CN107778307B - Preparation method of central alpha 2 adrenoreceptor agonist - Google Patents
Preparation method of central alpha 2 adrenoreceptor agonist Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 229940121947 Alpha 2 adrenoreceptor agonist Drugs 0.000 title description 2
- ZWUKMNZJRDGCTQ-UHFFFAOYSA-N Tizanidine hydrochloride Chemical compound Cl.ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 ZWUKMNZJRDGCTQ-UHFFFAOYSA-N 0.000 claims abstract description 52
- 229960002388 tizanidine hydrochloride Drugs 0.000 claims abstract description 52
- 239000007787 solid Substances 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 30
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 22
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims abstract description 14
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 13
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000019253 formic acid Nutrition 0.000 claims abstract description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 10
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims abstract description 10
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 10
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims abstract description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract description 8
- 239000011976 maleic acid Substances 0.000 claims abstract description 8
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 5
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 5
- 229960005215 dichloroacetic acid Drugs 0.000 claims abstract description 5
- 239000001530 fumaric acid Substances 0.000 claims abstract description 5
- 239000011975 tartaric acid Substances 0.000 claims abstract description 5
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 5
- 239000012065 filter cake Substances 0.000 claims description 127
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 103
- 238000001914 filtration Methods 0.000 claims description 91
- 238000003756 stirring Methods 0.000 claims description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- 238000001035 drying Methods 0.000 claims description 53
- 238000005406 washing Methods 0.000 claims description 52
- 238000001816 cooling Methods 0.000 claims description 49
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 48
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 31
- MURNIACGGUSMAP-UHFFFAOYSA-N 5-chloro-2,1,3-benzothiadiazol-4-amine Chemical compound NC1=C(Cl)C=CC2=NSN=C12 MURNIACGGUSMAP-UHFFFAOYSA-N 0.000 claims description 29
- JTRHTNVGGLWMFV-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-3-ium-2-sulfonate Chemical compound OS(=O)(=O)C1=NCCN1 JTRHTNVGGLWMFV-UHFFFAOYSA-N 0.000 claims description 27
- 238000010438 heat treatment Methods 0.000 claims description 26
- 238000010992 reflux Methods 0.000 claims description 26
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 24
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical class Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 23
- 235000019441 ethanol Nutrition 0.000 claims description 22
- 239000000706 filtrate Substances 0.000 claims description 22
- 238000005303 weighing Methods 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims 10
- 229960000488 tizanidine Drugs 0.000 abstract description 13
- 150000007524 organic acids Chemical class 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 239000003960 organic solvent Substances 0.000 abstract description 10
- -1 tizanidine organic acid salt Chemical class 0.000 abstract description 10
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 230000001376 precipitating effect Effects 0.000 abstract description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 2
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 238000009776 industrial production Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000003158 myorelaxant agent Substances 0.000 description 4
- 210000002027 skeletal muscle Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002462 imidazolines Chemical class 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011112 process operation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 206010049816 Muscle tightness Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 206010061533 Myotonia Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A method for preparing central alpha 2 adrenergic receptor stimulant. The invention discloses a preparation method of tizanidine hydrochloride, which comprises the following steps: (1) reacting organic acid A, a compound S1 and a compound S2 serving as raw materials in an organic solvent, and precipitating a solid to obtain tizanidine organic acid salt S3; (2) preparing tizanidine hydrochloride by taking the tizanidine organic acid salt S3 obtained in the step (1) as a raw material; wherein the organic acid A is formic acid, dichloroacetic acid, glycolic acid, maleic acid, fumaric acid, tartaric acid, caproic acid or benzoic acid; r1Is hydrogen, methyl, acetyl, propionyl, benzoyl, tert-butylmethylcarbonyl or COOR2，R2Methyl, ethyl, allyl, benzyl, tert-butyl or phenyl. The method has the advantages of high yield and purity, simple operation, high production efficiency, environmental protection, safety, suitability for industrial mass production and wide market application prospect.
Description
Technical Field
The invention relates to the field of medicine preparation methods, and in particular relates to a preparation method of tizanidine hydrochloride.
Background
Tizanidine is a central skeletal muscle relaxant with an imidazoline structure, has a chemical name of 5-chloro-N- (4, 5-dihydro-1H-imidazole-2-yl) -2,1, 3-benzothiadiazole-4-amine, and has a molecular structural formula as follows:
tizanidine is the only novel central skeletal muscle relaxant and central alpha with gastrointestinal tract protection effect in the current market2The adrenergic receptor agonist, which was originally developed by Nowa of Switzerland, was first marketed in Denmark and Switzerland in 1988, and subsequently, was sold and approved in more than 20 countries such as Europe, America, Japan, etc., is clinically used for treating diseases such as increased skeletal muscle tension, muscle spasm and myotonia caused by brain and spinal cord trauma, cerebral hemorrhage, encephalitis, multiple sclerosis, etc. Tizanidine can relieve spasticity, but does not cause myasthenia, does not produce psychological dependence on treatment dosage, and is a central muscle relaxant with better tolerance and curative effect. Currently, tizanidine hydrochloride is used in clinical therapy in many cases. The tizanidine and the salt thereof have very wide clinical application and market development prospect as a novel central skeletal muscle relaxant.
At present, many documents disclose the preparation method of tizanidine hydrochloride, such as the journal of chinese medical industry, 2005,36,593, the journal of chinese new drug, 2006,8,621, the university of Yanbian (natural science edition), 2001,27,277, EP644192, CN102140095, etc., and the main synthetic route thereof can be summarized as follows: taking o-nitro parachloroaniline as an initial raw material, carrying out nitro reduction and cyclization to obtain diazosulfide, and carrying out nitration, nitro reduction, condensation with acylated imidazoline, acyl removal and hydrochloric acid acidification to obtain tizanidine hydrochloride. However, the tizanidine hydrochloride prepared by the above route has more impurities, and the quality of the tizanidine hydrochloride is difficult to reach the standard. In addition, the key reaction in the route, namely the condensation reaction of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and acylated imidazoline, phosphorus oxychloride is used as a dehydrating agent and/or a solvent, the substance has extremely strong corrosivity and lacrimation property, the physical health of operators is seriously harmed, and the acidic tail gas generated in the reaction process has great harm to human bodies and the environment; in industrial production, phosphorus oxychloride has extremely strong corrosivity to equipment, is easy to cause equipment damage, and is not suitable for industrial mass production.
Therefore, it is necessary to develop a novel process for producing tizanidine hydrochloride in high yield and in high purity, which is suitable for industrial mass production by avoiding the use of corrosive reagents.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of tizanidine hydrochloride, which comprises the following steps:
(1)
reacting organic acid A, a compound S1 and a compound S2 serving as raw materials in an organic solvent, and precipitating a solid to obtain tizanidine organic acid salt S3;
(2) preparing tizanidine hydrochloride by taking the tizanidine organic acid salt S3 obtained in the step (1) as a raw material;
wherein the organic acid A is formic acid, dichloroacetic acid, glycolic acid, maleic acid, fumaric acid, tartaric acid, caproic acid or benzoic acid;
R1is hydrogen, methyl, acetyl, propionyl, benzoyl, tert-butylmethylcarbonyl or COOR2，R2Methyl, ethyl, allyl, benzyl, tert-butyl or phenyl.
Further, in the step (1), the organic solvent is selected from C1～C4Alcohol solvent of (1) or DMF.
Further, in the step (1), the organic solvent is selected from methanol, and the organic acid A is selected from formic acid;
or, the organic solvent is selected from ethanol, and the organic acid A is selected from dichloroacetic acid;
or, the organic solvent is selected from isopropanol, and the organic acid A is selected from formic acid, maleic acid or fumaric acid;
or, the organic solvent is selected from n-butanol, and the organic acid A is selected from glycolic acid;
or the organic solvent is selected from sec-butyl alcohol, and the organic acid A is selected from formic acid, caproic acid, maleic acid, tartaric acid or benzoic acid;
or the organic solvent is selected from DMF, and the organic acid A is selected from caproic acid.
Further, said R1Is hydrogen.
Further, in the step (1), the volume-to-mass ratio of the organic solvent to the compound S1 is 3-20 mL: 1g, preferably 5-15 mL: 1g of the total weight of the composition.
Further, in the step (1), the molar ratio of the organic acid A to the compound S1 is 2-15: 1, preferably 2 to 10: 1.
further, in the step (1), the molar ratio of the compound S2 to the compound S1 is 0.9-2.0: 1, preferably 1.0 to 1.5: 1.
further, in the step (1), the reaction temperature is 30-160 ℃, preferably 65-125 ℃.
Further, in the step (1), the precipitated solid is cooled to 70-130 ℃ to precipitate the solid.
Further, the step (2) comprises the steps of:
and adding tizanidine organic acid salt S3 into alcoholic solvent solution of hydrogen chloride for reaction to prepare tizanidine hydrochloride.
Further, in the step (2), the reaction is followed by a recrystallization step, wherein the recrystallization solvent is selected from methanol, ethanol or isopropanol.
In the present invention, said C1～C4The alcohol solvent of (A) is C1、C2、C3、C4The alcohol solvent of (1) is a linear or branched alcohol solvent having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, and the like.
Compared with the prior art, the method has the following remarkable advantages:
1. the organic acid salt intermediate prepared by the method can be subjected to hydrochloric acid acidification operation without further purification and drying, so that the production period is shortened, the time cost and the purification process cost are saved, and the total yield of tizanidine hydrochloride synthesis and the quality of a finished product are greatly improved. The yield of the finished product prepared by the method can reach more than 85 percent, and the purity of the finished product can reach more than 99.97 percent.
2. After the condensation reaction is carried out by adopting the condensation substrate, the tizanidine can be directly prepared without carrying out the operation of acyl hydrolysis, thereby greatly simplifying the process operation, avoiding the product loss caused by the hydrolysis step, and reducing the time cost and the process production cost.
3. The method shortens the reaction time and improves the industrial production efficiency. Compared with the prior art, the method shortens the reaction time by at least more than 44%, not only effectively improves the reaction efficiency, but also further improves the industrial production efficiency, and greatly reduces the time cost, the labor cost and the production cost.
4. The method adopts a cooling crystallization mode, not only avoids the complicated operations of extraction, concentration and the like in the prior art, simplifies the process operation, but also is beneficial to improving the product quality and the yield.
5. The method has the characteristics of environmental protection and safety. Phosphorus oxychloride is mostly used as a dehydrating agent in the existing condensation reaction, so that the method has great harm to operators and environment and is easy to cause equipment corrosion.
6. The method is suitable for industrial mass production. The method is simple to operate, has no special requirements on equipment, is environment-friendly and safe, meets the requirements of large-scale industrial production, greatly saves materials, and reduces the industrial production cost.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The starting material 4-amino-5-chloro-2, 1, 3-benzothiadiazole can be obtained commercially, or can be prepared according to methods reported in the literature, for example, in the journal of Chinese New medicine, 2006, 15, 621. The starting imidazoline-2-sulfonic acid is prepared according to literature methods, for example, the university of Yanbian (Nature science edition), 2001,27, 277. The saturated ethanolic hydrogen chloride solution and the organic acid used in the examples were commercially available.
Example 1
Weighing 5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.85g of imidazoline-2-sulfonic acid, adding the weighed materials into 75ml of isopropanol, adding 18.76g of maleic acid, and heating to 85-90 ℃ for reaction for 10 hours. The solvent was recovered under reduced pressure, and 96ml of water was added to the residue to precipitate crystals with stirring. Filtration was carried out and the filter cake was washed successively with ethyl acetate and dichloromethane. Filtering, adding the filter cake into 50ml of saturated hydrogen chloride ethanol solution, stirring for 4 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying.
Adding the filter cake into 50ml of 95% ethanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethyl alcohol, and drying to obtain 4.63g of solid tizanidine hydrochloride, wherein the yield is 59.2%, and the purity is 95.59%.1H-NMR(400MHz,d6-DMSO):δ3.69(s,4H,CH2CH2) 7.92(d,1H, J9.6 Hz, Ar-H),8.18(d,1H, J9.6 Hz, Ar-H),8.58(brs,2H, NH + HCl),11.30(brs,1H, NH) mass spectra show their FAB m/z: 254 (M)++H-Cl)。
Comparative experiment 1 (see prior art: Chinese New medicine journal 2006, 15, 621)
Weighing 18.6g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 15.4g of 1-acetyl imidazoline-2-ketone, adding into 120ml of phosphorus oxychloride, and heating to 60-65 ℃ for reacting for 36 hours. The solvent was distilled off under reduced pressure, 160ml of methanol was added to the resulting oily substance, and the reaction was refluxed at elevated temperature for 4 hours. And cooling to room temperature, pouring the reaction liquid into 160ml of ice water, and adjusting the pH value to 9-10 by using a sodium hydroxide aqueous solution. Filtering and drying. 17.8g of powdery solid tizanidine is obtained, and the yield is 70%.
The obtained tizanidine was added to 100ml of a saturated ethanol solution of hydrogen chloride and stirred at room temperature for 2 hours. Filtering, washing the filter cake with absolute ethyl alcohol and drying. Adding the filter cake into 200ml of 95% ethanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethyl alcohol, and drying to obtain 17g of solid tizanidine hydrochloride, wherein the yield is 83.5%, and the purity is 99.22%.
Comparative experiment 2 (see prior art: Yanbian university Notice (Nature science edition), 2001,27, 277)
Weighing 1.86g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 3g of imidazoline-2-sulfonic acid, adding into 50ml of acetonitrile, adding 2.53g of triethylamine, and carrying out reflux reaction for 48 hours under the protection of nitrogen. And recovering the solvent under reduced pressure, adding 50ml of trichloromethane, washing for 1 time by using 1mol/L NaOH, drying by using anhydrous magnesium sulfate, and recovering the solvent to obtain a crude product of tizanidine. Dissolving in ether, introducing hydrochloric acid gas, and precipitating. Filtering, adding the filter cake into 30ml of methanol, refluxing until the filter cake is completely dissolved, cooling and crystallizing, filtering, washing the filter cake with anhydrous methanol, and drying to obtain 1.45g of tizanidine hydrochloride, wherein the yield is 50%, and the purity is 90.65%.
Comparative experiment 3
5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.38g of imidazoline-2-sulfonic acid are weighed, added into 96ml of isopropanol, added with 13.48g of acetic acid, and heated to 120 ℃ by a microwave heating method for reaction for 10 minutes. The solvent was recovered under reduced pressure, and 96ml of water was added to the residue to precipitate crystals with stirring. Filtration was carried out and the filter cake was washed successively with ethyl acetate and dichloromethane. Adding the filter cake into 50ml of saturated hydrogen chloride ethanol solution, stirring for 4 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. Adding the filter cake into 50ml of 95% ethanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethyl alcohol, and drying to obtain 1.69g of solid tizanidine hydrochloride, wherein the yield is 21.6%, and the purity is 85.84%.
Example 2
5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.85g of imidazoline-2-sulfonic acid are weighed into 75ml of methanol, and 7.44g of formic acid are added. Heating to 65-70 ℃, and stirring for reaction for 12 hours. 25mg of activated carbon was added, stirred for about 30 minutes and filtered while hot. Cooling the filtrate to-5-0 ℃, and stirring for 2 hours. Filtering, adding the filter cake into 65ml of saturated hydrogen chloride ethanol solution, stirring for 2 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. Adding the filter cake into 60ml of 95% ethanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethyl alcohol, and drying to obtain solid tizanidine hydrochloride 6.84g, wherein the yield is 87.5%, and the purity is 99.98%.
Example 3
5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.45g of imidazoline-2-sulfonic acid are weighed, added to 60ml of ethanol, and 10.42g of dichloroacetic acid are added. Heating to 75-80 ℃, and stirring for reaction for 10 hours. 25mg of activated carbon was added, stirred for about 30 minutes and filtered while hot. Cooling the filtrate to 0-5 ℃, and stirring for 3 hours. Filtering, adding the filter cake into 70ml of saturated hydrogen chloride ethanol solution, stirring for 3 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. Adding the filter cake into 60ml of methanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with anhydrous methanol, and drying to obtain solid tizanidine hydrochloride 6.79g, wherein the yield is 86.9%, and the purity is 99.97%.
Example 4
10g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 9.70g of imidazoline-2-sulfonic acid are weighed into 130ml of sec-butanol, 31.26g of maleic acid are added. Heating to 95-100 ℃, and stirring for reaction for 15 hours. 50mg of activated carbon was added, stirred for about 30 minutes and filtered while hot. Cooling the filtrate to-5-0 ℃, and stirring for 4 hours. Filtering, adding the filter cake into 100ml of saturated hydrogen chloride ethanol solution, stirring for 3 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. Adding the filter cake into 200ml of isopropanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with isopropanol, and drying to obtain 13.37g of solid tizanidine hydrochloride, wherein the yield is 85.5%, and the purity is 99.97%.
Example 5
20g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 16.18g of imidazoline-2-sulfonic acid are weighed into 350ml of isopropanol and 14.88g of formic acid are added. Heating to 85-90 ℃, and stirring for reaction for 16 hours. 100mg of activated carbon was added, stirred for about 30 minutes and filtered while hot. Cooling the filtrate to 5-10 ℃, and stirring for 5 hours. Filtering, adding the filter cake into 220ml saturated ethanol solution of hydrogen chloride, stirring for 4 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. Adding the filter cake into 240ml of 95% ethanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethyl alcohol, and drying to obtain 27.54g of solid tizanidine hydrochloride, wherein the yield is 88.1%, and the purity is 99.98%.
Example 6
5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 5.26g of imidazoline-2-sulfonic acid are weighed out, added to 75ml of n-butanol and 7.17g of glycolic acid are added. Heating to 110-115 ℃, and stirring for reaction for 13 hours. 30mg of activated carbon was added, stirred for about 30 minutes, and filtered while hot. Cooling the filtrate to 10-15 ℃, and stirring for 1 hour. Filtering, adding the filter cake into 60ml of saturated hydrogen chloride ethanol solution, stirring for 3 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. Adding the filter cake into 65ml of 95% ethanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethyl alcohol, and drying to obtain solid tizanidine hydrochloride 6.97g, wherein the yield is 89.2%, and the purity is 99.99%.
Example 7
10g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 9.70g of imidazoline-2-sulfonic acid are weighed out, added to 120ml of sec-butanol and 13.16g of benzoic acid are added. Heating to 95-100 ℃, and stirring for reaction for 16 hours. 50mg of activated carbon was added, stirred for about 30 minutes and filtered while hot. Cooling the filtrate to 0-5 ℃, and stirring for 3 hours. Filtering, adding the filter cake into 150ml of saturated hydrogen chloride ethanol solution, stirring for 2 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. Adding the filter cake into 120ml of methanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with anhydrous methanol, and drying to obtain 13.52g of solid tizanidine hydrochloride, wherein the yield is 86.5%, and the purity is 99.99%.
Example 8
5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.45g of imidazoline-2-sulfonic acid were weighed out, 50ml of DMF were added, and 31.29g of hexanoic acid were added. Heating to 120-125 ℃, and stirring for reaction for 10 hours. 35mg of activated carbon was added, stirred for about 30 minutes, and filtered while hot. Cooling the filtrate to-5-0 ℃, and stirring for 3 hours. Filtering, adding the filter cake into 70ml of saturated hydrogen chloride ethanol solution, stirring for 2 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. Adding the filter cake into 65ml of methanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with anhydrous methanol, and drying to obtain solid tizanidine hydrochloride 6.91g, wherein the yield is 88.4%, and the purity is 99.97%.
Example 9
5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.25g of imidazoline-2-sulfonic acid are weighed into 40ml of isopropanol and 31.26g of fumaric acid are added. Heating to 85-90 ℃, and stirring for reaction for 12 hours. 25mg of activated carbon was added, stirred for about 30 minutes and filtered while hot. Cooling the filtrate to 15-20 ℃, and stirring for 3 hours. Filtering, adding the filter cake into 65ml of saturated hydrogen chloride ethanol solution, stirring for 3 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. Adding 60ml of isopropanol into the filter cake, refluxing until the mixture is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with isopropanol, and drying to obtain solid tizanidine hydrochloride 6.69g, wherein the yield is 85.6%, and the purity is 99.99%.
Example 10
5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 6.07g of imidazoline-2-sulfonic acid are weighed into 25ml of sec-butanol, and 12.13g of tartaric acid are added. Heating to 95-100 ℃, and stirring for reaction for 8 hours. 25mg of activated carbon was added, stirred for about 30 minutes and filtered while hot. Cooling the filtrate to 20-25 ℃, and stirring for 2 hours. Filtering, adding the filter cake into 60ml of saturated hydrogen chloride ethanol solution, stirring for 4 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. Adding 65ml of isopropanol into the filter cake, refluxing until the mixture is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with isopropanol, and drying to obtain solid tizanidine hydrochloride 6.82g, wherein the yield is 87.3%, and the purity is 99.99%.
Example 11
15g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 15.77g of imidazoline-2-sulfonic acid are weighed out, added to 225ml of sec-butanol and 42.24g of hexanoic acid. Heating to 95-100 ℃, and stirring for reaction for 15 hours. 75mg of activated carbon was added, stirred for about 30 minutes and filtered while hot. Cooling the filtrate to-10-5 ℃ and stirring for 3 hours. Filtering, adding the filter cake into 210ml of saturated hydrogen chloride ethanol solution, stirring for 2 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying. 160ml of 95 percent ethanol is added into the filter cake, the reflux is carried out until the dissolution is complete, the natural cooling crystallization is carried out, the filtration is carried out, the filter cake is washed by absolute ethyl alcohol and dried, and 20.02g of solid tizanidine hydrochloride is obtained, the yield is 85.4 percent, and the purity is 99.98 percent.
Example 12
300g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 291g of imidazoline-2-sulfonic acid are weighed out, added to 3600ml of sec-butanol and 297.6g of formic acid are added. Heating to 95-100 ℃, and stirring for reaction for 20 hours. 1.5g of activated carbon was added, stirred for about 30 minutes and filtered while hot. Cooling the filtrate to-5-0 ℃, and stirring for 5 hours. Filtering, adding filter cake into 3000ml saturated ethanol solution of hydrogen chloride, stirring for 4 hr, filtering, washing filter cake with anhydrous ethanol, and drying. 3600ml of 95 percent ethanol is added into the filter cake, the mixture is refluxed until the mixture is completely dissolved, the mixture is naturally cooled and crystallized, filtered, the filter cake is washed by absolute ethyl alcohol and dried, and 404g of solid tizanidine hydrochloride is obtained, the yield is 86.0 percent, and the purity is 99.97 percent.
In conclusion, the method has the advantages of high yield and purity, simple and convenient operation, high production efficiency, environmental protection, safety, suitability for industrial mass production and wide market application prospect.
Claims (12)
1. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.85g of imidazoline-2-sulfonic acid, adding the weighed materials into 75ml of isopropanol, adding 18.76g of maleic acid, and heating to 85-90 ℃ for reaction for 10 hours; recovering solvent under reduced pressure, adding 96ml water into residue, stirring, and crystallizing; filtering, and washing a filter cake with ethyl acetate and dichloromethane in sequence; filtering, adding the filter cake into 50ml of saturated hydrogen chloride ethanol solution, stirring for 4 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; and adding the filter cake into 50ml of 95% ethanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethanol, and drying to obtain solid tizanidine hydrochloride.
2. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps:
weighing 5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.85g of imidazoline-2-sulfonic acid, adding into 75ml of methanol, and adding 7.44g of formic acid; heating to 65-70 ℃, and stirring for reaction for 12 hours; adding 25mg of active carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to-5-0 ℃, and stirring for 2 hours; filtering, adding the filter cake into 65ml of saturated hydrogen chloride ethanol solution, stirring for 2 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; adding the filter cake into 60ml of 95% ethanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethyl alcohol, and drying to obtain solid tizanidine hydrochloride.
3. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.45g of imidazoline-2-sulfonic acid, adding into 60ml of ethanol, and adding 10.42g of dichloroacetic acid; heating to 75-80 ℃, and stirring for reaction for 10 hours; adding 25mg of active carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to 0-5 ℃, and stirring for 3 hours; filtering, adding the filter cake into 70ml of saturated hydrogen chloride ethanol solution, stirring for 3 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; adding the filter cake into 60ml of methanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with anhydrous methanol, and drying to obtain the solid tizanidine hydrochloride.
4. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 10g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 9.70g of imidazoline-2-sulfonic acid, adding into 130ml of sec-butyl alcohol, and adding 31.26g of maleic acid; heating to 95-100 ℃, and stirring for reaction for 15 hours; adding 50mg of active carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to-5-0 ℃, and stirring for 4 hours; filtering, adding the filter cake into 100ml of saturated hydrogen chloride ethanol solution, stirring for 3 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; adding the filter cake into 200ml of isopropanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with isopropanol, and drying to obtain solid tizanidine hydrochloride.
5. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 20g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 16.18g of imidazoline-2-sulfonic acid, adding into 350ml of isopropanol, and adding 14.88g of formic acid; heating to 85-90 ℃, and stirring for reacting for 16 hours; adding 100mg of active carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to 5-10 ℃, and stirring for 5 hours; filtering, adding the filter cake into 220ml of saturated hydrogen chloride ethanol solution, stirring for 4 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; adding the filter cake into 240ml of 95% ethanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethyl alcohol, and drying to obtain solid tizanidine hydrochloride.
6. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 5.26g of imidazoline-2-sulfonic acid, adding into 75ml of n-butanol, and adding 7.17g of glycolic acid; heating to 110-115 ℃, and stirring for reaction for 13 hours; adding 30mg of active carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to 10-15 ℃, and stirring for 1 hour; filtering, adding the filter cake into 60ml of saturated hydrogen chloride ethanol solution, stirring for 3 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; adding the filter cake into 65ml of 95% ethanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethyl alcohol, and drying to obtain solid tizanidine hydrochloride.
7. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 10g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 9.70g of imidazoline-2-sulfonic acid, adding into 120ml of sec-butyl alcohol, and adding 13.16g of benzoic acid; heating to 95-100 ℃, and stirring for reacting for 16 hours; adding 50mg of active carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to 0-5 ℃, and stirring for 3 hours; filtering, adding the filter cake into 150ml of saturated hydrogen chloride ethanol solution, stirring for 2 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; adding the filter cake into 120ml of methanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with anhydrous methanol, and drying to obtain solid tizanidine hydrochloride.
8. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.45g of imidazoline-2-sulfonic acid, adding into 50ml of DMF, and adding 31.29g of caproic acid; heating to 120-125 ℃, and stirring for reaction for 10 hours; adding 35mg of active carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to-5-0 ℃, and stirring for 3 hours; filtering, adding the filter cake into 70ml of saturated hydrogen chloride ethanol solution, stirring for 2 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; and adding the filter cake into 65ml of methanol, refluxing until the filter cake is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with anhydrous methanol, and drying to obtain the solid tizanidine hydrochloride.
9. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 4.25g of imidazoline-2-sulfonic acid, adding into 40ml of isopropanol, and adding 31.26g of fumaric acid; heating to 85-90 ℃, and stirring for reaction for 12 hours; adding 25mg of active carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to 15-20 ℃, and stirring for 3 hours; filtering, adding the filter cake into 65ml of saturated hydrogen chloride ethanol solution, stirring for 3 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; adding 60ml of isopropanol into the filter cake, refluxing until the isopropanol is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with isopropanol, and drying to obtain solid tizanidine hydrochloride.
10. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 5g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 6.07g of imidazoline-2-sulfonic acid, adding into 25ml of sec-butyl alcohol, and adding 12.13g of tartaric acid; heating to 95-100 ℃, and stirring for reaction for 8 hours; adding 25mg of active carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to 20-25 ℃, and stirring for 2 hours; filtering, adding the filter cake into 60ml of saturated hydrogen chloride ethanol solution, stirring for 4 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; adding 65ml of isopropanol into the filter cake, refluxing until the isopropanol is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with isopropanol, and drying to obtain the solid tizanidine hydrochloride.
11. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 15g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 15.77g of imidazoline-2-sulfonic acid, adding into 225ml of sec-butyl alcohol, and adding 42.24g of caproic acid; heating to 95-100 ℃, and stirring for reaction for 15 hours; adding 75mg of active carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to-10 to-5 ℃, and stirring for 3 hours; filtering, adding the filter cake into 210ml of saturated hydrogen chloride ethanol solution, stirring for 2 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; and adding 160ml of 95% ethanol into the filter cake, refluxing until the mixture is completely dissolved, naturally cooling and crystallizing, filtering, washing the filter cake with absolute ethanol, and drying to obtain solid tizanidine hydrochloride.
12. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps: weighing 300g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 291g of imidazoline-2-sulfonic acid, adding into 3600ml of sec-butyl alcohol, and adding 297.6g of formic acid; heating to 95-100 ℃, and stirring for reaction for 20 hours; adding 1.5g of activated carbon, stirring for 30 minutes, and filtering while the solution is hot; cooling the filtrate to-5-0 ℃, and stirring for 5 hours; filtering, adding the filter cake into 3000ml saturated hydrogen chloride ethanol solution, stirring for 4 hours, filtering, washing the filter cake with absolute ethyl alcohol, and drying; 3600ml of 95 percent ethanol is added into the filter cake, the mixture is refluxed until the mixture is completely dissolved, the mixture is naturally cooled and crystallized, filtered, the filter cake is washed by absolute ethyl alcohol and dried, and the solid tizanidine hydrochloride is obtained.
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