CN107660204B - 制备吲唑衍生物的方法 - Google Patents
制备吲唑衍生物的方法 Download PDFInfo
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- CN107660204B CN107660204B CN201680029002.0A CN201680029002A CN107660204B CN 107660204 B CN107660204 B CN 107660204B CN 201680029002 A CN201680029002 A CN 201680029002A CN 107660204 B CN107660204 B CN 107660204B
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- 238000004519 manufacturing process Methods 0.000 title description 2
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 150000003839 salts Chemical class 0.000 claims abstract description 111
- 238000000034 method Methods 0.000 claims abstract description 58
- 238000002360 preparation method Methods 0.000 claims abstract description 26
- -1 tetrahydro-2H-pyran-2-yl Chemical group 0.000 claims description 50
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 44
- 239000003054 catalyst Substances 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 229910052763 palladium Inorganic materials 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 239000000543 intermediate Substances 0.000 abstract description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- 239000000243 solution Substances 0.000 description 38
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 14
- 238000000634 powder X-ray diffraction Methods 0.000 description 13
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 11
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 10
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 8
- 238000004821 distillation Methods 0.000 description 7
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- WHKWMTXTYKVFLK-UHFFFAOYSA-N 1-propan-2-ylpiperazine Chemical compound CC(C)N1CCNCC1 WHKWMTXTYKVFLK-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- BKLOVTNYVMYOLE-UHFFFAOYSA-N benzoic acid 2-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-5-[(4-propan-2-ylpiperazin-1-yl)methyl]-1,3-oxazole Chemical compound OC(=O)c1ccccc1.CC(C)N1CCN(Cc2cnc(o2)-c2cc(cc3[nH]ncc23)-c2cccc3[nH]ccc23)CC1 BKLOVTNYVMYOLE-UHFFFAOYSA-N 0.000 description 4
- HMVLPXGCMMODGA-UHFFFAOYSA-N benzoic acid;1,3-oxazole Chemical compound C1=COC=N1.OC(=O)C1=CC=CC=C1 HMVLPXGCMMODGA-UHFFFAOYSA-N 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- GJVXQAIKAKUZAZ-UHFFFAOYSA-N 1,3-oxazol-5-yl-(4-propan-2-ylpiperazin-1-yl)methanone Chemical compound C(C)(C)N1CCN(CC1)C(=O)C1=CN=CO1 GJVXQAIKAKUZAZ-UHFFFAOYSA-N 0.000 description 3
- QCGMEWVZBGQOFN-UHFFFAOYSA-N 1,3-oxazole-5-carboxylic acid Chemical compound OC(=O)C1=CN=CO1 QCGMEWVZBGQOFN-UHFFFAOYSA-N 0.000 description 3
- UGRNAAOSAUZBIT-UHFFFAOYSA-N 4-propan-2-ylpiperazine-1-carbaldehyde Chemical class CC(C)N1CCN(C=O)CC1 UGRNAAOSAUZBIT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- NZOIZXYFNHTMQX-UHFFFAOYSA-N benzoic acid;1h-indazole Chemical compound C1=CC=C2C=NNC2=C1.OC(=O)C1=CC=CC=C1 NZOIZXYFNHTMQX-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- KRMORCCAHXFIHF-UHFFFAOYSA-N ethyl 1,3-oxazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=CO1 KRMORCCAHXFIHF-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- WPEQESCHNHMPFW-UHFFFAOYSA-N methanol;1,3-oxazole Chemical compound OC.C1=COC=N1 WPEQESCHNHMPFW-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 3
- 229910000080 stannane Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000001384 succinic acid Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- MNKCGUKVRJZKEQ-MIXQCLKLSA-N (1z,5z)-cycloocta-1,5-diene;iridium;methanol Chemical compound [Ir].[Ir].OC.OC.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 MNKCGUKVRJZKEQ-MIXQCLKLSA-N 0.000 description 2
- HNVIQLPOGUDBSU-OLQVQODUSA-N (2s,6r)-2,6-dimethylmorpholine Chemical compound C[C@H]1CNC[C@@H](C)O1 HNVIQLPOGUDBSU-OLQVQODUSA-N 0.000 description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ZUVPLKVDZNDZCM-UHFFFAOYSA-N 3-chloro-2-methylaniline Chemical compound CC1=C(N)C=CC=C1Cl ZUVPLKVDZNDZCM-UHFFFAOYSA-N 0.000 description 2
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 2
- WUBBRNOQWQTFEX-UHFFFAOYSA-M 4-aminosalicylate(1-) Chemical compound NC1=CC=C(C([O-])=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-M 0.000 description 2
- SVLZRCRXNHITBY-UHFFFAOYSA-N 4-chloro-1h-indole Chemical compound ClC1=CC=CC2=C1C=CN2 SVLZRCRXNHITBY-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229960004308 acetylcysteine Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 2
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical class OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- IEHJKGRLVGZCMX-UHFFFAOYSA-N 1,3-oxazol-2-ylmethanol Chemical compound OCC1=NC=CO1 IEHJKGRLVGZCMX-UHFFFAOYSA-N 0.000 description 1
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- NATULDXOXIBHEB-UHFFFAOYSA-N 1H-indazole 1,3-oxazole Chemical compound N1N=CC2=CC=CC=C12.O1C=NC=C1 NATULDXOXIBHEB-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- LXFQSRIDYRFTJW-UHFFFAOYSA-M 2,4,6-trimethylbenzenesulfonate Chemical compound CC1=CC(C)=C(S([O-])(=O)=O)C(C)=C1 LXFQSRIDYRFTJW-UHFFFAOYSA-M 0.000 description 1
- HNVIQLPOGUDBSU-UHFFFAOYSA-N 2,6-dimethylmorpholine Chemical compound CC1CNCC(C)O1 HNVIQLPOGUDBSU-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- NPAXPTHCUCUHPT-UHFFFAOYSA-N 3,4,7,8-tetramethyl-1,10-phenanthroline Chemical compound CC1=CN=C2C3=NC=C(C)C(C)=C3C=CC2=C1C NPAXPTHCUCUHPT-UHFFFAOYSA-N 0.000 description 1
- WOWFGZLCKNNPIV-UHFFFAOYSA-N 3-phenylbenzene-1,2-disulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC(C=2C=CC=CC=2)=C1S(O)(=O)=O WOWFGZLCKNNPIV-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical class NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- MFGIVPTZAMUOSU-UHFFFAOYSA-N 4-chloro-1-(oxan-2-yl)indazole Chemical compound N1=CC=2C(Cl)=CC=CC=2N1C1CCCCO1 MFGIVPTZAMUOSU-UHFFFAOYSA-N 0.000 description 1
- CQTGQYVQJOJQCM-UHFFFAOYSA-N 4-chloro-1h-indazole Chemical compound ClC1=CC=CC2=C1C=NN2 CQTGQYVQJOJQCM-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供了用于制备式(IV)化合物及其盐的新方法、新中间体及其新的盐和多晶型物。
Description
发明领域
本发明涉及用于制备化合物及其盐的新方法,所述化合物是磷酸肌醇3’OH激酶δ亚型(PI3Kδ)的活性或功能的抑制剂;新中间体;及其新的盐和多晶型物。
发明背景
国际专利申请PCT/EP2010/055666 (公开号WO2010/125082)描述了具有通式(I)的化合物:
其中
R1’是9-或10-元二环杂芳基,其中所述9-或10-元二环杂芳基含有1-3个独立地选自氧和氮的杂原子并且任选地被C1-6烷基、C3-6环烷基、卤素、-CN或-NHSO2R5’取代,或
任选地被一个或两个独立地选自C1-6烷基、-OR6’、卤素和-NHSO2R7’的取代基取代的吡啶基;
R2’和R3’与它们所连接的氮原子一起连接形成6-或7-元杂环基,其中所述6-或7-元杂环基任选地含有一个氧原子或一个另外的氮原子并且任选地被一个或两个独立地选自C1-6烷基的取代基取代;
R4’是氢或甲基;
R6’是氢或C1-4烷基;和
R5’和R7’各自独立地是C1-6烷基或任选地被一个或两个独立地选自卤素的取代基取代的苯基;
及其盐。
WO2010/125082的实施例描述了6-(1H-吲哚-4-基)-4-(5-{[4-(1-甲基乙基)-1-哌嗪基]甲基}-1,3-噁唑-2-基)-1H-吲唑的制备,其可以由式(II)代表:
其在下文中称为“化合物A”及其盐酸盐,以及N-[5-[4-(5-{[(2R,6S)-2,6-二甲基-4-吗啉基]甲基}-1,3-噁唑-2-基)-1H-吲唑-6-基]-2-(甲基氧基)-3-吡啶基]甲磺酰胺的制备,其可以由式(III)代表:
其在下文中称为“化合物B”及其(R)-扁桃酸盐。
国际专利申请PCT/EP2011/068604 (公开号WO2012/055846)描述了化合物A的新的多晶型物和化合物A的盐及其多晶型物,其制备方法,包含它们的药物组合物及其在治疗各种病症中的用途。
国际专利申请PCT/EP2011/065419 (公开号WO2012/032067)描述了化合物B的新的多晶型物和盐,其制备方法,包含它们的药物组合物及其在治疗各种病症中的用途。
WO2010/125082、WO2012/055846和WO2012/032067中描述的用于制备化合物A和B的方法不适合于以商业规模制备化合物。例如,所述方法之一在关键的噁唑-吲唑偶联步骤中使用锡烷试剂。锡烷试剂通常是有毒的和对环境有害的。在WO2012/055846中描述了避免使用锡烷试剂的替代方法。然而,该方法需要大量的步骤,从昂贵的起始原料开始并且具有差的总产率。
因此,仍然需要开发可适合用于商业规模的用于制备化合物A和B的改进的方法。
发明概述
本发明提供了用于制备式(IV)化合物及其盐的新方法
其中 R1和R2如下所定义,新的中间体及其新的盐和多晶型物。
附图简要说明
附图1展示了6-(1H-吲哚-4-基)-4-(5-{[4-(1-甲基乙基)-1-哌嗪基]甲基}-1,3-噁唑-2-基)-1H-吲唑苯甲酸盐的多晶型物的X射线粉末衍射(XRPD)图。
发明详述
本发明提供了与方法有关的多个方面,所述方法总结在以下方案1中:
因此,一方面,本发明提供了用于制备式(IV)化合物及其盐的方法
其中
所述方法包括:
(a) 在钯催化剂存在下,使式(VII)化合物或其盐与式(X)化合物或其盐反应
其中 X是卤素并且P是保护基,得到式(XI)化合物或其盐
其中 R1a 和P如上面所定义,随后将式(XI)化合物或其盐转化成式(IV)化合物或其盐,
(b) 在催化剂系统存在下,使式(XI)化合物或其盐与硼基化试剂反应,得到式(XII)化合物或其盐
其中 R1a 和P如上面所定义,随后将式(XII)化合物或其盐转化成式(IV)化合物或其盐,
(c) 在钯催化剂存在下,使式(XII)化合物或其盐与式(XIV)化合物或其盐反应
其中 R2 如上面所定义并且X1是卤素,得到式(XIII)化合物或其盐
其中 R1a、R2 和P如上面所定义,随后将式(XIII)化合物或其盐转化成式(IV)化合物或其盐, 和/或
(d) 使式(XIII)化合物或其盐与还原剂反应,然后脱保护。
本发明提供了用于制备式IV化合物的方法,其包括步骤a至d中的至少一个。本发明的方法可以包括步骤a、b、c和d中的所有四个步骤或一个、两个或三个步骤。
可根据本发明制备的化合物A和B的盐包括盐酸盐、氢溴酸盐、硝酸盐、甲基硝酸盐、硫酸盐、硫酸氢盐、氨基磺酸盐、磷酸盐、乙酸盐、羟基乙酸盐、苯乙酸盐、丙酸盐、丁酸盐、异丁酸盐、戊酸盐、马来酸盐、羟基马来酸盐、丙烯酸盐、富马酸盐(例如半富马酸盐)、苹果酸盐、酒石酸盐、柠檬酸盐、水杨酸盐、对氨基水杨酸盐(p-aminosalicyclate)、乙醇酸盐、乳酸盐、庚酸盐、邻苯二甲酸盐、草酸盐、琥珀酸盐(例如半琥珀酸盐)、苯甲酸盐、邻乙酰氧基苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、萘甲酸盐、羟基萘甲酸盐、扁桃酸盐、鞣酸盐、甲酸盐、硬脂酸盐、抗坏血酸盐、棕榈酸盐、油酸盐、丙酮酸盐、双羟萘酸盐(例如半双羟萘酸盐)、丙二酸盐、月桂酸盐、戊二酸盐、谷氨酸盐、丙酸酯十二烷基硫酸盐(estolate)、甲烷磺酸盐(甲磺酸盐)、乙烷磺酸盐(乙磺酸盐)、2-羟基乙烷磺酸盐、苯磺酸盐(benzenesulfonate)(苯磺酸盐(besylate))、对氨基苯磺酸盐、对甲苯磺酸盐(p-toluenesulfonate)(甲苯磺酸盐(tosylate))、萘-2-磺酸盐、萘二磺酸盐(例如半萘二磺酸盐)、均三甲苯磺酸盐、联苯二磺酸盐(例如半联苯二磺酸盐)、肉桂酸盐(例如半肉桂酸盐)、癸二酸盐(例如半癸二酸盐)、均苯四甲酸盐(例如半均苯四甲酸盐)和苯二丙烯酸盐(例如半苯二丙烯酸盐)。
在一个实施方案中,本发明的方法可用于制备化合物A的半琥珀酸盐。在另一个实施方案中,本发明的方法可用于制备化合物A的苯甲酸盐。化合物A的苯甲酸盐具有某些性质,所述性质可以使其特别适合于作为吸入药物的开发,特别是其具有在模拟肺液中的合适的溶解度、良好的化学和物理稳定性以及合适的吸湿性。 因此,6-(1H-吲哚-4-基)-4-(5-{[4-(1-甲基乙基)-1-哌嗪基]甲基}-1,3-噁唑-2-基)-1H-吲唑苯甲酸盐形成了本发明的另一方面。
在本发明范围内还包括6-(1H-吲哚-4-基)-4-(5-{[4-(1-甲基乙基)-1-哌嗪基]甲基}-1,3-噁唑-2-基)-1H-吲唑苯甲酸盐的任何溶剂合物如水合物、络合物和多晶型形式。6-(1H-吲哚-4-基)-4-(5-{[4-(1-甲基乙基)-1-哌嗪基]甲基}-1,3-噁唑-2-基)-1H-吲唑苯甲酸盐可以以结晶或非结晶形式存在,或以其混合物形式存在。对于结晶形式的盐,技术人员将理解可以形成药学上可接受的溶剂合物,其中溶剂分子在结晶期间结合到晶格中。溶剂合物可以包括非水溶剂如乙醇、异丙醇、DMSO、乙酸、乙醇胺和EtOAc,或者它们可以包含水作为结合到晶格中的溶剂。 其中水是结合到晶格中的溶剂的溶剂合物通常被称为“水合物”。 水合物包括化学计量的水合物以及含有可变量的水的组合物。如技术人员将理解的,水的量可以取决于条件,例如湿度。例如,随着湿度降低,水的量可以减少,并且随着湿度的增加,水的量可以增加。水的量的这种变化包括在本发明的范围内。
在一个实施方案中,本发明提供了6-(1H-吲哚-4-基)-4-(5-{[4-(1-甲基乙基)-1-哌嗪基]甲基}-1,3-噁唑-2-基)-1H-吲唑苯甲酸盐的多晶型物,其特征在于其提供了包含在约6.7 和/或约8.7 和/或约11.6 和/或约12.9 和/或约13.3 和/或约16.2处的峰(°2θ)的XRPD图。
在一个实施方案中,本发明提供了6-(1H-吲哚-4-基)-4-(5-{[4-(1-甲基乙基)-1-哌嗪基]甲基}-1,3-噁唑-2-基)-1H-吲唑苯甲酸盐的多晶型物,其特征在于其提供了包含在约6.7、约8.7、约11.6、约12.9、约13.3和约16.2处的峰(°2θ)的XRPD图。
在另一个实施方案中,本发明提供了6-(1H-吲哚-4-基)-4-(5-{[4-(1-甲基乙基)-1-哌嗪基]甲基}-1,3-噁唑-2-基)-1H-吲唑苯甲酸盐的多晶型物,其特征在于其提供了包含基本上如表1中所示的峰的XRPD图。
在另一个实施方案中,本发明提供了6-(1H-吲哚-4-基)-4-(5-{[4-(1-甲基乙基)-1-哌嗪基]甲基}-1,3-噁唑-2-基)-1H-吲唑苯甲酸盐的多晶型物,其特征在于其提供了基本上根据图1的XRPD图 。
当本文指出在给定值处存在XRPD图中的峰时,通常意味着峰在所引用的值的±0.2内,例如在所引用的值的±0.1内。
在另一方面,本发明提供了用于制备式(XI)化合物及其盐的方法
所述方法包括在钯催化剂存在下,使式(VII)化合物或其盐与式(X)化合物或其盐反应
其中R1a如上面所定义,
其中 X是卤素并且P如上面所定义。
在另一方面,本发明提供了用于制备式(IV)化合物及其盐的方法
其中
所述方法包括在钯催化剂存在下,使式(VII)化合物或其盐与式(X)化合物或其盐反应
其中R1a如上面所定义,
其中 X 和P如上面所定义,得到式(XI)化合物或其盐
其中 R1a 和P如上面所定义,随后将式(XI)化合物或其盐转化成式(IV)化合物或其盐。
保护基P可以是在例如Wuts和Greene的Protective Groups in OrganicSynthesis (John Wiley & Sons)中描述的任何合适的保护基。在一个实施方案中,保护基是四氢-2H-吡喃-2-基。
在一个实施方案中,X是氯。在另一个实施方案中,X是溴。
用于形成上述式(XI)化合物的钯催化剂可以是任何合适的钯催化剂络合物,例如具有合适的配位体的钯络合物。配位体可以是,例如,Buchwald配位体如XPhos (2-二环己基膦基-2′,4′,6′-三异丙基联苯)或RuPhos (2-二环己基膦基-2′,6′-二异丙氧基联苯)。在一个实施方案中,钯催化剂是具有XPhos的钯络合物。
式(VII)化合物或其盐可以如下从噁唑-5-甲酸乙酯(ethyl oxazole-5-carboxylic acid),即式(V)化合物或其盐制备:
将其水解,得到噁唑-5-甲酸,即式(VI)化合物或其盐
随后用1-(异丙基)哌嗪或(2R, 6S)-2,6-二甲基吗啉胺化。
可替代地,式(VII)化合物或其盐可以通过在酶存在下用1-(异丙基)哌嗪或(2R,6S)-2,6-二甲基吗啉处理噁唑-5-甲酸乙酯而直接制备。在一个实施方案中,所述酶是冻干的脂肪酶TL。
式(X)化合物或其盐可以如下制备:使式(VIII)化合物或其盐与亚硝酸异戊酯反应,随后进行保护
其中 X如上面所定义。
可替代地,在另一方面,本发明提供了用于制备式(XI)化合物及其盐的方法
其中R1a是和P如上面所定义,所述方法包括在钯催化剂存在下,使式(Va)化合物或其盐与式(X)化合物或其盐反应
其中 R3是C1-6烷基如乙基(以得到如上面所定义的式(V)化合物),
其中 X是卤素并且P如上面所定义,随后水解并用1-(异丙基)哌嗪或(2R, 6S)-2,6-二甲基吗啉胺化。
在另一方面,本发明提供了用于制备式(IV)化合物及其盐的方法
其中 R1和R2 如上面所定义,
所述方法包括在钯催化剂存在下,使式(Va)化合物或其盐与式(X)化合物或其盐反应
其中 R3如上面所定义,
其中 X 和P如上面所定义,随后水解并用1-(异丙基)哌嗪或(2R, 6S)-2,6-二甲基吗啉胺化,得到式(XI)化合物或其盐
其中 R1a 和P如上面所定义,随后将式(XI)化合物或其盐转化成式(IV)化合物或其盐。
在另一方面,本发明提供了用于制备式(XII)化合物及其盐的方法
其中 R1a和P如上面所定义,
所述方法包括在催化剂系统存在下,使式(XI)化合物或其盐与硼基化试剂反应
其中 R1a 和P如上面所定义。
在另一方面,本发明提供了用于制备式(IV)化合物及其盐的方法
其中 R1和R2 如上面所定义,
所述方法包括在催化剂系统存在下,使式(XI)化合物或其盐与硼基化试剂反应
其中 R1a 和P如上面所定义,得到式(XII)化合物或其盐
其中 R1a 和P如上面所定义, 随后将式(XII)化合物或其盐转化成式(IV)化合物或其盐。
根据本发明使用的硼基化试剂可以是任何合适的硼基化试剂,例如频哪醇硼烷。
根据本发明使用的催化剂系统可以是任何合适的催化剂系统,例如铱、镍、铁、铑或钴催化剂系统。合适的催化剂系统描述于例如Chem. Commun., 2015, 51, 6508-6511;J. Am. Chem. Soc., 2013, 135, 17258-17261;和J. Am. Chem. Soc., 2014, 136,4133-4136中。在一个实施方案中,催化剂系统是铱催化剂系统,例如 (1,5-环辛二烯)(甲氧基)铱(I)二聚体。
在另一方面,本发明提供了用于制备式(XIII)化合物及其盐的方法
其中 R1a、R2 和P如上面所定义,
所述方法包括在钯催化剂存在下,使式(XII)化合物或其盐与式(XIV)化合物或其盐反应
其中 R1a 和P如上面所定义,
其中 R2 如上面所定义并且X1是卤素。
在另一方面,本发明提供了用于制备式(IV)化合物及其盐的方法
其中 R1和R2 如上面所定义,
所述方法包括在钯催化剂存在下,使式(XII)化合物与式(XIV)化合物反应
其中 R1a 和P如上面所定义,
其中 R2 如上面所定义并且X1是卤素,得到式(XIII)化合物
其中 R1a、R2 和P如上面所定义,随后将式(XIII)化合物或其盐转化成式(IV)化合物或其盐。
在一个实施方案中,X1是氯。 在另一个实施方案中,X1是溴。
用于形成上述式(XIII)化合物的钯催化剂可以是任何合适的钯催化剂络合物,例如具有合适的配位体的钯络合物。配位体可以是,例如,Buchwald配位体如XPhos (2-二环己基膦基-2′,4′,6′-三异丙基联苯)或三环己基膦。在一个实施方案中,钯催化剂是具有XPhos的钯络合物。
另一方面,本发明提供了用于制备式(IV)化合物及其盐的方法
其中 R1和R2 如上面所定义,
所述方法包括使式(XIII)化合物或其盐与还原剂反应,然后脱保护
其中 R1a、R2 和P如上面所定义。
还原剂可以是任何合适的还原剂如氢化物,例如氢化铝锂、硼氢化钠、二异丁基氢化铝(DIBAL)或双(2-甲氧基乙氧基)氢化铝钠(Red-AI)。在一个实施方案中,还原剂是氢化铝锂。
如本领域技术人员将理解的那样,脱保护所需的条件将取决于保护基的性质。如果使用的保护基是四氢-2H-吡喃-2-基,则其可以在酸性条件下除去。式(VII)、(XI)、(XII)和(XIII)的中间体化合物是新的,因此所述化合物及其盐形成了本发明的另一方面。
本发明的具体实施方案在下面的方案2中示出,并且在以下实施例中详细描述,其仅用于说明,而不是意图以任何方式限制本发明的范围。
如本文所使用的,在这些方法、方案和实施例中使用的符号和惯例与在当代科学文献,例如,Journal of the American Chemical Society或Journal of Biological Chemistry中使用的那些是一致的。除非另有说明,否则所有起始原料均得自商业供应商并且未经进一步纯化地使用。具体来说,可以在实施例和整个说明书中使用以下缩写:
Ac 乙酰基
COD 1,5-环辛二烯
CPME 环戊基甲基醚
DHP 3,4-二氢-2H-吡喃
DMSO 二甲基亚砜
Et 乙基
EtOAc 乙酸乙酯
g 克
h 小时
IPA 异丙醇
iPr 异丙基
HPLC 高效液相色谱法
kg 千克
L 升
Me 甲基
Mg 毫克
MIBK 甲基异丁基酮
Min 分钟
ml 毫升
mol 摩尔
mmol 毫摩尔
Pin 频哪醇
RuPhos 2-二环己基膦基-2′,6′-二异丙氧基联苯
Rt 保留时间
TFA 三氟乙酸
THF 四氢呋喃
TMS 三甲基甲硅烷
XPhos 2-二环己基膦基-2′,4′,6′-三异丙基联苯
XRPD X射线粉末衍射。
实施例
中间体1
噁唑-5-甲酸
将氢氧化锂一水合物的水溶液(由将49.44 kg 氢氧化锂一水合物溶解于319 kg水中制备的124.5 kg溶液, 398 mol)加入到5-噁唑甲酸乙酯(54 kg, 382.7 mol)于水(54kg)中的溶液中(保持温度低于25℃)。将反应搅拌6.5 h,然后加入浓HCl水溶液(64.8 kg)(保持温度低于25℃),将结晶冷却至5℃并保持1 h。将产物滤出,用冷水(88 kg)洗涤,然后用异丙醇(171 kg)洗涤并在50℃真空干燥,得到标题化合物(37.88 kg, 87.5%)。
1H NMR (400 MHz, DMSO-d 6) δ ppm 13.68 (br. s., 1 H), 8.59 (s, 1 H)和7.88 (s, 1 H)。
中间体2
(4-异丙基哌嗪-1-基)(噁唑-5-基)甲酮
方法A
将草酰氯(47.7 kg, 375.8 mol)加入到噁唑-5-甲酸(32.88 kg, 290.8 mol)于乙酸异丙酯(144 kg)中的溶液中(保持温度在52-58℃)。将温度升至58.5℃,搅拌5 h,然后冷却至20℃。将反应混合物加入到1-(异丙基)哌嗪(41 kg, 319.8 mol)和碳酸钾(118.4kg)于乙酸异丙酯(348 kg)和水(103 kg)中的溶液中(保持温度低于25℃)。将反应搅拌15 min,将温度升至33℃并将有机相用水(191 kg)洗涤,减压浓缩至95 L并冷却至20℃。加入正庚烷(157 kg)并将结晶搅拌2 h,并将产物滤出,用正庚烷(157 kg)洗涤并40℃真空干燥,得到标题化合物(57.14 kg, 88.0%)。
1H NMR (400 MHz, CDCl3-d) δ ppm 7.94 (s, 1 H), 7.56 (s, 1 H), 3.91-3.73 (m, 4 H), 2.75 (spt., J=6.5 Hz, 1 H), 2.63-2.52 (m, 4 H)和1.06 (d, J=6.6Hz, 6 H)。
方法B
将1-异丙基哌嗪(1.06 g, 8.24 mmol)和噁唑-5-甲酸乙酯(1.16 g, 8.24 mmol)加入到5 Å分子筛(8.0 g)于环戊基甲基醚(40 mL)中的悬浮液中并在55℃搅拌1 h。加入冻干的脂肪酶TL (2.0 g),将反应混合物搅拌28.75 h,然后通过玻璃纤维纸过滤,用环戊基甲基醚(3 x 6 mL)彻底洗涤。将合并的滤液和洗涤液减压浓缩并将粗残余物在甲基环己烷(6 mL)中再浆化,滤出,用甲基环己烷(2 x 5 mL)洗涤并真空干燥,得到标题化合物(1.40g, 76%)。
中间体3
4-氯-1H-吲唑
在25℃将乙酸酐(69 kg, 675.9 mol)加入到3-氯-2-甲基苯胺(30 kg, 211.9mol)、乙酸钾(25 kg, 254.7 mol)和甲基四氢呋喃(302 L)的搅拌的浆料中,然后搅拌2 h。将亚硝酸异戊酯(44.5 kg, 379.9 mol)加入到浆料中并将内容物加热至73℃保持18 h。将浆料冷却至20℃,然后加入水(90 L),并将反应冷却至5℃。加入NaOH的水溶液(105 L,32%w/w),将溶液加热至40℃并搅拌2 h。除去下面的水相并将有机层用水(150 L)洗涤,然后用盐水(18 kg于90 L水中)洗涤。通过常压蒸馏将有机层浓缩至90 L并通过常压蒸馏进行至正庚烷的溶剂交换,达到240 L的最终体积。将浆料冷却至7℃,搅拌2 h并通过过滤分离固体。将滤饼用庚烷(2 x 60 L)洗涤并真空干燥,得到标题化合物(23.6 kg, 73%)。
1H NMR (400MHz, MeOD-d4) δ = 8.08 (s, 1H), 7.48 (d, J=8.6 Hz, 1H),7.33 (dd, J=7.5, 8.4 Hz, 1H), 7.14 (d, J=7.3 Hz, 1H)
HPLC r.t – 1.94 min。
中间体4
4-氯-1-(四氢-2H-吡喃-2-基)-1H-吲唑
将三氟乙酸(3.5 kg, 30.7 mol)加入到4-氯-1H-吲唑(23 kg, 15.1 mol)和3,4-二氢-2H-吡喃(43.1 kg, 512.7 mol)于乙酸乙酯(235 L)中的溶液中。将反应混合物加热至80℃保持4 h,然后冷却至23℃,加入三乙胺(3.2 kg, 31.6 mol)并搅拌30 min。使用常压蒸馏将溶剂交换成异丙醇,达到138 L的最终体积。将溶液冷却至55℃并加入水(138 L)(保持温度)。将溶液冷却至42℃并加入晶种(8 g),然后冷却至30℃,保持10 h,并加入水(46 L),冷却至18℃,并将浆料搅拌2 h,然后滤出,用6:1 v/v水/2-丙醇(2 x 46 L)洗涤并在50℃真空干燥,得到标题化合物(28.8 kg, 80.7%)。
1H NMR (500MHz, DMSO-d6) δ = 8.18 (s, 1H), 7.74 (d, J=8.5 Hz, 1H),7.42 (dd, J=7.5, 8.4 Hz, 1H), 7.27 (d, J=7.3 Hz, 1H), 5.88 (dd, J=2.5, 9.5Hz, 1H), 3.90 - 3.85 (m, 1H), 3.79 - 3.70 (m, 1H), 2.44 - 2.35 (m, 1H), 2.07- 1.95 (m, 2H), 1.81 - 1.69 (m, 1H), 1.64-1.53 (m, 2H)。
中间体5
(4-异丙基哌嗪-1-基)(2-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)噁唑-5-基)
甲酮
方法A
将氯化钯(0.74 kg, 4.2 mol)和XPhos (4.36 kg, 9.1 mol)悬浮于环戊基甲基醚(372 L)中。加入4-氯-1-(四氢-2H-吡喃-2-基)-1H-吲唑(36 kg, 152.1 mol)、(4-异丙基哌嗪-1-基)(噁唑-5-基)甲酮(34.78 kg, 155.8 mol)和碳酸钾(325 目, 35.64 kg,257.9 mol)并用环戊基甲基醚(2.58 kg)漂洗。加入溶解于环戊基甲基醚(10 L)中的新戊酸溶液(9.294 kg, 91.0 mol),随后用环戊基甲基醚(10 L)漂洗一次。将反应真空脱气并用氮气回填三次,然后加热至回流保持5 h并将内容物冷却至40℃。将反应混合物用水(144L)洗涤,然后用5%w/v氯化钠水溶液 (151.2 kg)洗涤并将有机相在大气压下浓缩至288 L。将反应混合物过滤至另一容器中并将过滤器用环戊基甲基醚(36 L)洗涤,然后在大气压下蒸馏至108 L。将甲基环己烷(162 L)加入到容器(保持温度在75℃)中,然后将内容物冷却至62-65℃并且加入在冷冻的甲基环己烷(0.52 L)中浆化的(4-异丙基哌嗪-1-基)(2-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)噁唑-5-基)甲酮 (90 g)的晶种来结晶。将结晶在62℃保持30 min,冷却至7℃,然后在7℃保持过夜。将产物滤出,用甲基环己烷(2 x 72 L)洗涤并在真空烘箱中在50℃干燥,得到标题化合物(57.2 kg, 88.9%)。
1H NMR (400MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.00 (d, J=8.6 Hz, 1 H),7.95 (s, 1H), 7.91 (d, J =7.3 Hz, 1 H),7.62 (dd, J=7.3, 8.3 Hz, 1H), 5.97(dd, J=2.0, 9.5 Hz, 1H), 4.03 - 3.85 (m, 1H), 3.84 - 3.70 (m, 1H), 3.66 (br.s., 4H), 2.72 (spt., J=6.5 Hz, 1 H), 2.57 - 2.40 (m, 5H), 2.11 - 1.96 (m,2H), 1.85 - 1.68 (m, 1H), 1.68 - 1.47 (m, 2H), 0.99 (d, J=6.4 Hz, 6 H)。
方法B
将4-氯-1-(四氢-2H-吡喃-2-基)-1H-吲唑(10 g, 42.2 mmol)、(4-异丙基哌嗪-1-基)(噁唑-5-基)甲酮(9.67 g, 43.3 mmol)、碳酸钾(325 目, 9.93 g, 71.8 mmol)和新戊酸(2.59 g, 25.3 mmol)悬浮于CPME (90 mL)中。将反应在室温搅拌10 min,然后真空脱气并用氮气回填三次。加入氯化钯(206 mg, 1.16 mmol)和XPhos (1.21 g, 2.53 mmol)并用CPME (10 mL)漂洗。将反应混合物真空脱气并用氮气回填三次,然后加热至回流保持5 h并将内容物冷却回50℃。将反应混合物用3%w/w氯化钠水溶液(30 mL)洗涤,然后用20%w/w氯化钠水溶液(30 mL)洗涤并将有机相在大气压下浓缩至80 mL。将反应混合物冷却至室温并保持过夜。然后将反应混合物过滤到另一个容器中并将滤器用CPME (20 mL)洗涤,然后在大气压下蒸馏至30 mL。将内容物冷却至80℃并将甲基环己烷(45 mL)加入到容器中(保持温度在75℃),然后将内容物冷却至62-65℃并且加入(4-异丙基哌嗪-1-基)(2-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)噁唑-5-基)甲酮的晶种来结晶。结晶在63℃保持30min,经6 h冷却至5℃,然后在5℃保持过夜。将产物滤出,用冷冻的甲基环己烷(2 x 20 mL)洗涤并在真空烘箱中在50℃干燥,得到标题化合物(13.52 g, 76%)。
1H NMR (400MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.00 (d, J=8.6 Hz, 1 H),7.95 (s, 1H), 7.91 (d, J =7.3 Hz, 1 H),7.62 (dd, J=7.3, 8.3 Hz, 1H), 5.97(dd, J=2.0, 9.5 Hz, 1H), 4.03 - 3.85 (m, 1H), 3.84 - 3.70 (m, 1H), 3.66 (br.s., 4H), 2.72 (spt., J=6.5 Hz, 1 H), 2.57 - 2.40 (m, 5H), 2.11 - 1.96 (m,2H), 1.85 - 1.68 (m, 1H), 1.68 - 1.47 (m, 2H), 0.99 (d, J=6.4 Hz, 6 H)。
中间体6
(4-异丙基哌嗪-1-基)(2-(1-(四氢-2H-吡喃-2-基)-6-(4,4,5,5-四甲基-1,3,2-
二氧杂硼杂环戊烷-2-基)-1H-吲唑-4-基)噁唑-5-基)甲酮
在20℃将频哪醇硼烷(40.80 kg, 318.8 mol)加入到(4-异丙基哌嗪-1-基)(2-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)噁唑-5-基)甲酮(54.00 kg, 127.5 mol)、(1,5-环辛二烯)(甲氧基)铱(I)二聚体(0.864 kg, 1.30 mol)和3,4,7,8-四甲基-1,10-菲咯啉(1.51 kg, 6.39 mol)于THF (243.2 kg)中的搅拌的溶液中。将反应加热至回流保持8 h,然后冷却至20℃并转移到含有异丙醇(253.8 kg)的容器中,用THF (23.8 kg)彻底洗涤。将溶剂在200 mbar下蒸馏至270 L并加入异丙醇(253.8 kg),然后在100 mbar下再蒸馏至324L。将结晶加热至40℃ 保持4 h,冷却至20℃,搅拌过夜,滤出,用异丙醇(84.8 kg)洗涤,并在真空烘箱中在50℃干燥,得到标题化合物(57.35 kg, 82.8%)。
1H NMR (400MHz, CDCl3-d) δ ppm 8.70 (s, 1H), 8.40 (s, 1H), 8.17 (s,1H), 7.74 (s, 1H), 5.85 (dd, J=2.4, 9.5 Hz, 1H), 4.11 – 4.03 (m, 1H), 3.97 -3.77 (m, 5H), 2.78 (spt., J=6.4 Hz, 1 H), 2.70 - 2.59 (m, 5H), 2.24 - 2.14(m, 1H), 2.14 - 2.03 (m, 1H), 1.86 - 1.72 (m, 2H), 1.72 - 1.62 (m, 1H), 1.40(s, 12H), 1.08 (d, J=6.4 Hz, 6H)。
中间体7
(2-(6-(1H-吲哚-4-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)噁唑-5-基)(4-
异丙基哌嗪-1-基)甲酮
方法A
将4-氯吲哚(13.8 kg, 91.04 mol)加入到(4-异丙基哌嗪-1-基)(2-(1-(四氢-2H-吡喃-2-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑-4-基)噁唑-5-基)甲酮(50 kg, 91.00 mol)、乙酸钯(0.2 kg, 0.89 mol)、XPhos (0.65 kg, 1.36mol)和磷酸钾(46.4 kg, 218.6 mol)于MIBK (176 kg)和水(250 kg)中的搅拌的溶液中。将反应混合物真空脱气3 x,然后加热至82℃保持78 min,并加入MIBK (300L)。将各相混合30 min,然后分离并将有机相用由碳酸钾(2.75 kg)、N-乙酰半胱氨酸(5.2 kg)和水(250kg)组成的水溶液洗涤,然后用水(250 kg)洗涤并在大气压下蒸馏至300 L。将结晶冷却至20℃,搅拌5 h,滤出,用MIBK (80 kg)洗涤并在真空烘箱中在50℃干燥,得到标题化合物(36.15 kg, 73.7%)。
1H NMR (400 MHz, CDCl3-d) δ ppm 8.72 (s, 1 H), 8.38 (br. s, 1 H), 8.35(d, J=1.0 Hz, 1 H), 8.06 (s, 1 H), 7.81 (s, 1 H), 7.52-7.46 (m, 1 H), 7.36-7.30 (m, 3 H), 6.79-6.75 (m, 1 H), 5.84 (dd, J=9.17, 2.32 Hz, 1 H), 4.10-4.04(m, 1 H), 3.88 (br. s., 4 H), 3.84-3.72 (m, 1 H), 2.76 (spt., J=6.5 Hz, 1 H),2.68-2.59 (m, 5 H), 2.30-2.12 (m, 2 H), 1.86-1.73 (m, 2 H), 1.73-1.64 (m, 1H), 1.07 (d, J=6.60 Hz, 6 H)。
方法B
将4-氯吲哚(8.71 kg, 57.46 mol)加入到(4-异丙基哌嗪-1-基)(2-(1-(四氢-2H-吡喃-2-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑-4-基)噁唑-5-基)甲酮(34.55 kg, 62.88 mol)和磷酸钾(32.1 kg, 151.2 mol)于MIBK (139.2kg)和水(172.8 kg)中的搅拌的溶液中。将反应混合物真空脱气3 x,然后加入乙酸钯(0.14kg, 0.62 mol)和XPhos (0.45 kg, 0.94 mol),用MIBK (1 kg)漂洗。将反应加热至回流保持1 h。将反应冷却至低于40℃并加入N-乙酰半胱氨酸(3.59 kg),随后加入MIBK(138.2kg)。将各相加热至82℃,混合,然后 分离并将有机相用由碳酸钾(1.9 kg)、N-乙酰半胱氨酸(3.59 kg)、MIBK (27.6 kg)和水(173.8 kg)组成的水溶液洗涤,然后用水(172.8 kg)洗涤并在大气压下蒸馏至155 L。将结晶冷却至20℃,搅拌22 h,滤出,用MIBK (2 x 55.3 kg)洗涤并在真空烘箱中在50℃干燥,得到标题化合物24.72 kg, 73%)。
1H NMR (400 MHz, CDCl3-d) δ ppm 8.72 (s, 1 H), 8.38 (br. s, 1 H), 8.35(d, J=1.0 Hz, 1 H), 8.06 (s, 1 H), 7.81 (s, 1 H), 7.52-7.46 (m, 1 H), 7.36-7.30 (m, 3 H), 6.79-6.75 (m, 1 H), 5.84 (dd, J=9.17, 2.32 Hz, 1 H), 4.10-4.04(m, 1 H), 3.88 (br. s., 4 H), 3.84-3.72 (m, 1 H), 2.76 (spt., J=6.5 Hz, 1 H),2.68-2.59 (m, 5 H), 2.30-2.12 (m, 2 H), 1.86-1.73 (m, 2 H), 1.73-1.64 (m, 1H), 1.07 (d, J=6.60 Hz, 6 H)。
实施例1
2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑甲醇
溶剂合物
方法A
将氯化铝(2.94 kg, 22 mol)加入到THF (216 kg)中并搅拌至溶解。将(2-(6-(1H-吲哚-4-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)噁唑-5-基)(4-异丙基哌嗪-1-基)甲酮(34.75 kg, 64.5 mol)加入到容器中,用THF (0.5 kg)洗涤并将内容物冷却至0℃。加入氢化铝锂于THF (10%w/w, 22.6 kg, 59.6 mol)中的溶液(保持温度在低于20℃),随后用THF (0.9 kg)洗涤管道(line)。将反应搅拌30 min,然后加入EtOAc (15.6 kg),随后搅拌1 h。加入三乙醇胺(2.36 kg)于THF (2.1 L)中的溶液,随后加入三乙醇胺(36.8kg),然后加入NaOH水溶液(15%w/w, 121 kg)。将各相分离并将有机相用NaOH水溶液(15%w/w, 121 kg)洗涤,加入THF (17 kg),并将溶剂在大气压下蒸馏至104 L。通过加入MeOH(174 L)进行恒定体积蒸馏(104 L),然后加入MeOH (193.3 kg)。加入氯三甲基甲硅烷(35.8 kg, 329.5 mol)并将反应加热至50℃保持3 h,然后加入三乙胺(35.8 kg, 353.8mol)并将结晶冷却至20℃,滤出,用MeOH (2 x 55 kg)洗涤并在真空烘箱中在50℃干燥,得到标题化合物(24.80 kg, 81%)。
1H NMR (400MHz, DMSO-d6) δ ppm 13.43 (br. s., 1H), 11.36 (br. s., 1H),8.61 (s, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.92 (m, 1H), 7.51 - 7.46 (m, 2H), 7.32(s, 1H), 7.28 - 7.22 (m, 2H), 6.61 (m, 1H), 4.09 (q, J=5.3 Hz, 1H), 3.73 (s,2H), 3.18 (d, J=4.9 Hz, 3H), 2.60 (br. s., 1H), 2.56 - 2.40 (m, 4H), 0.94 (d,J=6.4 Hz, 6H)。
方法B
将氯化铝(4.25 g, 31.8 mmol)加入到THF (250 mL)中并搅拌至溶解。将(2-(6-(1H-吲哚-4-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)噁唑-5-基)(4-异丙基哌嗪-1-基)甲酮(50 g, 93 mmol)加入到容器中,用THF(100 mL)洗涤并将内容物冷却至0-5℃。加入氢化铝锂于THF (10%w/w, 35.6 mL, 85 mmol)中的溶液(保持温度在低于20℃)。将反应搅拌105 min,然后加入EtOAc (25 mL),随后搅拌1 h。加入三乙醇胺(50.5 mL),随后加入NaOH水溶液(15%w/w, 150 mL)。将各相分离并将有机相用NaOH水溶液(15%w/w, 150 mL)洗涤,并将溶剂在大气压下蒸馏至150 mL。通过加入MeOH (250 mL)进行恒定体积蒸馏(150mL)。在单独的容器中,将氯三甲基甲硅烷(59.3 mL, 464 mol)小心地加入至MeOH (400mL)中。将反应加热至50-55℃并经大约2 h加入底物的甲醇溶液。将反应在55℃搅拌3.25h,然后加入三乙胺(71.2 mL, 511 mmol)(保持温度在低于60℃)并将结晶在50℃保持2 h,经2 h冷却至20℃,在20℃保持2天,滤出,并用MeOH (2 x 100 mL)洗涤并在真空烘箱中在50℃干燥,得到标题化合物(35.4 g, 81%)。
1H NMR (400MHz, DMSO-d6) δ ppm 13.43 (br. s., 1H), 11.36 (br. s., 1H),8.61 (s, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.92 (m, 1H), 7.51 - 7.46 (m, 2H), 7.32(s, 1H), 7.28 - 7.22 (m, 2H), 6.61 (m, 1H), 4.09 (q, J=5.3 Hz, 1H), 3.73 (s,2H), 3.18 (d, J=4.9 Hz, 3H), 2.60 (br. s., 1H), 2.56 - 2.40 (m, 4H), 0.94 (d,J=6.4 Hz, 6H)。
实施例2
2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑半琥
珀酸盐
方法A
在85℃将2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑甲醇溶剂合物(729.1 g, 1.54 mol)和琥珀酸(109.6 g, 0.93 mol)溶解于10%w/w水于DMSO中的溶液(4.35 L)。将溶液过滤到另一个容器中,将管道用热的10%w/w水于DMSO中的溶液(725 mL)洗涤并将溶液保持在85℃。加入水(725 mL)(保持温度在85℃),然后将内容物经2 h冷却至40℃,并加入在25%w/w水于DMSO中的溶液(54 mL)中浆化的2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑半琥珀酸盐(3.63 g)的晶种来结晶,随后用25%w/w水于DMSO中的溶液(18.5 mL)洗涤管道。将浆料在40℃老化30min,然后经1 h加入水 (1.81 L),将内容物在40℃搅拌1 h,然后经1 h将结晶冷却至20℃,然后老化17 h,滤出,用40%w/w水于DMSO中的溶液(1.45 L)、水 (1.45 L)、异丙醇(2 x1.45 L)洗涤并在50℃真空干燥,得到标题化合物(626 g, 81%)。
1H NMR (400MHz, DMSO-d6) δ ppm 13.43 (1H, br s), 11.36 (1H, s), 10.00(br. s, 1H) 8.60 (1H, d, J = 0.9 Hz), 8.08 (1H, d, J = 1.3 Hz), 7.90-7.92(1H, m), 7.47-7.50 (1H, m), 7.47 (1H, t, J = 2.8 Hz), 7.41 (1H, m), 7.24 (1H,t, J = 7.3 Hz), 7.23 (1H, dd, J = 7.3, 1.7 Hz), 6.59-6.62 (1H, m), 2.66 (1H,m), 2.40-2.61 (8H, m), 2.38 (2H, s), 1.22 (6H, d, J = 6.5 Hz)。
方法B
在85℃将2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑甲醇溶剂合物(10.0 kg, 21.2 mol)和琥珀酸(1.50 kg, 12.7 mol)溶解于 DMSO (50L)中。将溶液过滤到另一个容器中,将管道用热的DMSO (10 L)洗涤并将溶液保持在85℃。加入水(17 L)(保持温度在82-88℃),然后将内容物以0.2℃/min冷却至40℃,并加入在25%w/w水于DMSO中的溶液(500 mL)中浆化的2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑半琥珀酸盐(50 g)的晶种来结晶,随后用25%w/w水于DMSO中的溶液(500 mL)洗涤管道。将浆料老化30 min,然后经8 h加入水(30 L),将内容物搅拌1 h,然后经1 h将结晶冷却至20℃,然后老化14 h,滤出,用40%w/w水于DMSO中的溶液(40 L)、水(40 L)、异丙醇(3 x 60 L)洗涤(作为浆料洗涤液)并在50℃真空干燥,得到标题化合物(7.25 kg, 68%)。
1H NMR (400MHz, DMSO-d6) δ ppm 13.43 (1H, br s), 11.36 (1H, s), 10.00(br. s, 1H) 8.60 (1H, d, J = 0.9 Hz), 8.08 (1H, d, J = 1.3 Hz), 7.90-7.92(1H, m), 7.47-7.50 (1H, m), 7.47 (1H, t, J = 2.8 Hz), 7.41 (1H, m), 7.24 (1H,t, J = 7.3 Hz), 7.23 (1H, dd, J = 7.3, 1.7 Hz), 6.59-6.62 (1H, m), 2.66 (1H,m), 2.40-2.61 (8H, m), 2.38 (2H, s), 1.22 (6H, d, J = 6.5 Hz)。
方法C
在85℃将2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑甲醇溶剂合物(629.3 g, 1.33 mol)和琥珀酸(94.4 g, 0.80 mol)溶解于DMSO (2.83L)中。将溶液过滤到另一个容器中,将管道用热的DMSO (629 mL)洗涤并将溶液保持在85℃。加入水(1.132 L)(保持温度在85℃),然后经1 h将内容物冷却至70℃,并加入在25%v/v水于DMSO中的溶液(31.5 mL)中浆化的2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑半琥珀酸盐(3.147 g)的晶种来结晶,随后用25%w/w水于DMSO中的溶液(31.5 mL)洗涤管道。将浆料老化120 min,然后经2.5 h加入水(1.573 L),将内容物搅拌0.5 h,然后经3 h将结晶冷却至20℃,然后老化17 h,滤出,用40%v/v水于DMSO中的溶液(2.52 L)、水(2.52 L)、异丙醇(2 x 2.52 L)洗涤并在50℃真空干燥,得到标题化合物(501.4 g, 75%)。
1H NMR (700MHz, DMSO-d6) δ ppm 13.43 (1H, br s), 11.36 (1H, s), 10.00(br. s, 1H) 8.60 (1H, d, J = 0.9 Hz), 8.08 (1H, d, J = 1.3 Hz), 7.90-7.92(1H, m), 7.47-7.50 (1H, m), 7.47 (1H, t, J = 2.8 Hz), 7.41 (1H, m), 7.24 (1H,t, J = 7.3 Hz), 7.23 (1H, dd, J = 7.3, 1.7 Hz), 6.59-6.62 (1H, m), 3.75 (2H,s), 2.66 (1H, m), 2.40-2.61 (8H, m), 2.38 (2H, s), 1.22 (6H, d, J = 6.5 Hz)。
实施例3
2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑苯甲
酸盐
在加入异丙醇(57 mL)前将2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑(28.55 g, 64.8 mmol)和苯甲酸(8.326 g, 68.2 mmol)溶解于DMSO(57 mL)中并温热至40℃。加入2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑苯甲酸盐* (183.6 mg)的晶种来结晶并搅拌20 min,加入异丙醇(114mL),冷却至20℃ 并老化过夜,然后滤出,用异丙醇(171 mL)洗涤并在40℃真空干燥,得到标题化合物(25.95 g, 71%)。
1H NMR (400MHz, DMSO-d6) δ = 13.41 (br. s., 1H), 11.36 (br. s., 1H),8.60 (d, J=0.7 Hz, 1H), 8.08 (d, J=1.0 Hz, 1H), 8.00 - 7.86 (m, 3H), 7.64 -7.57 (m, 1H), 7.52 - 7.45 (m, 5H), 7.32 (s, 1H), 7.28 - 7.21 (m, 2H), 6.61(br. s., 1H), 3.74 (s, 2H), 2.63 (sept, J=6.6 Hz, 1H) 2.55 - 2.41 (m, 8H),0.95 (d, J=6.6 Hz, 6H)。
在PANalytical X’Pert Pro粉末衍射仪,型号PW3040/60(使用X’Celerator检测器)上获得X射线粉末衍射(XRPD)数据。采集条件为:辐射: Cu Kα, 发生器电压(generatortension): 40 kV, 发生器电流: 45 mA, 起始角: 2.0° 2θ, 终止角: 40.0° 2θ, 步长:0.0167° 2θ, 每步时间: 31.75秒。通过将几毫克样品安置在硅片(零背景板)上制备样品,得到一薄层粉末。
2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑苯甲酸盐的多晶型物的XRPD数据显示于图1中。
固态形式的特征性XRPD角度和d间距总结在表1中。使用X’Pert Highscore软件测量峰位置。
衍射角2θ (º) | d间距(Å) |
6.7 | 13.2 |
8.7 | 10.1 |
11.2 | 7.9 |
11.6 | 7.6 |
12.9 | 6.9 |
13.3 | 6.6 |
16.2 | 5.5 |
17.5 | 5.1 |
18.7 | 4.7 |
19.8 | 4.5 |
20.0 | 4.4 |
21.0 | 4.2 |
22.0 | 4.0 |
22.4 | 4.0 |
25.6 | 3.5 |
表1。
*在如下进行的盐筛中得到2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑苯甲酸盐晶种:
1. 将750μl溶剂分配到含有2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑(~20 mg)的2-mL HPLC小瓶中
2. 向小瓶中加入化学计量的量的酸
3. 搅拌溶液/悬浮液,同时将温度在40℃和5℃之间循环48小时
4. 通过过滤分离结晶固体
5. 将作为溶液或非结晶产物的样品在-20℃下快速冷却,然后在室温下进行缓慢溶剂蒸发。
具体地说,通过将作为溶剂的乙腈加入到2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑(19mg)中,随后加入一当量的苯甲酸于THF中的溶液(3M)获得2-(6-(1H-吲哚-4-基)-1H-吲唑-4-基)-5-((4-异丙基哌嗪-1-基)甲基)噁唑苯甲酸盐晶种。
Claims (10)
1.用于制备式(IV)化合物或其盐的方法
其中
所述方法包括:
(a)在钯催化剂存在下,使式(VII)化合物或其盐与式(X)化合物或其盐反应
其中 X是卤素并且P是保护基,得到式(XI)化合物或其盐
其中 R1a 和P如上面所定义,随后将式(XI)化合物或其盐转化成式(IV)化合物或其盐,
(b) 在催化剂系统存在下使式(XI)化合物或其盐与硼基化试剂反应,得到式(XII)化合物或其盐
其中 R1a 和P如上面所定义,随后将式(XII)化合物或其盐转化成式(IV)化合物或其盐,
(c) 在钯催化剂存在下,使式(XII)化合物或其盐与式(XIV)化合物或其盐反应
其中 R2 如上面所定义并且X1是卤素,得到式(XIII)化合物或其盐
其中 R1a、R2 和P如上面所定义,随后将式(XIII)化合物或其盐转化成式(IV)化合物或其盐, 和
(d) 使式(XIII)化合物或其盐与还原剂反应,然后脱保护。
3.根据权利要求1的方法,其中 X和X1各自独立地是氯。
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