CN113072462A - 来曲唑关键中间体的制备方法 - Google Patents
来曲唑关键中间体的制备方法 Download PDFInfo
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- CN113072462A CN113072462A CN202110288382.2A CN202110288382A CN113072462A CN 113072462 A CN113072462 A CN 113072462A CN 202110288382 A CN202110288382 A CN 202110288382A CN 113072462 A CN113072462 A CN 113072462A
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- Prior art keywords
- cyanophenyl
- reaction
- formic acid
- iii
- letrozole
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- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229960003881 letrozole Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 150000008359 benzonitriles Chemical class 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000005580 one pot reaction Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- -1 CuOAc Inorganic materials 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical class N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- DHDHJYNTEFLIHY-UHFFFAOYSA-N 4,7-diphenyl-1,10-phenanthroline Chemical compound C1=CC=CC=C1C1=CC=NC2=C1C=CC1=C(C=3C=CC=CC=3)C=CN=C21 DHDHJYNTEFLIHY-UHFFFAOYSA-N 0.000 claims description 3
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 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
- 229910021605 Palladium(II) bromide Inorganic materials 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910021606 Palladium(II) iodide Inorganic materials 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- HNNUTDROYPGBMR-UHFFFAOYSA-L palladium(ii) iodide Chemical compound [Pd+2].[I-].[I-] HNNUTDROYPGBMR-UHFFFAOYSA-L 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 18
- HQSCPPCMBMFJJN-UHFFFAOYSA-N 4-bromobenzonitrile Chemical compound BrC1=CC=C(C#N)C=C1 HQSCPPCMBMFJJN-UHFFFAOYSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000009776 industrial production Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229940122815 Aromatase inhibitor Drugs 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000003886 aromatase inhibitor Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 2
- UKOXPTLWNQHMJV-UHFFFAOYSA-N 4-(4-cyanobenzoyl)benzonitrile Chemical compound C=1C=C(C#N)C=CC=1C(=O)C1=CC=C(C#N)C=C1 UKOXPTLWNQHMJV-UHFFFAOYSA-N 0.000 description 2
- UMLFTCYAQPPZER-UHFFFAOYSA-N 4-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=C(C#N)C=C1 UMLFTCYAQPPZER-UHFFFAOYSA-N 0.000 description 2
- VCZNNAKNUVJVGX-UHFFFAOYSA-N 4-methylbenzonitrile Chemical compound CC1=CC=C(C#N)C=C1 VCZNNAKNUVJVGX-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000009615 deamination Effects 0.000 description 2
- 238000006481 deamination reaction Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 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
- 238000010189 synthetic method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- FMCUPJKTGNBGEC-UHFFFAOYSA-N 1,2,4-triazol-4-amine Chemical compound NN1C=NN=C1 FMCUPJKTGNBGEC-UHFFFAOYSA-N 0.000 description 1
- GDHXJNRAJRCGMX-UHFFFAOYSA-N 2-fluorobenzonitrile Chemical compound FC1=CC=CC=C1C#N GDHXJNRAJRCGMX-UHFFFAOYSA-N 0.000 description 1
- YBRVSVVVWCFQMG-UHFFFAOYSA-N 4,4'-diaminodiphenylmethane Chemical compound C1=CC(N)=CC=C1CC1=CC=C(N)C=C1 YBRVSVVVWCFQMG-UHFFFAOYSA-N 0.000 description 1
- FZMGMDLGMVXWCF-UHFFFAOYSA-N 4-bromo-n-tert-butylbenzamide Chemical compound CC(C)(C)NC(=O)C1=CC=C(Br)C=C1 FZMGMDLGMVXWCF-UHFFFAOYSA-N 0.000 description 1
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 229910004679 ONO2 Inorganic materials 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- ZWPWLKXZYNXATK-UHFFFAOYSA-N bis(4-methylphenyl)methanone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(C)C=C1 ZWPWLKXZYNXATK-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002395 mineralocorticoid Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- VBCFDVLVYCYDFZ-UHFFFAOYSA-N potassium;1h-1,2,4-triazole Chemical compound [K].C=1N=CNN=1 VBCFDVLVYCYDFZ-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- MDUSUFIKBUMDTJ-UHFFFAOYSA-N sodium;1h-1,2,4-triazole Chemical compound [Na].C=1N=CNN=1 MDUSUFIKBUMDTJ-UHFFFAOYSA-N 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
技术领域
本发明属于药物中间体制备技术领域,特别涉及一种第三代芳香化酶抑制剂来曲唑中间体的合成方法。
背景技术
来曲唑(Letrozole),化学名4,4'-(1H-1,2,4-三氮唑-1-次甲基)-二苯甲腈,是诺华公司开发的第三代高选择性芳香化酶抑制剂,通过抑制芳香化酶,使雌激素水平下降,体内活性比第一代芳香化酶抑制剂氨鲁米特强150-250倍,特别适用于绝经后的乳腺癌患者。由于其选择性较高,不影响糖皮质激素、盐皮质激素和甲状腺功能,大剂量使用对肾上腺皮质类固醇类物质分泌无抑制作用,因此具有较高的治疗指数。
江西师范大学硕士论文《芳香化酶抑制剂来曲唑的合成工艺研究》第二章中总结了2014年以前公开的六条主要的来曲唑合成路线,结合2014年以后关于来曲唑合成路线的报道,现有技术中公开的来曲唑合成方法主要有:
路线一
专利US4749713最早公开了来曲唑的合成路线:以对甲基苯腈为原料,经溴化生成对溴甲基苯腈,再与1H-1,2,4-三氮唑反应生成4-[1-(1,2,4-三氮唑)甲基]-苯腈,最后与对氟苯腈反应,制得目标产物来曲唑。该路线除了生成目标产物来曲唑外,还会得到相应的l,3,4-位异构体副产物。
为减少副产物的生成,CN200410080092.5等专利对第二步反应后的产物进行了异构体分离。通过控制加入盐酸的量,控制两异构体成盐后析出的顺序,进而分离两者成盐后的产物,用碱解离,再进行第三步反应。该改进后两步的收率为45.1%,可有效提高来曲唑的纯度,但是该改进方法需要用到一定量腐蚀性的强酸、强碱,且产生大量废水,不适用于工业化生产。
WO2004076409等使用4-氨基-1,2,4-三唑替换1H-1,2,4-三氮唑,提高了N-烷基化反应的选择性,再经过去氨基化得到第二步反应产物,减少了异构体的生成。但是采用此改进方法总产率没有增加,且去氨基化的重氮化反应不适宜用于工业化生产。
《中国医药工业杂志,2015,46(3),225-227》公开了用1H-1,2,4-三唑钠替换1H-1,2,4-三氮唑的改进方法。该方法将后两步的收率提高至54.8%,但是仍需要使用强酸强碱,且两步反应均需要控制在低温下进行,同样不适用于工业化生产。
路线二
US4978672公开了N-叔丁基对溴苯甲酰胺与甲酸乙酯反应,在正丁基锂存在下生成4,4'-二(N-叔丁基氨甲酰苯基)甲醇,经氯化得到4,4'-二氰基二苯基氯甲烷,然后与1H-1,2,4-三氮唑缩合制得目标产物来曲唑。该路线需要-60℃低温和有机锂,规模化生产成本高,安全隐患大。
路线三
《中国药科大学报,2003,34(4):375-376》中以苯胺作为起始原料,与甲醛缩合得到4,4'-二氨基二苯基甲烷,再与亚硝酸钠反应得到重氮盐溶液,后再加入氰化亚铜,经重氮化反应制得4,4'-二氰基二苯基甲烷,经NBS溴代合成4,4'-二氰基二苯基溴甲烷,最后与1H-1,2,4-三氮唑钾发生缩合反应,最终制得目标产物来曲唑。该合成路线长,重氮化反应中使用的氰化亚铜毒性大,安全隐患大,且总收率仅5.3%,不适于工业生产。
路线四
WO2007144896通过一步反应制得了路线三中第三步反应后的中间体,后采用与路线三相同的方法,共三步制得目标产物来曲唑。该路线避免了有毒试剂氰化亚铜的使用,但第一步反应收率较低,且产物分离难度大,总收率仅10.3%。
上述硕士论文《芳香化酶抑制剂来曲唑的合成工艺研究》对该路线进行了改进,通过对各步中各个反应参数的研究控制,将总收率提高至15.6%,依然不适于工业化大规模生产。
路线五
WO2007074474以对甲基苯甲酰氯和甲苯为原料,经Friedel-Crafts反应得到4,4'-二甲基二苯甲酮,再经NaBH4还原、与1H-1,2,4-三氮唑缩合,得到α-(1H-1,2,4-三氮唑基)-4,4'-二甲基二苯基甲烷,后与醋酐经过酰化反应,再经肟化、水解得到目标产物来曲唑。该合成路线太长,总收率低。
路线六
CN200710068474.X、US7538230、US7465749等采用4,4'-二氰基二苯甲酮为起始原料,经还原、卤代反应得到4,4'-二氰基二苯卤甲烷,再与1H-l,2,4-三氮唑缩合,制得目标产物来曲唑。
该路线合成路线短,反应条件不苛刻,总收率高达54.8%。《Eur.J.Org.Chem.2014,4115–4122》在第二步中使用甲磺酰氯卤代,将改路线总收率提升至67%。但原料4,4'-二氰基二苯甲酮较难合成。
路线七
CN201310676671.5公开了一种一锅法制备来曲唑的方法。有氧条件下,对卤苯甲醛、4-卤代甲基苯甲醛在醋酸铜和氨水催化下充分反应,后加入1H-l,2,4-三氮唑反应,得到目标产物来曲唑。该工艺路线新颖,步骤简洁,但副反应多,收率21-43%,产物难于分离,不适于工业化生产。
从上述合成路线不难看出,目前合成路线均存在一定缺陷。考虑到需要符合工业化生产要求,即合成路线步骤较短,反应条件不苛刻,可以选择路线一、四、六和七。再从产率角度考虑,路线六产率最高。所以如能解决其存在的原料4,4'-二氰基二苯甲酮的合成问题,该路线将具有良好的工业化应用前景。
发明内容
本发明的目的在于克服现有技术中的不足,提供一种来曲唑的关键中间体的制备方法,该制备方法路线新颖,工艺简单,后处理操作方便,产率高,适合工业化生产。本发明的目的可以通过以下技术方案来实现:
一种来曲唑关键中间体(I)的制备方法,其特征在于:由2-(4-氰基苯基)甲酰甲酸(II)和4-卤代苯腈(III)反应生成。
其中,4-卤代苯腈(III)的卤素为氯、溴、碘或其他类似卤素的取代基,优选氯或溴。
类似卤素的取代基可以但不限于为-OMs、-OTs、-OCO-C1-6烷基、-OTf、-ONO2等。
在一种优选实施方式中,中间体(I)由2-(4-氰基苯基)甲酰甲酸(II)和4-卤代苯腈(III)在碱、催化剂条件下,于溶剂中一锅法反应制备。
在一种优选实施方式中,原料2-(4-氰基苯基)甲酰甲酸(II)和4-卤代苯腈(III)的投料摩尔比是1:0.5-5,优选1:1。
在一种优选实施方式中,反应所用的碱选自碳酸氢钠、碳酸钠、碳酸钾、磷酸钾、氢氧化钠、氢氧化钾、碳酸铯、氢化钠、甲醇钠、乙醇钠或叔丁醇钾中的任一种。
在一种优选实施方式中,反应所用的碱为2-(4-氰基苯基)甲酰甲酸(II)用量的1-50倍,优选2倍。
在一种优选实施方式中,反应所用的溶剂是四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、甲苯、二甲苯、N-甲基吡咯烷酮中的任一种或任意两种溶剂的混合溶液。
在一种优选实施方式中,反应的溶剂为2-(4-氰基苯基)甲酰甲酸(II)用量的1-1000倍。
在一种优选实施方式中,反应的催化剂为钯配合物、铜盐及氮配体。
所述的钯催化剂选自Pd(OAc)2、PdCl2、PdBr2、PdI2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd2(PPh3)2Cl4、Pd(acac)2或Pd(dba)2。
所述的铜催化剂选自CuI、CuBr、CuOAc、CuCl、CuOTf,优选CuI。
所述的氮配体为2,2'-联吡啶、1,10-菲咯啉、吡啶、4,7-二苯基-1,10-菲咯啉、三苯基磷、三环己基膦、三叔丁基膦、1,1'-双(二苯基磷)二茂铁、4,5-双二苯基膦-9,9-二甲基氧杂蒽、(±)-2,2'-双-(二苯膦基)-1,1'-联萘或任意两种配体混合使用,优选1,10-菲咯啉。
在一种优选实施方式中,钯催化剂为2-(4-氰基苯基)甲酰甲酸(II)用量的0.5%-20%。
在一种优选实施方式中,铜催化剂为2-(4-氰基苯基)甲酰甲酸(II)用量的1%-30%。
在一种优选实施方式中,氮配体为2-(4-氰基苯基)甲酰甲酸(II)用量的1%-40%。
在一种优选实施方式中,反应的反应温度为50-200℃。
在一种优选实施方式中,反应的时间为5-100小时,优选24小时。
本发明选用2-(4-氰基苯基)甲酰甲酸(II)和4-卤代苯腈(III)为原料,提供了一种路线新颖,简洁高效,仅需一步反应制得来曲唑关键中间体的制备方法。该制备方法避免了腐蚀性及有毒的物料的使用,提高了生产的安全性,设备节约,环境友好;并且反应操作简单,重现性好,收率高,经济性好,并可确保后续制备得到高纯度的来曲唑,为高纯度来曲唑的规模化工业生产提供了保障。
附图说明
图1为由实施例1所得中间体(I)制备得到的来曲唑的HPLC色谱图,纯度为99.9%。
具体实施方式
为了更好地理解本发明的内容,下面结合具体实施例对本发明的技术方案做进一步的说明,但具体的实施方式并不意味着对本发明有任何限制。
本发明所用原料和试剂均可通过常规方法制备得到或市售购得。
实施例一
于500mL三口瓶中加入N,N-二甲基甲酰胺(200mL),氮气下依次加入2-(4-氰基苯基)甲酰甲酸(II)(35.1g,0.2mol),4-溴代苯腈(III)(36.3g,0.2mol),碳酸铯(40.0g,0.4mol),PdCl2(1.79g,0.01mol),CuI(3.8g,0.02mol)和2,2'-联吡啶(3.2g,0.02mol),搅拌,升温至100℃反应12小时,HPLC检测反应完全(2-(4-氰基苯基)甲酰甲酸含量低于1%),降温至室温,缓慢加水有固体析出。固体用乙酸乙酯溶解后萃取(50mL x 3),所得有机相依次用5%的盐酸水溶液(100mL)和饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得粗品,粗品经甲基叔丁基醚(150mL)重结晶,得到白色固体产物(42.2g,收率:90.9%)。
实施例二
于500mL三口瓶中加入1,4-二氧六环(200mL),氮气下加入2-(4-氰基苯基)甲酰甲酸(II)(35.1g,0.2mol),4-溴代苯腈(III)(36.3g,0.2mol),乙醇钠(27.3g,0.4mol),Pd(PPh3)4(11.8g,0.01mol),CuBr(4.3g,0.03mol),1,10-菲咯啉(7.3g,0.04mol),搅拌,升温至80℃回流反应24小时,HPLC检测反应完全(2-(4-氰基苯基)甲酰甲酸(III)含量低于1%),降温至室温,缓慢加水析出固体,固体用乙酸乙酯溶解后萃取(50mL x 3)。所得有机相用5%的盐酸水溶液(100mL)和饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,过滤后滤液浓缩,用甲基叔丁基醚(150mL)重结晶得到白色固体产物(41.9g,收率:90.3%)。
实施例三
于500mL三口瓶中加入二甲基亚砜(200mL),氮气下加入2-(4-氰基苯基)甲酰甲酸(II)(35.1g,0.2mol),4-溴代苯腈(III)(18.2g,0.1mol),氢氧化钠(40.1g,1mol),PdBr2(0.53g,0.002mol),CuOAc(0.49g,0.004mol),1,10-菲咯啉(1.46g,0.008mol)和三环己基膦(2.24g,0.008mol),搅拌,升温至140℃,反应5小时,HPLC检测反应完全(4-溴代苯腈(III)含量低于1%),降温至室温,缓慢加水析出固体,固体用乙酸乙酯溶解后萃取(50mL x3)。所得有机相依次用5%的盐酸水溶液(100mL)和饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用甲基叔丁基醚(150mL)重结晶得到白色固体产物(21.7g,收率:93.5%)。
实施例四
于500mL三口瓶中加入N,N-二甲基乙酰胺(200mL),氮气下加入2-(4-氰基苯基)甲酰甲酸(II)(35.1g,0.2mol),4-溴代苯腈(III)(72.6g,0.4mol),磷酸钾(85.7g,0.4mol),Pd(OAc)2(0.45g,0.002mol),CuOTf(12.8g,0.06mol),吡啶(9.7g,0.12mol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(2.32g,0.004mol),搅拌,升温至120℃,反应12小时,HPLC检测反应完全(2-(4-氰基苯基)甲酰甲酸(II)含量低于1%),降温至室温,缓慢加水析出固体,固体用乙酸乙酯溶解后萃取(50mLx 3)。所得有机相用5%的盐酸水溶液(100mL)和饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得粗品,粗品用甲基叔丁基醚(150mL)重结晶,得到白色固体产物(44.7g,收率:96.3%)。
实施例五
于500mL三口瓶中加入甲苯(200mL),氮气下加入2-(4-氰基苯基)甲酰甲酸(II)(35.1g,0.2mol),4-溴代苯腈(III)(36.3g,0.2mol),叔丁醇钾(45.1g,0.4mol),Pd(acac)2(1.8g,0.006mol),CuI(3.8g,0.02mol),4,7-二苯基-1,10-菲咯啉(6.7g,0.02mol),搅拌,升温至回流反应48小时,HPLC检测反应完全(2-(4-氰基苯基)甲酰甲酸(II)含量低于1%),降温至室温,缓慢加水析出固体,固体用乙酸乙酯溶解后萃取(50mL x 3)。所得有机相用5%的盐酸水溶液(100mL)和饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,过滤后滤液浓缩,残留物用甲基叔丁基醚(150mL)重结晶得到白色固体产物(43.5g,收率:93.7%)。
实施例六
以实施例一所得中间体产物(42.2g,0.18mol)为原料,参照文献《Eur.J.Org.Chem.2014,4115–4122》中的制备方法,制得白色固体来曲唑(36.4g,总收率:70.3%,HPLC:99.9%),HPLC色谱图如图1所示。
需要指出的是,上述几个较佳实施例是对本发明技术方案作的进一步非限制的详细说明,仅为说明本发明的技术构思和特点。其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
Claims (11)
1.一种来曲唑关键中间体(I)的制备方法,其特征在于:由2-(4-氰基苯基)甲酰甲酸(II)和4-卤代苯腈(III)反应生成;
其中,4-卤代苯腈(III)的卤素为氯、溴、碘或其他类似卤素的取代基;
其中,中间体(I)由2-(4-氰基苯基)甲酰甲酸(II)和4-卤代苯腈(III)在碱、催化剂条件下,于溶剂中一锅法反应制备;
其中,所述的催化剂为钯催化剂和铜催化剂及其配体;
其中,所述的碱选自碳酸氢钠、碳酸钠、碳酸钾、磷酸钾、氢氧化钠、氢氧化钾、碳酸铯、氢化钠、甲醇钠、乙醇钠或叔丁醇钾;
其中,所述的钯催化剂为Pd(OAc)2、PdCl2、PdBr2、PdI2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd2(PPh3)2Cl4、Pd(AcAc)2或Pd(dba)2;所述的铜催化剂为CuI、CuBr、CuOAc、CuCl或CuOTf;所述的配体为2,2'-联吡啶、1,10-菲咯啉、吡啶、4,7-二苯基-1,10-菲咯啉、三苯基磷、三环己基膦、三叔丁基膦、1,1'-双(二苯基磷)二茂铁、4,5-双二苯基膦-9,9-二甲基氧杂蒽、(±)-2,2'-双-(二苯膦基)-1,1'-联萘或任意两种配体混合使用。
2.根据权利要求1所述的制备方法,其特征在于:4-卤代苯腈的卤素为氯或溴。
3.根据权利要求1所述的制备方法,其特征在于:2-(4-氰基苯基)甲酰甲酸(II)和4-卤代苯腈(III)的原料投料摩尔比是1:0.5-5。
4.根据权利要求3所述的制备方法,其特征在于:2-(4-氰基苯基)甲酰甲酸(II)和4-卤代苯腈(III)的原料投料摩尔比是1:1。
5.根据权利要求1所述的制备方法,其特征在于:所述的碱为2-(4-氰基苯基)甲酰甲酸(II)用量的1-50倍。
6.根据权利要求6所述的制备方法,其特征在于:所述碱为2-(4-氰基苯基)甲酰甲酸(II)用量的2倍。
7.根据权利要求1所述的制备方法,其特征在于:所述反应溶剂是四氢呋喃,1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、甲苯、二甲苯、N-甲基吡咯烷酮中的任一种或任意两种溶剂的混合溶液;用量为2-(4-氰基苯基)甲酰甲酸(II)用量的1-1000倍。
8.根据权利要求1所述的制备方法,其特征在于:所述的铜催化剂为CuI;所述的配体为1,10-菲咯啉。
9.根据权利要求1所述的制备方法,其特征在于:钯催化剂为2-(4-氰基苯基)甲酰甲酸(II)用量的0.5%-20%;所述的铜催化剂为2-(4-氰基苯基)甲酰甲酸(II)用量的1%-30%;所述的配体为2-(4-氰基苯基)甲酰甲酸(II)用量的1%-40%。
10.根据权利要求1所述的制备方法,其特征在于:所述反应的反应温度为50-200℃;反应时间为5-100小时。
11.根据权利要求13所述的制备方法,其特征在于:所述的反应时间为24小时。
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