-09-22 | 2019-03-29 | 四川科瑞德制药股份有限公司 | Methanesulfonic acid Tizanidine compound and its preparation method and application |
| CN109535150A (en) * | 2017-09-22 | 2019-03-29 | 四川科瑞德制药股份有限公司 | Phenylacetic acid Tizanidine crystal form A and its preparation method and application |
| CN109535152A (en) * | 2017-09-22 | 2019-03-29 | 四川科瑞德制药股份有限公司 | Nitric acid Tizanidine crystal form A and its preparation method and application |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109535151A (en) * | 2017-09-22 | 2019-03-29 | 四川科瑞德制药股份有限公司 | P-methyl benzenesulfonic acid Tizanidine crystal form A and its preparation method and application |
| CN109535149A (en) * | 2017-09-22 | 2019-03-29 | 四川科瑞德制药股份有限公司 | Methanesulfonic acid Tizanidine compound and its preparation method and application |
| CN109535150A (en) * | 2017-09-22 | 2019-03-29 | 四川科瑞德制药股份有限公司 | Phenylacetic acid Tizanidine crystal form A and its preparation method and application |
| CN109535152A (en) * | 2017-09-22 | 2019-03-29 | 四川科瑞德制药股份有限公司 | Nitric acid Tizanidine crystal form A and its preparation method and application |
| CN109535150B (en) * | 2017-09-22 | 2023-02-17 | 四川科瑞德制药股份有限公司 | Tizanidine phenylacetate crystal form A and preparation method and application thereof |
| CN109535151B (en) * | 2017-09-22 | 2023-04-21 | 四川科瑞德制药股份有限公司 | Crystal form A of tizanidine tosylate, preparation method and application thereof |
| CN109535149B (en) * | 2017-09-22 | 2023-04-21 | 四川科瑞德制药股份有限公司 | Tizanidine mesylate compound and preparation method and application thereof |
| CN109535152B (en) * | 2017-09-22 | 2023-04-21 | 四川科瑞德制药股份有限公司 | Tizanidine nitrate crystal form A and preparation method and application thereof |
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