CN113135908A - Preparation method of tizanidine hydrochloride - Google Patents
Preparation method of tizanidine hydrochloride Download PDFInfo
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- CN113135908A CN113135908A CN202110357189.XA CN202110357189A CN113135908A CN 113135908 A CN113135908 A CN 113135908A CN 202110357189 A CN202110357189 A CN 202110357189A CN 113135908 A CN113135908 A CN 113135908A
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Abstract
The invention discloses a preparation method of tizanidine hydrochloride, belonging to the field of medicine preparation. The preparation method takes 5-chloro-4-amino-2, 1, 3-benzothiadiazole and 1-acetyl-2-imidazolidinone as raw materials, and the tizanidine hydrochloride can be prepared by condensation, alcoholysis and salification, and further can comprise refining, so that the operation is simpler and safer, and the method is more suitable for industrial production. The tizanidine hydrochloride prepared by the method has higher yield, higher purity of the obtained tizanidine hydrochloride, important industrial value, capability of protecting the supply of the raw material drug tizanidine hydrochloride and benefiting the public.
Description
Technical Field
The invention belongs to the field of medicine preparation, and particularly relates to a preparation method of tizanidine hydrochloride.
Background
Tizanidine hydrochloride, which is chemically named as 5-chloro-N- (4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazole-4-amine hydrochloride (structural formula is shown in figure 1), is a central skeletal muscle relaxant with an imidazoline structure developed by Novartis, Switzerland, which is first marketed in Denmark and Switzerland in 1988, and then successively obtains sales approval in more than 20 countries such as Europe, America, Japan, etc., Chinese medicine manufacturers have successfully developed tizanidine hydrochloride tablets (such as Kaieton) with various specifications, and the pharmacokinetics and relative bioavailability of tizanidine imported at home are almost the same. Is clinically used for treating diseases such as skeletal muscle tension increase, muscle spasm, myotonia and the like caused by central injury. Has good effects on tension headache, trigeminal neuralgia, myofascial pain syndrome and the like. Can also be used as adjuvant drug for general anesthesia or regional anesthesia, sedative before and after operation, and analgesic after operation. The product can relieve spasm without causing muscle weakness, and does not produce psychological dependence under therapeutic dosage, and is a central muscle relaxant with good tolerance and curative effect.
In the prior art (such as China New drug journal, 2006, 15, 621-623; European patent EP 644192; Japanese patent JP8176150, China pharmaceutical industry journal, 2005, 36, 593-595; chemical reagents, 2003, 25, 115-116), the main method and route for synthesizing tizanidine hydrochloride are shown in FIG. 2. The raw material of the route is 4-chloro-2-nitroaniline, nitro is reduced by zinc powder or hydrazine hydrate to obtain 4-chloro-1, 2-phenylenediamine, 5-chloro-2, 1, 3-benzothiadiazole is obtained by cyclization with thionyl chloride, 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is obtained by nitration, and then 4-amino-5-chloro-2, 1, 3-benzothiadiazole is obtained by reduction with iron powder. 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 1-acetyl imidazoline are cyclized under the condition of taking phosphorus oxychloride as a solvent, and tizanidine hydrochloride is obtained after salification. The two-step nitro reduction uses zinc powder and iron powder or hydrazine hydrate with high toxicity, so that the operation is complicated, the heat release is severe, the material flushing is easy, and a large amount of iron mud and zinc mud are generated in the reaction, so that the environmental hazard is high.
Disclosure of Invention
In order to solve at least one of the above technical problems, the present invention aims to provide a tizanidine hydrochloride preparation method which is simpler and safer to operate and is more suitable for industrial production.
In order to achieve the aim, the invention provides a preparation method of tizanidine hydrochloride, which comprises the following specific steps:
s1, condensation: the method comprises the following steps of taking 5-chloro-4-amino-2, 1, 3-benzothiadiazole and 1-acetyl-2-imidazolidinone as raw materials, and carrying out condensation in a first solvent in the presence of a dehydrating agent to generate 5-chloro-N- (1-acetyl-4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazole-4-amine (shown as a formula (1), which is called a product 1 for short), wherein the reaction formula is as follows:
s2, alcoholysis: in the presence of alkali, the 5-chloro-N- (1-acetyl-4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazol-4-amine obtained in step S1 is subjected to alkaline catalytic alcoholysis in a second solvent to obtain tizanidine, that is, 5-chloro-N- (4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazol-4-amine (as shown in formula (2), product 2 for short), and the reaction formula is as follows:
s3, salifying: adding hydrochloric acid into the tizanidine obtained in the step S2 in a third solvent to form salt, so as to obtain tizanidine hydrochloride, namely 5-chloro-N- (4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazole-4-amine hydrochloride (shown as formula (3), referred to as product 3 for short), wherein the reaction formula is as follows:
wherein the content of the first and second substances,
is a byproduct of 4-chloro-o-phenylenediamine.
In some embodiments of the invention, in step S1, the dehydrating agent is selected from the group consisting of phosphorus oxychloride (POCl)3) Thionyl chloride (SOCl)2) Oxalyl chloride (C)2Cl2O2) Phosphorus pentoxide (P)2O5) Polyphosphoric acid (H)n+2PnO3n+1) Trifluoromethanesulfonic anhydride (C)2F6O5S2) And cyanuric chloride (C)3Cl3N3) At least one of the group of (1). In some preferred embodiments of the invention, the dehydrating agent is POCl3And/or SOCl2. In some embodiments of the invention, the dehydrating agent is POCl3。
In some embodiments of the present invention, in step S1, the first solvent is at least one selected from the group consisting of anhydrous methanol, anhydrous ethanol, and toluene. In some embodiments of the invention, the first solvent is toluene.
Further, in the step S1, the condensation temperature is 30-80 ℃. In some preferred embodiments of the invention, the temperature of the condensation is from 50 to 70 ℃. In some embodiments of the invention, the temperature of the condensation is 65 ℃. Further, in step S1, the condensation is performed by a reflux method.
In the invention, in step S1, after condensation reaction, the obtained solution containing the product 1 is extracted by an extractant, the pH value of the water phase is adjusted to 8-9, the solution is stirred for 20-40min and then filtered, and the product 1 is rinsed by water and then dried to obtain a dry product of the product 1 which can be used for the next reaction. In some embodiments of the invention, the extraction is performed with dichloromethane and the pH is adjusted with sodium hydroxide.
In some embodiments of the invention, in step S2, the base is selected from the group consisting of sodium hydroxide (NaOH), lithium hydroxide (LiOH), triethylamine (C)6H15N), platinum oxide (PtO)2) And palladium hydroxide (Pd (OH)2) At least one of the group of (1). In some embodiments of the invention, the base is NaOH.
In some embodiments of the present invention, the second solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, and water. In some embodiments of the invention, the second solvent is methanol.
In some preferred embodiments of the present invention, in step S2, the product 1 obtained in step S1 is added to a mixture of 10% NaOH and methanol in a mass to volume ratio of 1: 1 in the combined mixture.
In some embodiments of the invention, the temperature of the alcoholysis is from 30 to 80 ℃. In some preferred embodiments of the invention, the temperature of the alcoholysis is from 50 to 70 ℃. In some embodiments of the invention, the temperature of the condensation is 65 ℃.
In some embodiments of the invention, the time for alcoholysis is from 3 to 6 hours. In some embodiments of the invention, the time for alcoholysis is 5 hours.
In the present invention, after alcoholysis, the product 2 is rinsed several times with methanol to obtain a wet product 2.
In some embodiments of the present invention, in step S3, the third solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, and water. In some preferred embodiments of the invention, the third solvent is methanol and/or ethanol. In some embodiments of the invention, the third solvent is absolute ethanol.
In some embodiments of the invention, the third solvent is used in an amount of 5-50 times (v/m) the amount of the product 2, namely tizanidine. In some preferred embodiments of the present invention, the third solvent is used in an amount of 5 to 20 times (v/m) as much as the product 2, namely tizanidine. In some embodiments of the invention, the third solvent is used in an amount 12 times (v/m) that of the product 2, namely tizanidine.
In the present invention, the hydrochloric acid is concentrated hydrochloric acid (volume fraction 37%). In some embodiments of the invention, the amount of hydrochloric acid is 0.2 to 2.0 times (v/m) the amount of product 2, namely tizanidine. In some preferred embodiments of the invention, the amount of hydrochloric acid is 0.2 to 1.5 times (v/m) the amount of product 2, namely tizanidine. In some embodiments of the invention, the amount of hydrochloric acid is 1.2 times (v/m) the amount of product 2, namely tizanidine.
In the invention, after salifying, rinsing with absolute ethyl alcohol for a plurality of times to obtain a wet product 3, and drying to obtain a dry product 3. Meanwhile, filtrate and washing liquid are collected, and a byproduct 4-chloro-o-phenylenediamine can be obtained.
Further, the method may further comprise the steps of:
s4, refining: heating up and dissolving tizanidine hydrochloride (product 3) to be refined in a fourth solvent, filtering, cooling and crystallizing to finally obtain the refined tizanidine hydrochloride.
In some embodiments of the present invention, in step S4, the fourth solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, and water. In some preferred embodiments of the present invention, the fourth solvent is methanol, ethanol and/or water. In some more preferred embodiments of the present invention, the fourth solvent is a mixed solution of absolute ethanol and methanol. In some embodiments of the present invention, the fourth solvent is absolute ethanol and methanol in a volume ratio of 1: 1 mixing the resulting mixed solution.
In some embodiments of the invention, in step S4, the fourth solvent is used in an amount of 5 to 50 times (v/m) the amount of product 3. In some preferred embodiments of the present invention, in step S4, the fourth solvent is used in an amount of 5 to 30 times (v/m) the amount of the product 3. In some preferred embodiments of the present invention, in step S4, the fourth solvent is used in an amount of 20 times (v/m) that of the product 3.
In some embodiments of the invention, in step S4, product 3 is dissolved in a fourth solvent at elevated temperature to 30-80 ℃. In some preferred embodiments of the present invention, in step S4, product 3 is dissolved in a fourth solvent at elevated temperature to 50-70 ℃. In some embodiments of the invention, in step S4, product 3 is dissolved in a fourth solvent at elevated temperature up to 60 ℃.
In some embodiments of the invention, in step S4, the solution is crystallized at a temperature of 5-30 ℃ after being dissolved by heating. In some preferred embodiments of the present invention, in step S4, the solution is post-crystallized at 5-20 ℃ after dissolution. In some embodiments of the invention, in step S4, the solution is post-crystallized at 5-10 ℃ after dissolution.
In the invention, after crystallization, the obtained tizanidine hydrochloride is rinsed for a plurality of times by using the fourth solvent, and the tizanidine hydrochloride is obtained.
The invention has the advantages of
Compared with the prior art, the invention has the following beneficial effects:
the tizanidine hydrochloride is prepared by taking 5-chloro-4-amino-2, 1, 3-benzothiadiazole and 1-acetyl-2-imidazolidinone as raw materials through condensation, alcoholysis and salt formation, and further or including refining, so that the tizanidine hydrochloride is simpler and safer to operate and is more suitable for industrial production.
The tizanidine hydrochloride prepared by the method has higher yield, higher purity of the obtained tizanidine hydrochloride, important industrial value, capability of protecting the supply of the raw material drug tizanidine hydrochloride and benefiting the public.
Drawings
Fig. 1 shows the structural formula of tizanidine hydrochloride.
Figure 2 shows a process flow diagram for the prior art preparation of tizanidine hydrochloride.
Fig. 3 shows a process flow diagram for preparing tizanidine hydrochloride according to the present invention.
Fig. 4 shows a process flow diagram for preparing tizanidine hydrochloride in example 1 of the present invention.
Fig. 5 shows a process flow diagram for preparing tizanidine hydrochloride in example 2 of the present invention.
Figure 6 shows a process flow diagram for the preparation of tizanidine hydrochloride according to example 3 of the present invention.
Detailed Description
Unless otherwise indicated, implied from the context, or customary in the art, all parts and percentages herein are by weight and the testing and characterization methods used are synchronized with the filing date of the present application. Where applicable, the contents of any patent, patent application, or publication referred to in this application are incorporated herein by reference in their entirety and their equivalent family patents are also incorporated by reference, especially as they disclose definitions relating to synthetic techniques, products and process designs, polymers, comonomers, initiators or catalysts, and the like, in the art. To the extent that a definition of a particular term disclosed in the prior art is inconsistent with any definitions provided herein, the definition of the term provided herein controls.
The numerical ranges in this application are approximations, and thus may include values outside of the ranges unless otherwise specified. A numerical range includes all numbers from the lower value to the upper value, in increments of 1 unit, provided that there is a separation of at least 2 units between any lower value and any higher value. For example, if a compositional, physical, or other property (e.g., molecular weight, melt index, etc.) is recited as 100 to 1000, it is intended that all individual values, e.g., 100, 101, 102, etc., and all subranges, e.g., 100 to 166, 155 to 170, 198 to 200, etc., are explicitly recited. For ranges containing a numerical value less than 1 or containing a fraction greater than 1 (e.g., 1.1, 1.5, etc.), then 1 unit is considered appropriate to be 0.0001, 0.001, 0.01, or 0.1. For ranges containing single digit numbers less than 10 (e.g., 1 to 5), 1 unit is typically considered 0.1. These are merely specific examples of what is intended to be expressed and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application.
When used with respect to chemical compounds, the singular includes all isomeric forms and vice versa (e.g., "hexane" includes all isomers of hexane, individually or collectively) unless expressly specified otherwise. In addition, unless explicitly stated otherwise, the use of the terms "a", "an" or "the" are intended to include the plural forms thereof.
The terms "comprising," "including," "having," and derivatives thereof do not exclude the presence of any other component, step or procedure, and are not intended to exclude the presence of other elements, steps or procedures not expressly disclosed herein. To the extent that any doubt is eliminated, all compositions herein containing, including, or having the term "comprise" may contain any additional additive, adjuvant, or compound, unless expressly stated otherwise. Rather, the term "consisting essentially of … …" excludes any other components, steps or processes from the scope of any of the terms hereinafter recited, insofar as such terms are necessary for performance. The term "consisting of … …" does not include any components, steps or processes not specifically described or listed. Unless explicitly stated otherwise, the term "or" refers to the listed individual members or any combination thereof.
The process flow diagram for preparing tizanidine hydrochloride of the invention is shown in figure 3, and the specific steps are as follows:
s1, condensation: condensing 5-chloro-4-amino-2, 1, 3-benzothiadiazole and 1-acetyl-2-imidazolidinone serving as raw materials in a first solvent in the presence of a dehydrating agent to generate 5-chloro-N- (1-acetyl-4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazole-4-amine;
s2, alcoholysis: carrying out alkaline catalytic alcoholysis on the 5-chloro-N- (1-acetyl-4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazol-4-amine obtained in the step S1 in a second solvent in the presence of alkali to obtain tizanidine, namely 5-chloro-N- (4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazol-4-amine;
s3, salifying: adding hydrochloric acid into the tizanidine obtained in the step S2 in a third solvent to form salt, so as to obtain tizanidine hydrochloride, namely 5-chloro-N- (4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazole-4-amine hydrochloride;
s4, refining (optional step in this step): heating to dissolve the tizanidine hydrochloride to be refined in a fourth solvent, filtering, cooling and crystallizing to finally obtain the refined tizanidine hydrochloride.
In order to make the technical problems, technical solutions and advantageous effects solved by the present invention more apparent, the present invention is further described in detail below with reference to the following embodiments.
Examples
The following examples are used herein to demonstrate preferred embodiments of the invention. It will be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function in the invention, and thus can be considered to constitute preferred modes for its practice. Those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit or scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and the disclosures and references cited herein and the materials to which they refer are incorporated by reference.
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.
The experimental methods not specifically described in the following examples are conventional methods unless otherwise specified. The instruments used in the following examples are, unless otherwise specified, laboratory-standard instruments; the test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
Example 1 preparation of hydrochloric acid in place of nifedine method # 1
The present example provides a preparation method of hydrochloric acid replacing nifedipine, and the process flow chart is shown in fig. 4.
Synthesis-condensation of 1, 5-chloro-N- (1-acetyl-4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazol-4-amine
100g of 5-chloro-4-amino-2, 1, 3-benzothiadiazole and 69g of 1-acetyl-2-imidazolidinone were added to a 1L three-necked flask, and then 200mL of phosphorus oxychloride and 200mL of toluene are poured into the mixture, the mixture is heated to 65 ℃ for reflux reaction for 24L, the reaction solution is slowly poured into ice water for complete dissolution, 200mL of dichloromethane is used for extraction twice, the pH of the water phase is adjusted by sodium hydroxide to 8-9, a large amount of solid is separated out, the mixture is stirred for 30min and then filtered, 500g of water is used for rinsing to obtain a wet product, and the wet product is dried at 50 ℃ to obtain 106g of a dried product of 5-chloro-N- (1-acetyl-4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazole-4-amine (product 1), wherein the yield is 67%.
2. Synthesis-alcoholysis of tizanidine
In a 2L three-necked flask, 60g of intermediate 1 was added, followed by 10% NaOH: methanol 300 g: and (3) raising the temperature of 300mL of mixed solution to 65 ℃ for reaction for 5h, filtering after the reaction is finished, and rinsing twice by using 50mL of methanol to obtain 70g of a wet product of tizanidine (product 2) with the yield of 92%.
3. Synthesis-salification of tizanidine hydrochloride
Adding 150g of the intermediate 2 into a 2L three-necked bottle, adding 1800mL of anhydrous ethanol and 180mL of 37% concentrated hydrochloric acid, stirring by a stirrer, stirring for 2h, cooling to 5-10 ℃, preserving heat for 2h, filtering, rinsing twice by 100mL of anhydrous ethanol to obtain 169g of an intermediate 3 wet product, drying the wet product in a 50 ℃ oven for 16h to obtain 140g of a tizanidine hydrochloride (product 3) dry product, wherein the yield is 90%.
4. Refining of tizanidine hydrochloride
In a 500mL three-necked flask, 15g of intermediate 3 was added, and absolute ethanol was poured: methanol 150 mL: heating 150mL of mixed solution to 60 ℃ for dissolution, filtering while the solution is hot, keeping the temperature at 60 ℃ and stirring, slowly cooling to 5-10 ℃ for crystallization for 4h, filtering, and adding absolute ethyl alcohol: methanol 10 mL: rinsing twice with 10mL of mixed solution to obtain 11g of fine tizanidine hydrochloride wet product, and drying at 50 ℃ for 16h to obtain 9.86g of fine tizanidine hydrochloride dry product with the yield of 65%.
Example 2 preparation of hydrochloric acid in place of nifedine method # 2
The overall process flow diagram is essentially the same as in example 1, with the following exceptions:
in step 1, the same amount of SOCl is used2Replacement of POCl3。
In step 2, the same amount of the same concentration C is used6H15And replacing NaOH with N.
Thus, the process flow diagram is shown in FIG. 5.
Example 3 preparation of hydrochloric acid in place of nifedine method # 3
The overall process flow diagram is essentially the same as in example 1, with the following exceptions:
in step 1, toluene was replaced with an equal amount of absolute ethanol.
In step 2, methanol was replaced with an equal amount of isopropanol.
In step 3, the absolute ethanol is replaced by an equal amount of tetrahydrofuran.
Thus, the process flow diagram is shown in FIG. 6.
Example 4 preparation of hydrochloric acid in place of nifedine method #4
The overall process flow diagram is essentially the same as in example 3, except for the following differences:
in step 4, the absolute ethanol is replaced by an equal amount of tetrahydrofuran.
Comparative example 1
The conventional manufacturing process shown in fig. 2 is used.
Comparative example 2
The same comparative example 1 was conducted by the conventional process shown in FIG. 2, except that the same amount of SOCl was used2Replacement of POCl3。
The above preparation methods were compared in combination, and the yield and purity of each product are shown in table 1:
TABLE 1 yield and purity of tizanidine hydrochloride obtained by different preparation methods
As can be seen from table 1, the tizanidine hydrochloride prepared in examples 1-3 was higher in yield and higher in purity.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A preparation method of tizanidine hydrochloride is characterized by comprising the following steps:
s1, condensation: the method comprises the following steps of condensing 5-chloro-4-amino-2, 1, 3-benzothiadiazole and 1-acetyl-2-imidazolidinone serving as raw materials in a first solvent in the presence of a dehydrating agent to generate 5-chloro-N- (1-acetyl-4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazole-4-amine, wherein the reaction formula is as follows:
s2, alcoholysis: and (2) carrying out alkaline catalytic alcoholysis on the 5-chloro-N- (1-acetyl-4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazole-4-amine obtained in the step (S1) in a second solvent in the presence of alkali to obtain tizanidine, wherein the reaction formula is as follows:
s3, salifying: adding hydrochloric acid into the tizanidine obtained in the step S2 in a third solvent to form salt, so as to obtain tizanidine hydrochloride, wherein the reaction formula is as follows:
2. the method according to claim 1, wherein in step S1, the dehydrating agent is at least one selected from the group consisting of phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus pentoxide, polyphosphoric acid, trifluoromethanesulfonic anhydride, and cyanuric chloride;
optionally, the first solvent is at least one selected from the group consisting of anhydrous methanol, anhydrous ethanol, and toluene.
3. The method according to claim 2, wherein the condensation temperature is 30 to 80 ℃.
4. The production method according to claim 1, wherein in step S2, the base is at least one selected from the group consisting of sodium hydroxide, lithium hydroxide, triethylamine, platinum oxide, and palladium hydroxide;
optionally, the second solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, and water.
5. The method of claim 4, wherein the alcoholysis temperature is from 30 to 80 ℃.
6. The method according to claim 1, wherein in step S3, the third solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, and water;
optionally, the third solvent is used in an amount of 0.2 to 2.0 times (v/m) the amount of tizanidine.
7. The method according to claim 6, wherein the hydrochloric acid is used in an amount of 5 to 50 times (v/m) as much as the tizanidine in step S3.
8. The method of any one of claims 1 to 7, further comprising the steps of:
s4, refining: heating to dissolve the tizanidine hydrochloride to be refined in a fourth solvent, filtering, cooling and crystallizing to finally obtain the refined tizanidine hydrochloride.
9. The production method according to claim 8, wherein the fourth solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, and water;
optionally, the amount of the third solvent is 0.2-2.0 times (v/m) the amount of tizanidine hydrochloride to be refined.
10. The method according to claim 8, wherein in step S4, tizanidine hydrochloride to be purified is dissolved in the fourth solvent by raising the temperature to 30 to 80 ℃.
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| EP0644192A1 (en) * | 1993-09-09 | 1995-03-22 | Permachem Asia, Ltd. | A process for making a benzothiadiazole derivative |
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