CN111793016A - 一种拉罗替尼中间体的制备方法以及中间体化合物 - Google Patents
一种拉罗替尼中间体的制备方法以及中间体化合物 Download PDFInfo
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- CN111793016A CN111793016A CN202010804146.7A CN202010804146A CN111793016A CN 111793016 A CN111793016 A CN 111793016A CN 202010804146 A CN202010804146 A CN 202010804146A CN 111793016 A CN111793016 A CN 111793016A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 32
- XCRCSPKQEDMVBO-UHFFFAOYSA-N 2-bromo-1,4-difluorobenzene Chemical compound FC1=CC=C(F)C(Br)=C1 XCRCSPKQEDMVBO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 5
- 238000005859 coupling reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 57
- 239000003960 organic solvent Substances 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 239000003054 catalyst Substances 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 230000009471 action Effects 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical group [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 8
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 5
- ULDHMXUKGWMISQ-SECBINFHSA-N (-)-carvone Chemical compound CC(=C)[C@@H]1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-SECBINFHSA-N 0.000 claims description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 4
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims description 4
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 4
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000004210 ether based solvent Substances 0.000 claims description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 claims description 2
- 229960000443 hydrochloric acid Drugs 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims description 2
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 2
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 claims description 2
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 2
- 229960004838 phosphoric acid Drugs 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
- 229940032330 sulfuric acid Drugs 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000009467 reduction Effects 0.000 abstract description 3
- 230000008878 coupling Effects 0.000 abstract 1
- 238000010168 coupling process Methods 0.000 abstract 1
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- NCXSNNVYILYEBC-SNVBAGLBSA-N (2r)-2-(2,5-difluorophenyl)pyrrolidine Chemical compound FC1=CC=C(F)C([C@@H]2NCCC2)=C1 NCXSNNVYILYEBC-SNVBAGLBSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000005551 L01XE03 - Erlotinib Substances 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
- 229960001433 erlotinib Drugs 0.000 description 5
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical group O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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- 238000001914 filtration Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
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- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical compound C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 1
- VVVOJODFBWBNBI-UHFFFAOYSA-N 2,5-difluorobenzaldehyde Chemical compound FC1=CC=C(F)C(C=O)=C1 VVVOJODFBWBNBI-UHFFFAOYSA-N 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- JJPYDOUEWNXUMD-UHFFFAOYSA-N O1CCCC1.C1(=CC=CC=C1)S(=O)(=O)O Chemical compound O1CCCC1.C1(=CC=CC=C1)S(=O)(=O)O JJPYDOUEWNXUMD-UHFFFAOYSA-N 0.000 description 1
- SAYWEMZILDPDKS-UHFFFAOYSA-N [C].[Pt].CO Chemical compound [C].[Pt].CO SAYWEMZILDPDKS-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- YCDXNPAEENQLOW-UHFFFAOYSA-N cyclohexanol;1-phenylethanone Chemical compound OC1CCCCC1.CC(=O)C1=CC=CC=C1 YCDXNPAEENQLOW-UHFFFAOYSA-N 0.000 description 1
- SDVCLJGNNFXMMT-UHFFFAOYSA-N cyclohexanol;4-methylpentan-2-one Chemical compound CC(C)CC(C)=O.OC1CCCCC1 SDVCLJGNNFXMMT-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- ACYVLFLWPIDTQP-UHFFFAOYSA-N dioxoplatinum;methanol Chemical compound OC.O=[Pt]=O ACYVLFLWPIDTQP-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- SFSNRRMPXZWJGX-UHFFFAOYSA-N methanesulfonic acid;oxolane Chemical compound CS(O)(=O)=O.C1CCOC1 SFSNRRMPXZWJGX-UHFFFAOYSA-N 0.000 description 1
- ZMBGEOHZPOUFHR-UHFFFAOYSA-N methanol;nickel Chemical compound [Ni].OC ZMBGEOHZPOUFHR-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
本发明公开了一种如V所示拉罗替尼中间体的制备方法以及中间体化合物,该方法包括以2,5‑二氟溴苯与N‑叔丁氧羰基‑L‑焦谷氨酸酯为起始原料,进行偶联,脱保护基关环,还原,脱羧得到式V所示的化合物。本发明的制备方法新颖,成本低,原料廉价易得,产率高,适于大规模工业化生产。
Description
技术领域
本发明具体的涉及一种拉罗替尼中间体的制备方法以及中间体化合物。
背景技术
拉罗替尼(larotrectinib)是一种可口服的、选择性的、ATP竞争性的原肌球蛋白受体激酶TRK的有效抑制剂,于2018年11月获得美国食品和药物管理局FDA批准上市,用于治疗带有NTRK融合基因的成人或儿童实体瘤。这意味着拉罗替尼并不仅仅是可用于治疗某一种具体部位的肿瘤,而是可用于治疗带有某种基因特征或某种生物标记的一类肿瘤,包括结肠、肺、胰腺、甲状腺、唾液和胃肠癌等17种癌症有效。现已成为第一个获得FDA批准的具有重大突破性疗法的抗癌药物。
(R)-2-(2,5-二氟苯基)吡咯烷是拉罗替尼的关键中间体,目前罗拉替尼的合成通常都是采用一定的工艺路线先制备(R)-2-(2,5-二氟苯基)吡咯烷进行后续的合成,最终制得拉罗替尼。
目前,制备(R)-2-(2,5-二氟苯基)吡咯烷,主要有以下三条合成路线:
一、WO2010048314的合成路线如下:
该路线以2,5-二氟溴苯为起始原料,以(-)-Sparteine为手性诱导试剂合成(R)-2-(2,5-二氟苯基)吡咯烷。该路线使用昂贵(-)-Sparteine,成本高昂,操作繁琐,反应条件苛刻(需要无水无氧,低温-78度),不适用工业化生产。
二、US20160168156的合成路线如下:
该路线以2,5-二氟溴苯为起始原料,以(S)-2-叔丁基磺酰胺手性诱导试剂,经过多步合成(R)-2-(2,5-二氟苯基)吡咯烷,并且制备过程中需要使用价格贵的(S)-2-叔丁基磺酰胺,同时需要使用危险的三乙基硼氢化锂以及-78度的低温反应,反应条件苛刻,成本高,不适用工业化生产。
三、WO2017201241的合成路线如下:
该路线以2,5-二氟苯甲醛与(R)-2-叔丁基磺酰胺缩合成亚胺,接着与(1,3-二氧戊烷-2-乙基)溴化镁进行加成反应,再经环化以及还原得到(R)-2-(2,5-二氟苯基)吡咯烷,制备过程中使用了价格昂贵的格式试剂,生产成本较高,也不适用于工业化生产。
发明内容
本发明所要解决的技术问题是为了克服现有的拉罗替尼中间体的制备方法中,试剂价格贵,成本较高,产率较低等缺陷,而提供了一种拉罗替尼中间体的制备方法以及中间体化合物。本发明的制备方法成本低,原料廉价易得,产率较高,适于工业化生产。
因此,本发明涉及一种如式V所示的拉罗替尼中间体的制备方法,其特征在于包含下列步骤:有机溶剂中,在催化剂作用下,式IV所示的化合物进行脱羧反应,即可;
其中,所述的化合物IV的脱羧反应的方法和条件均可为本领域此类反应的常规方法和条件,本发明特别优选下述方法和条件:有机溶剂中,加入催化剂和式IV所示的化合物进行反应,即可;其中,所述的较佳的催化剂与式IV所示的化合物的物料摩尔比0.05~0.3∶1;所述的较佳的催化剂为2-环己烯-1-酮、苯乙酮、4-甲基苯乙酮、4-甲基-2-戊酮或左旋香芹酮;所述的较佳的有机溶剂为二甲苯、均三甲苯、环己醇或聚乙二醇;所述的较佳的反应的温度为100~200℃;所述的较佳的反应的时间以检测反应完成为止。
本发明中,所述的化合物IV制备方法,其特征在于包含下列下列方法制得:
(1)其中,R为乙基,所述的化合物II的还原反应的方法和条件均可为本领域此类反应的常规方法和条件,本发明特别优选下述方法和条件:有机溶剂中,加入催化剂和化合物II,在氢气作用下,或者还原剂作用下,反应制得化合物III,化合物III在碱作用下脱掉R,得化合物IV,即可;其中,所述的较佳的催化剂与式II所示的化合物的物料质量比0.01~0.3∶1;所述的较佳的催化剂为钯碳、氢氧化钯、铂碳、二氧化铂、雷尼镍或铑碳;所述的较佳的还原剂为硼氢化钠、硼氢化钾、氰基硼氢化钠或三乙酰氧基硼氢化钠;所述的较佳的碱为氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡、碳酸钾或碳酸铯;所述的较佳的氢气的压力为1~20个大气压;所述的较佳的有机溶剂为C1~C5的烷基醇溶剂;所述的较佳的反应的温度为25~100℃;所述的较佳的反应的时间以检测反应完成为止;
(2)其中,R为苄基,所述的化合物II的还原反应的方法和条件均可为本领域此类反应的常规方法和条件,本发明特别优选下述方法和条件:有机溶剂中,加入催化剂和化合物II,在氢气作用下,反应制得化合物IV,即可;其中,所述的较佳的催化剂与式II所示的化合物的物料质量比0.01~0.3∶1;所述的较佳的催化剂为钯碳、氢氧化钯、铂碳、二氧化铂、雷尼镍或铑碳;所述的较佳的氢气的压力为1~20个大气压;所述的较佳的有机溶剂为C1~C5的烷基醇溶剂;所述的较佳的反应的温度为25~100℃;所述的较佳的反应的时间以检测反应完成为止。
本发明中,所述的化合物II由下列方法制得:有机溶剂中,化合物I在酸作用下,进行如下所示的反应,即可;
其中,所述的化合物I进行脱叔丁氧羰基反应和关环反应的方法和条件均可为本领域此类反应的常规方法和条件,本发明特别优选下述方法和条件:有机溶剂中,化合物I在酸作用下,进行脱叔丁氧羰基反应和关环反应,即可;其中,所述的较佳的酸为三氟乙酸、苯磺酸、甲磺酸、盐酸、硫酸、磷酸、氢溴酸、氯化氢甲醇溶液、氯化氢乙醇溶液、氯化氢乙酸乙酯溶液、氯化氢二氧六环溶液或溴化氢乙酸溶液;所述的较佳的有机溶剂为二氯甲烷、1,2-二氯乙烷、乙酸乙酯、二氧六环或C1~C5的烷基醇溶剂;所述的较佳的反应的温度为-20~50℃;所述的较佳的反应的时间以检测反应完成为止。
本发明中,所述的化合物I由下列方法制得:在有机金属试剂作用下,2,5-二氟溴苯和N-叔丁氧羰基-L-焦谷氨酸酯在有机溶剂中进行如下所示的反应,即可;
其中,所述的2,5-二氟溴苯与N-叔丁氧羰基-L-焦谷氨酸酯的偶联反应的方法和条件均可为本领域此类反应的常规方法和条件,本发明特别优选下述方法和条件:在有机金属试剂作用下,2,5-二氟溴苯和N-叔丁氧羰基-L-焦谷氨酸酯在有机溶剂中进行偶联反应,即可;其中,所述的较佳的有机金属试剂为异丙基氯化镁、异丙基溴化镁、异丙基氯化镁氯化锂、乙基溴化镁,乙基氯化镁、甲基氯化镁、苯基溴化镁、正丁基锂或叔丁基锂;所述的较佳的有机溶剂为C1~C5的醚类溶剂;所述的较佳的反应的温度为-78~25℃;所述的较佳的反应的时间以检测反应完成为止。
上述各反应完成后,进行的后处理过程均为常规操作,即可得到纯的目标化合物。
本发明中,所述的拉罗替尼中间体的制备方法,其路线较佳的如下所示:
本发明进一步涉及制备拉罗替尼的中间体化合物Ia、Ib、IIa、IIb和III,其结构式分别如下所示:
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
除特殊说明外,本发明所用试剂和原料均市售可得。
本发明的制备方法原料廉价易得,产率较高,路线新颖,在合成过程中得到多个全新的中间体,切中间体的性质稳定,适于工业化生产。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
下述各实施例中,所述的室温为20~35℃。
实施例1 中间体I(Ia,Ib)的合成
Ia的合成:在500mL三口瓶中,加入对2,5-二氟溴苯19.3g(0.1mol)和四氢呋喃160ml,冷却至0度,开始滴加异丙基氯化镁60ml(2M的THF溶液,0.12mol),滴加完毕后,继续反应2h;然后滴加N-叔丁氧羰基-L-焦谷氨酸乙酯25.7g(0.1mol)四氢呋喃80ml溶液,滴加完毕后,0度反应4h,TLC显示反应完全。向反应混合物中滴加2N的盐酸溶液50ml,搅拌20分钟,分液,水相再用甲基叔丁基醚120ml萃取两次,合并有机相,并用饱和食盐水60ml洗涤,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱层析分离得到油状物Ia 35.2g,产率95%,纯度99%。
1HNMR(400Hz,CDCl3)δ:6.82-7.58(m,3H),4.12-5.41(m,4H),2.95-3.20(m,2H),1.96-2.42(m,2H),1.21-1.46(m,12H);[M+H+]:372.3。
Ib的合成:在500mL三口瓶中,加入对2,5-二氟溴苯19.3g(0.1mol)和四氢呋喃160ml,冷却至0度,开始滴加异丙基氯化镁60ml(2M的THF溶液,0.12mol),滴加完毕后,继续反应2h;然后滴加N-叔丁氧羰基-L-焦谷氨酸苄酯32g(0.1mol)四氢呋喃80ml溶液,滴加完毕后,0度反应4h,TLC显示反应完全。向反应混合物中滴加2N的盐酸溶液50ml,搅拌20分钟,分液,水相再用甲基叔丁基醚120ml萃取两次,合并有机相,并用饱和食盐水60ml洗涤,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱层析分离得到白色固体Ia 40.2g,产率93%,纯度98.1%。
1HNMR(400Hz,CDCl3)δ:7.52(m,1H),7.33(m,5H),7.20(m,1H),7.09(m,1H),5.18(m,3H),4.42(m,1H),3.05(m,2H),2.30(m,1H),2.06(m,1H),1.40(s,9H);[M+H+]:434.2
按照上述化合物Ia的制备方法,采用不同的有机金属试剂、不同溶剂和不同反应温度,制备式Ia化合物,反应结果如下表所示:
实施例2 中间体II(IIa、IIb)的合成
IIa的合成:在250ml烧瓶中,加入化合物Ia 18.6g(0.05mol)和二氯甲烷15ml,冷却至0度,滴加三氟乙酸15ml(0.2mol)。滴加完毕后,0度搅拌反应,TLC跟踪反应至化合物Ia原料消失。接着用10%的氢氧化钠溶液调PH值至8,加入二氯甲烷80ml分层,水层用二氯甲烷萃取两次,每次50ml,合并有机相,无水硫酸钠干燥,减压浓缩,硅胶柱层析分离得到IIa11.6g,产率92%,纯度98.3%。
1HNMR(400Hz,CDCl3)δ:7.72-7.81(m,1H),7.05-7.17(m,2H),4.85-4.95(m,1H),4.25(q,2H),3.14-3.26(m,1H),3.00-3.12(m,1H),2.31-2.45(m,1H),2.15-2.32(m,1H),1.34(t,3H);[M+H+]:254.2。
IIb的合成:在250ml烧瓶中,加入化合物Ib 21.6g(0.05mol)和二氯甲烷15ml,冷却至0度,滴加三氟乙酸15ml(0.2mol)。滴加完毕后,0度搅拌反应,TLC跟踪反应至化合物Ib原料消失。接着用10%的氢氧化钠溶液调PH值至8,加入二氯甲烷80ml分层,水层用二氯甲烷萃取两次,每次50ml,合并有机相,无水硫酸钠干燥,减压浓缩,硅胶柱层析分离得到IIb14g,产率89%,纯度98.6%。
1HNMR(400Hz,CDCl3)δ:7.76(m,1H),7.35(m,5H),7.06(m,2H),5.22(s,2H);4.89(m,1H),3.15(m,1H),3.04(m,1H),2.35(m,1H),2.25(m,1H);[M+H+]:316.3。
按照上述化合物IIa的制备方法,采用不同的酸,不同反应温度和不同溶剂,制备式IIa化合物,反应结果如下表所示:
酸 | 溶剂 | 温度 | 产率 |
苯磺酸 | 四氢呋喃 | 25度 | 78% |
甲磺酸 | 四氢呋喃 | 0度 | 80% |
氯化氢甲醇溶液(4M) | 甲醇 | 0度 | 75% |
氯化氢乙醇溶液(4M) | 乙醇 | 0度 | 79% |
氯化氢乙酸乙酯溶液(2M) | 乙酸乙酯 | 0度 | 85% |
氯化氢二氧六环溶液(4M) | 二氧六环 | 0度 | 81% |
溴化氢乙酸溶液(33wt%) | 四氢呋喃 | 0度 | 73% |
实施例3 中间体IV的合成
方法一:
在氢化反应釜中加入化合物IIa 10g(0.04mol)、10%钯碳1g和甲醇150ml加氢到5个大气压,室温反应5h,TLC跟踪反应至原料消失。过滤,减压浓缩,硅胶柱层析分离得到III9.7g,产率95%,纯度99%。
或者采用以下方法制备III:
在250ml烧瓶中,加入化合物IIa 5.0g(0.02mol),甲醇50ml和乙酸20ml,冷却至-40度,分批加硼氢化钠1.52g(0.04mol)。滴加完毕后,搅拌1h后,升至0度搅拌2h,TLC跟踪反应至化合物IIa原料消失。接着用10%的碳酸钠溶液调淬灭,减压浓缩,加入水,甲基叔丁基醚萃取,硅胶柱层析分离得到III 4.5g,产率90%,纯度98.5%。
在100ml反应瓶中加入化合物III 5.1g(0.02mol)和甲醇30ml,加入氢氧化钠4g(0.1mol)溶于3ml水的溶液,氮气保护下室温搅拌过夜,TLC监测反应完全。冷却至5到10度,加入稀盐酸调PH值,减压浓缩除去甲醇和水得到粗产品,硅胶柱层析分离得到IV 4.3g,产率94%,纯度98%。
1HNMR(400Hz,D2O)δ:7.35(t,J=8.0Hz,1H),7.27(m,2H),5.05(m,1H);4.60(m,1H),2.58(m,3H),2.35(m,1H),2.25(m,1H);[M+H+]:228.1。
方法二:
在氢化反应釜中加入化合物IIb 10g(0.032mol)、10%钯碳1g和甲醇150ml加氢到5个大气压,室温反应5h,TLC跟踪反应至原料消失。过滤,减压浓缩,硅胶柱层析分离得到IV6.3g,产率87%,纯度98%。
按照上述化合物IV的制备方法,采用不同催化剂,不同溶剂和不同氢气压力,制备式IV化合物,反应结果如下表所示:
催化剂 | 溶剂 | 氢气压力(个) | 产率 |
钯碳 | 乙醇 | 5 | 94% |
钯碳 | 异丙醇 | 5 | 85% |
钯碳 | 甲醇 | 2 | 75% |
钯碳 | 甲醇 | 8 | 68% |
氢氧化钯 | 甲醇 | 5 | 88% |
铂碳 | 甲醇 | 5 | 92% |
二氧化铂 | 甲醇 | 5 | 88% |
雷尼镍 | 甲醇 | 5 | 53% |
铑碳 | 甲醇 | 5 | 86% |
实施例4 中间体V的合成
在100ml反应瓶中加入化合物IV 8.6g(0.038mol)、环己醇25ml及2-环己烯-1-酮1ml,氮气保护下加热至160度反应10h,TLC监测反应完全。冷却至室温,加入乙酸乙酯和稀盐酸,分液,水层用稀氢氧化钠溶液调PH值至10,二氯甲烷萃取3次,每次100ml,合并有机相,无水硫酸钠干燥,减压浓缩得到液体V 5.9g,产率85%,纯度99%,ee值99%。
1HNMR(400Hz,CDCl3)δ:7.28(m,1H),6.96(m,1H),6.88(m,1H);4.45(t,J=7.6Hz,1H),3.90(m,1H),3.24(m,1H),3.13(m,1H),2.28(m,1H),1.95(m,2H),1.71(m,1H);[M+H+]:184.2。
按照上述化合物V的制备方法,采用不同催化剂,不同溶剂和不同反应温度,制备式V化合物,反应结果如下表所示:
催化剂 | 溶剂 | 温度 | 产率 |
2-环己烯-1-酮 | 二甲苯 | 140度 | 53% |
2-环己烯-1-酮 | 均三甲苯 | 160度 | 60% |
2-环己烯-1-酮 | 聚乙二醇 | 160度 | 82% |
苯乙酮 | 环己醇 | 160度 | 62% |
4-甲基苯乙酮 | 环己醇 | 160度 | 61% |
4-甲基-2-戊酮 | 环己醇 | 130度 | 52% |
左旋香芹酮 | 环己醇 | 160度 | 84% |
Claims (9)
2.如权利要求1所述的制备方法,其特征在于:所述的制备方法包含下列步骤:有机溶剂中,加入催化剂和式IV所示的化合物进行脱羧反应,即可;其中,所述的催化剂与式IV所示的化合物的物料摩尔比0.05~0.3∶1;所述的催化剂为2-环己烯-1-酮、苯乙酮、4-甲基苯乙酮、4-甲基-2-戊酮或左旋香芹酮;所述的有机溶剂为二甲苯、均三甲苯、环己醇或聚乙二醇;所述的反应的温度为100~200℃;所述的反应的时间以检测反应完成为止。
4.如权利要求3所述的制备方法,其特征在于:所述的制备方法包含下列步骤:
(1)R为乙基,有机溶剂中,加入催化剂和化合物II,在氢气作用下,或者化合物II在还原剂作用下,反应制得化合物III,化合物III在碱作用下脱掉R,得化合物IV,即可;其中,所述的催化剂与式II所示的化合物的物料质量比0.01~0.3∶1;所述的催化剂为钯碳、氢氧化钯、铂碳、二氧化铂、雷尼镍或铑碳;所述的还原剂为硼氢化钠、硼氢化钾、氰基硼氢化钠或三乙酰氧基硼氢化钠;所述的碱为氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡、碳酸钾或碳酸铯;所述的氢气的压力为1~20个大气压;所述的有机溶剂为C1~C5的烷基醇溶剂;所述的反应的温度为25~100℃;所述的反应的时间以检测反应完成为止;
(2)R为苄基,有机溶剂中,加入催化剂和化合物II,在氢气作用下,反应制得化合物IV,即可;其中,所述的催化剂与式II所示的化合物的物料质量比0.01~0.3∶1;所述的催化剂为钯碳、氢氧化钯、铂碳、二氧化铂、雷尼镍或铑碳;所述的氢气的压力为1~20个大气压;所述的有机溶剂为C1~C5的烷基醇溶剂;所述的反应的温度为25~100℃;所述的反应的时间以检测反应完成为止。
6.如权利要求5所述的制备方法,其特征在于:所述的化合物II由下列方法制得:有机溶剂中,化合物I在酸作用下,进行脱叔丁氧羰基反应和关环反应,即可;其中,所述的酸为三氟乙酸、苯磺酸、甲磺酸、盐酸、硫酸、磷酸、氢溴酸、氯化氢甲醇溶液、氯化氢乙醇溶液、氯化氢乙酸乙酯溶液、氯化氢二氧六环溶液或溴化氢乙酸溶液;所述的有机溶剂为二氯甲烷、1,2-二氯乙烷、乙酸乙酯、二氧六环或C1~C5的烷基醇溶剂;所述的反应的温度为-20~50℃;所述的反应的时间以检测反应完成为止。
8.如权利要求7所述的制备方法,其特征在于:所述的化合物I由下列方法制得:在有机金属试剂作用下,2,5-二氟溴苯和N-叔丁氧羰基-L-焦谷氨酸酯在有机溶剂中进行偶联反应,即可;其中,所述的有机金属试剂为异丙基氯化镁、异丙基溴化镁、异丙基氯化镁氯化锂、乙基溴化镁,乙基氯化镁、甲基氯化镁、苯基溴化镁、正丁基锂或叔丁基锂;所述的有机溶剂为C1~C5的醚类溶剂;所述的反应的温度为-78~25℃;所述的反应的时间以检测反应完成为止。
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