CN114206873A - Novel preparation method of epinastine - Google Patents
Novel preparation method of epinastine Download PDFInfo
- Publication number
- CN114206873A CN114206873A CN202080056099.0A CN202080056099A CN114206873A CN 114206873 A CN114206873 A CN 114206873A CN 202080056099 A CN202080056099 A CN 202080056099A CN 114206873 A CN114206873 A CN 114206873A
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- Prior art keywords
- chemical formula
- compound
- epinastine
- acid
- preparing
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- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 229960003449 epinastine Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- 239000010948 rhodium Substances 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical group CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 239000000739 antihistaminic agent Substances 0.000 abstract description 7
- 238000001308 synthesis method Methods 0.000 abstract description 7
- 230000002194 synthesizing effect Effects 0.000 abstract description 6
- -1 lithium aluminum hydride Chemical compound 0.000 description 16
- 229960002548 epinastine hydrochloride Drugs 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YZCYKOPNFLUUIN-UHFFFAOYSA-N n-(2-benzylphenyl)-2-chloroacetamide Chemical compound ClCC(=O)NC1=CC=CC=C1CC1=CC=CC=C1 YZCYKOPNFLUUIN-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- DWOBGCPUQNFAFB-UHFFFAOYSA-N 2-benzylaniline Chemical compound NC1=CC=CC=C1CC1=CC=CC=C1 DWOBGCPUQNFAFB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- NOVHEGOWZNFVGT-UHFFFAOYSA-N hydrazine Chemical compound NN.NN NOVHEGOWZNFVGT-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- GCXUHGZBBGZTII-UHFFFAOYSA-N a828071 Chemical compound ClC(Cl)=O.ClC(Cl)=O GCXUHGZBBGZTII-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000010485 coping Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- VKXSGUIOOQPGAF-UHFFFAOYSA-N epinastine hydrochloride Chemical compound [H+].[Cl-].C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 VKXSGUIOOQPGAF-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910052745 lead Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Inorganic materials O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel preparation method for synthesizing an antihistaminic drug epinastine. According to the novel method for producing epinastine synthesis of the present invention, since the number of synthesis steps is small and the synthesis method is safe as compared with the conventional epinastine production method, it is expected that epinastine, an antihistaminic drug, can be synthesized inexpensively by the above-mentioned production method and supplied to the market.
Description
Technical Field
The invention relates to a novel preparation method for synthesizing an antihistaminic drug epinastine.
The present invention was made in accordance with the subject number 201800000000361 with the support of the city of Anshan Korea, and the research and management institution for the above subjects was "Korea institute of manufacturing and technology", the research project name "strong small business support development project in Anshan City", the research project name "development and mass production of a novel synthesis method for epinastine hydrochloride", and the research period was "2016.10.01. -2018.12.31".
The present invention was made in accordance with the subject number 20170000002998 with the support of the korean ministry of education, and the research and management institution for the above subjects was "korean research consortium", the name of the research project was "personal basic research (ministry of education)", the name of the research subject was "research on endoplasmic reticulum stress regulating substances", and the research period was "2017.11.01. -2018.10.31".
This patent application claims the priority of korean patent application No. 10-2019-0095561, filed by the korean patent office at 8/6/2019, the disclosure of which is incorporated herein by reference.
Background
As a result of environmental pollution, epinastine, a second-generation antihistaminic drug, is a drug that greatly improves the degree of action on the central nerve and the phenomenon of lethargy, as a therapeutic agent for allergic disease patients, which is increasing every year, compared to the first-generation antihistaminic drug. In korea, sales are on the increase every year, and export demand is also very high. The known synthesis methods have the disadvantages of long synthesis steps, the use of explosive and highly toxic reagents. The synthesis method is a method for synthesizing epinastine hydrochloride by using a reagent with low toxicity through a short synthesis step, which improves the disadvantages.
As a known method for synthesizing epinastine hydrochloride, there is a Meilijian patent (Meilijian registration patent No. 4313931) for using phosgene (Phos)gene) and lithium aluminum hydride (LiAlH)4) As a core reaction; european patent (european registered patent No. 0496306a 1) uses a palladium/carbon (Pd/C) reagent and a hydrazine (hydrazine) reagent as core reactions; recently, Korean patent (Korean registration patent No. 10-1576620) introduced the introduction of amine group with cyclopropylamine (cycloprophylamine) and used sodium borohydride (NaBH)4) A method for preparing a reduced imino group by a reagent, and the like. Further, korean patent (korean registered patent No. 10-1859516) describes a method for preparing 2-benzylaniline, 2-benzylaniline being a starting material for synthesis used together in a known synthesis method.
For the American national registration patent No. 4313931, for example, [ equation 1]]As indicated, highly toxic substances such as Phosgene (Phosgene) are used, and lithium aluminium hydride (LiAlH) is used4) Are very explosive and therefore are very disadvantageous from a technological standpoint.
[ reaction formula 1]
For European registered patent No. 0496306A1, as shown in [ equation 2], a hydrogen reaction and a toxic hydrazine (hydrazine) reagent are used at 50 atm and 140 ℃ using a palladium/carbon (Pd/C) reagent.
[ reaction formula 2]
For Korean registered patent No. 10-1576620, for example, [ equation 3]]It is shown that, despite the very inexpensive and non-toxic cyclopropylamine (cyclopropyramine) and the inexpensive reducing agent sodium borohydride (NaBH)4) Reagents, and the absence of highly toxic reagents, but have the disadvantage that the synthesis steps are long and bromate, which requires special equipment, is used as an intermediate, compared to the present technique.
Disclosure of Invention
Problems to be solved by the invention
The present invention has been made to solve the above problems, and has been made in order to find a method for synthesizing epinastine, which is a second-generation antihistamine drug capable of coping with allergic patients, at low cost.
Accordingly, an object of the present invention is to provide a novel method for synthesizing epinastine.
However, the technical problems to be solved by the present invention are not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.
Means for solving the problems
In order to achieve the above-mentioned objects,
the invention provides a preparation method of epinastine, which comprises the following steps: a first step of reacting a compound of the following chemical formula 1 with cyanamide to obtain a compound of the following chemical formula 2; and a second step of reducing the compound of the following chemical formula 2 to obtain the compound of the following chemical formula 3.
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
In the above chemical formula 3, a is absent or means a pharmaceutically acceptable acid addition salt.
In one embodiment of the present invention, the first step of reacting the compound of chemical formula 1 of the present invention with cyanamide to obtain the compound of chemical formula 2 below may be performed in a solvent phase to which a base is added.
Here, the "alkalis" refer to the properties of substances that release hydroxide ions or absorb hydrogen ions in an aqueous solution. Also known as alkali (alkali), as a substance corresponding to an acid, cause a neutralization reaction with each other to form a salt and water. As the strong base, there are sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca (OH)2) Etc., as the weak base, there is ammonia (NH)4OH), magnesium hydroxide (Mg (OH)2) But is not limited thereto.
According to the present invention, the solvent in the step 1 reaction may be a polar aprotic solvent, and more specifically, may be any one of dimethylformamide, tetrahydrofuran, acetonitrile, dichloroethane, dimethylsulfur monoxide, dichloromethane, ethyl acetate, acetone, dimethylacetamide, N-methylpyrrolidone, but is not limited thereto.
In one embodiment of the present invention,
the second step of preparing the inventive compound of chemical formula 2 into the compound of chemical formula 3 may be performed in a solvent phase under hydrogen gas in the presence of an acid and/or a catalyst.
Here, "acid" refers to a substance that ionizes and releases hydrogen ions when dissolved in water. As a substance corresponding to the base, a neutralization reaction is caused to each other to form a salt and water. In addition, it reacts with metals having higher ionization tendency than hydrogen to generate hydrogen gas. Among the representative acids, hydrochloric acid (HCl) and sulfuric acid (H) are used as strong acids2SO4) Nitric acid (HNO)3) Etc., the weak acid is acetic acid (CH)3COOH), carbonic acid (H)2CO3) And the like.
Here, the "catalyst" refers to a substance that is not consumed during the reaction to change the reaction rate. Even small amounts can affect the reaction rate, and in general, in the presence of a catalyst, the reaction proceeds faster because less activation energy is required in the presence of a catalyst.The catalyst includes noble metal catalyst (Pt, Pb, Ir, Rh, etc.), metal catalyst (Fe, Ni, Co), metal oxide catalyst (MgO, TiO)2Etc.), composite oxide catalyst (Fe)2O3-MoO3) Solid acid catalysts (zeolites, heteropolyacids), mineral acid catalysts (HF, H)2SO4、H3PO4Etc.), ion exchange resin catalysts, etc. Further, the catalyst may be in a state of being supported on carbon.
The cyanamide in the above first step is 2 to 5 equivalents with respect to 1 equivalent of the compound of chemical formula 1, for example, 2 to 3 equivalents, 2 to 4 equivalents, 2 to 5 equivalents, 3 to 5 equivalents or any interval within the above range, or 2, 3, 4, 5 equivalents may be used, but is not limited thereto.
In one embodiment of the present invention, the reaction temperature in step 1 is room temperature to 200 ℃, for example, room temperature to 50 ℃, room temperature to 90 ℃, room temperature to 120 ℃, room temperature to 160 ℃, room temperature to 200 ℃, 50 ℃ to 90 ℃, 50 ℃ to 120 ℃, 50 ℃ to 160 ℃, 50 ℃ to 200 ℃, 90 ℃ to 120 ℃, 90 ℃ to 160 ℃, 90 ℃ to 200 ℃, 120 ℃ to 160 ℃, 120 ℃ to 200 ℃, 160 ℃ to 200 ℃, and any interval within the above-mentioned range, or any temperature, for example, 90 ℃, 120 ℃, 160 ℃, 200 ℃, but not limited thereto.
In the present invention, any one of heating and microwave may be used as the temperature adjusting method, but the method is not limited thereto.
In one embodiment of the invention, the reaction time of step 1 is from 20 minutes to 24 hours, for example, may be 20 minutes to 50 minutes, 20 minutes to 8 hours, 20 minutes to 12 hours, 20 minutes to 18 hours, 20 minutes to 24 hours, 30 minutes to 50 minutes, 30 minutes to 8 hours, 30 minutes to 12 hours, 30 minutes to 18 hours, 30 minutes to 24 hours, 50 minutes to 8 hours, 50 minutes to 12 hours, 50 minutes to 18 hours, 50 minutes to 24 hours, 8 hours to 12 hours, 8 hours to 18 hours, 8 hours to 24 hours, 12 hours to 18 hours, 12 hours to 24 hours, 18 hours to 24 hours, or any interval within the above range, or any time, such as 20 minutes, 30 minutes, 50 minutes, 8 hours, 12 hours, 18 hours, 24 hours, but is not limited thereto.
According to the present invention, the base in the first step reaction may be one or more selected from the group consisting of diisopropylethylamine, potassium carbonate, sodium tert-butoxide, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium hydroxide, and sodium iodide.
In one embodiment of the present invention, the equivalent of the base in the first step reaction is 1 to 3 equivalents, for example, 1 to 1.5, 1 to 2, 2 to 3, 1.5 to 2, 1.5 to 3, 2 to 3 equivalents and any interval within the above range, or 1, 1.5, 2, 3 equivalents, with respect to 1 equivalent of the compound of chemical formula 1, but is not limited thereto.
According to the present invention, the acid in the second step reaction may be any one selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, acetic acid and sulfuric acid.
In one embodiment of the present invention, a of the above chemical formula 3 is not present or may be any one of hydrochloride, hydrobromide, nitrate, acetate and sulfate. Preferably, but not limited to, hydrochloride.
"acid addition salts" are formed by pharmaceutically acceptable free acids and are obtained from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, nitrous or phosphorous acids, and non-toxic organic acids such as aliphatic monocarboxylic and dicarboxylic acid salts, phenyl-substituted alkanoic acid salts, hydroxyalkanoic and alkanedicarboxylic acid salts, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Acid addition salts may be prepared by conventional methods, for example, by dissolving the compound in an excess of an aqueous acid solution and precipitating the salt using a water-soluble organic solvent, for example, methanol, ethanol, acetone or acetonitrile. Alternatively, the salt may be prepared by evaporating the solvent or excess acid in the mixture and then drying the resultant, or by subjecting the precipitated salt to suction filtration.
In the present invention, the final target substance is preferably a hydrochloride, but in chemical formula 3, a may be absent or may be a hydrochloride, a bromate, a nitrate, an acetate and a sulfate. In the case of bromates, nitrates, acetates and sulfates, they can be converted to epinastine free base and then epinastine hydrochloride by neutralization.
"reduction" is a chemical reaction in which the oxidation number of an atom changes. Reduction in the present invention means obtaining hydrogen.
According to the present invention, the catalyst of the second step may be any one of palladium, platinum, nickel and rhodium. Preferably, palladium may be used, and the above metal catalyst may be in a state of being supported on carbon, but is not limited thereto.
According to the present invention, the solvent of the above-mentioned second step may be selected from the group consisting of alcohol, ethyl acetate, acetic acid, tetrahydrofuran, dichloromethane, cyclohexane, chloroform and diethyl ether. Preferably, it may be methanol, but is not limited thereto.
The present invention provides a method for preparing a compound of chemical formula 2, comprising the step of reacting a compound of chemical formula 1 with cyanamide to obtain a compound of chemical formula 2 as an intermediate, under the conditions as described above.
[ chemical formula 1]
[ chemical formula 2]
The present invention provides a method for preparing a compound of chemical formula 3, comprising the step of reducing a compound of chemical formula 2 to obtain a compound of chemical formula 3, under the specific conditions as described above.
[ chemical formula 2]
[ chemical formula 3]
In the above chemical formula 3, a is absent or means a pharmaceutically acceptable acid addition salt.
Effects of the invention
According to the novel method for producing epinastine synthesis of the present invention, since epinastine is synthesized in fewer steps and is a safe synthesis method as compared with the conventional epinastine production method, epinastine, which is a second-generation antihistaminic drug to be administered to allergic patients, can be synthesized inexpensively by the above-mentioned production method and supplied to the market.
Drawings
FIG. 1 is a process for the synthesis of epinastine hydrochloride of the present invention.
Detailed Description
In the following, preferred preparation examples are shown to aid understanding of the present invention. However, the following examples are provided only for easier understanding of the present invention, and the contents of the present invention are not limited by the following preparation examples.
< preparation example 1> preparation of N- (2-benzylphenyl) -2-chloroacetamide (1)
Commercial 2-benzylaniline (1841mg, 10.05mmol) was treated with chloroacetyl chloride (0.82mL, 10.25mmol) and pyridine (0.98mL, 12.11mmol) in toluene (10mL) at 0 deg.C under an argon atmosphere. The reaction mixture was stirred at 0 ℃ for 30 minutes and at room temperature for 1 hour, and then water (5mL) was added to the reaction to terminate the reaction. The resulting mixture was stirred for 20 min, diluted with ethyl acetate (200mL), washed with 1N hydrochloric acid (3 × 30mL) and saturated aqueous sodium chloride solution, and dried (MgSO)4) After this time, concentration under reduced pressure afforded N- (2-benzylphenyl) -2-chloroacetamide (2205mg, 85%) as a gray solid:
1H NMR(CDCl3,400MHz)δ7.99(br s,1H),7.84(d,J＝8.0Hz,1H),7.34-7.11(m,8H),4.06(s,2H),4.00(s,2H) (ii) a CAS Registry (Registry) 21535-43-3.
< preparation example 2> preparation of 6- (chloromethyl) -11H-dibenzo [ b, e ] azepine (6- (chloromethyl) -11H-dibenz [ b, e ] azepine) (2)
The flask containing polyphosphoric acid (4.0g, 46.9mmol) was treated with 1(610mg, 2.3mmol) and phosphorus oxychloride (1.0 mL). The reaction mixture was fitted with a reflux condenser and heated at 120 ℃ for 2 hours without stirring. The reaction mixture was poured into ice water (200mL) and the flask was washed with diethyl ether (200 mL). The combined aqueous and organic washes were stirred for 1 hour and the phases were separated. The organic phase was washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and dried (MgSO)4) After this time, concentration under reduced pressure gave compound 2(509mg, 90%):
1H NMR(CDCl3,400MHz)δ7.44(d,J＝8.0Hz,1H),7.31(td,J＝7.2,1.2Hz,1H),7.22-7.02(m,6H),4.69(br s,2H),3.53(s,2H)；13C NMR(CDCl3100MHz) delta 164.8,144.5,143.6,132.9,131.8,130.6,127.4,127.3,127.2,127.1,126.69,126.68,125.5,49.0, 39.0; CAS Registry 21535-44-4.
< example 1> preparation of epinastine hydrochloride
Step 1: synthesis of dihydroepinastine (3)
A solution of compound 2(479mg, 1.98mmol) in acetonitrile (MeCN, 20mL) was treated with commercially available cyanamide (250mg, 5.94mmol) and sodium tert-butoxide (285mg, 2.97 mmol). The reaction mixture was exposed to microwave reaction conditions (120 ℃, 30 minutes, normal absorption). The reaction mixture was diluted with ethyl acetate (200mL), washed with saturated aqueous sodium chloride solution, and dried (MgSO)4) Then, the mixture was concentrated under reduced pressure. By flash chromatography (SiO)2Gradient (0)～3％MeOH-CH2Cl2) The residue was separated to give dihydroepinastine (323mg, 66%): mp 181-184 ℃;
1H NMR(DMSO-d6,400MHz)δ7.60(dd,J＝8.0,1.2Hz,1H),7.48(dd,J＝7.2,1.6Hz,1H),7.38(dd,J＝7.4,1.4Hz,1H),7.35-7.13(m,5H),6.87(s,1H),5.72(s,2H),3.80(dd,J＝8.0,1.2Hz,2H)；13C NMR(DMSO-d6,100MHz)δ149.0,138.1,136.8,134.4,129.3,129.1,128.8,127.6,127.54(2C),127.47,127.29,127.27,123.5,122.5,39.1；MS(ESI+)m/z 248[M+H]+
step 2: synthesis of epinastine hydrochloride (4)
A solution of compound 3(100mg, 0.40mmol) in ethanol (20mL) and 6N aqueous hydrochloric acid (4mL) was treated with 10 wt.% palladium on activated carbon (100 mg). The reaction mixture was stirred under hydrogen for 24 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give epinastine hydrochloride as a white solid (98mg, 87%):
1H NMR(DMSO-d6,400MHz)δ8.51(s,1H),8.23(br s,2H),7.53-7.31(m,5H),7.28-7.13(m,3H),5.36(t,J＝9.8Hz,1H),4.50(d,J＝14.4Hz,1H),4.30(t,J＝9.6Hz,1H),3.71(d,J＝14.4Hz,1H),3.53(t,J＝9.8Hz,1H)；13c NMR (DMSO-d6,100MHz) delta 157.8,139.9,135.1,134.8,133.3,130.0,128.9,128.5,128.2,128.0,127.5,127.1,126.6,62.5,49.7, 36.9; CAS Registry 108929-04-0.
Experimental example 1 optimization study of Synthesis of Dihydroiepinastine
Although no route to epinastine hydrochloride synthesis using dihydroepinastine (3) has been reported, since the olefinic double bond of the imidazole ring of dihydroepinastine (3) can be selectively reduced to obtain the desired epinastine, the present inventors decided to use 3 as a precursor of epinastine, and optimized studies were conducted on 3 under the conditions and results shown below (table 1).
[ TABLE 1]
Experimental example 2 preparation of epinastine hydrochloride
The selective reduction process of the C-C double bond of the 3 compound prepared under the above conditions was investigated. Sodium borohydride (NaBH)4) Lithium borohydride (LiBH)4) Diisobutylaluminum hydride (DiBAL-H) and lithium aluminum hydride (LiAlH)4) When the metal hydride does not undergo a reduction reaction, most of the starting material (2) is recovered.
Next, compound 3 was exposed to hydrogenation conditions in various solvents, but when methanol, ethanol, ethyl acetate, dimethylformamide and tetrahydrofuran were used as solvents, the hydrogenation of 3 proceeded in low yield and was unsuccessful. When hydrogenated in a mixture of methanol and 6N aqueous hydrochloric acid as co-solvent, the final compound epinastine hydrochloride (3) is obtained. The method has the advantages of high yield up to 87 percent and simple synthesis method.
The present invention has been described above for illustrative purposes, and those skilled in the art to which the present invention pertains will appreciate that the present invention can be easily converted into other specific forms without changing the technical idea or essential features of the present invention. It is therefore to be understood that the above embodiments are illustrative in all respects and not restrictive.
Claims (18)
1. A method of making epinastine, comprising:
a first step of reacting a compound of the following chemical formula 1 with cyanamide to obtain a compound of the following chemical formula 2; and
a second step of reducing the compound of the following chemical formula 2 to obtain a compound of the following chemical formula 3:
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
In the above chemical formula 3, a is absent or means a pharmaceutically acceptable acid addition salt.
2. The method of preparing epinastine according to claim 1, wherein the first step of reacting the compound of chemical formula 1 with cyanamide to obtain the compound of chemical formula 2 is performed in a solvent phase to which a base is added.
3. The method of preparing epinastine according to claim 1, wherein the second step of reducing the compound of chemical formula 2 to obtain the compound of chemical formula 3 is performed in a solvent phase under hydrogen gas and in the presence of an acid and/or a catalyst.
4. The method of preparing epinastine according to claim 1, wherein 2 to 5 equivalents of cyanamide in the first step is used with respect to 1 equivalent of the compound of chemical formula 1.
5. The method of preparing epinastine according to claim 4, wherein 2 to 3 equivalents of cyanamide in the first step is used with respect to 1 equivalent of the compound of chemical formula 1.
6. The method for producing epinastine according to claim 1, wherein the reaction temperature in the first step is from room temperature to 200 ℃.
7. The method of producing epinastine according to claim 6, wherein the reaction temperature in the first step is achieved by using any one of heating and microwaves.
8. The method of producing epinastine according to claim 1, wherein the reaction time in the first step is 20 minutes to 24 hours.
9. The method of producing epinastine according to claim 1, wherein the solvent in the first step is a polar aprotic solvent.
10. The method of claim 9, wherein the polar aprotic solvent is any one of dimethylformamide, tetrahydrofuran, acetonitrile, dichloroethane, dimethylthio oxide, dichloromethane, ethyl acetate, acetone, dimethylacetamide, and N-methylpyrrolidone.
11. The method of producing epinastine according to claim 2, wherein the base in the first step is one or more members selected from the group consisting of diisopropylethylamine, potassium carbonate, sodium tert-butoxide, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium hydroxide, and sodium iodide.
12. The method of preparing epinastine according to claim 2, wherein 1 to 3 equivalents of the base in the first step are used with respect to 1 equivalent of the compound of chemical formula 1.
13. The method of producing epinastine of claim 3, wherein the acid in the second step is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, acetic acid and sulfuric acid.
14. The method of claim 1, wherein the compound of formula 3 is epinastine free salt without A, or A is any one of hydrochloride, hydrobromide, nitrate, acetate and sulfate.
15. The method according to claim 3, wherein the catalyst used in the second step is any one of palladium, platinum, nickel and rhodium.
16. The method of preparing epinastine according to claim 1, wherein the solvent in the second step is selected from the group consisting of alcohol, ethyl acetate, acetic acid, tetrahydrofuran, dichloromethane, cyclohexane, chloroform and diethyl ether.
17. The method of claim 16, wherein the alcohol is methanol.
18. A method for preparing a compound of chemical formula 2, comprising the step of reacting a compound of chemical formula 1 with cyanamide to obtain a compound of chemical formula 2:
[ chemical formula 1]
[ chemical formula 2]
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| PCT/KR2020/010290 WO2021025442A1 (en) | 2019-08-06 | 2020-08-05 | Novel method for producing epinastine |
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