CN117924249A - 一种jak1抑制剂azd4604的制备方法 - Google Patents
一种jak1抑制剂azd4604的制备方法 Download PDFInfo
- Publication number
- CN117924249A CN117924249A CN202311763426.8A CN202311763426A CN117924249A CN 117924249 A CN117924249 A CN 117924249A CN 202311763426 A CN202311763426 A CN 202311763426A CN 117924249 A CN117924249 A CN 117924249A
- Authority
- CN
- China
- Prior art keywords
- fluoro
- compound
- reaction
- methylsulfonyl
- azd4604
- 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.)
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- JNUZADQZHYFJGW-JOCHJYFZSA-N (2R)-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide Chemical compound FC=1C(=NC(=NC=1)NC1=C(C(=CC=C1)S(=O)(=O)C)F)C1=CNC2=C(C=CC=C12)NC([C@@H](COC)N1CCN(CC1)C)=O JNUZADQZHYFJGW-JOCHJYFZSA-N 0.000 title claims abstract description 17
- 229940126054 AZD4604 Drugs 0.000 title claims abstract description 17
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- -1 2-chloro-5-fluoropyrimidine compound Chemical class 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- XCPZERVGUAFTAX-UHFFFAOYSA-N 2-fluoro-3-methylsulfonylaniline Chemical compound CS(=O)(=O)C1=CC=CC(N)=C1F XCPZERVGUAFTAX-UHFFFAOYSA-N 0.000 claims abstract description 6
- JCIZGYTVKCJDRF-YCBDHFTFSA-N (2R)-3-methoxy-2-(4-methylpiperazine-1,4-diium-1-yl)propanoic acid dichloride Chemical compound [Cl-].[Cl-].C(=O)(O)[C@@H](COC)[NH+]1CC[NH+](CC1)C JCIZGYTVKCJDRF-YCBDHFTFSA-N 0.000 claims abstract description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- QCTLXEOMKWPHPJ-UHFFFAOYSA-N 5-fluoro-N-(2-fluoro-3-methylsulfonylphenyl)-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine Chemical compound FC=1C(=NC(=NC=1)NC1=C(C(=CC=C1)S(=O)(=O)C)F)C1=CNC2=C(C=CC=C12)[N+](=O)[O-] QCTLXEOMKWPHPJ-UHFFFAOYSA-N 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- DTPIHBVSENJKRN-UHFFFAOYSA-N 5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)-1H-pyrimidin-6-one Chemical compound S(=O)(=O)(C)C1=C(F)C(NC2=NC(=C(F)C=N2)O)=CC=C1 DTPIHBVSENJKRN-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- IBKMUQRMLHJBHT-UHFFFAOYSA-N 3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-amine Chemical compound FC=1C(=NC(=NC=1)NC1=C(C(=CC=C1)S(=O)(=O)C)F)C1=CNC2=C(C=CC=C12)N IBKMUQRMLHJBHT-UHFFFAOYSA-N 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 9
- 239000003054 catalyst Substances 0.000 claims 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 6
- 238000000746 purification Methods 0.000 claims 5
- 230000035484 reaction time Effects 0.000 claims 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 4
- 238000010009 beating Methods 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 4
- 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 4
- 238000005406 washing Methods 0.000 claims 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 3
- 239000003513 alkali Substances 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 claims 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 3
- 229910052763 palladium Inorganic materials 0.000 claims 3
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 2
- 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 2
- 150000002367 halogens Chemical group 0.000 claims 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims 2
- 229910052698 phosphorus Inorganic materials 0.000 claims 2
- 239000011574 phosphorus Substances 0.000 claims 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 239000003377 acid catalyst Substances 0.000 claims 1
- 230000003213 activating effect Effects 0.000 claims 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 229910052808 lithium carbonate Inorganic materials 0.000 claims 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims 1
- 238000004537 pulping Methods 0.000 claims 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims 1
- 239000012312 sodium hydride Substances 0.000 claims 1
- 229910000104 sodium hydride Inorganic materials 0.000 claims 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000026030 halogenation Effects 0.000 abstract 1
- 238000005658 halogenation reaction Methods 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 6
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- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- STQZMOAIBXVRLB-UHFFFAOYSA-N 4-chloro-5-fluoro-N-(2-fluoro-3-methylsulfonylphenyl)pyrimidin-2-amine Chemical compound ClC1=NC(=NC=C1F)NC1=C(C(=CC=C1)S(=O)(=O)C)F STQZMOAIBXVRLB-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HLVJKADQILYNGE-UHFFFAOYSA-N 2-chloro-5-fluoro-4-methoxypyrimidine Chemical compound COC1=NC(Cl)=NC=C1F HLVJKADQILYNGE-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
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- 229950000971 baricitinib Drugs 0.000 description 1
- XUZMWHLSFXCVMG-UHFFFAOYSA-N baricitinib Chemical compound C1N(S(=O)(=O)CC)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 XUZMWHLSFXCVMG-UHFFFAOYSA-N 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound 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 description 1
- 239000012267 brine Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
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- 238000011083 clear filtration Methods 0.000 description 1
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- XNQULTQRGBXLIA-UHFFFAOYSA-O phosphonic anhydride Chemical compound O[P+](O)=O XNQULTQRGBXLIA-UHFFFAOYSA-O 0.000 description 1
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Abstract
本发明属药物化学合成技术领域,具体为一种JAK1抑制剂AZD4604的制备方法。本发明合成方法反应步骤为:由原料2‑氯‑5‑氟嘧啶类化合物(1)与2‑氟‑3‑(甲磺酰基)苯胺(9)发生取代反应得到关键中间体(2),经水解、卤代、suzuki偶联、脱对甲苯磺酰保护基、还原反应得到化合物(7),最后,与(R)‑3‑甲氧基‑2‑(4‑甲基哌嗪‑1‑基)丙酸二盐酸反应得到目标化合物AZD4604
Description
技术领域
本发明属于药物化学合成领域,涉及一种JAK1抑制剂AZD4604的新的制备方法。
背景技术
JAK-STAT细胞因子在免疫调节方面至关重要,当JAK-STAT信号通路受到细胞因子的持续活化,容易导致慢性炎症疾病如哮喘的发生,也会导致癌症、和组织损伤。JAK激酶属于非受体类的酪氨酸激酶。包含四个成员:JAK1、JAK2、JAK3和TyK2,但是其不同成员之间的组合,形成了不同细胞因子受体的胞内信号衔接蛋白,因此也对应控制着不同的细胞因子通路。成员之间序列保守,上市的药物如辉瑞的托法替尼和礼来的baricitinib对JAK-STAT信号的抑制是非选择性的,这可能会与临床严重的不良反应相关。目前JAK抑制剂已经发展为选择性抑制,只对某个或多个JAK家族成员起到抑制作用,理论上可能会降低临床不良事件的发生率。
通过研究JAK1和JAK3在介导T细胞和髓样细胞中IL-4信号转导的作用,发现JAK1和JAK3均参与IL-4的信号转导,但JAK1在髓样细胞的激活和单核细胞衍生的炎性树突状细胞的再生方面可能比JAK3更重要,而这些都是公认的IL-4驱动哮喘的关键因素。这一发现,为哮喘发病的分子机制研究提供了重要见解,并提示靶向JAK1信号转导可能是治疗哮喘的一种很有前途的治疗策略,通过合理药物设计得到强效、高选择性和药代性质等各方面性质优良的可吸入JAK1抑制剂化合物AZD4604,其对JAK1的高度选择性是JAK2的1000倍,目前正在进行II期临床试验用于治疗哮喘。
发明内容
鉴于上述情况,JAK1抑制剂AZD4604的制备非常重要。本发明人通过实验研究解决了该化合物的技术问题,其反应路线如下:
本发明包括下列步骤:
(a)由原料2-氯-5-氟嘧啶类化合物(1)与2-氟-3-(甲磺酰基)苯胺(9)在碱性条件下发生取代反应得到5-氟嘧啶类化合物(2)
其中,R=Me、Bn、PMB
(b)化合物(2)在酸性环境下水解生成5-氟-2-((2-氟-3-(甲磺酰基)苯基)氨基)嘧啶-4-醇(3)
(c)5-氟-2-((2-氟-3-(甲磺酰基)苯基)氨基)嘧啶-4-醇(3)发生卤代得到4-卤代-5-氟-N-(2-氟-3-(甲磺酰基)苯基)嘧啶-2-胺(4)
其中,X=Br,Cl
(d)4-卤代-5-氟-N-(2-氟-3-(甲磺酰基)苯基)嘧啶-2-胺(4)与7-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-甲苯磺酰基-1H-吲哚(10)经过suzuki偶联反应得到化合物5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-(7-硝基-1-甲苯磺酰基-1H-吲哚-3-基)嘧啶-2-胺(5)
(e)化合物(5)脱对甲苯磺酰基得到5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺(6)
(f)化合物5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺(6)发生还原反应得到化合物3-(5-氟-2-((2-氟-3-(甲磺酰基)苯基)氨基)嘧啶-4-基)-1H-吲哚-7-胺(7)
(g)最后与(R)-3-甲氧基-2-(4-甲基哌嗪-1-基)丙酸二盐酸反应得到目标化合物AZD4604
具体实施例
下面通过实施例对本发明做进一步描述说明,但并不因此而限制本发明的内容。
实施例1
步骤A
将2-氯-5-氟-4-甲氧基嘧啶(0.81g,4.97mmol)、2-氟-3-(甲磺酰基)苯胺(0.94g,4.97mmol)、Pd2(dba)3(0.09g,0.1mmol)、BINAP(0.12g,0.2mmol)、碳酸铯(3.23g,9.93mmol)溶于15mL甲苯,并在氮气条件下加热至120℃,在该温度下搅拌反应30分钟。通过LC-MS监测反应。反应完成后,向反应液中加入水(35mL),用乙酸乙酯(35mL×2)萃取混合物。将有机层合并,用盐水洗涤,用无水硫酸钠干燥。滤液减压蒸发,除去溶剂。粗品经柱层析纯化,得到5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-甲氧基嘧啶-2-胺(1.1g,产率70%)。LC-MS(ESI):m/z=315.3[M+H]+
步骤B
将5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-甲氧基嘧啶-2-胺(1.5g,4.8mmol)加入到含有4N盐酸的1,4-二氧六环(15ml)中,并将混合物在室温下搅拌30分钟,并用LC-MS监测反应。反应完成后,减压蒸发溶剂。向粗品中加入乙醇(2ml)、乙酸乙酯(20ml)和甲基叔丁基醚(20ml)进行重结晶,得到5-氟-2-((2-氟-3-(甲磺酰基)苯基)氨基)嘧啶-4-醇(1.04g,产率72%)。LC-MS(ESI):m/z=301.3[M+H]+
步骤C
将5-氟-2-((2-氟-3-(甲磺酰基)苯基)氨基)嘧啶-4-醇(0.99g,3.3mmol)的三氯氧磷(20ml)溶液加热至80℃,在此温度下保持3小时,并用LC-MS监测反应。反应完成后,将三氯氧磷旋干。粗产物经柱层析纯化,得到4-氯-5-氟-N-(2-氟-3-(甲磺酰基)苯基)嘧啶-2-胺(1.03g,产率98%)。LC-MS(ESI):m/z=319.7[M+H]+
步骤D
将4-氯-5-氟-N-(2-氟-3-(甲磺酰基)苯基)嘧啶-2-胺(0.58g,1.810mmol)和CS2CO3(1.77g,5.440mmol)在二氧六环(75mL)和H2O(25mL)中的混合物脱气。然后加入Pd(dppf)Cl2(133mg,0.18mmol)和7-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-甲苯磺酰基-1H-吲哚(1.04g,2.36mmol),并在N2条件下在100℃搅拌2.5小时。反应结束后,将反应混合物用水(10mL)淬灭,并用乙酸乙酯(5mL×3)萃取。合并的有机层用饱和盐水(5mL×2)洗涤,用NaiSCri干燥,过滤并在减压下浓缩。粗产物通过柱层析纯化,得到5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-(7-硝基-1-甲苯磺酰基-1H-吲哚-3-基)嘧啶-2-胺(567mg,产率52%)。LC-MS(ESI):m/z=599.6[M+H]+
步骤E
将5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-(7-硝基-1-甲苯磺酰基-1H-吲哚-3-基)嘧啶-2-胺(0.65g,1.1mmol)在室温下装入5L反应器中。加入THF(2mL)和3.8M NaOH(水溶液)(10mL)。将混合物加热至75℃,搅拌回流48h。将THF(5vol)和庚烷(5vol)装入反应混合物中。然后将其冷却至17℃,并在布氏漏斗上过滤固体。滤饼用1M柠檬酸(4mL,直至pH中性)、水(5x2.5mL,直至pH中性)洗涤,然后用庚烷/EtOAc(4x3.5 mL)洗涤。将固体在真空下干燥,得到5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺(462.5mg,产率96%)。LC-MS(ESI):m/z=445.4[M+H]+
步骤F
在氮气室温条件下,将5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺(1.38g,3.09mmol)加入到THF/EtOH 2:1(15mL)中,搅拌悬浮液并加入10%Pd/C(0.3g,3.1mmol)和甲酸铵(1.17g,18.5mmol)的水溶液(10mL)。将反应混合物缓慢加热至70℃并搅拌30分钟,加入12克活性炭,搅拌15分钟。将反应混合物冷却至40℃,并在氮气条件下在布氏漏斗过滤。滤饼用THF/EtOH(4mL)洗涤。浓缩滤液减少体积,将所得反应液冷却至室温,并在氮气下过滤。固体用水(2vol)、乙醇(2vol)洗涤,并在40℃的真空下干燥,得到3-(5-氟-2-((2-氟-3-(甲磺酰基)苯基)氨基)嘧啶-4-基)-1H-吲哚-7-胺(1.04g,产率81%),为浅棕色固体。LC-MS(ESI):m/z=415.4[M+H]+
步骤G
在室温下向50mL低温反应器中加入(R)-3-甲氧基-2-(4-甲基哌嗪-l-基)丙酸二盐酸(0.14g,0.4mmol),然后加入3mL DMF。向浅棕色溶液中加入3-(5-氟-2-((2-氟-3-(甲磺酰基)苯基)氨基)嘧啶-4-基)-吲哚-7-胺(0.15g,0.36mmol)。将所得的深棕色透明溶液冷却至-20℃(夹套设置为-30℃)。在5分钟内向反应器中加入吡啶2mL。未观察到明显的放热。在-20℃下,缓慢加入溶于DMF(0.6mL,1.08mmol)的丙烷膦酸酐(T3P),温度不超过-l3℃。由于放热反应,夹套设置为-40℃。添加过程要在75分钟后完成。添加2/3后,取样并运行SFC-MS,几乎完成转换。完全添加后完成转换。最终分析UPLC-MS。在l h内,通过在-l5℃下缓慢加水来淬灭反应混合物。将淬灭混合物在-l5℃下再搅拌30分钟。在较大的反应器中,预先制备8.5%NaHCO3(4mL)并冷却至+5℃,为了尽量减少泡沫的产生,反应混合物缓慢转移到含有8.5%NaHCO3(4mL)的反应器中。添加一小时后,再加入20mL饱和碳酸氢钠盐溶液,使产物开始从澄清溶液产生沉淀。将沉淀混合物在+5℃下搅拌30分钟。过滤,该产品不适合过滤,该过程需要相当长的时间才能完成。将粗品装入反应器中,加入乙腈4mL。混合物回流搅拌,再加入乙腈2ml,以提高产品的溶解度。对不透明的溶液进行澄清过滤,从而开始一些结晶。将过滤后的透明有机物转移到另一个反应器中,体积减小至1mL。在24小时内通过回流缓慢冷却至5℃开始结晶。滤去产物,用2体积冷乙腈洗涤。将产品在40℃下减压干燥过夜,得到目标化合物AZD4604(0.121g,产率63%)。LC-MS(ESI):m/z=599.67[M+H]+。1HNMR(300MHz,DMSO-d6):δ2.14(s,3H),2.25-2.44(m,4H),2.55-2.67(m,2H),2.69-2.79(m,2H),3.26-3.79(m,9H),7.04(t,1H),7.42-7.55(m,2H),7.62(t,1H),8.19(t,J=7.3Hz,1H),8.22-8.33(m,2H),8.44(d,1H),9.46(s,1H),9.84(s,1H),11.47(s,1H)。
实例仅用于说明本发明的实施方式,但本发明不仅仅局限于上述实例。在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内,本发明要求保护范围由权利要求书及其等效物界定。
Claims (9)
1.一种JAK1抑制剂AZD4604的制备方法,其特征在于,具体步骤为:
(1)由原料2-氯-5-氟嘧啶类化合物(1)与2-氟-3-(甲磺酰基)苯胺(9)在碱性条件下发生取代反应得到5-氟嘧啶类化合物(2)
(2)化合物(2)在酸性条件下水解生成5-氟-2-((2-氟-3-(甲磺酰基)苯基)氨基)嘧啶-4-醇(3)
(3)5-氟-2-((2-氟-3-(甲磺酰基)苯基)氨基)嘧啶-4-醇(3)发生卤代得到4-卤代-5-氟-N-(2-氟-3-(甲磺酰基)苯基)嘧啶-2-胺(4)
(4)4-卤代-5-氟-N-(2-氟-3-(甲磺酰基)苯基)嘧啶-2-胺(4)与7-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-甲苯磺酰基-1H-吲哚(10)经过suzuki偶联反应得到化合物5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-(7-硝基-1-甲苯磺酰基-1H-吲哚-3-基)嘧啶-2-胺(5)
(5)化合物(5)脱对甲苯磺酰基得到5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺(6)
(6)化合物5-氟-N-(2-氟-3-(甲磺酰基)苯基)-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺(6)发生还原得到化合物3-(5-氟-2-((2-氟-3-(甲磺酰基)苯基)氨基)嘧啶-4-基)-1H-吲哚-7-胺(7)
(7)最后与(R)-3-甲氧基-2-(4-甲基哌嗪-1-基)丙酸二盐酸反应得到目标化合物AZD4604。
2.如权利要求1所述的一种JAK1抑制剂AZD4604的制备方法,其特征在于,步骤(1),原料2-氯-5-氟嘧啶类化合物中R选自Me、Bn、PMB,步骤(3)中卤代反应,卤素取代基选自氯、溴。
3.如权利要求1所述的一种JAK1抑制剂AZD4604的制备方法,其特征在于,步骤(1),反应温度选自10-200℃,时间选自0-72h,溶剂选自N,N-二甲基甲酰胺(DMF)、二氯甲烷、甲苯中的一种或几种。碱剂选自碳酸钠、碳酸钾、三乙胺、氢氧化钠、氢氧化钾、碳酸氢钠、氢化钠等中的一种或几种。纯化可以选过滤时洗涤滤饼、过柱、打浆或者重结晶。
4.如权利要求1所述的一种JAK1抑制剂AZD4604的制备方法,其特征在于,步骤(2),酸性催化剂选自磷酸、硫酸、盐酸中的一种,温度选自10-100℃,时间选自0-24h,溶剂选自乙醚、乙腈、THF、DMF、DME、1,4-二氧六环、H2O、NMP、DMA、DMSO、苯、甲苯中的一种或者几种。纯化可以选过滤时洗涤滤饼、过柱、打浆或者重结晶。
5.如权利要求1所述的一种JAK1抑制剂AZD4604的制备方法,其特征在于,步骤(3),反应温度选自50-120℃,时间选自0-10h,溶剂选自乙醇、丙酮、甲醇、二氯甲烷、水、甲腈、N,N-二甲基甲酰胺、二甲基亚砜、N,N-二异丙基乙胺中的一种或几种,卤化试剂选自氢卤酸,三卤化磷,五卤化磷,二氯亚砜中的一种,纯化可以选过滤时洗涤滤饼、过柱、打浆或者重结晶。
6.如权利要求1所述的一种JAK1抑制剂AZD4604的制备方法,其特征在于,步骤(4),suzuki偶联反应的反应温度选自10-200℃,反应时间选自0-72h,溶剂选自乙醚、乙腈、THF、DMF、DME、1,4-二氧六环、H2O、NMP、DMA、DMSO、苯、甲苯中的一种或者几种。反应所用的催化剂可选自为双(三苯基膦)-二氯化钯、二(三苯基膦)二茂铁二氯化钯、二(三苯基膦)二茂铁二氯化钯二氯甲烷复合物、Pd2(dba)3、pd(dppe)Cl2、四三苯基磷钯、二(三苯基膦)二茂铁二氯化镍中的一种或几种,化合物的0.01%-20%(M/M摩尔比),反应中所用的碱选自三乙胺、乙二胺、二异丙基乙胺、咪唑、哌啶、吡啶、CsCO3、KOAc、NaOAc、K2CO3、Na2CO3、Li2CO3、tBuOK、tBuONa、K3PO4、NaOH、KOH、Ba(OH)2中的一种。用量的1-10倍(M/M摩尔比)。纯化可以选自过柱、打浆或者重结晶。
7.如权利要求1所述的一种JAK1抑制剂AZD4604的制备方法,其特征在于,步骤(5)中,所用醇类溶剂选自甲醇、乙醇、异丙醇、叔丁醇中的一种或者几种。强碱试剂选自氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、甲醇钾、乙醇钾、叔丁醇钠、叔丁醇钾中的一种或者几种。所用强碱与化合物摩尔比为(1-5):1,反应条件为回流反应,反应时间为10-72小时。
8.如权利要求1所述的一种JAK1抑制剂AZD4604的制备方法,其特征在于,步骤(6)中,溶剂选自甲醇、乙醇、异丙醇、二氯甲烷、水、甲腈、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃中的一种或几种。所述化合物、溶剂、甲酸铵和钯催化剂的重量比为1:3-20:0.9-10:0.03-0.96,所述钯催化剂为钯/炭催化剂或氢氧化钯/炭催化剂中的一种。所述钯/炭催化剂为10%的钯/炭催化剂,反应时间选自0-25h,温度为20-80℃。所述钯催化剂循环使用3-10次,然后活化再生。
9.如权利要求1所述的一种JAK1抑制剂AZD4604的制备方法,其特征在于,步骤(7)中,溶剂选自二氯甲烷、三氯甲烷、乙酸乙酯、四氢呋喃、乙腈、二甲基亚酰胺(DMA)中的一种或几种。反应的温度为-40-50℃,催化剂选自N,N-二甲基甲酰胺(DMF)、磷酸等活化剂,反应时间0-24h,纯化可以选过滤时洗涤滤饼、过柱、打浆或者重结晶。
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