CN103601702A - Preparation method of lomerizine hydrochloride - Google Patents
Preparation method of lomerizine hydrochloride Download PDFInfo
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- CN103601702A CN103601702A CN201310591413.7A CN201310591413A CN103601702A CN 103601702 A CN103601702 A CN 103601702A CN 201310591413 A CN201310591413 A CN 201310591413A CN 103601702 A CN103601702 A CN 103601702A
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- JQSAYKKFZOSZGJ-UHFFFAOYSA-N 1-[bis(4-fluorophenyl)methyl]-4-[(2,3,4-trimethoxyphenyl)methyl]piperazine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCN(C(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 JQSAYKKFZOSZGJ-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229950007692 lomerizine Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 239000012043 crude product Substances 0.000 claims abstract description 18
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 56
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 30
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 28
- 235000019253 formic acid Nutrition 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 238000004821 distillation Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 6
- 238000007865 diluting Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 235000021050 feed intake Nutrition 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 20
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 27
- 238000000034 method Methods 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000013078 crystal Substances 0.000 description 14
- 238000005755 formation reaction Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229960000935 dehydrated alcohol Drugs 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- -1 benzyl halide Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000019695 Migraine disease Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 206010027599 migraine Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HEAQHTKDZPKODU-UHFFFAOYSA-N 1-(chloromethyl)-2,3,4-trimethoxybenzene Chemical compound COC1=CC=C(CCl)C(OC)=C1OC HEAQHTKDZPKODU-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- RXKMOPXNWTYEHI-RDRKJGRWSA-N Flunarizine hydrochloride Chemical compound Cl.Cl.C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C\C=C\C=2C=CC=CC=2)CC1 RXKMOPXNWTYEHI-RDRKJGRWSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960002807 flunarizine hydrochloride Drugs 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001550 time effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of lomerizine hydrochloride, belonging to the technical field of preparation of crude drugs. According to the technical scheme, a solvent is added into a reaction system and the input ratio of the materials is adjusted, so that the yield is improved; meanwhile, the quality of the product is also effectively controlled, and the purity of the crude product of lomerizine hydrochloride reaches over 99.8 percent.
Description
Technical field
The present invention relates to a kind of preparation method of Lomerizine hydrochloride, belong to bulk drug preparing technical field.
Background technology
Lomerizine hydrochloride is a kind of new calcium channel blocker, is mainly used in treating migraine.Migraine is a kind of common disease of outbreak repeatedly, and its cause of disease is still not clear.With flunarizine hydrochloride comparison, in a short time effect more obviously and untoward reaction more lightly.In addition stronger to cerebrovascular selectivity, the effect that increases cerebral blood flow, protection cerebral tissue is stronger, less on the impact of heart.Aspect treatment and prevention of migraine, having its unique advantage, so the exploitation of Lomerizine hydrochloride there are good market outlook.
There are two kinds of crystal formations in Lomerizine hydrochloride, crystal formation I and II, referring to document [Journal of Pharmaceutical Sciences, 85 (7), 761-766; 1996], crystal formation I is being stable, nonhygroscopic below 64% at 25 ℃ of normal temperature and humidity.And crystal form II is under 25 ℃ of conditions of normal temperature, humidity is greater than 0% and just starts the moisture absorption, when reaching humidity 20%, can absorb the water of 2 molar equivalents.Therefore preparation needs the product of preparation change into the storage that crystal formation I could be steady in a long-term at normal temperatures and be suitable for pharmaceutical preparation.The preparation method who has simultaneously reported crystal formation I and II, crystal formation I obtains from acetonitrile recrystallization, and crystal form II prepares from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol and butanone.
Prior art Lomerizine hydrochloride synthetic has following several method:
The one, benzyl halide method of substitution:
Document [Synthesis, (12), 1989-1991; 2010] adopt 2,3,4-trimethoxy bromobenzyl and 1-[two-(4-fluorophenyl) methyl] piperazine reacts, then passes through silicagel column separation, obtains lomerizine, yield 90%, does not carry out salt-forming reaction.Owing to will using silicagel column separation, impurity removal, be not suitable for suitability for industrialized production.
Document Chinese Journal of Pharmaceuticals, 34 (11), 539-540; 2003, adopt 2,3,4-trimethoxy benzyl chloride and 1-[two-(4-fluorophenyl) methyl] piperazine enters 4 row and react, then obtains Lomerizine hydrochloride crude product through salify, yield is 73%, turns crystalline substance.
Document China Medicine University journal, 33 (2): 164～166; 2002 also adopt this method, and after salify, turning brilliant rear total recovery is 56% again.Because the reactive behavior of 2,3,4-trimethoxy benzyl chloride is lower, cause yield obviously on the low side, be unfavorable for the reduction of large production cost.
In addition compound V is for containing benzyl chloride or bromotoluene, and this compounds has larger pungency and tearing property, therefore to labor protection rank, requires high especially.Restriction is applied to large production.
The 2nd, Leuckart-Wallach method:
The starting material of this reaction have easily been bought, and low to labor protection rank.Therefore most of bibliographical information adopts this method.Document Chemical & Pharmaceutica1Bulletin, 35 (8), 3270-5; 1987, Compound I and Compound I I are heated to 120 ℃ of meltings, then drip formic acid reaction, the yield of salify is 40%.
Document Radioisotopes, 37 (5), 265-8; 1988, Compound I and Compound I I are heated to 150 ℃ of meltings, then drip formic acid reaction, the yield of salify is 50.6%.
Document China pharmaceutical chemistry magazine, 13 (5), 297-298; 2003, adopt Compound I and Compound I I are heated to 100 ℃ of meltings, then drip formic acid reaction, through salify, turning brilliant total recovery is 83% again.Chinese patent CN1562988A adopts and uses the same method, and after salify, turning brilliant total recovery is 55.6% again.
From the experimentation of report, prior art is not added any solvent and is made thinner in reaction, and total recovery is on the low side.All products of preparing have no purity report and impurity are wherein carried out to control method report above.
Summary of the invention
The primary technical problem solving of the present invention is the synthesis technique total recovery problem on the low side that overcomes existing Lomerizine hydrochloride.Second object of the present invention is to solve the poor problem of product purity.
The present invention still adopts Leuckart-Wallach method.By research, find, raw material II can be reacted with formic acid and be generated formylation impurity IV, and this is an inevitable side reaction, more or less.
By research, react, temperature is during lower than 100 ℃, and the growing amount of impurity IV can showed increased and the amount of product reduces.Therefore the temperature of reaction system can not be lower than 100 ℃, otherwise affect yield.By test, find that lomerizine is under high mild acidic conditions in addition, can demethylation occur and generate following two kinds of impurity V and VI.
Due to impurity V and VI and lomerizine structure very approaching, in salification process and treating process, form eutectic with Lomerizine hydrochloride, be difficult to remove.Once these two impurity form, and just cannot remove by crystallization method, therefore must control the formation of carrying out these two impurity by reaction process.
Because formic acid is reactant, participation is reacted and is obtained lomerizine, but itself is also to produce impurity IV, the reason of V and VI.Therefore reduce the concentration of formic acid in reaction solution, and immediately to separate be the best approach that reduces these foreign matter contents in finished product.In order to achieve this end, while we adopt to adding solvent to dilute in reaction system and adopting, drip the method for distilling and react, immediately the formic acid of not immediate reaction is distilled immediately, prevent formic acid enrichment in reaction system.By research, add suitable solvent effect very obvious.Technical grade formic acid has two kinds, and a kind of is anhydrous formic acid, and another kind is 85%～88% water-containing formic acid, and both drop into reaction effect no significant difference.Water and formic acid can be evaporated when higher than 100 ℃, but water and amount of formic acid during due to instant dropping in reaction system are fewer, in the situation that there is no solubilizing agent, be difficult to be steamed out, and add, can form azeotrope after non-aqueous solvent and immediately the two is all taken away simultaneously, temperature that simultaneously like this can guarantee system is more stable.
The solvent adding must meet the following conditions, under normal pressure boiling point higher than the organic solvent of 100 ℃, and this solvent can not with Compound I, II and formic acid reaction, can not dissolve each other with water.Because of the solvent of boiling point lower than 100 ℃, though can react but reaction conversion ratio is obviously on the low side and make yield low, as benzene, methylene dichloride, chloroform, normal hexane, hexanaphthene, sherwood oil, ethyl acetate, the low boiling point solvents such as isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), acetonitrile.
All alcohol, ketone, amine solvent can participate in reaction and be not suitable for doing diluting solvent, as methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, butanone, 2 pentanone, propione, cyclopentanone, pimelinketone, triethylamine, Isopropylamine equal solvent.
The solvent dissolving each other with water is not suitable for doing diluting solvent, due to the formic acid of the water that needs reaction to generate in reaction process and not immediate reaction not engler distillation remove.And dewater when the distillation effect of ability and the moisture of withing a hook at the end of the solvent dissolving each other with water, after reclaiming, water content is large, is unfavorable for recycling, this kind solvent is as dioxane, dimethyl sulfoxide (DMSO), N, dinethylformamide, N,N-dimethylacetamide, diglycol ethylene dme etc.
Consider that production cost controls, the conventional solvent of the preferential recommendation of reaction solvent is as toluene, dimethylbenzene, suberane, mono chloro benzene, methyl-phenoxide, but is not limited to cited.
By research, to test after adding reaction solvent, effect is very obvious, has not only improved yield, has also effectively controlled the quality of product simultaneously, and the crude product purity of Lomerizine hydrochloride reaches more than 99.8%.
Different from the technical scheme of existing report is, in reaction system of the present invention, must add a kind of solvent that meets above-mentioned condition restriction, as toluene, dimethylbenzene, suberane, mono chloro benzene, methyl-phenoxide etc., heating becomes after homogeneous system, more than being warmed up to again 100 ℃, could drip formic acid, and keep distillation state, make system steady temperature, time for adding is controlled at 1-4 hour and dropwises reaction and within 0.5-1 hour, gets final product stopped reaction, after concentrated, adding anhydrous HCl/ ethanolic soln to stir can obtain crude product by crystallization again, and step is as follows:
(1) by Compound I and II in molar ratio 1:1～1:1.1 feed intake, add Compound I and II gross weight 0.10-10 solvent doubly, as toluene, dimethylbenzene, suberane, mono chloro benzene, methyl-phenoxide etc., stirring heating is dissolved and continuous heating to 100 ℃～140 ℃ between.
(2) by being 1:1～1:2 with Compound I mol ratio, formic acid is added drop-wise in above-mentioned reaction system, and keeps distillation state, and formic acid azeotropic together with solvent of moisture and not immediate reaction is steamed, and time for adding is controlled at 1～4 hour.
(3) dropwise, continue to keep azeotropic temperature reaction 0.5～1 hour.
(4) underpressure distillation goes out diluting solvent
(5) add anhydrous alcohol solution residue, filter, then add anhydrous HCl/ ethanolic soln, controlling with the mol ratio of II is 1:2～1:3.
(6) be cooled to 10～20 ℃ of crystallizatioies to filter and obtain crude product.
(7) with acetonitrile, carry out recrystallization and turn brilliant.
Technique of the present invention compared with prior art, has improved reaction yield and quality product, has reduced the generation of the three wastes simultaneously.After distilling, can apply mechanically by diluting solvent.And dehydrated alcohol crystallization mother liquor and turn the acetonitrile mother liquor after crystalline substance, can recycling.After distillation, a small amount of organism residue can burning disposal.
Embodiment:
Reference examples 1:
By 19.6g Compound I (0.1mol) and 28.8g Compound I I (0.1mol), be stirred and heated to 105 ℃, keep reflux state, for melting homogeneous system, drip 88% formic acid 6.9g (0.132mol), within two hours, drip off, after dripping off, continue again reaction 1 hour.Steam except low boiling point component, add dehydrated alcohol 100ml, filter, then add 20% anhydrous HCl/ ethanolic soln 90ml, be cooled to 10～20 ℃, stirring and crystallizing, filters, and 70 ℃ dry, obtains product 41.0g, yield 75.8%, HPLC purity: 98.19%.
Add 160ml acetonitrile to reflux 6 hours gained crude product, cooling, filter, 70 ℃ dry obtains crystal formation I Lomerizine hydrochloride 38.0g, turns brilliant yield 92.7%, HPLC purity: 98.96%.
| Reference examples 1 | Impurity IV | Impurity V | Impurity IV | Total purity |
| Crude product | 0.27％ | 0.33％ | 0.16％ | 98.19％ |
| Turn brilliant product | 0.05％ | 0.31％ | 0.17％ | 98.96％ |
Reference examples 2:
By 9.8g Compound I (0.05mol) and 14.4g Compound I I (0.05mol), add dimethyl sulfoxide (DMSO) 24.2g, be stirred and heated to 115 ℃, drip 88% formic acid 3.6g (0.069mol), within two hours, drip off, after dripping off, continue again reaction 1 hour.Methyl-sulphoxide is removed in molecular distillation, adds dehydrated alcohol 50ml, filters, then adds 20% anhydrous HCl/ ethanolic soln 45ml, is cooled to 10～20 ℃ of stirring and crystallizing, filters, and 70 ℃ dry, obtains product 18.70g, yield 69.1%, HPLC purity: 97.98%.
Add 75ml acetonitrile to reflux 6 hours gained crude product, cooling, filter, 70 ℃ dry obtains crystal formation I Lomerizine hydrochloride 17.4g, turns brilliant yield 93.0%, HPLC purity: 98.56%.
| Reference examples 2 | Impurity IV | Impurity V | Impurity IV | Total purity |
| Crude product | 0.33％ | 0.23％ | 0.11％ | 97.98％ |
| Turn brilliant product | 0.07％ | 0.20％ | 0.11％ | 98.56％ |
Reference examples 3
19.6g Compound I (0.1mol), 28.8g Compound I I (0.1mol) being mixed, install water distilling apparatus additional, starting the first melting that heats up, then continuing to be stirred and heated to 115 ℃, there is serious curing phenomenon in reaction system.Drip again 88% formic acid 6.9g (0.132mol), within two hours, drip off, keep dripping process temperature 115 ℃ of left and right, after dripping off, continue again reaction 1 hour.After reaction, underpressure distillation goes out low boiling point component, and debris adds dehydrated alcohol 100ml, filters, then adds 20% anhydrous HCl/ ethanolic soln 90ml, be cooled to 10～20 ℃ of stirring and crystallizing, filter, 70 ℃ dry, obtain product 44.9g, yield 83.0%, HPLC purity: 98.11%.
Add 200ml acetonitrile to reflux 6 hours gained crude product, cooling, filter, 70 ℃ dry obtains crystal formation I Lomerizine hydrochloride 48.0g, turns brilliant yield 92.7%, HPLC purity: 98.95%.
| Reference examples 3 | Impurity IV | Impurity V | Impurity IV | Total purity |
| Crude product | 0.22％ | 0.23％ | 0.16％ | 98.11％ |
| Turn brilliant product | 0.03％ | 0.22％ | 0.17％ | 98.95％ |
Embodiment 1:
19.6g Compound I (0.1mol), 28.8g Compound I I (0.1mol) and 48.4g toluene are mixed, install water distilling apparatus additional, be stirred and heated to 115 ℃, drip 88% formic acid 6.9g (0.132mol), within two hours, drip off, keep dripping process temperature 115 ℃ of left and right, after dripping off, continue again reaction 1 hour.Reclaim under reduced pressure toluene after reaction, debris adds dehydrated alcohol 100ml, filters, then adds 20% anhydrous HCl/ ethanolic soln 90ml, be cooled to 10～20 ℃ of stirring and crystallizing, filter, 70 ℃ dry, obtain product 51.83g, yield 95.8%, HPLC purity: 99.86%.
Add 200ml acetonitrile to reflux 6 hours gained crude product, cooling, filter, 70 ℃ dry obtains crystal formation I Lomerizine hydrochloride 49.1g, turns brilliant yield 94.7%, HPLC purity: 99.96%.
| Embodiment 1 | Impurity IV | Impurity V | Impurity IV | Total purity |
| Crude product | 0.07％ | 0.02％ | 0.01％ | 99.86％ |
| Turn brilliant product | 0 | 0.02％ | 0.01％ | 99.96％ |
Embodiment 2:
100g Compound I (0.51mol), 161g Compound I I (0.56mol) and 2600g dimethylbenzene are mixed, install water distilling apparatus additional, be stirred and heated to 140 ℃, drip 88% formic acid 53.3g (1.02mol), within one hour, drip off, keep dripping process temperature 137-140 ℃ of left and right, after dripping off, continue again reaction 1 hour.Reclaim under reduced pressure dimethylbenzene after reaction, debris adds dehydrated alcohol 500ml, filters, then adds 20% anhydrous HCl/ ethanolic soln 186ml (1.02mol), be cooled to 10～20 ℃ of stirring and crystallizing, filter, 70 ℃ dry, obtain product 265g, yield 96.0%, HPLC purity: 99.82%.
Add 1000ml acetonitrile to reflux 6 hours gained crude product, cooling, filter, 70 ℃ dry obtains crystal formation I Lomerizine hydrochloride 252g, turns brilliant yield 95.1%, HPLC purity: 99.95%.
| Embodiment 2 | Impurity IV | Impurity V | Impurity IV | Total purity |
| Crude product | 0.03％ | 0.04％ | 0.01％ | 99.82％ |
| Turn brilliant product | 0 | 0.03％ | 0.01％ | 99.95％ |
Embodiment 3:
30.0kg Compound I (153mol), 45.4kg Compound I I (157.6mol) and 15kg suberane are mixed, install water distilling apparatus additional, be stirred and heated to 100 ℃, drip 88% formic acid 8.0kg (153mol), within four hours, drip off, keep dripping process temperature 110 ℃ of left and right, after dripping off, continue again reaction 0.5 hour.After reaction, reclaim suberane, debris adds dehydrated alcohol 120kg, filters, then adds 30% anhydrous HCl/ ethanolic soln 55.9kg, be cooled to 10～20 ℃ of stirring and crystallizing, filter, 70 ℃ dry, obtain product 78.4kg, yield 94.7%, HPLC purity: 99.87%.
Add 248kg acetonitrile to reflux 6 hours gained crude product, cooling, filter, 70 ℃ dry obtains crystal formation I Lomerizine hydrochloride 75.1kg, turns brilliant yield 95.8%, HPLC purity: 99.99%.
| Embodiment 3 | Impurity IV | Impurity V | Impurity IV | Total purity |
| Crude product | 0.03％ | 0.01％ | 0 | 99.87％ |
| Turn brilliant product | 0 | 0.01％ | 0 | 99.99％ |
Claims (5)
1. a preparation method for Lomerizine hydrochloride, reaction formula is as follows,
It is characterized in that, according to the following steps preparation:
(1) by Compound I and II in molar ratio 1:1～1:1.1 feed intake, add Compound I and II gross weight 0.10-10 solvent doubly, stirring heating is dissolved and continuous heating to 100 ℃～140 ℃ between;
Described in this step, thinner is selected from a kind of in toluene, dimethylbenzene, suberane, mono chloro benzene, methyl-phenoxide;
(2) by being 1:1～1:2 with Compound I mol ratio, formic acid is added drop-wise in above-mentioned reaction system, and keeps distillation state, and formic acid azeotropic together with solvent of moisture and not immediate reaction is steamed, and time for adding is controlled at 1～4 hour;
(3) dropwise, continue to keep azeotropic temperature reaction 0.5～1 hour;
(4) underpressure distillation goes out diluting solvent;
(5) add anhydrous alcohol solution residue, filter, then add anhydrous HCl/ ethanolic soln, controlling with the mol ratio of II is 1:2～1:3;
(6) be cooled to 10～20 ℃ of crystallizatioies to filter and obtain crude product;
(7) with acetonitrile, carry out recrystallization and turn brilliant.
2. preparation method described in claim 1, is characterized in that, in step (1), the mol ratio of Compound I and II is 1:1.
3. preparation method described in claim 1, is characterized in that, in step (1), the mol ratio of Compound I and II is 1:1.1.
4. preparation method described in claim 1, is characterized in that, in step (2), the mol ratio of Compound I and formic acid is 1:1.3.
5. preparation method described in claim 1, is characterized in that, in step (2), the mol ratio of Compound I and formic acid is 1:2.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175359A (en) * | 2015-07-31 | 2015-12-23 | 四川省百草生物药业有限公司 | Lomerizine Hydrochloride isomeride and preparation method therefor |
| CN114057667A (en) * | 2021-12-22 | 2022-02-18 | 湖南增达生物科技有限公司 | Preparation method of cinnarizine impurity and impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1562988A (en) * | 2004-03-17 | 2005-01-12 | 南京长澳医药科技有限公司 | Method for synthesizing Lomerizine Hydrochlortde |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1562988A (en) * | 2004-03-17 | 2005-01-12 | 南京长澳医药科技有限公司 | Method for synthesizing Lomerizine Hydrochlortde |
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| 彭东明，肖方青: "盐酸洛美利嗪的合成", 《中国医药工业杂志》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175359A (en) * | 2015-07-31 | 2015-12-23 | 四川省百草生物药业有限公司 | Lomerizine Hydrochloride isomeride and preparation method therefor |
| CN114057667A (en) * | 2021-12-22 | 2022-02-18 | 湖南增达生物科技有限公司 | Preparation method of cinnarizine impurity and impurity |
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