CN107759582B - Preparation method of novel central skeletal muscle relaxant - Google Patents
Preparation method of novel central skeletal muscle relaxant Download PDFInfo
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- CN107759582B CN107759582B CN201610680747.5A CN201610680747A CN107759582B CN 107759582 B CN107759582 B CN 107759582B CN 201610680747 A CN201610680747 A CN 201610680747A CN 107759582 B CN107759582 B CN 107759582B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000003158 myorelaxant agent Substances 0.000 title abstract description 7
- 210000002027 skeletal muscle Anatomy 0.000 title abstract description 7
- 229960000488 tizanidine Drugs 0.000 claims abstract description 56
- ZWUKMNZJRDGCTQ-UHFFFAOYSA-N Tizanidine hydrochloride Chemical compound Cl.ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 ZWUKMNZJRDGCTQ-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229960002388 tizanidine hydrochloride Drugs 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000001816 cooling Methods 0.000 claims abstract description 23
- -1 tizanidine organic acid salt Chemical class 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 150000007524 organic acids Chemical class 0.000 claims abstract description 21
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 238000002425 crystallisation Methods 0.000 claims abstract description 6
- 230000008025 crystallization Effects 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 87
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 23
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 20
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 20
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 13
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 10
- YZGQDNOIGFBYKF-UHFFFAOYSA-N Ethoxyacetic acid Chemical compound CCOCC(O)=O YZGQDNOIGFBYKF-UHFFFAOYSA-N 0.000 claims description 8
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 8
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 6
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000001914 filtration Methods 0.000 description 55
- 238000003756 stirring Methods 0.000 description 49
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 41
- 238000001035 drying Methods 0.000 description 32
- 238000010438 heat treatment Methods 0.000 description 27
- 239000000203 mixture Substances 0.000 description 27
- 235000019441 ethanol Nutrition 0.000 description 26
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 23
- 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 description 20
- 239000000243 solution Substances 0.000 description 19
- JECXKZJEVHOYCM-UHFFFAOYSA-N 1-(2-ethylsulfanyl-4,5-dihydroimidazol-1-yl)ethanone Chemical compound CCSC1=NCCN1C(C)=O JECXKZJEVHOYCM-UHFFFAOYSA-N 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 9
- 239000012362 glacial acetic acid Substances 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 5
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 4
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical class Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 3
- KNFXXAGQEUUZAZ-UHFFFAOYSA-N ethyl ethaneperoxoate Chemical compound CCOOC(C)=O KNFXXAGQEUUZAZ-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 150000002462 imidazolines Chemical class 0.000 description 3
- HYPMQJSKHPUPFW-UHFFFAOYSA-N methyl 2-methylsulfanyl-4,5-dihydroimidazole-1-carboxylate Chemical compound COC(=O)N1CCN=C1SC HYPMQJSKHPUPFW-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 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
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010062575 Muscle contracture 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
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 208000006111 contracture Diseases 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000011161 development Methods 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
- 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
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water 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
- 239000000463 material Substances 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
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
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- 230000008733 trauma Effects 0.000 description 1
- 238000005303 weighing Methods 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)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of a novel central skeletal muscle relaxant, in particular to a preparation method of tizanidine hydrochloride, which comprises the following steps: (1) using organic acid A, compound S1 and compound S2 as raw materials, reacting in organic solvent X, removingSolvent to obtain crude tizanidine organic acid salt S3; (2) adding an organic acid A and an organic solvent Y into the crude product obtained in the step (1), and dissolving at 50-120 ℃; (3) cooling to 50-75 ℃, keeping the temperature for crystallization for 2-10 h, then cooling again to 10-30 ℃, keeping the temperature for continuous crystallization for 3-10 h to obtain tizanidine organic acid salt S3; (4) and (4) preparing tizanidine hydrochloride by using the tizanidine organic acid salt S3 obtained in the step (3) as a raw material. 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 spasmThe medicine for treating the contracture but not causing the myasthenia does not produce psychological dependence on the 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)
taking an organic acid A, a compound S1 and a compound S2 as raw materials, reacting in an organic solvent X, and removing the solvent to obtain a crude product of tizanidine organic acid salt S3;
(2) adding an organic acid A and an organic solvent Y into the crude product obtained in the step (1), and dissolving at 50-120 ℃;
(3) cooling to 50-75 ℃, keeping the temperature for crystallization for 2-10 h, then cooling again to 10-30 ℃, keeping the temperature for continuous crystallization for 3-10 h to obtain tizanidine organic acid salt S3;
(4) preparing tizanidine hydrochloride by taking the tizanidine organic acid salt S3 obtained in the step (3) as a raw material;
wherein the organic acid A is C2～C7An organic acid of (4);
R1is methyl, ethyl, allyl or benzyl; r2Is hydrogen, methyl, acetyl, propionyl, benzoyl, tert-butylmethylcarbonyl or COOR3，R3Methyl, ethyl, allyl, benzyl, tert-butyl or phenyl.
Further, the organic acid A is acetic acid, ethoxyacetic acid, caproic acid, glycolic acid, butyric acid, 2-hydroxypropionic acid, oxalic acid, malonic acid, salicylic acid, citric acid or malic acid.
Further, in the step (2), the organic solvent Y is selected from C1～C4The alcohol solvent of (1).
Further, the organic solvent Y is selected from methanol, ethanol or isopropanol.
Further, in the step (2), the volume weight ratio of the organic solvent Y to the organic acid A is 20 mL: 1-2 g.
Further, in the step (2), the volume-to-mass ratio of the organic solvent Y to the compound S1 is 6-15 mL: 1g of the total weight of the composition.
Further, in the step (2), the dissolving temperature is 65-90 ℃.
Further, in the step (2), the dissolving time is 0.5-10 hours, preferably 0.5-5 hours.
Further, in the step (1), the organic solvent X is C1～C4Or a mixed solvent of the alcohol solvent and DMF.
Further, in the step (1), the C1～C4The alcohol solvent is selected from methanol, ethanol or isopropanol.
Further, in the step (1), the volume ratio of the alcohol solvent to DMF is 2-15: 1, preferably 5-10: 1.
Further, in the step (1), the volume-to-mass ratio of the organic solvent X to the compound S1 is 6.0-40.0 mL: 1g, preferably 8.0-37.0 mL: 1g of the total weight of the composition. .
Further, in the step (1), the molar ratio of the compound S2 to the compound S1 is 0.9-2.0: 1, preferably 1.0-1.5: 1.
Further, in the step (1), the molar ratio of the organic acid A to the compound S1 is 2-15: 1, preferably 2-9: 1.
Further, in the step (1), the reaction temperature is 50-120 ℃, preferably 65-90 ℃.
Further, the step (4) comprises the steps of:
and adding tizanidine organic acid salt S3 into alcoholic solvent solution of hydrogen chloride for reaction to prepare tizanidine hydrochloride.
In some embodiments, the alcoholic solvent solution of hydrogen chloride may be hydrogen chloride C1～C4Such as methanol, ethanol or isopropanol. After the reaction is fully carried out at room temperature, tizanidine hydrochloride is separated out.
The invention also provides a method for preparing the tizanidine organic acid salt, which is the method for preparing the tizanidine organic acid salt through the steps (1) to (3) in the method.
In the present invention, said C2～C7The organic acid of (A) is C2、C3、C4、C5、C6、C7The organic acid of (2) is an organic acid having 2 to 7 carbon atoms. In some embodiments of the present invention, the organic acid comprises 1 to 2 carboxyl groups and may further comprise 0 to 1 hydroxyl group.
In the present invention, said C1～C4The alcohol solvent of (A) is C1、C2、C3、C4The alcohol solvent of (2) is a straight-chain or branched-chain alcohol solvent having 1 to 4 carbon atoms, such as methanol, ethanol, ethylene glycol, propanol, 2-propanol, isopropanol, butanol, etc.
Compared with the prior art, the method has the following remarkable advantages:
1. the preparation method of the invention is characterized in that the organic acid, 4-amino-5-chloro-2, 1, 3-benzothiadiazole and acylated imidazoline are used as raw materials to prepare the crude product of organic acid salt of tizanidine through screening of the process. In the recrystallization process of the crude product, the organic acid salt of tizanidine is obtained with high yield and high purity by a gradient cooling mode, and finally the total yield of the tizanidine hydrochloride synthesis and the quality of the finished product are greatly improved by taking the organic acid salt as a raw material.
The tizanidine organic acid salt prepared by the method has the yield of over 86 percent and the purity of over 99.9 percent. By using the tizanidine hydrochloride as a raw material, the yield of a finished product of the tizanidine hydrochloride can reach more than 96 percent, and the purity is as high as more than 99.95 percent; the total yield of the two steps reaches more than 83 percent. Therefore, the method avoids the introduction of unnecessary impurities, and greatly improves the total yield of the synthesis of the tizanidine hydrochloride and the quality of finished products.
2. The method finishes the condensation of the substrate and the acyl hydrolysis on the imidazoline ring of the condensation product through one-step reaction, has simple and convenient operation, saves the time, improves the industrial production efficiency and greatly reduces the process production cost.
3. The finished product prepared by the method does not need further purification, the purity can reach more than 99.95 percent, the process operation is greatly simplified, and the loss of the finished product caused by recrystallization is avoided.
4. The method has the characteristics of environmental protection and safety. Phosphorus oxychloride is mostly used as a dehydrating agent and/or a solvent in the existing condensation reaction, so that the method has great harm to operators and the environment and is easy to cause equipment corrosion.
5. 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, 2006,8, 621. The starting materials N-acetyl-2-ethylthio-2-imidazoline and N-carbomethoxy-2-methylsulfanyl-2-imidazoline are prepared according to literature methods, for example the literature Journal of Medicinal Chemistry, Vol.20(1977) pp.158-160. The saturated ethanolic hydrogen chloride solution and the organic acid used in the examples were commercially available.
Example 1
393g of glacial acetic acid are weighed, added to 5000mL of isopropanol, and 136g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 189g N-acetyl-2-ethylthio-2-imidazoline are added. Heating to 90-95 ℃ and reacting for 19 hours. The solvent was evaporated under reduced pressure, and the residue was added to 1100mL of isopropanol and 55g of glacial acetic acid, heated to 65-70 ℃ and stirred for 2 hours. Cooling to 15 deg.C, stirring for 3 hr, cooling to-5 deg.C, and stirring for 3 hr. Filtering and drying. 203.4g of tizanidine glacial acetate is obtained, the yield is 88.5 percent, and the purity is 99.91 percent
The resulting tizanidine glacial acetate was added to 2800mL of saturated ethanolic hydrogen chloride and stirred at room temperature for 3 hours. Filtering and drying. 182g of tizanidine hydrochloride is obtained, the yield is 96.7 percent, and the purity is 99.96 percent.1H-NMR(400MHz,d6-DMSO):δ3.68(s,4H,CH2CH2) 7.93(d,1H, J9.6 Hz, Ar-H),8.19(d,1H, J9.6 Hz, Ar-H),8.58(brs,2H, NH + HCl),11.25(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. 18g of powdery solid tizanidine is obtained, and the yield is 71 percent.
The obtained tizanidine was added to 100mL of a saturated ethanol solution of hydrogen chloride and stirred at room temperature for 1 hour. And (3) carrying out suction filtration, washing a filter cake by using absolute ethyl alcohol, drying, and recrystallizing by using ethyl alcohol to obtain 17.5g of solid tizanidine hydrochloride, wherein the yield is 85.0%, and the purity is 99.25%.
Comparative experiment 2
39.3g of glacial acetic acid are weighed, added to 500mL of isopropanol, and 13.6g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 19.2g N-carbomethoxy-2-methylthio-2-imidazoline are added. Heating to 90-95 ℃ and reacting for 19 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in isopropanol and stirred at room temperature. Filtering to obtain 12.3g of tizanidine glacial acetate. The yield was 53.3% and the purity was 78.45%.
Adding the obtained tizanidine glacial acetate into 280mL of saturated hydrogen chloride ethanol solution, stirring for 3 hours at room temperature, carrying out suction filtration, washing a filter cake by using absolute ethyl alcohol, drying, and recrystallizing by using ethanol to obtain 9.4g of solid tizanidine hydrochloride, wherein the yield is 82.3%, and the purity is 86.98%.
Comparative experiment 3
39.3g of glacial acetic acid are weighed, added to 500mL of isopropanol and 13.6g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 18.9g of 18.9g N-acetyl-2-ethylthio-2-imidazoline are added. Heating to 90-95 ℃ and reacting for 19 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in isopropanol and stirred at room temperature. Filtering to obtain 12.9g of tizanidine acetate. The yield was 56.1% and the purity was 79.56%.
Adding the obtained tizanidine acetate into 280mL of saturated hydrogen chloride ethanol solution, stirring for 4 hours at room temperature, carrying out suction filtration, washing a filter cake with absolute ethyl alcohol, drying, and recrystallizing with ethanol to obtain solid tizanidine hydrochloride 10.1g, wherein the yield is 85.0%, and the purity is 88.21%.
Example 2
158g of glacial acetic acid are weighed, added to 2000mL of ethanol, and 100g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 132.6g N-acetyl-2-ethylthio-2-imidazoline are added. Heating to reflux, and reacting under reflux state until the reaction is complete. Decolorizing with 4g of active carbon, filtering, cooling the filtrate to room temperature, and filtering. Adding 1500mL of ethanol and 75g of glacial acetic acid into the filter cake, heating to 75-80 ℃, and stirring for 2 hours. Cooled to 25 ℃ and stirred for 4 hours. Then the temperature is reduced to-5 ℃ and the mixture is stirred for 5 hours. Filtering and drying. 146g of tizanidine glacial acetate is obtained, the yield is 86.3%, and the purity is 99.93%.
The obtained tizanidine glacial acetate was added to 3000mL of a saturated hydrogen chloride ethanol solution, and stirred at room temperature for 4 hours. Filtering and drying. 132g of tizanidine hydrochloride is obtained, the yield is 97.9 percent, and the purity is 99.97 percent.
Example 3
393g of glacial acetic acid is weighed and added into 5000mL of isopropanol, 136g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 192g of 192g N-carbomethoxy-2-methylthio-2-imidazoline are added, and the temperature is increased to 90-95 ℃ for reaction for 19 hours. The solvent is evaporated under reduced pressure, and the residue is added into 1600mL of isopropanol and 80g of glacial acetic acid, heated to 65-70 ℃ and stirred for 2 hours. Cooling to 15 deg.C, stirring for 3 hr, cooling to-5 deg.C, and stirring for 4 hr. Filtering and drying. 200g of tizanidine glacial acetate are obtained, the yield is 87 percent, and the purity is 99.95 percent
The resulting tizanidine ethoxyacetate was added to 3500mL of a saturated ethanol solution of hydrogen chloride, and the mixture was stirred at room temperature for 4 hours. Filtering and drying. 179.4g of solid tizanidine hydrochloride is obtained, the yield is 97 percent, and the purity is 99.98 percent.
Example 4
336.5g of ethoxyacetic acid is weighed, added into 3182mL of mixed solvent of methanol and 318mLDMF, 200g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 186g N-acetyl-2-ethylthio-2-imidazoline are added, and the mixture is heated to 65-70 ℃ and stirred for 10 hours. 7g of activated carbon are added, stirring is continued for about 30 minutes and filtration is carried out while hot. Cooling the filtrate to 15 deg.C, stirring for 2 hr, cooling to-5 deg.C, and stirring for 6 hr. Filtration and addition of 2000mL of methanol and 200g of ethoxyacetic acid to the filter cake. Heating to 65-70 ℃ and stirring for 0.5 hour. Cooling to 15 deg.C, stirring for 2 hr, cooling to-5 deg.C, and stirring for 3 hr. Filtering and drying. 334g of tizanidine ethoxy acetate is obtained, the yield is 86.5 percent, and the purity is 99.91 percent.
The resulting tizanidine ethoxyacetate was added to 3500mL of a saturated ethanol solution of hydrogen chloride, and the mixture was stirred at room temperature for 4 hours. Filtering and drying. 262g of solid tizanidine hydrochloride is obtained, the yield is 96.8 percent, and the purity is 99.95 percent.
Example 5
375.5g of hexanoic acid was weighed, and added to 2400mL of a mixed solvent of ethanol and 300mL of DMF, and 200g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 278g N-acetyl-2-ethylthio-2-imidazoline were added. Heating to 75-80 ℃ and stirring for 8 hours. 5.4g of activated carbon are added, stirring is continued for about 30 minutes and filtration is carried out while hot. The filtrate was cooled to 10 ℃ and stirred for 5 hours. Then the temperature is reduced to 0 ℃ and the mixture is stirred for 5 hours. Filtration and addition of 1800mL of ethanol and 90g of hexanoic acid to the filter cake. Heating to 75-80 ℃ and stirring for 2 hours. Cooled to 10 ℃ and stirred for 4 hours. Then the temperature is reduced to 0 ℃ and the mixture is stirred for 5 hours. Filtering and drying. 349g of tizanidine caproate is obtained, the yield is 87.5 percent, and the purity is 99.92 percent.
The obtained tizanidine caproate was added to 5000mL of a saturated ethanol solution of hydrogen chloride, and stirred at room temperature for 5 hours. Filtering and drying. 265g of solid tizanidine hydrochloride is obtained, the yield is 96.9 percent, and the purity is 99.97 percent.
Example 6
327.7g of glycolic acid is weighed and added into 1714mL of mixed solvent of isopropanol and 286mLDMF, and 200g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 241g N-acetyl-2-ethylthio-2-imidazoline are added. Heating to 85-90 ℃ and stirring for 12 hours. 4g of activated carbon are added, stirring is continued for about 30 minutes and filtration is carried out while hot. The filtrate was cooled to 20 ℃ and stirred for 4 hours. Then the temperature is reduced to 5 ℃ and the mixture is stirred for 10 hours. Filtration and addition of 1200mL of isopropanol and 84g of glycolic acid to the filter cake. Heating to 85-90 ℃ and stirring for 1 hour. Cooled to 20 ℃ and stirred for 4 hours. Then the temperature is reduced to 5 ℃ and the mixture is stirred for 10 hours. Filtering and drying. 306g of tizanidine hydroxyacetate is obtained, the yield is 86.2 percent, and the purity is 99.92 percent.
The obtained tizanidine hydroxyacetate was added to 6000mL of a saturated ethanol solution of hydrogen chloride, and stirred at room temperature for 6 hours. Filtering and drying. 263g of solid tizanidine hydrochloride is obtained, the yield is 97.5 percent, and the purity is 99.98 percent.
Example 7
284.8g of butyric acid was weighed, 2188mL of a mixed solvent of ethanol and 312mL of DMF was added, and 200g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 210g N-acetyl-2-ethylthio-2-imidazoline were added. Heating to 75-80 ℃ and stirring for 10 hours. 5g of activated carbon are added, stirring is continued for about 30 minutes and filtration is carried out while hot. The filtrate is cooled to 20 ℃ and stirred for 10 hours. Then the temperature is reduced to-10 ℃ and the mixture is stirred for 4 hours. Filtration and addition of 2000mL of ethanol and 160g of butyric acid to the filter cake. Heating to 75-80 ℃ and stirring for 5 hours. Cooling to 20 deg.C and stirring for 5 hr. Then the temperature is reduced to-5 ℃ and the mixture is stirred for 4 hours. Filtering and drying. 317g of tizanidine butyrate is obtained, the yield is 86.0 percent, and the purity is 99.95 percent.
The obtained tizanidine butyrate was added to 4000mL of a saturated ethanol solution of hydrogen chloride, and stirred at room temperature for 8 hours. Filtering and drying. 264g of solid tizanidine hydrochloride is obtained, the yield is 98.1 percent, and the purity is 99.98 percent.
Example 8
340g of 2-hydroxypropionic acid was weighed, added to 3333mL of a mixed solvent of isopropanol and 667mL of DMMF, and 200g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 215g N-acetyl-2-ethylthio-2-imidazoline were added. Heating to 85-90 ℃ and stirring for 12 hours. 8g of activated carbon are added, stirring is continued for about 30 minutes and filtration is carried out while hot. The filtrate was cooled to 25 ℃ and stirred for 6 hours. Then the temperature is reduced to-5 ℃ and the mixture is stirred for 7 hours. Filtration and addition of 1600mL of isopropanol and 80g of 2-hydroxypropionic acid to the filter cake. Heating to 85-90 ℃ and stirring for 3 hours. Cooling to 25 deg.C and stirring for 10 hr. Then the temperature is reduced to-5 ℃ and the mixture is stirred for 8 hours. Filtering and drying. 327g of tizanidine 2-hydroxypropionate is obtained, the yield is 88.3 percent, and the purity is 99.93 percent.
The obtained tizanidine 2-hydroxypropionate was added to 3800mL of a saturated ethanol solution of hydrogen chloride, and stirred at room temperature for 6 hours. Filtering and drying. 268g of solid tizanidine hydrochloride is obtained, the yield is 97.2 percent, and the purity is 99.99 percent.
Example 9
294g of oxalic acid was weighed, added to 1333mL of a mixed solvent of methanol and 267mL of DMF, and 200g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 223g N-acetyl-2-ethylthio-2-imidazoline were added. Heating to 65-70 ℃ and stirring for 13 hours. 3.2g of activated carbon was added, stirring was continued for about 30 minutes, and filtration was carried out while hot. The filtrate was cooled to 10 ℃ and stirred for 5 hours. Then the temperature is reduced to 0 ℃ and the mixture is stirred for 3 hours. Filtration and addition of 1400mL of methanol and 70g of oxalic acid to the filter cake. Heating to 65-70 ℃ and stirring for 2 hours. Cooling to 10 deg.C and stirring for 5 hr. Then the temperature is reduced to 0 ℃ and the mixture is stirred for 3 hours. Filtering and drying. 322g of tizanidine oxalate is obtained, the yield is 86.9 percent, and the purity is 99.95 percent.
The obtained tizanidine oxalate was added to 3500mL of a saturated ethanol solution of hydrogen chloride, and the mixture was stirred at room temperature for 5 hours. Filtering and drying. 262g of solid tizanidine hydrochloride is obtained, the yield is 96.5 percent, and the purity is 99.98 percent.
Example 10
280g malonic acid was weighed, added to a mixed solvent of 1925mL ethanol and 275mL DMF, and 200g 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 186g N-acetyl-2-ethylthio-2-imidazoline were added. Heating to 75-80 ℃ and stirring for 15 hours. 4.4g of activated carbon are added, stirring is continued for about 30 minutes and filtration is carried out while hot. The filtrate is cooled to 5 ℃ and stirred for 8 hours. Then the temperature is reduced to minus 10 ℃ and the mixture is stirred for 5 hours. Filtration was carried out and 2400mL of ethanol and 144g of malonic acid were added to the filter cake. Heating to 75-80 ℃ and stirring for 1 hour. Cooled to 5 ℃ and stirred for 4 hours. Then the temperature is reduced to minus 10 ℃ and the mixture is stirred for 5 hours. Filtering and drying. 333g of tizanidine malonate is obtained, the yield is 86.3 percent, and the purity is 99.92 percent.
The obtained tizanidine malonate was added to 6000mL of a saturated ethanolic hydrogen chloride solution, and stirred at room temperature for 3 hours. Filtering and drying. 266g of solid tizanidine hydrochloride is obtained, the yield is 98.4 percent, and the purity is 99.98 percent.
Example 11
744g of malonic acid was weighed, 2667mL of a mixed solvent of isopropanol and 333mL of DMF was added, and 200g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 195g N-acetyl-2-ethylthio-2-imidazoline were added. Heating to 85-90 ℃ and stirring for 9 hours. 6g of activated carbon are added, stirring is continued for about 30 minutes and filtration is carried out while hot. The filtrate was cooled to 15 ℃ and stirred for 5 hours. Then the temperature is reduced to-5 ℃ and the mixture is stirred for 3 hours. Filtration and addition of 2000mL of isopropanol and 100g of malonic acid to the filter cake. Heating to 85-90 ℃ and stirring for 4 hours. Cooling to 15 deg.C and stirring for 6 hr. Then the temperature is reduced to-5 ℃ and the mixture is stirred for 4 hours. Filtering and drying. 335g of tizanidine malonate is obtained, the yield is 86.8%, and the purity is 99.91%.
The resulting tizanidine malonate was added to 7000mL of a saturated ethanolic hydrogen chloride solution and stirred at room temperature for 3 hours. Filtering and drying. 262g of solid tizanidine hydrochloride is obtained, the yield is 96.6 percent, and the purity is 99.99 percent.
Example 12
621g of citric acid was weighed, added to 1714mL of a mixed solvent of ethanol and 286mL of DMF, and 200g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 205g N-acetyl-2-ethylthio-2-imidazoline were added. Heating to 75-80 ℃ and stirring for 12 hours. 4g of activated carbon are added, stirring is continued for about 30 minutes and filtration is carried out while hot. The filtrate was cooled to 25 ℃ and stirred for 6 hours. Then the temperature is reduced to-5 ℃ and the mixture is stirred for 7 hours. Filtration and addition of 3000mL of ethanol and 150g of citric acid to the filter cake. Heating to 75-80 ℃ and stirring for 2 hours. Cooled to 25 ℃ and stirred for 7 hours. Then the temperature is reduced to-5 ℃ and the mixture is stirred for 6 hours. Filtering and drying. 414g of tizanidine citrate is obtained, the yield is 86.1 percent, and the purity is 99.93 percent.
The obtained tizanidine citrate was added to 10L of a saturated ethanol solution of hydrogen chloride, and stirred at room temperature for 10 hours. Filtering and drying. 261g of tizanidine hydrochloride is obtained, the yield is 96.9%, and the purity is 99.98%.
Example 13
650g of malic acid was weighed, added to 2222mL of a mixed solvent of isopropyl alcohol and 278mL of DMMF, and 200g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 220g N-acetyl-2-ethylthio-2-imidazoline was added. Heating to 85-90 ℃ and stirring for 15 hours. 5g of activated carbon are added, stirring is continued for about 30 minutes and filtration is carried out while hot. The filtrate was cooled to 20 ℃ and stirred for 3 hours. Then the temperature is reduced to-10 ℃ and the mixture is stirred for 4 hours. Filtration and addition of 2000mL of isopropanol and 100g of malic acid to the filter cake. Heating to 85-90 ℃ and stirring for 0.5 hour. Cooling to 20 deg.C and stirring for 5 hr. Then the temperature is reduced to minus 10 ℃ and the mixture is stirred for 5 hours. Filtering and drying. 340g of tizanidine malate is obtained, the yield is 87.5 percent, and the purity is 99.93 percent.
The obtained tizanidine malate was added to 13L of a saturated ethanol solution of hydrogen chloride, and stirred at room temperature for 9 hours. Filtering and drying. 266g of tizanidine hydrochloride is obtained, the yield is 97.4 percent and the purity is 99.97 percent.
Example 14
375.5g of hexanoic acid was weighed, and added to 1886mL of a mixed solvent of ethanol and 314mL of DMMF, and 200g of 4-amino-5-chloro-2, 1, 3-benzothiadiazole and 232g N-acetyl-2-ethylthio-2-imidazoline were added. Heating to 75-80 ℃ and stirring for 13 hours. 4.4g of activated carbon are added, stirring is continued for about 30 minutes and filtration is carried out while hot. The filtrate was cooled to 10 ℃ and stirred for 4 hours. Then the temperature is reduced to 0 ℃ and the mixture is stirred for 5 hours. Filtration and addition of 1800mL of ethanol and 90g of hexanoic acid to the filter cake. Heating to 75-80 ℃ and stirring for 3 hours. Cooling to 10 deg.C and stirring for 3 hr. Then the temperature is reduced to 0 ℃ and the mixture is stirred for 4 hours. Filtering and drying. 325g of tizanidine caproate is obtained, the yield is 87.8 percent, and the purity is 99.92 percent.
The obtained tizanidine caproate was added to 5100mL of a saturated ethanol solution of hydrogen chloride, and stirred at room temperature for 5 hours. Filtering and drying. 264g of solid tizanidine hydrochloride is obtained, the yield is 96.2 percent, and the purity is 99.98 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 (6)
1. A preparation method of tizanidine hydrochloride is characterized in that: the method comprises the following steps:
(1)
by combination of organic acids AThe S1 and the compound S2 are used as raw materials and react in an organic solvent X, and the solvent is removed to obtain a crude product of tizanidine organic acid salt S3; the organic acid A is acetic acid, ethoxyacetic acid, caproic acid, glycolic acid, butyric acid, 2-hydroxypropionic acid, oxalic acid, malonic acid, salicylic acid, citric acid or malic acid; the organic solvent X is C1～C4Or a mixed solvent of the alcohol solvent of (1) and DMF; said C is1～C4The alcohol solvent is selected from methanol, ethanol or isopropanol;
(2) adding an organic acid A and an organic solvent Y into the crude product obtained in the step (1), and dissolving at 65-90 ℃; the dissolving time is 0.5-10 h; the organic solvent Y is selected from methanol, ethanol or isopropanol; the volume mass ratio of the organic solvent Y to the organic acid A is 20 mL: 1-2 g; the volume-mass ratio of the organic solvent Y to the compound S1 is 6-15 mL: 1g of a compound;
(3) cooling to 75 ℃, keeping the temperature for crystallization for 2-10 h, cooling again to 10-30 ℃, keeping the temperature for continuous crystallization for 3-10 h to obtain tizanidine organic acid salt S3;
(4) preparing tizanidine hydrochloride by taking the tizanidine organic acid salt S3 obtained in the step (3) as a raw material;
R1is methyl, ethyl, allyl or benzyl; r2Is hydrogen, methyl, acetyl, propionyl, benzoyl, tert-butylmethylcarbonyl or COOR3，R3Methyl, ethyl, allyl, benzyl, tert-butyl or phenyl.
2. The method of claim 1, wherein: in the step (2), the dissolving time is 0.5-5 h.
3. The method of claim 1, wherein: in the step (1), the volume ratio of the alcohol solvent to DMF is 2-15: 1;
the volume-mass ratio of the organic solvent X to the compound S1 is 6.0-40.0 mL: 1g of a compound;
the molar ratio of the compound S2 to the compound S1 is 0.9-2.0: 1;
the molar ratio of the organic acid A to the compound S1 is 2-15: 1;
the reaction temperature is 50-120 ℃.
4. The method of claim 3, wherein: in the step (1), the volume ratio of the alcohol solvent to DMF is 5-10: 1;
the volume-mass ratio of the organic solvent X to the compound S1 is 8.0-37.0 mL: 1g of a compound;
the molar ratio of the compound S2 to the compound S1 is 1.0-1.5: 1;
the molar ratio of the organic acid A to the compound S1 is 2-9: 1;
the reaction temperature is 65-90 ℃.
5. The method according to any one of claims 1-4, wherein: the step (4) comprises the following steps:
and adding tizanidine organic acid salt S3 into alcoholic solvent solution of hydrogen chloride for reaction to prepare tizanidine hydrochloride.
6. A method for preparing tizanidine organic acid salt is characterized in that: the method for preparing tizanidine organic acid salt according to the steps (1) to (3) of the method according to any one of claims 1 to 5.
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Address after: 646100 Pharmaceutical Industrial Park, national high tech Zone, Luzhou City, Sichuan Province Patentee after: SICHUAN CREDIT PHARMACEUTICAL Co.,Ltd. Country or region after: China Patentee after: Sichuan Tiandao Pharmaceutical Co.,Ltd. Address before: 646100 Pharmaceutical Industrial Park, national high tech Zone, Luzhou City, Sichuan Province Patentee before: SICHUAN CREDIT PHARMACEUTICAL Co.,Ltd. Country or region before: China Patentee before: Luzhou kered Pharmaceutical Co.,Ltd. |