CN103601702B - A kind of preparation method of lomerizine hydrochloride - Google Patents
A kind of preparation method of lomerizine hydrochloride Download PDFInfo
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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 17
- 229950007692 lomerizine Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 239000012043 crude product Substances 0.000 claims abstract description 18
- 239000000126 substance Substances 0.000 claims abstract description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- 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
- 150000001875 compounds Chemical class 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 12
- 235000019441 ethanol Nutrition 0.000 claims description 12
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 2
- 235000021050 feed intake Nutrition 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 20
- 239000000463 material Substances 0.000 abstract 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 43
- 239000012535 impurity Substances 0.000 description 28
- 238000000034 method Methods 0.000 description 19
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 16
- 239000013078 crystal Substances 0.000 description 14
- 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 10
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000004821 distillation Methods 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 206010013786 Dry skin Diseases 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002460 anti-migrenic effect Effects 0.000 description 3
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- -1 benzyl halide Chemical class 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 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
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 0 *C(CCC1)CCN1C(c(cc1)ccc1F)c(cc1)ccc1F Chemical compound *C(CCC1)CCN1C(c(cc1)ccc1F)c(cc1)ccc1F 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- GSAIAIZAIFNBBV-UHFFFAOYSA-N Fc1ccc(C(c(cc2)ccc2F)N(CC2)CCN2I)cc1 Chemical compound Fc1ccc(C(c(cc2)ccc2F)N(CC2)CCN2I)cc1 GSAIAIZAIFNBBV-UHFFFAOYSA-N 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
- 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
- 239000002253 acid Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001412 amines Chemical class 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
- 230000008344 brain blood flow Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960002807 flunarizine hydrochloride Drugs 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 230000007794 irritation Effects 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
- 239000000155 melt Substances 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
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001550 time effect Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000010792 warming Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation method of lomerizine hydrochloride, belong to bulk pharmaceutical chemicals preparing technical field.Technical solution of the present invention has also efficiently controlled the quality of product by adding solvent in the reaction system and by adjusting material input ratio, improving yield, and the crude product purity of lomerizine hydrochloride reaches more than 99.8%.
Description
Technical field
The present invention relates to a kind of preparation method of lomerizine hydrochloride, belong to bulk pharmaceutical chemicals preparing technical field.
Background technology
Lomerizine hydrochloride is a kind of new calcium channel blocker, is mainly used for treating antimigraine.Antimigraine is a kind of anti-
The common disease made is recurred, its cause of disease is still not clear.Compared with flunarizine hydrochloride, in a short time effect become apparent from and adverse reaction more
Lightly.In addition stronger to cerebrovascular selectivity, increase brain blood flow, protect the effect of brain tissue stronger, influence to heart compared with
It is small.There is the advantages of it is unique in terms for the treatment of and preventing antimigraine, therefore before the exploitation of lomerizine hydrochloride has good market
Scape.
There are two kinds of crystal forms, crystal form I and II, referring to document [Journal of Pharmaceutical for lomerizine hydrochloride
Sciences, 85 (7), 761-766；1996], crystal form I is stable below 64% in 25 DEG C of room temperature and humidity, is not inhaled
Tide.And crystal form II, under the conditions of 25 DEG C of room temperature, humidity begins to the moisture absorption more than 0%, when reaching humidity 20%, can absorb 2
The water of molar equivalent.Therefore preparing needs product to be prepared to change into the storage that crystal form I could be steady in a long-term at normal temperatures and be adapted to
For pharmaceutical preparation.The preparation method of crystal form I and II is reported at the same time, and crystal form I is obtained from recrystallized from acetonitrile, and crystal form II is from first
It is prepared in alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol and butanone.
The synthesis of prior art lomerizine hydrochloride has following several method：
First, benzyl halide method of substitution：
Document [Synthesis, (12), 1989-1991；2010] using 2,3,4- trimethoxy bromobenzyls and 1- [double-(4-
Fluorophenyl) methyl] piperazine is reacted, then by silica gel post separation, obtains Lomerizine, yield 90%, it is anti-not carry out into salt
Should.Due to silicagel column separation, impurity removal to be used, be not suitable for industrialized production.
Document Chinese Journal of Pharmaceuticals, 34 (11), 539-540；2003, using 2,3,4- trimethoxy benzyl chlorine and 1-
[double-(4- fluorophenyls) methyl] piperazine is reacted into 4 rows, then by obtaining lomerizine hydrochloride crude product into salt, yield 73%, not
Carry out turning crystalline substance.
Document China Medicine University journal, 33 (2)：164~166；2002 also use the method, into salt after turn total after crystalline substance again
Yield is 56%.Since the reactivity of 2,3,4- trimethoxy benzyl chlorine is relatively low, causes yield substantially relatively low, be unfavorable for big life
Produce the reduction of cost.
In addition compound V is to have larger irritation and tearing property containing benzyl chloride or benzyl bromide a-bromotoluene, this kind of compound, because
This requires labor protection rank especially high.Limitation is applied to big production.
Second, Leuckart-Wallach methods：
The raw material of this reaction are readily available, and low to labor protection rank.Therefore most of document report uses this
Method.Document Chemical ＆ Pharmaceutica1Bulletin, 35 (8), 3270-5；1987, by compound I and compound
II is heated to 120 DEG C of meltings, then formic acid reaction is added dropwise, and the yield into salt is 40%.
Document Radioisotopes, 37 (5), 265-8；1988, compound I and compound II are heated to 150 DEG C and melted
Melt, then formic acid reaction is added dropwise, the yield into salt is 50.6%.
Document China journal of Medicinal Chemistry, 13 (5), 297-298；2003, it is heated to using by compound I and compound II
100 DEG C of meltings, then formic acid reaction is added dropwise, it is 83% through turning brilliant total recovery again into salt.Chinese patent CN1562988A is using same
The method of sample, into salt after to turn brilliant total recovery again be 55.6%.
From the point of view of the experimentation of report, the prior art in the reaction and is not added with any solvent and makees diluent, total recovery
It is relatively low.The all of above product prepared has no purity report and method report is controlled to impurity therein.
The content of the invention
Head technical problems to be solved of the invention are to overcome the synthesis technique total recovery of existing lomerizine hydrochloride relatively low
Problem.Second object of the present invention is to solve the problems, such as that product purity is poor.
The present invention still uses Leuckart-Wallach methods.Found by studying, raw material II can be reacted with formic acid
Formylated impurity IV is generated, this is an inevitable side reaction, more or less.
By research reaction, when temperature is less than 100 DEG C, the growing amount meeting showed increased of impurity IV, the amount of product is reduced.
Therefore the temperature of reaction system cannot be below 100 DEG C, otherwise influence yield.Additionally by experiment find Lomerizine in high temperature and
Under acid condition, demethylation can occur and generate following two impurity V and VI.
Since impurity V and VI and Lomerizine structure are very close, in salification process and subtractive process with hydrochloric acid Lome
Sharp piperazine forms eutectic, it is difficult to removes.The two impurity once being formed, can not just be removed, therefore must pass through by method for crystallising
Reaction process carries out the formation of the two impurity to control.
Because formic acid is reactant, participates in reaction and obtain Lomerizine, but itself be also the original for producing impurity IV, V and VI
Cause.Therefore the concentration of formic acid in reaction solution is reduced, and it is the best of these impurity contents in reduction finished product to separate immediately
Method.In order to realize this purpose, we using into reaction system add solvent be diluted and use be added dropwise while
The method of distillation is reacted, and immediately distills the formic acid of non-immediate reaction immediately, prevents that formic acid is rich in the reaction system
Collection.By research, appropriate solvent effect is added clearly.Technical grade formic acid has two kinds, and one kind is anhydrous formic acid, another
It is 85%~88% water-containing formic acid, both put into reaction effect no significant difference.Water and formic acid can steam when higher than 100 DEG C
Issue, but due to immediately be added dropwise when reaction system in water and amount of formic acid it is fewer, in the case of no solubilizer be difficult
It is steamed out, and can forms azeotropic mixture after adding nonaqueous solvents and immediately take away both of which at the same time, while so can guarantee that system
Temperature it is more stable.
The solvent added must meet the following conditions, and boiling point is higher than 100 DEG C of organic solvent, and this solvent under normal pressure
Cannot be with compound I, II and formic acid reaction, it is impossible to miscible with water.Because boiling point is less than 100 DEG C of solvent, though it can react
Conversion ratio is obvious relatively low and makes yield low, different such as benzene, dichloromethane, chloroform, n-hexane, hexamethylene, petroleum ether, ethyl acetate
The low boiling point solvents such as propyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, acetonitrile.
All alcohol, ketone, amine solvent can participate in reacting and being not suitable for making retarder thinner, such as methanol, ethanol, isopropanol, just
Butanol, acetone, butanone, 2 pentanone, propione, cyclopentanone, cyclohexanone, triethylamine, isopropylamine equal solvent.
Solvent miscible with water is not suitable for making retarder thinner, due to need during the reaction by react generation water and
The formic acid of non-immediate reaction is constantly distilled off.And solvent miscible with water water-scavenging capability difference and moisture of withing a hook at the end in distillation
Effect, water content is big after recycling, is unfavorable for recycling, this kind of solvent such as dioxane, dimethyl sulfoxide (DMSO), N, N- dimethyl
Formamide, n,N-dimethylacetamide, diglycol ethylene dimethyl ether etc..
Controlled in view of production cost, reaction dissolvent preferential recommendation uses common solvent such as toluene, dimethylbenzene, cycloheptyl
Alkane, monochloro-benzene, methyl phenyl ethers anisole, but be not limited to cited.
By research, tested after adding reaction dissolvent, effect clearly, not only increases yield, while also have
The quality of product is controlled to effect, the crude product purity of lomerizine hydrochloride reaches more than 99.8%.
One kind must be added to meet above-mentioned condition limit unlike the technical solution of existing report, in reaction system of the present invention
The solvent of system, such as toluene, dimethylbenzene, cycloheptane, monochloro-benzene, methyl phenyl ethers anisole, after heating is changed into homogeneous system, then are warming up to 100
Formic acid could be added dropwise more than DEG C, and keep distillation state, make system steady temperature, time for adding control is dripped when 1-4 is small
Bi Fanying 0.5-1 can stop reacting when small, added after concentration the stirring of anhydrous HCl/ ethanol solutions can crystallization obtain
Crude product, step are as follows：
(1) by compound I and II in molar ratio 1：1~1：1.1 feed intake, along with compound I and II gross weight 0.10-10
Times solvent, such as toluene, dimethylbenzene, cycloheptane, monochloro-benzene, methyl phenyl ethers anisole, agitating and heating dissolve and continue to be heated to 100 DEG C~
Between 140 DEG C.
(2) it is 1 to press with compound I molar ratios：1~1：2 formic acid is added drop-wise in above-mentioned reaction system, and keeps distillation shape
State, by moisture and the formic acid of non-immediate reaction, the azeotropic together with solvent steams, and time for adding is controlled when 1~4 is small.
(3) it is added dropwise, when continuing to keep azeotropic temperature reaction 0.5~1 small.
(4) it is evaporated under reduced pressure out retarder thinner
(5) absolute ethyl alcohol dissolution residual substance is added, filtering, adds anhydrous HCl/ ethanol solutions, control and mole of II
Than for 1：2~1：3.
(6) 10~20 DEG C of crystallizations are cooled to crude product is obtained by filtration.
(7) carry out recrystallization with acetonitrile and turn crystalline substance.
The technique of the present invention compared with prior art, improves reaction yield and product quality, while reduce the three wastes
Produce.Retarder thinner can be applied mechanically after distilling.And the acetonitrile mother liquor after absolute ethyl alcohol crystallization mother liquor and turn crystalline substance, it can recycle
Recycle.A small amount of debris can burning disposal after distillation.
Embodiment：
Reference examples 1：
By 19.6g compounds I (0.1mol) and 28.8g compounds II (0.1mol), 105 DEG C are stirred and heated to, is kept back
Stream mode, to melt homogeneous system, is added dropwise 88% formic acid 6.9g (0.132mol), drips off within two hours, reaction 1 is further continued for after dripping off
Hour.Low boiling point component is evaporated off, adds absolute ethyl alcohol 100ml, filtering, adds 20% anhydrous HCl/ ethanol solutions 90ml, cold
But to 10~20 DEG C, stirring and crystallizing, filtering, 70 DEG C of dryings, obtain product 41.0g, yield 75.8%, HPLC purity：98.19%.
By gained crude product add 160ml acetonitriles reflux 6 it is small when, cool down, filtering, 70 DEG C are dried to obtain crystal form I hydrochloric acid Lome
Sharp piperazine 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 compounds I (0.05mol) and 14.4g compounds II (0.05mol), dimethyl sulfoxide (DMSO) 24.2g is added, is stirred
Mix and be heated to 115 DEG C, 88% formic acid 3.6g (0.069mol) is added dropwise, drips off within two hours, be further continued for after dripping off reaction 1 it is small when.It is high
Vacuum distillation removes dimethyl sulfoxide, adds absolute ethyl alcohol 50ml, filtering, adds 20% anhydrous HCl/ ethanol solutions 45ml, cold
But to 10~20 DEG C of stirring and crystallizings, filtering, 70 DEG C of dryings, obtain product 18.70g, yield 69.1%, HPLC purity：97.98%.
By gained crude product add 75ml acetonitriles reflux 6 it is small when, cool down, filtering, 70 DEG C are dried to obtain crystal form I hydrochloric acid Lome profit
Piperazine 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 compounds I (0.1mol), 28.8g compounds II (0.1mol) are mixed, distilling apparatus is installed additional, is starting
Heating first melts, and is further continued for being stirred and heated to 115 DEG C, serious curing phenomenon occurs for reaction system.88% formic acid is added dropwise again
6.9g (0.132mol), drips off for two hours, keep be added dropwise process temperature at 115 DEG C or so, be further continued for after dripping off reaction 1 it is small when.
Low boiling point component is evaporated under reduced pressure out after reaction, Liquid Residue adds absolute ethyl alcohol 100ml, and filtering, adds 20% anhydrous HCl/ second
Alcoholic solution 90ml, is cooled to 10~20 DEG C of stirring and crystallizings, and filtering, 70 DEG C of dryings, obtain product 44.9g, yield 83.0%, HPLC is pure
Degree：98.11%.
By gained crude product add 200ml acetonitriles reflux 6 it is small when, cool down, filtering, 70 DEG C are dried to obtain crystal form I hydrochloric acid Lome
Sharp piperazine 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 compounds I (0.1mol), 28.8g compounds II (0.1mol) and 48.4g toluene are mixed, install distillation additional
Device, is stirred and heated to 115 DEG C, and 88% formic acid 6.9g (0.132mol) is added dropwise, drips off within two hours, keeps dropwise addition process temperature to exist
115 DEG C or so, be further continued for after dripping off reaction 1 it is small when.Toluene is recovered under reduced pressure after reaction, Liquid Residue adds absolute ethyl alcohol 100ml, mistake
Filter, adds 20% anhydrous HCl/ ethanol solutions 90ml, is cooled to 10~20 DEG C of stirring and crystallizings, filters, 70 DEG C of dryings, obtain product
51.83g, yield 95.8%, HPLC purity：99.86%.
By gained crude product add 200ml acetonitriles reflux 6 it is small when, cool down, filtering, 70 DEG C are dried to obtain crystal form I hydrochloric acid Lome
Sharp piperazine 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 compounds I (0.51mol), 161g compounds II (0.56mol) and 2600g dimethylbenzene are mixed, installs additional and steams
Distillation unit, is stirred and heated to 140 DEG C, and 88% formic acid 53.3g (1.02mol) is added dropwise, drips off within one hour, keeps that process temperature is added dropwise
At 137-140 DEG C or so, be further continued for after dripping off reaction 1 it is small when.Dimethylbenzene is recovered under reduced pressure after reaction, Liquid Residue adds absolute ethyl alcohol
500ml, filtering, adds 20% anhydrous HCl/ ethanol solutions 186ml (1.02mol), is cooled to 10~20 DEG C of stirring and crystallizings, mistake
Filter, 70 DEG C of dryings, obtain product 265g, yield 96.0%, HPLC purity：99.82%.
By gained crude product add 1000ml acetonitriles reflux 6 it is small when, cool down, filtering, 70 DEG C are dried to obtain crystal form I hydrochloric acid Lome
Sharp piperazine 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 compounds I (153mol), 45.4kg compounds II (157.6mol) and 15kg cycloheptane are mixed, installed additional
Distilling apparatus, is stirred and heated to 100 DEG C, and 88% formic acid 8.0kg (153mol) is added dropwise, drips off within four hours, keeps dropwise addition process temperature
Degree at 110 DEG C or so, be further continued for after dripping off reaction 0.5 it is small when.Cycloheptane is recycled after reaction, Liquid Residue adds absolute ethyl alcohol
120kg, filtering, adds 30% anhydrous HCl/ ethanol solutions 55.9kg, is cooled to 10~20 DEG C of stirring and crystallizings, filters, 70 DEG C
It is dry, obtain product 78.4kg, yield 94.7%, HPLC purity：99.87%.
By gained crude product add 248kg acetonitriles reflux 6 it is small when, cool down, filtering, 70 DEG C are dried to obtain crystal form I hydrochloric acid Lome
Sharp piperazine 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 kind of preparation method of lomerizine hydrochloride, reaction equation is as follows,
Explanation: C:\Documents and Settings\user\Application Data\Tencent\Users\1392798666\QQ\WinTemp\RichOle\[K7_5M]3H`XCRC4ZF7)XD_6.png
It is characterized in that, prepare according to the following steps：
(1) by compound I and II in molar ratio 1：1~1：1.1 feed intake, along with compound I and II gross weight
0.10-10 times of solvent, agitating and heating are dissolved and continued to be heated between 100 DEG C~140 DEG C；
The one kind of solvent described in this step in toluene, dimethylbenzene, cycloheptane；
(2) it is 1 to press with compound I molar ratios：1~1：2 formic acid is added drop-wise in above-mentioned reaction system, and keeps steaming
State is evaporated, the azeotropic together with solvent steams by moisture and the formic acid of non-immediate reaction, and time for adding is controlled when 1~4 is small；
(3) it is added dropwise, when continuing to keep azeotropic temperature reaction 0.5~1 small；
(4) it is evaporated under reduced pressure out retarder thinner；
(5) absolute ethyl alcohol dissolution residual substance is added, filtering, adds anhydrous HCl/ethanol solution, control and the molar ratio of II
For 1：2~1：3 ；
(6) 10~20 DEG C of crystallizations are cooled to crude product is obtained by filtration；
(7) carry out recrystallization with acetonitrile and turn crystalline substance.
2. preparation method described in claim 1, it is characterised in that in step (1), the molar ratio of compound I and II are 1：
1。
3. preparation method described in claim 1, it is characterised in that in step (1), the molar ratio of compound I and II are 1：
1.1。
4. preparation method described in claim 1, it is characterised in that in step (2), the molar ratio of compound I and formic acid is 1
：1.3.
5. preparation method described in claim 1, it is characterised in that in step (2), the molar ratio of compound I and formic acid is 1
：2.
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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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| 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 |
Non-Patent Citations (3)
| Title |
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| 洛美利嗪的合成;王立升;《广西大学学报（自然科学版）》;20010630;第26卷(第2期);第105-107页 * |
| 盐酸洛美利嗪的合成;彭东明，肖方青;《中国医药工业杂志》;20031231;第34卷(第7期);第317-318页 * |
| 盐酸洛美利嗪的合成工艺改进;王华等;《中国药物化学杂志》;20031031;第13卷(第5期);第297-298页 * |
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