CN115417859A - 一种苯甲酸利扎曲坦的合成方法 - Google Patents
一种苯甲酸利扎曲坦的合成方法 Download PDFInfo
- Publication number
- CN115417859A CN115417859A CN202211135359.0A CN202211135359A CN115417859A CN 115417859 A CN115417859 A CN 115417859A CN 202211135359 A CN202211135359 A CN 202211135359A CN 115417859 A CN115417859 A CN 115417859A
- Authority
- CN
- China
- Prior art keywords
- triazole
- rizatriptan
- rizatriptan benzoate
- tert
- bromobenzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- JPRXYLQNJJVCMZ-UHFFFAOYSA-N Rizatriptan benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1.C1=C2C(CC[NH+](C)C)=CNC2=CC=C1CN1C=NC=N1 JPRXYLQNJJVCMZ-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229960004789 rizatriptan benzoate Drugs 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 19
- -1 aryl hydrazine Chemical compound 0.000 claims abstract description 17
- GIMRDIDKYYDTBN-UHFFFAOYSA-N 1-[(4-bromophenyl)methyl]-1,2,4-triazole Chemical compound C1=CC(Br)=CC=C1CN1N=CN=C1 GIMRDIDKYYDTBN-UHFFFAOYSA-N 0.000 claims abstract description 14
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 12
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 claims abstract description 11
- WDZKKBDOGYBYBG-UHFFFAOYSA-N 4,4-dimethoxy-n,n-dimethylbutan-1-amine Chemical compound COC(OC)CCCN(C)C WDZKKBDOGYBYBG-UHFFFAOYSA-N 0.000 claims abstract description 7
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims abstract description 7
- YLRBJYMANQKEAW-UHFFFAOYSA-N 1-bromo-4-(bromomethyl)benzene Chemical compound BrCC1=CC=C(Br)C=C1 YLRBJYMANQKEAW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 6
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 229960000425 rizatriptan Drugs 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 150000002815 nickel Chemical class 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- VHSVJTYBTJCDFL-UHFFFAOYSA-L 1,2-dimethoxyethane;nickel(2+);dibromide Chemical compound Br[Ni]Br.COCCOC VHSVJTYBTJCDFL-UHFFFAOYSA-L 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 229940078494 nickel acetate Drugs 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 7
- 239000012299 nitrogen atmosphere Substances 0.000 claims 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000002153 concerted effect Effects 0.000 abstract description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052759 nickel Inorganic materials 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 239000003638 chemical reducing agent Substances 0.000 abstract description 2
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 7
- 239000012300 argon atmosphere Substances 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- HEALSPFCFYXUNT-UHFFFAOYSA-N 4,4-dimethyl-2-pyridin-2-yl-3h-pyridine Chemical compound C1=CC(C)(C)CC(C=2N=CC=CC=2)=N1 HEALSPFCFYXUNT-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- RRHNGIRRWDWWQQ-UHFFFAOYSA-N n-iodoaniline Chemical compound INC1=CC=CC=C1 RRHNGIRRWDWWQQ-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 2
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FUJKUTJPEGEMHG-UHFFFAOYSA-N [4-(1,2,4-triazol-1-ylmethyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1CN1N=CN=C1 FUJKUTJPEGEMHG-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZISSAWUMDACLOM-UHFFFAOYSA-N triptane Chemical compound CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- FMCUPJKTGNBGEC-UHFFFAOYSA-N 1,2,4-triazol-4-amine Chemical compound NN1C=NN=C1 FMCUPJKTGNBGEC-UHFFFAOYSA-N 0.000 description 1
- VFSVFGIODYZMOF-UHFFFAOYSA-N 1-(3-methylphenyl)-1h-benzimidazol-5-amine Chemical compound CC1=CC=CC(N2C3=CC=C(N)C=C3N=C2)=C1 VFSVFGIODYZMOF-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- ISPRGDKNJYQULU-UHFFFAOYSA-N 1h-indol-2-yl(trimethyl)silane Chemical compound C1=CC=C2NC([Si](C)(C)C)=CC2=C1 ISPRGDKNJYQULU-UHFFFAOYSA-N 0.000 description 1
- ICKCDMQZVXCGLB-UHFFFAOYSA-N 2-[5-(1,2,4-triazol-1-ylmethyl)-1h-indol-3-yl]ethanamine Chemical compound C1=C2C(CCN)=CNC2=CC=C1CN1C=NC=N1 ICKCDMQZVXCGLB-UHFFFAOYSA-N 0.000 description 1
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- NPVSJHHEHSZIGE-UHFFFAOYSA-N 3,3-dimethyl-6-pyridin-2-yl-4h-pyridine Chemical compound N1=CC(C)(C)CC=C1C1=CC=CC=N1 NPVSJHHEHSZIGE-UHFFFAOYSA-N 0.000 description 1
- BIWJXEPRNRDVPB-UHFFFAOYSA-N 3-bromo-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCBr BIWJXEPRNRDVPB-UHFFFAOYSA-N 0.000 description 1
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 1
- 238000006641 Fischer synthesis reaction Methods 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
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- 206010047139 Vasoconstriction Diseases 0.000 description 1
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- 125000003172 aldehyde group Chemical group 0.000 description 1
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- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
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- 239000012298 atmosphere Substances 0.000 description 1
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- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
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- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
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- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- CIXSDMKDSYXUMJ-UHFFFAOYSA-N n,n-diethylcyclohexanamine Chemical compound CCN(CC)C1CCCCC1 CIXSDMKDSYXUMJ-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
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- 230000003518 presynaptic effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 210000003901 trigeminal nerve Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种苯甲酸利扎曲坦的合成方法，该方法以商业化的对溴苄溴为起始原料，在碳酸钾存在下与商业化的1,2,4‑三氮唑经历一步SN2反应得到1‑(4‑溴苄基)‑1H‑1,2,4‑三唑，再与商业化的肼基甲酸叔丁酯经历一步光/镍协同催化反应来构建C‑N键，随后在酸性条件下脱保护，进而与4,4‑二甲氧基‑N,N‑二甲基丁胺经历Fisher吲哚合成，最后与苯甲酸成盐得到苯甲酸利扎曲坦。该方法采用更为温和、绿色环保的光/镍协同催化策略来合成芳基肼，避免了使用浓酸和强还原剂等对环境造成不友好的问题。本发明所用原料均为商业可得且价格低廉，合成步骤短，可大大降低其合成成本，有望实现工业化生产。
Description
技术领域
本发明属于化学制药合成技术领域，具体涉及一种苯甲酸利扎曲坦的合成方法。
背景技术
苯甲酸利扎曲坦化学名为N,N-二甲基-5-(1H-1,2,4-三氮唑-1-基甲基)-1H-吲哚-3-基乙胺苯甲酸盐，其结构式如下所示。
苯甲酸利扎曲坦是一种抗偏头痛的药物，系美国默克公司研制，1998年10月在荷兰首次上市，为第4个获准上市的曲坦类药物。临床上该药物通过刺激大脑血管壁的后接点5-HT1B受体引起大脑的血管收缩，同时刺激三叉神经末端突触前5-HT1D受体抑制神经肽的释放。该药物5mg或10mg剂量被认为是一种对中度或重度偏头痛急性治疗的有效药物，现已作为治疗偏头痛的一线选择药，具有吸收快、起效快、耐受性良好的优点。
专利EP497512是以对硝基溴苄和1,2,4-三唑钠为起始原料，制备路线中将得到的1-(4-肼基苯基)甲基-1,2,4-三氮唑与4-氯丁醛缩二甲醇进行Fischer反应合成吲哚环即2-[5-(1,2,4-三氮唑-1-基甲基)-1H-吲哚-3-基]乙胺，并以甲醛、氰基硼氢化钠甲基化后成盐得到苯甲酸利扎曲坦。此法中需要使用有毒试剂氯化亚锡；且Fisher反应和甲基化反应两步需要采用色谱法提纯，使用大量的溶剂，周期长，效率低；甲基化反应中需要使用氰基硼氢化钠价格较为昂贵，导致成本较高，不适合规模化生产。合成路线如下所示：
专利WO2004/014877通过1-(4-肼基苯基)甲基-1,2,4-三氮唑与α-氧代-δ-1,5-戊内酯缩合反应形成腙化合物，此腙经过Fisher反应得到吲哚并α吡喃酮，之后进行水解、酯化、胺基化、成盐得到苯甲酸利扎曲坦。该法虽然不需要进行柱色谱分离，但步骤繁琐，总收率低，同样不合适工业化生产。
专利EP573221将4-氨基-1,2,4-三唑用4-硝基苄溴在异丙醇中回流，分离得到氨基三唑(化合物7)，氨基三唑在亚硝酸钠的条件下去氨基，在钯碳、甲酸铵的条件下还原硝基到胺，接着用一锅法完成胺的重氮化、还原，再与4,4-二甲氧基-N,N-二甲基丁胺完成Fisher合成吲哚反应得到利扎曲坦，此法需要使用贵金属钯催化剂，价格昂贵，导致工业化生产成本较高。合成路线如下所示：
默克工艺小组利用钯催化的吲哚化开发出了两条新路线，如下所示。第一条路线是由芳胺化合物4开始，化合物4在氯化碘和碳酸钙下反应生成碘代苯胺(化合物8)。化合物8与双三乙基硅基保护的炔丁醇在碳酸钠的存在下钯催化偶联得到吲哚，在甲醇中去硅烷得到β-吲哚乙醇(化合物11)，化合物11转化为甲磺酰酯再用二甲胺处理得到利扎曲坦。第二条路线是通过碘代苯胺(化合物8)与酰基硅烷(化合物15)在DABCO的存在下通过钯催化偶联得到2-三甲基硅基吲哚(化合物16)。化合物15则是由1,3-二硫三甲硅烷与(3-溴丙基)二甲胺基化得到化合物14后用HgO和HgCl2除去缩二硫醇制备。这两条路线都需要使用昂贵的钯催化剂，以及氯化碘、双三乙基硅基、正丁基锂等特殊试剂，反应条件苛刻，操作复杂。
文献中以3-羟基-4-硝基苯甲醇为起始原料，经历酚羟基上保护、还原醛基、钯催化的区域选择性的Heck偶联反应得到含末端烯烃化合物20，再经历溴化、1H-1,2,4-三唑的钠盐选择性置换苄位溴得到化合物22，在三氯化钛的作用下环化合成吲哚，再经历一步二甲胺胺基化得到利扎曲坦(Angew.Chem.Int.Ed.,2015,54,11809–11812)。此法同样需要使用昂贵的钯催化剂、复杂的磷配体、步骤繁琐、反应条件苛刻，操作复杂。
发明内容
本发明的目的是提供一种原料价格低廉，反应步骤短，操作工艺简易，条件温和，适用于工业化生产的苯甲酸利扎曲坦的合成方法。
本发明提供的苯甲酸利扎曲坦的合成路线和具体合成方法如下所示：
1、在碳酸钾存在下，将对溴苄溴与1,2,4-三氮唑反应，得到1-(4-溴苄基)-1H-1,2,4-三唑。
2、在氮气氛围下，将1-(4-溴苄基)-1H-1,2,4-三唑与肼基甲酸叔丁酯加入溶剂中，再依次加入镍盐、配体和碱，将反应液升温至60～90℃，在紫光照射下反应10～14小时，得到2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯。
3、将2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯溶于四氢呋喃中，加入4mol/L盐酸二氧六环溶液，室温反应3～6小时，过滤，将所得固体和4,4-二甲氧基-N,N-二甲基丁胺溶于2～4mol/L盐酸水溶液中，升温至60～70℃反应2～4小时，得到利扎曲坦化合物。
4、将利扎曲坦与苯甲酸溶于乙醇中，回流反应3～6小时，冷却析出晶体，过滤，得到苯甲酸利扎曲坦。
上述步骤1中，反应温度为70～75℃，反应时间为6～8小时；优选对溴苄溴与1,2,4-三氮唑、碳酸钾的摩尔比为1:1.2～1.5:2.0～2.5。
上述步骤2中，所述镍盐为醋酸镍、溴化镍、氯化镍、镍(II)溴化乙烯二醇二甲基醚络合物中任意一种，配体为4,4-二-叔丁基联吡啶、4,4-二甲基联吡啶、5,5-二-甲基联吡啶中任意一种，碱为N,N-二环己基甲胺、N,N-二乙基环己胺、N,N-二异丙基乙胺中任意一种。优选所述1-(4-溴苄基)-1H-1,2,4-三唑与肼基甲酸叔丁酯、镍盐、配体、碱的摩尔比为1:1.2～2.0:0.02～0.08:0.02～0.08:1.2～2.0。
上述步骤2中，所述溶剂为二甲基亚砜、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺当中的任意一种。
上述步骤2中，优选紫光的波长范围为360～365nm或390～395nm。
上述步骤3中，优选所述2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯与4,4-二甲氧基-N,N-二甲基丁胺的摩尔比为1:1.0～1.2。
上述步骤4中，优选所述利扎曲坦与苯甲酸的摩尔比1:1.0～1.1。
本发明的有益效果如下：
本发明采用光/镍协同催化策略来构建C-N键合成芳基肼，缩短了利扎曲坦的合成步骤，避免了现有方法中合成芳基肼使用浓酸和强还原剂等对环境造成不友好的问题。本发明所用原料均为商业可得且价格低廉，合成步骤短，可大大降低其合成成本，有望实现工业化生产。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明的保护范围不仅限于这些实施例。
实施例1
1、将1.38g(20mmol)1,2,4-三氮唑与1.65g(12mmol)碳酸钾加入100mL圆底烧瓶中，加入20mL四氢呋喃，室温搅拌1小时，然后将2.48g(10mmol)对溴苄溴溶于6mL DMF并加入到反应液中，升温至70℃回流反应7小时，TLC显示反应完全，停止反应冷却至室温。将反应液用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后浓缩，粗品用DCM:MeOH(v:v＝50:1)分离，得到1.96g白色固体1-(4-溴苄基)-1H-1,2,4-三唑，收率为83％，结构表征数据为：1HNMR(400MHz,CDCl3)δ8.14(s,1H),7.99(s,1H),7.51(d,J＝8.1Hz,2H),7.15(d,J＝8.1Hz,2H),5.31(s,2H)；13C NMR(100MHz,CDCl3)δ152.4,143.2,133.7,132.3,129.7,122.9,52.9；HRMS(ESI)m/z C9H8BrF3N3Na[M+Na]+:理论值259.9794,实测值259.9794。
2、在氩气氛围下，将1.19g(5.0mmol)1-(4-溴苄基)-1H-1,2,4-三唑、0.99g(7.5mmol)肼基甲酸叔丁酯、46mg(0.25mmol)4,4-二甲基联吡啶、75mg(0.25mmol)镍(II)溴化乙烯二醇二甲基醚络合物、1.46g(7.5mmol)N,N-二环己基甲胺、20mL乙腈加入100mL反应瓶中，在390～395nm紫光光照下，80℃反应12小时。反应完后冷却至室温，加入饱和氯化钠水溶液和乙酸乙酯稀释萃取得到有机相，减压蒸馏得到粗产物，以DCM:MeOH(v:v＝50:1)柱层析分离产物，得到1.3g白色固体2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯，收率为90％，结构表征数据为：1H NMR(400MHz,DMSO)δ8.74(s,1H),8.56(s,1H),7.92(s,1H),7.62(s,1H),7.10(d,J＝8.4Hz,2H),6.61(d,J＝8.5Hz,2H),5.23(s,2H),1.39(s,9H)；13C NMR(100MHz,DMSO)δ156.0,151.5,149.6,143.7,128.9,125.6,111.6,78.9,52.0,28.1；HRMS(ESI)m/z C14H19N5O2Na[M+Na]+:理论值312.1431,实测值312.1437。
3、将1.3g(4.5mmol)2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯溶于10mL四氢呋喃中，并加入4.5mL 4mol/L盐酸二氧六环溶液，室温反应5小时。反应完后过滤得到固体，将所得固体和724mg(4.5mmol)4,4-二甲氧基-N,N-二甲基丁胺溶于5mL2mol/L盐酸水溶液中，升温至70℃反应3小时。反应完后冷却至室温，加质量浓度为40％的氢氧化钠水溶液调节pH为8.5～9.0，用异丙醇作展开剂，柱层析分离得到485mg利扎曲坦，收率为40％，结构表征数据为：1H NMR(400MHz,CDCl3)δ8.22(br,1H),7.99(s,1H),7.96(s,1H),7.56(s,1H),7.34(d,J＝8.3Hz,1H),7.11(dd,J＝8.3,1.5Hz,1H),7.07(d,J＝2.0Hz,1H),5.43(s,2H),2.95-2.90(m,2H),2.65-2.61(m,2H),2.34(s,6H)；13C NMR(100MHz,CDCl3)δ151.9,142.9,136.4,127.9,124.9,122.9,122.3,119.3,114.5,112.0,60.2,54.7,45.5,23.6；HRMS(ESI)m/z C15H20N5[M+H]+:理论值292.1533,实测值292.1533。
4、将270mg(1.0mmol)利扎曲坦与122mg(1.0mmol)苯甲酸溶于2mL乙醇中，80℃回流搅拌4小时，冷却到室温，析出白色晶体，过滤，干燥得到370mg苯甲酸利扎曲坦，收率为95％，结构表征数据为：1H NMR(400MHz,DMSO)δ10.96(s,1H),8.61(s,1H),7.97(s,1H),7.95(d,J＝2.4Hz,2H),7.59(s,1H),7.51(t,J＝7.3Hz,1H),7.43(t,J＝7.4Hz,2H),7.32(d,J＝8.3Hz,1H),7.20(s,1H),7.04(d,J＝8.4Hz,1H),5.42(s,2H),2.98-2.89(m,2H),2.85-2.81(m,2H),2.46(s,6H)；13C NMR(100MHz,DMSO)δ168.7,151.4,143.7,135.9,133.9,131.5,129.2,128.1,127.1,126.0,123.6,121.4,118.4,111.7,111.6,58.5,53.2,43.7,21.8。
实施例2
本实施例的步骤2中，在氩气氛围下，将119mg(0.5mmol)1-(4-溴苄基)-1H-1,2,4-三唑、99mg(0.75mmol)肼基甲酸叔丁酯、4.6mg(0.025mmol)4,4-二甲基联吡啶、4.4mg(0.025mmol)醋酸镍、146mg(0.75mmol)N,N-二环己基甲胺、2mL乙腈加入10mL反应管中，在390～395nm紫光光照下，80℃反应12小时。反应完后冷却至室温，加入饱和氯化钠水溶液和乙酸乙酯稀释萃取得到有机相，减压蒸馏得到粗产物，以DCM:MeOH(v:v＝50:1)柱层析分离产物，得到125mg白色固体2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯，收率为87％。其他步骤与实施例1相同。
实施例3
本实施例的步骤2中，在氩气氛围下，将119mg(0.5mmol)1-(4-溴苄基)-1H-1,2,4-三唑、99mg(0.75mmol)肼基甲酸叔丁酯、4.6mg(0.025mmol)5,5-二甲基联吡啶、7.5mg(0.025mmol)镍(II)溴化乙烯二醇二甲基醚络合物、146mg(0.75mmol)N,N-二环己基甲胺、2mL乙腈加入10mL反应管中，在390～395nm紫光光照下，80℃反应12小时。反应完后冷却至室温，加入饱和氯化钠水溶液和乙酸乙酯稀释萃取得到有机相，减压蒸馏得到粗产物，以DCM:MeOH(v:v＝50:1)柱层析分离产物，得到120mg白色固体2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯，收率为83％。其他步骤与实施例1相同。
实施例4
本实施例的步骤2中，在氩气氛围下，将119mg(0.5mmol)1-(4-溴苄基)-1H-1,2,4-三唑、99mg(0.75mmol)肼基甲酸叔丁酯、4.6mg(0.025mmol)4,4-二甲基联吡啶、7.5mg(0.025mmol)镍(II)溴化乙烯二醇二甲基醚络合物、116mg(0.75mmol)N,N-二乙基环己胺、2mL乙腈加入10mL反应管中，在390～395nm紫光光照下，80℃反应12小时。反应完后冷却至室温，加入饱和氯化钠水溶液和乙酸乙酯稀释萃取得到有机相，减压蒸馏得到粗产物，以DCM:MeOH(v:v＝50:1)柱层析分离产物，得到120mg白色固体2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯，收率为83％。其他步骤与实施例1相同。
实施例5
本实施例的步骤2中，在氩气氛围下，将119mg(0.5mmol)1-(4-溴苄基)-1H-1,2,4-三唑、99mg(0.75mmol)肼基甲酸叔丁酯、4.6mg(0.025mmol)4,4-二甲基联吡啶、7.5mg(0.025mmol)镍(II)溴化乙烯二醇二甲基醚络合物、146mg(0.75mmol)N,N-二环己基甲胺、2mL N,N-二甲基乙酰胺加入10mL反应管中，在390～395nm紫光光照下，80℃反应12小时。反应完后冷却至室温，加入饱和氯化钠水溶液和乙酸乙酯稀释萃取得到有机相，减压蒸馏得到粗产物，以DCM:MeOH(v:v＝50:1)柱层析分离产物，得到118mg白色固体2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯，收率为82％。其他步骤与实施例1相同。
实施例6
本实施例的步骤2中，在氩气氛围下，将119mg(0.5mmol)1-(4-溴苄基)-1H-1,2,4-三唑、99mg(0.75mmol)肼基甲酸叔丁酯、4.6mg(0.025mmol)4,4-二甲基联吡啶、7.5mg(0.025mmol)镍(II)溴化乙烯二醇二甲基醚络合物、146mg(0.75mmol)N,N-二环己基甲胺、2mL乙腈加入10mL反应管中，在360～365nm紫光光照下，80℃反应12小时。反应完后冷却至室温，加入饱和氯化钠水溶液和乙酸乙酯稀释萃取得到有机相，减压蒸馏得到粗产物，以DCM:MeOH(v:v＝50:1)柱层析分离产物，得到104mg白色固体2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯，收率为72％。其他步骤与实施例1相同。
Claims (8)
1.一种制备苯甲酸利扎曲坦的新方法，其特征在于，所述方法包括以下步骤：
(1)在碳酸钾存在下，将对溴苄溴与1,2,4-三氮唑反应，得到结构式如下的1-(4-溴苄基)-1H-1,2,4-三唑；
(2)在氮气氛围下，将1-(4-溴苄基)-1H-1,2,4-三唑与肼基甲酸叔丁酯加入溶剂中，再依次加入镍盐、配体和碱，将反应液升温至60～90℃，在紫光照射下反应10～14小时，得到结构式如下的2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯；
所述镍盐为醋酸镍、溴化镍、氯化镍、镍(II)溴化乙烯二醇二甲基醚络合物中任意一种；
所述配体为4,4-二-叔丁基联吡啶、4,4-二甲基联吡啶、5,5-二-甲基联吡啶中任意一种；
所述碱为N,N-二环己基甲胺、N,N-二乙基环己胺、N,N-二异丙基乙胺中任意一种；
(3)将2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯溶于四氢呋喃中，加入4mol/L盐酸二氧六环溶液，室温反应3～6小时，过滤，将所得固体和4,4-二甲氧基-N,N-二甲基丁胺溶于2～4mol/L盐酸水溶液中，升温至60～70℃反应2～4小时，得到结构式如下的利扎曲坦化合物；
(4)将利扎曲坦与苯甲酸溶于乙醇中，回流反应3～6小时，冷却析出晶体，过滤，得到苯甲酸利扎曲坦。
2.根据权利要求1所述的苯甲酸利扎曲坦的合成方法，其特征在于：步骤(1)中，反应温度为70～75℃，反应时间为6～8小时。
3.根据权利要求1所述的苯甲酸利扎曲坦的合成方法，其特征在于：步骤(1)中，所述对溴苄溴与1,2,4-三氮唑、碳酸钾的摩尔比为1:1.2～1.5:2.0～2.5。
4.根据权利要求1所述的苯甲酸利扎曲坦的合成方法，其特征在于：步骤(2)中，所述1-(4-溴苄基)-1H-1,2,4-三唑与肼基甲酸叔丁酯、镍盐、配体、碱的摩尔比为1:1.2～2.0:0.02～0.08:0.02～0.08:1.2～2.0。
5.根据权利要求1所述的苯甲酸利扎曲坦的合成方法，其特征在于：步骤(2)中，所述溶剂为二甲基亚砜、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺当中的任意一种。
6.根据权利要求1所述的苯甲酸利扎曲坦的合成方法，其特征在于：步骤(2)中，所述紫光的波长范围为360～365nm或390～395nm。
7.根据权利要求1所述的苯甲酸利扎曲坦的合成方法，其特征在于：步骤(3)中，所述2-[4-((1H-1,2,4-三唑-1-基)甲基)苯基]肼-1-羧酸叔丁酯与4,4-二甲氧基-N,N-二甲基丁胺的摩尔比为1:1.0～1.2。
8.根据权利要求1所述的苯甲酸利扎曲坦的合成方法，其特征在于：步骤(4)中，所述利扎曲坦与苯甲酸的摩尔比1:1.0～1.1。
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