CN107759582A - A kind of preparation method of new central skeletal muscle relaxant - Google Patents
A kind of preparation method of new central skeletal muscle relaxant Download PDFInfo
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- CN107759582A CN107759582A CN201610680747.5A CN201610680747A CN107759582A CN 107759582 A CN107759582 A CN 107759582A CN 201610680747 A CN201610680747 A CN 201610680747A CN 107759582 A CN107759582 A CN 107759582A
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- tizanidine
- acid
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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 6
- 229960000488 tizanidine Drugs 0.000 claims abstract description 84
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 claims abstract description 72
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 150000007524 organic acids Chemical class 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000012043 crude product Substances 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 6
- 230000008025 crystallization Effects 0.000 claims abstract description 6
- 238000009413 insulation Methods 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 116
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 22
- -1 pi-allyl Chemical group 0.000 claims description 18
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- YZGQDNOIGFBYKF-UHFFFAOYSA-N Ethoxyacetic acid Chemical compound CCOCC(O)=O YZGQDNOIGFBYKF-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 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
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 239000000203 mixture Substances 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- KBIWNQVZKHSHTI-UHFFFAOYSA-N 4-n,4-n-dimethylbenzene-1,4-diamine;oxalic acid Chemical compound OC(=O)C(O)=O.CN(C)C1=CC=C(N)C=C1 KBIWNQVZKHSHTI-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=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
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- IYDIGKJHQKUYRZ-UHFFFAOYSA-N acetic acid;2-hydroxyguanidine Chemical compound CC(O)=O.NC(N)=NO IYDIGKJHQKUYRZ-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 238000003756 stirring Methods 0.000 description 65
- 235000019441 ethanol Nutrition 0.000 description 42
- 238000001914 filtration Methods 0.000 description 34
- 238000010792 warming Methods 0.000 description 31
- 239000000243 solution Substances 0.000 description 21
- 239000007787 solid Substances 0.000 description 18
- 125000003047 N-acetyl group Chemical group 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 9
- 239000012362 glacial acetic acid Substances 0.000 description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 5
- 230000007613 environmental effect Effects 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-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
- 150000007513 acids Chemical class 0.000 description 4
- 238000001816 cooling Methods 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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229910019213 POCl3 Inorganic materials 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 150000002462 imidazolines Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 238000011084 recovery 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- ZWUKMNZJRDGCTQ-UHFFFAOYSA-N Tizanidine hydrochloride Chemical compound Cl.ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 ZWUKMNZJRDGCTQ-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 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
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960002388 tizanidine hydrochloride Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 208000033999 Device damage Diseases 0.000 description 1
- 208000002038 Muscle Hypertonia Diseases 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 206010061533 Myotonia Diseases 0.000 description 1
- UHKWJFCLUIAKLD-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C12.C(C)(=O)N1C=NC=C1 Chemical compound N1=CC=CC2=CC=CC=C12.C(C)(=O)N1C=NC=C1 UHKWJFCLUIAKLD-UHFFFAOYSA-N 0.000 description 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction 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
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 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
- 229960004275 glycolic acid Drugs 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 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
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
Abstract
The invention discloses a kind of preparation method of the preparation method, specifically Tizanidine of new central skeletal muscle relaxant, comprise the following steps：(1) using organic acid A, compound S1 and compound S2 as raw material, reacted in organic solvent X, remove solvent, obtain Tizanidine acylate S3 crude products；(2) crude product for taking step (1) to obtain, organic acid A and organic solvent Y is added, is dissolved at 50~120 DEG C；(3) cool 50~75 DEG C, after 2~10h of insulation crystallization, cool 10~30 DEG C again, insulation continues 3~10h of crystallization, obtains Tizanidine acylate S3；(4) Tizanidine is prepared as raw material in the Tizanidine acylate S3 obtained using step (3).The inventive method has higher yield and purity simultaneously, and it is easy to operate, production efficiency is high, environmentally friendly, safe, suitable for industrialized production, there is wide market application foreground.
Description
Technical field
The present invention relates to process for preparing medicine field, and in particular to a kind of preparation method of Tizanidine.
Background technology
Tizanidine is a kind of central skeletal muscle relaxant with imidazoline structure, the entitled chloro- N- (4,5- of 5- of chemistry
Dihydro -1H- imidazoles -2- bases) -2,1,3- diazosulfide -4- amine, its molecular structural formula is as follows：
Tizanidine be in the market uniquely have pipe intestinal protection effect new central skeletal muscle relaxant and
Central α2Adrenoceptor agonists, developed by Novartis Co., Ltd of Switzerland earliest, in 1988 first in Denmark and
Switzerland lists, and then obtains selling licenses in more than 20 countries such as Europe, the U.S., Japan successively, be clinically used for treatment because brain with
Bone hypermyotonia, muscle spasmus and myotonia caused by trauma of spinal cord, cerebral hemorrhage, encephalitis, and multiple sclerosis etc. etc.
Disease.Tizanidine can alleviate spasticity, but not cause myasthenia, and therapeutic dose does not produce psychologic dependence, be tolerance
Property and the preferable central muscle relaxant of curative effect.At present, in clinical treatment, the hydrochlorides for using Tizanidine more.Make
It is very wide for new central skeletal muscle relaxant, the clinical practice of Tizanidine and its salt and the prospect of marketing.
At present, existing more document discloses the preparation method of Tizanidine, such as Chinese Journal of Pharmaceuticals,
2005,36,593rd, Chinese Journal of New Drugs, 2006,8,621, Yanbian University's journal (natural science edition), 2001,27,277,
EP644192, CN102140095 etc., its principal synthetic routes can be summarized as：Using ortho-nitro-parachloroaniline as initiation material, through nitre
Base reduces, cyclization obtains diazosulfide, then is condensed through nitrification, nitro reduction, with acylated imidazoline, goes acyl group, hydrochloric acid to be acidified
Obtain Tizanidine.But the Tizanidine impurity that above-mentioned route is prepared is more, quality is difficult to up to standard.And
And the key reaction in the route, i.e. 4- amino -5- chloro- 2, the condensation reaction of 1,3- diazosulfide and acylated imidazoline,
Make dehydrating agent and/or solvent using POCl3, the material has extremely strong corrosivity and tearing property, seriously endangers operating personnel
Health, caused acid tail gas is also very big to human body and environmental hazard during the course of the reaction for it；In industrial production, trichlorine oxygen
Phosphorus has extremely strong corrosivity to equipment, easily causes device damage, is not suitable for being applied to industrialized production.
Therefore, it is necessary to explore a kind of new preparation method, the Tizanidine of high-purity can be obtained in high yield,
The use of corrosive reagents is also avoided that, so as to be adapted to industrialized production.
The content of the invention
To solve the above problems, the invention provides a kind of preparation method of Tizanidine, comprise the following steps：
(1)
Using organic acid A, compound S1 and compound S2 as raw material, reacted in organic solvent X, remove solvent, replaced
Zha Niding acylate S3 crude products；
(2) crude product for taking step (1) to obtain, organic acid A and organic solvent Y is added, is dissolved at 50~120 DEG C；
(3) cooling 50~75 DEG C, after 2~10h of insulation crystallization, cool 10~30 DEG C again, insulation continues 3~10h of crystallization,
Obtain Tizanidine acylate S3；
(4) Tizanidine is prepared as raw material in the Tizanidine acylate S3 obtained using step (3)；
Wherein, the organic acid A is C2~C7Organic acid；
R1For methyl, ethyl, pi-allyl or benzyl；R2For hydrogen, methyl, acetyl group, propiono, benzoyl, tert-butyl group first
Carbonyl or COOR3, R3For methyl, ethyl, pi-allyl, benzyl, the tert-butyl group or phenyl.
Further, the organic acid A be acetic acid, ethoxyacetic acid, caproic acid, hydroxyacetic acid, butyric acid, 2 hydroxy propanoic acid,
Ethanedioic acid, malonic acid, salicylic acid, citric acid or malic acid.
Further, in step (2), the organic solvent Y is selected from C1~C4Alcohols solvent.
Further, the organic solvent Y is selected from methanol, ethanol or isopropanol.
Further, in step (2), the organic solvent Y and organic acid A envelope-bulk to weight ratio is 20mL：1~2g.
Further, in step (2), the organic solvent Y and compound S1 volume mass ratio is 6~15mL：1g.
Further, in step (2), 65~90 DEG C of the temperature of the dissolving.
Further, in step (2), the time of the dissolving is 0.5~10h, preferably 0.5~5h.
Further, in step (1), the organic solvent X is C1~C4Alcohols solvent or its composition with DMF mixing
Solvent.
Further, in step (1), the C1~C4Alcohols solvent be selected from methanol, ethanol or isopropanol.
Further, in step (1), the alcohols solvent is 2~15 with DMF volume ratios:1, preferably 5~10:1.
Further, in step (1), the organic solvent X and compound S1 volume mass ratio is 6.0~40.0mL：
1g, preferably 8.0~37.0mL：1g..
Further, in step (1), compound S2 and compound S1 mol ratio is 0.9~2.0:1, preferably 1.0~
1.5:1。
Further, in step (1), organic acid A and compound S1 mol ratio is 2~15:1, preferably 2~9:1.
Further, in step (1), reaction temperature is 50~120 DEG C, preferably 65~90 DEG C.
Further, the step (4) comprises the following steps：
Tizanidine acylate S3 is taken, is added in the alcohols solvent solution of hydrogen chloride and reacts, hydrochloric acid is prepared and replaces
Zha Niding.
In some specific embodiments, the alcohols solvent solution of the hydrogen chloride can be the C of hydrogen chloride1~C4's
Alcohols solvent, such as methanol, ethanol or isopropanol.At room temperature fully after reaction, Tizanidine is separated out.
Present invention also offers a kind of method for preparing Tizanidine acylate, and it is the step (1) in preceding method
~(3), the method that Tizanidine acylate is prepared.
In the present invention, the C2~C7Organic acid refer to C2、C3、C4、C5、C6、C7Organic acid, i.e., with 2~7 carbon
The organic acid of atom.In some specific embodiments of the invention, the organic acid includes 1-2 carboxyl, can also include
0-1 hydroxyl.
In the present invention, the C1~C4Alcohols solvent refer to C1、C2、C3、C4Alcohols solvent, i.e., with 1~4 carbon original
The alcohols solvent of the straight or branched of son, such as methanol, ethanol, ethylene glycol, propyl alcohol, 2- propyl alcohol, isopropanol, butanol etc..
Compared with prior art, the inventive method has the advantages of following notable：
1st, preparation method of the invention, by the screening of technique, with organic acid, the benzo thiophenes two of 4- amino -5- chloro- 2,1,3-
Azoles and acylated imidazoline are raw material, and the acylate crude product of Tizanidine is prepared.In the recrystallization process of crude product, lead to
The mode of gradient cooling is crossed, so as to high yield, the acylate of Tizanidine has been obtained to high-purity, finally as raw material pole
The quality of the big total recovery and finished product for improving Tizanidine synthesis.
The Tizanidine acylate being prepared by the inventive method, yield is up to more than 86%, high purity
More than 99.9%.As raw material, the product yield of Tizanidine is up to more than 96%, high purity more than 99.95%；
Two step total recoverys are up to more than 83%.It can be seen that this method avoids the introducing of unnecessary impurity, Tizanidine is substantially increased
The total recovery of synthesis and the quality of finished product.
2nd, the inventive method is to complete the acyl group in the condensation and condensation product imidazoline ring of substrate by single step reaction
Hydrolysis, it is easy to operate, the time has not only been saved, has improved industrial production efficiency, has more greatly reduced technique productions cost.
3rd, the finished product being prepared by the inventive method without being further purified again, purity i.e. up to 99.95%
More than, technological operation is enormously simplify, avoids yield loss caused by recrystallization.
4th, the inventive method has the characteristics of environmentally friendly, safe.It is in existing condensation reaction to use POCl3 as dehydration more
Agent and/or solvent, it is very big to operating personnel and environmental hazard, equipment corrosion is more easily caused, but the condensation in the inventive method is anti-
The use of POCl3 should be avoided, not only avoid equipment corrosion, the body for being more beneficial for environmental protection and operating personnel is good for
Health.
5th, the inventive method is applied to industrialized production.This method is simple to operate, to equipment without particular/special requirement, environmental protection peace
Entirely, meet the needs of large-scale industrial production, greatly save material, reduce industrial production cost.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The embodiment of form by the following examples, the above of the present invention is remake further specifically
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment
Raw material 4- amino -5- chloro- 2,1,3- diazosulfide can be commercially available by purchase, can also be according to document report
The method in road is prepared, such as document Chinese Journal of New Drugs, and 2006,8,621.Raw material N- acetyl group -2- ethylmercapto group -2- imidazoles
Quinoline and N- carbomethoxy -2- methyl mercapto -2- imidazolines are prepared according to literature method, such as document Journal of Medicinal
Chemistry,Vol.20(1977)pp.158-160.Saturation ethanol solution of hydrogen chloride and organic acid used can be with embodiment
It is commercially available by purchase.
Embodiment 1
393g glacial acetic acid is weighed, is added in 5000mL isopropanols, adds the benzo thiophenes two of 136g 4- amino -5- chloro- 2,1,3-
Azoles and 189g N- acetyl group -2- ethylmercapto group -2- imidazolines.90~95 DEG C are warming up to react 19 hours.Remove solvent under reduced pressure, it is residual
Stay thing to add in 1100mL isopropanols and 55g glacial acetic acid, be warming up to 65~70 DEG C and stir 2 hours.It is small to be cooled to 15 DEG C of stirrings 3
When, then be cooled to -5 DEG C and stir 3 hours.Filtering, dry.It there are Tizanidine glacial acetic acid salt 203.4g, yield 88.5%, purity
For 99.91%
Gained Tizanidine glacial acetic acid salt is added in 2800mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 3 hours.Cross
Filter, dry.It there are solid Tizanidine 182g, yield 96.7%, purity 99.96%.1H-NMR(400MHz,d6-
DMSO):δ3.68(s,4H,CH2CH2), 7.93 (d, 1H, J=9.6Hz, Ar-H), 8.19 (d, 1H, J=9.6Hz, Ar-H),
8.58 (brs, 2H, NH+HCl), 11.25 (brs, 1H, NH) mass spectrums show its FAB m/z：254(M++H-Cl)。
Contrast experiment 1 is (with reference to existing document：Chinese Journal of New Drugs, 2006,15,621)
18.6g 4- amino -5- chloro- 2,1,3- diazosulfide and 15.4g 1- acetyl imidazole quinoline -2- ketone are weighed, is added
Enter in 120mL POCl3s, be warming up to 60~65 DEG C and react 36 hours.Decompression steams solvent, is added into gained grease
160mL methanol, temperature rising reflux react 4 hours.It is cooled to room temperature, reaction solution is poured into 160mL frozen water, sodium hydrate aqueous solution regulation
PH to 9~10.Filtering, dry.Obtain pulverulent solids Tizanidine 18g, yield 71%.
Gained Tizanidine is added into 100mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 1 hour.Filter, filter cake nothing
Dried after water-ethanol washing, ethyl alcohol recrystallization, obtain solid Tizanidine 17.5g, yield 85.0%, purity 99.25%.
Contrast experiment 2
39.3g glacial acetic acid is weighed, is added in 500mL isopropanols, adds the benzo thiophenes of 13.6g 4- amino -5- chloro- 2,1,3-
Diazole and 19.2g N- carbomethoxy -2- methyl mercapto -2- imidazolines.90~95 DEG C are warming up to react 19 hours.Remove solvent under reduced pressure,
Residue is dissolved in isopropanol, is stirred at room temperature.Filtering, obtains Tizanidine glacial acetic acid salt 12.3g.Yield 53.3%, purity are
78.45%.
Gained Tizanidine glacial acetic acid salt is added into 280mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 3 hours, is filtered,
Filter cake is dried after being washed with absolute ethyl alcohol, ethyl alcohol recrystallization, obtains solid Tizanidine hydrochloride 9.4g, yield 82.3%, purity
For 86.98%.
Contrast experiment 3
39.3g glacial acetic acid is weighed, is added in 500mL isopropanols, adds the benzo thiophenes of 13.6g 4- amino -5- chloro- 2,1,3-
Diazole and 18.9g N- acetyl group -2- ethylmercapto group -2- imidazolines.90~95 DEG C are warming up to react 19 hours.Remove solvent under reduced pressure,
Residue is dissolved in isopropanol, is stirred at room temperature.Filtering, obtains Tizanidine acetate 12.9g.Yield 56.1%, purity are
79.56%.
Gained Tizanidine acetate is added into 280mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 4 hours, is filtered, filter
Cake is dried after being washed with absolute ethyl alcohol, and ethyl alcohol recrystallization obtains solid Tizanidine hydrochloride 10.1g, yield 85.0%, and purity is
88.21%.
Embodiment 2
158g glacial acetic acid is weighed, is added in 2000mL ethanol, adds 100g 4- amino -5- chloro- 2,1,3- diazosulfide
With 132.6g N- acetyl group -2- ethylmercapto group -2- imidazolines.Backflow is warming up to, is reacted under reflux state to complete.4g activated carbons
Decolourize, filtering, filtrate is down to room temperature, filters.Filter cake adds 1500mL ethanol and 75g glacial acetic acid, is warming up to 75~80 DEG C of stirrings 2
Hour.25 DEG C are cooled to stir 4 hours.- 5 DEG C are cooled to again to stir 5 hours.Filtering, dry.It there are Tizanidine glacial acetic acid salt
146g, yield 86.3%, purity 99.93%.
Gained Tizanidine glacial acetic acid salt is added in 3000mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 4 hours.Cross
Filter, dry.It there are solid Tizanidine 132g, yield 97.9%, purity 99.97%.
Embodiment 3
393g glacial acetic acid is weighed, is added in 5000mL isopropanols, adds the benzo thiophenes two of 136g 4- amino -5- chloro- 2,1,3-
Azoles and 192g N- carbomethoxy -2- methyl mercapto -2- imidazolines, it is warming up to 90~95 DEG C and reacts 19 hours.Remove solvent under reduced pressure, it is residual
Stay thing to add in 1600mL isopropanols and 80g glacial acetic acid, be warming up to 65~70 DEG C and stir 2 hours.It is small to be cooled to 15 DEG C of stirrings 3
When, then be cooled to -5 DEG C and stir 4 hours.Filtering, dry.Tizanidine glacial acetic acid salt 200g, yield 87% are there are, purity is
99.95%
Gained Tizanidine ethoxyacetic acid salt is added in 3500mL saturation ethanol solution of hydrogen chloride, it is small to be stirred at room temperature 4
When.Filtering, dry.It there are solid Tizanidine 179.4g, yield 97%, purity 99.98%.
Embodiment 4
336.5g ethoxyacetic acids are weighed, add 3182mL methanol and 318mLDMF in the mixed solvent, add 200g 4-
Amino -5- chloro- 2,1,3- diazosulfide and 186g N- acetyl group -2- ethylmercapto group -2- imidazolines, are warming up to 65~70 DEG C and stir
Mix 10 hours.7g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 15 DEG C and stirred 2 hours, then drops
Extremely -5 DEG C of temperature stirs 6 hours.Filtering, filter cake add 2000mL methanol and 200g ethoxyacetic acids.It is warming up to 65~70 DEG C of stirrings
0.5 hour.It is cooled to 15 DEG C to stir 2 hours, then is cooled to -5 DEG C and stirs 3 hours.Filtering, dry.It there are Tizanidine ethoxy
Guanidine-acetic acid salt 334g, yield 86.5%, purity 99.91%.
Gained Tizanidine ethoxyacetic acid salt is added in 3500mL saturation ethanol solution of hydrogen chloride, it is small to be stirred at room temperature 4
When.Filtering, dry.It there are solid Tizanidine 262g, yield 96.8%, purity 99.95%.
Embodiment 5
Weigh 375.5g caproic acids, add 2400mL ethanol and 300mLDMF in the mixed solvent, add 200g 4- amino-
The chloro- 2,1,3- diazosulfides of 5- and 278g N- acetyl group -2- ethylmercapto group -2- imidazolines.It is small to be warming up to 75~80 DEG C of stirrings 8
When.5.4g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 10 DEG C and stirred 5 hours.0 is cooled to again
DEG C stirring 5 hours.Filtering, filter cake add 1800mL ethanol and 90g caproic acids.75~80 DEG C are warming up to stir 2 hours.It is cooled to 10
DEG C stirring 4 hours.0 DEG C is cooled to again to stir 5 hours.Filtering, dry.It there are Tizanidine caproate 349g, yield 87.5%,
Purity is 99.92%.
Gained Tizanidine caproate is added in 5000mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 5 hours.Cross
Filter, dry.It there are solid Tizanidine 265g, yield 96.9%, purity 99.97%.
Embodiment 6
327.7g hydroxyacetic acids are weighed, add 1714mL isopropanols and 286mLDMF in the mixed solvent, add 200g 4-
The chloro- 2,1,3- diazosulfides of amino -5- and 241g N- acetyl group -2- ethylmercapto group -2- imidazolines.85~90 DEG C are warming up to stir
Mix 12 hours.4g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 20 DEG C and stirred 4 hours.Drop again
Warm to 5 DEG C are stirred 10 hours.Filtering, filter cake add 1200mL isopropanols and 84g hydroxyacetic acids.It is warming up to 85~90 DEG C of stirrings 1
Hour.20 DEG C are cooled to stir 4 hours.5 DEG C are cooled to again to stir 10 hours.Filtering, dry.It there are Tizanidine hydroxyacetic acid
Salt 306g, yield 86.2%, purity 99.92%.
Gained Tizanidine hydroxyl acetate is added in 6000mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 6 hours.
Filtering, dry.It there are solid Tizanidine 263g, yield 97.5%, purity 99.98%.
Embodiment 7
Weigh 284.8g butyric acid, add 2188mL ethanol and 312mLDMF in the mixed solvent, add 200g 4- amino-
The chloro- 2,1,3- diazosulfides of 5- and 210g N- acetyl group -2- ethylmercapto group -2- imidazolines.It is small to be warming up to 75~80 DEG C of stirrings 10
When.5g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 20 DEG C and stirred 10 hours.Be cooled to again-
10 DEG C are stirred 4 hours.Filtering, filter cake add 2000mL ethanol and 160g butyric acid.75~80 DEG C are warming up to stir 5 hours.Cooling
Stirred 5 hours to 20 DEG C.- 5 DEG C are cooled to again to stir 4 hours.Filtering, dry.It there are Tizanidine butyrate 317g, yield
86.0%, purity 99.95%.
Gained Tizanidine butyrate is added in 4000mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 8 hours.Cross
Filter, dry.It there are solid Tizanidine 264g, yield 98.1%, purity 99.98%.
Embodiment 8
Weigh 340g Lactic acids and add 3333mL isopropanols and 667mLDMF in the mixed solvent, add 200g
The chloro- 2,1,3- diazosulfides of 4- amino -5- and 215g N- acetyl group -2- ethylmercapto group -2- imidazolines.It is warming up to 85~90 DEG C
Stirring 12 hours.8g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 25 DEG C and stirred 6 hours.Again
- 5 DEG C are cooled to stir 7 hours.Filtering, filter cake add 1600mL isopropanols and 80g 2 hydroxy propanoic acids.It is warming up to 85~90 DEG C
Stirring 3 hours.25 DEG C are cooled to stir 10 hours.- 5 DEG C are cooled to again to stir 8 hours.Filtering, dry.It there are Tizanidine 2-
Hydracrylate 327g, yield 88.3%, purity 99.93%.
Gained Tizanidine 2 hydroxy propanoic acid salt is added in 3800mL saturation ethanol solution of hydrogen chloride, it is small to be stirred at room temperature 6
When.Filtering, dry.It there are solid Tizanidine 268g, yield 97.2%, purity 99.99%.
Embodiment 9
Weigh 294g ethanedioic acids, add 1333mL methanol and 267mLDMF in the mixed solvent, add 200g 4- amino-
The chloro- 2,1,3- diazosulfides of 5- and 223g N- acetyl group -2- ethylmercapto group -2- imidazolines.It is small to be warming up to 65~70 DEG C of stirrings 13
When.3.2g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 10 DEG C and stirred 5 hours.0 is cooled to again
DEG C stirring 3 hours.Filtering, filter cake add 1400mL methanol and 70g ethanedioic acids.65~70 DEG C are warming up to stir 2 hours.It is cooled to
10 DEG C are stirred 5 hours.0 DEG C is cooled to again to stir 3 hours.Filtering, dry.It there are Tizanidine oxalate 322g, yield
86.9%, purity 99.95%.
Gained Tizanidine oxalate is added in 3500mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 5 hours.Cross
Filter, dry.It there are solid Tizanidine 262g, yield 96.5%, purity 99.98%.
Embodiment 10
Weigh 280g malonic acid, add 1925mL ethanol and 275mLDMF in the mixed solvent, add 200g 4- amino-
The chloro- 2,1,3- diazosulfides of 5- and 186g N- acetyl group -2- ethylmercapto group -2- imidazolines.It is small to be warming up to 75~80 DEG C of stirrings 15
When.4.4g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 5 DEG C and stirred 8 hours.Be cooled to again-
10 DEG C are stirred 5 hours.Filtering, filter cake add 2400mL ethanol and 144g malonic acid.75~80 DEG C are warming up to stir 1 hour.Drop
Warm to 5 DEG C are stirred 4 hours.- 10 DEG C are cooled to again to stir 5 hours.Filtering, dry.Tizanidine malonate 333g is there are, is received
Rate 86.3%, purity 99.92%.
Gained Tizanidine malonate is added in 6000mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 3 hours.Cross
Filter, dry.It there are solid Tizanidine 266g, yield 98.4%, purity 99.98%.
Embodiment 11
744g malonic acid is weighed, adds 2667mL isopropanols and 333mLDMF in the mixed solvent, adds 200g 4- ammonia
The chloro- 2,1,3- diazosulfides of base -5- and 195g N- acetyl group -2- ethylmercapto group -2- imidazolines.It is warming up to 85~90 DEG C of stirrings 9
Hour.6g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 15 DEG C and stirred 5 hours.Be cooled to again-
5 DEG C are stirred 3 hours.Filtering, filter cake add 2000mL isopropanols and 100g malonic acid.85~90 DEG C are warming up to stir 4 hours.Drop
Warm to 15 DEG C are stirred 6 hours.- 5 DEG C are cooled to again to stir 4 hours.Filtering, dry.Tizanidine malonate 335g is there are, is received
Rate 86.8%, purity 99.91%.
Gained Tizanidine malonate is added in 7000mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 3 hours.Cross
Filter, dry.It there are solid Tizanidine 262g, yield 96.6%, purity 99.99%.
Embodiment 12
Weigh 621g citric acids, add 1714mL ethanol and 286mLDMF in the mixed solvent, add 200g 4- amino-
The chloro- 2,1,3- diazosulfides of 5- and 205g N- acetyl group -2- ethylmercapto group -2- imidazolines.It is small to be warming up to 75~80 DEG C of stirrings 12
When.4g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 25 DEG C and stirred 6 hours.- 5 are cooled to again
DEG C stirring 7 hours.Filtering, filter cake add 3000mL ethanol and 150g citric acids.75~80 DEG C are warming up to stir 2 hours.Cooling
Stirred 7 hours to 25 DEG C.- 5 DEG C are cooled to again to stir 6 hours.Filtering, dry.It there are Tizanidine citrate 414g, yield
86.1%, purity 99.93%.
Gained Tizanidine citrate is added in 10L saturation ethanol solution of hydrogen chloride, is stirred at room temperature 10 hours.Cross
Filter, dry.It there are solid Tizanidine 261g, yield 96.9%, purity 99.98%.
Embodiment 13
650g malic acid is weighed, adds 2222mL isopropanols and 278mLDMF in the mixed solvent, adds 200g 4- ammonia
The chloro- 2,1,3- diazosulfides of base -5- and 220g N- acetyl group -2- ethylmercapto group -2- imidazolines.It is warming up to 85~90 DEG C of stirrings
15 hours.5g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 20 DEG C and stirred 3 hours.Cool again
Stirred 4 hours to -10 DEG C.Filtering, filter cake add 2000mL isopropanols and 100g malic acid.It is warming up to 85~90 DEG C of stirrings 0.5
Hour.20 DEG C are cooled to stir 5 hours.- 10 DEG C are cooled to again to stir 5 hours.Filtering, dry.It there are Tizanidine malic acid
Salt 340g, yield 87.5%, purity 99.93%.
Gained Tizanidine malate is added in 13L saturation ethanol solution of hydrogen chloride, is stirred at room temperature 9 hours.Filtering,
Dry.It there are solid Tizanidine 266g, yield 97.4%, purity 99.97%.
Embodiment 14
Weigh 375.5g caproic acids, add 1886mL ethanol and 314mLDMF in the mixed solvent, add 200g 4- amino-
The chloro- 2,1,3- diazosulfides of 5- and 232g N- acetyl group -2- ethylmercapto group -2- imidazolines.It is small to be warming up to 75~80 DEG C of stirrings 13
When.4.4g activated carbons are added, continue stir about 30 minutes, are filtered while hot.Filtrate is cooled to 10 DEG C and stirred 4 hours.0 is cooled to again
DEG C stirring 5 hours.Filtering, filter cake add 1800mL ethanol and 90g caproic acids.75~80 DEG C are warming up to stir 3 hours.It is cooled to 10
DEG C stirring 3 hours.0 DEG C is cooled to again to stir 4 hours.Filtering, dry.It there are Tizanidine caproate 325g, yield 87.8%,
Purity is 99.92%.
Gained Tizanidine caproate is added in 5100mL saturation ethanol solution of hydrogen chloride, is stirred at room temperature 5 hours.Cross
Filter, dry.It there are solid Tizanidine 264g, yield 96.2%, purity 99.98%.
In summary, the inventive method has higher yield and purity simultaneously, and it is easy to operate, production efficiency is high,
Environmental protection, safety, suitable for industrialized production, have wide market application foreground.
Claims (10)
- A kind of 1. preparation method of Tizanidine, it is characterised in that：Comprise the following steps：(1)Using organic acid A, compound S1 and compound S2 as raw material, reacted in organic solvent X, remove solvent, obtained for Buddhist nun is pricked Determine acylate S3 crude products；(2) crude product for taking step (1) to obtain, organic acid A and organic solvent Y is added, is dissolved at 50~120 DEG C；(3) cool 50~75 DEG C, after 2~10h of insulation crystallization, cool 10~30 DEG C again, insulation continues 3~10h of crystallization, must replace Zha Niding acylates S3；(4) Tizanidine is prepared as raw material in the Tizanidine acylate S3 obtained using step (3)；Wherein, the organic acid A is C2~C7Organic acid；R1For methyl, ethyl, pi-allyl or benzyl；R2For hydrogen, methyl, acetyl group, propiono, benzoyl, tert-butyl group first carbonyl Or COOR3, R3For methyl, ethyl, pi-allyl, benzyl, the tert-butyl group or phenyl.
- 2. according to the method for claim 1, it is characterised in that：The organic acid A is acetic acid, ethoxyacetic acid, caproic acid, hydroxyl Guanidine-acetic acid, butyric acid, 2 hydroxy propanoic acid, ethanedioic acid, malonic acid, salicylic acid, citric acid or malic acid.
- 3. according to the method for claim 1, it is characterised in that：In step (2), the organic solvent Y is selected from C1~C4Alcohol Class solvent；Preferably, the organic solvent Y is selected from methanol, ethanol or isopropanol.
- 4. according to the method for claim 1, it is characterised in that：In step (2), the organic solvent Y and organic acid A body Product mass ratio is 20mL：1~2g；The organic solvent Y and compound S1 volume mass ratio is 6~15mL：1g.
- 5. according to the method for claim 1, it is characterised in that：In step (2), 65~90 DEG C of the temperature of the dissolving.
- 6. method according to claim 1 or 5, it is characterised in that：In step (2), time of the dissolving for 0.5~ 10h, preferably 0.5~5h.
- 7. according to the method described in claim any one of 1-6, it is characterised in that：In step (1), the organic solvent X is C1~ C4Alcohols solvent or its composition with DMF mixed solvent；Preferably, the C1~C4Alcohols solvent be selected from methanol, ethanol or Isopropanol.
- 8. according to the method for claim 7, it is characterised in that：In step (1), the alcohols solvent is 2 with DMF volume ratios ~15:1, preferably 5~10:1；The organic solvent X and compound S1 volume mass ratio is 6.0~40.0mL：1g, preferably 8.0~37.0mL：1g；The compound S2 and compound S1 mol ratio is 0.9~2.0:1, preferably 1.0~1.5:1；The organic acid A and compound S1 mol ratio is 2~15:1, preferably 2~9:1；The temperature of the reaction is 50~120 DEG C, preferably 65~90 DEG C.
- 9. according to the method described in claim any one of 1-8, it is characterised in that：The step (4) comprises the following steps：Tizanidine acylate S3 is taken, is added in the alcohols solvent solution of hydrogen chloride and reacts, hydrochloric acid is prepared for Buddhist nun is pricked It is fixed.
- A kind of 10. method for preparing Tizanidine acylate, it is characterised in that：It is according to any one of claim 1-9 institutes Step (1)~(3) in the method stated, the method that Tizanidine acylate is prepared.
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