CN104945404B - A kind of preparation method of N- propenecarbonyls piperidine derivative - Google Patents
A kind of preparation method of N- propenecarbonyls piperidine derivative Download PDFInfo
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- CN104945404B CN104945404B CN201510350917.9A CN201510350917A CN104945404B CN 104945404 B CN104945404 B CN 104945404B CN 201510350917 A CN201510350917 A CN 201510350917A CN 104945404 B CN104945404 B CN 104945404B
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- compound
- shandong
- buddhist nun
- alkali
- method described
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- 150000003053 piperidines Chemical class 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 84
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 238000011938 amidation process Methods 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000000908 ammonium hydroxide Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000003865 brosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)S(*)(=O)=O 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 8
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 description 6
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- ZJJRMIYJEBNPEY-ZDUSSCGKSA-N [(3S)-1-but-2-enoylpiperidin-3-yl] 4-nitrobenzenesulfonate Chemical class [N+](=O)([O-])C1=CC=C(C=C1)S(=O)(=O)O[C@@H]1CN(CCC1)C(=O)C=CC ZJJRMIYJEBNPEY-ZDUSSCGKSA-N 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 2
- 229960001507 ibrutinib Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 0 Cc(cc1)ccc1S(O[C@@](CCC1)C*1C(C=C)=O)(=O)=O Chemical compound Cc(cc1)ccc1S(O[C@@](CCC1)C*1C(C=C)=O)(=O)=O 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- WBOHXLDSPBIPTP-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-4-amine Chemical compound CN(C1=CC=NC2=NC=CC=C12)C WBOHXLDSPBIPTP-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- PUJDCZMCXWMZNV-UHFFFAOYSA-N [O].C1(=CC=CC=C1)N1CCCCC1 Chemical class [O].C1(=CC=CC=C1)N1CCCCC1 PUJDCZMCXWMZNV-UHFFFAOYSA-N 0.000 description 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- UIJXHKXIOCDSEB-QMMMGPOBSA-N tert-butyl (3s)-3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](O)C1 UIJXHKXIOCDSEB-QMMMGPOBSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of preparation methods of N propenecarbonyls piperidine derivative, and in particular to preparation for the new intermediate of Buddhist nun, preparation method and its is used to prepare the method for replacing Buddhist nun according to Shandong according to Shandong；Belong to pharmaceutical technology field.The reaction that the method includes being shown below：
Description
Technical field
The present invention relates to a kind of preparation methods of N- propenecarbonyls piperidine derivative, and in particular to prepares according to Shandong for the new of Buddhist nun
Intermediate, preparation method and its be used to prepare according to Shandong replace Buddhist nun method；Belong to pharmaceutical technology field.
Background technology
Bruton's tyrosine kinase (BTK) is the important medium of at least three kinds crucial B cell survival mechanisms, it can be made to refer to
It waves B cell malignant tumour and enters lymphoid tissue, tumour cell is enable to contact necessary microenvironment and existence.Selectively
Inhibit bruton's tyrosine kinase (BTK), the proliferation of tumour can be inhibited, to have the function that treat tumour.
Buddhist nun (English name Ibrutinib) is replaced according to Shandong, is a kind of selective depressant of bruton's tyrosine kinase (BTK),
It can be used for treating the diseases such as relapsed or stubborn lymphoma mantle cell (MCL), there is breakthrough status on the market；Its structure is such as
Shown in formula (1)：
Invention content
Summary of the invention
The present invention provides the preparation methods being used to prepare according to Shandong for the new compound and these noval chemical compounds of Buddhist nun.
The present invention provides prepare the method for replacing Buddhist nun according to Shandong by these noval chemical compounds.
Term defines
Buddhist nun (English name Ibrutinib) is replaced according to Shandong, refers to entitled 1- [(3R) -3- [4- amino -3- (the 4- phenoxy group benzene of chemistry
Base) -1H- pyrazolos [3,4-D] pyrimidine -1- bases] -1- piperidyls] and -2- propylene -1- ketone compound.
Detailed description of the invention
Inventor develops a kind of new intermediate by research, preparation method and its for preparing according to Shandong for Buddhist nun's
Method.It is this to prepare the method for replacing Buddhist nun according to Shandong using new intermediate, it is easy to operate, need not use the reagents such as triphenyl phosphorus and
It is also easy to produce the solvent of peroxide, the reaction time is short, at low cost, is conducive to preparation of industrialization and replaces Buddhist nun according to Shandong.
In a first aspect, the present invention provides the new intermediate compounds (3) as shown in formula (3)：
Wherein, R1For p-toluenesulfonyl, 4- tnBuoromethyl-benzenesulfonyls, brosyl, 2- nitrobenzenesulfonyls,
4- nitrobenzenesulfonyls, benzenesulfonyl, mesyl, trifyl, t-Butyldimethylsilyl or triethyl group silicon substrate.
There are a chiral carbons for compound (3), can be the mixture of R and S configurations, or single S configurations.One
In a little embodiments, compound (3) is S configurations.
Second aspect, the present invention provide the preparation method of the compound (3).
The preparation method of compound (3) includes：Such as following formula (2) compound represented (2) and formula (4) compound represented
(4) in the presence of alkali B3, in organic solvent S3, amidation process is carried out in temperature T3, compound (3) is made：
The preparation method of above compound (2) includes：Formula (1) compound represented (1) carries out deprotection reaction, prepares
Obtain compound (2)：
The preparation method of above compound (1) includes：Formula (0) compound represented (0) carries out protection group reaction, prepares
Obtain compound (1)：
In some embodiments, the preparation method of compound (3) includes：Compound (0) carries out protection group reaction, system
It is standby to obtain compound (1)；
Compound (1) carries out deprotection reaction, and compound (2) is prepared；Compound (2) is with compound (4) in alkali
In the presence of B3, in organic solvent S3, amidation process is carried out in temperature T3, compound (3) is made：
In above compound (1), compound (2), the preparation method of compound (3), LG1Selected from C1-C4 alkoxy carbonyls,
Benzyloxycarbonyl, trifluoroacetyl group, acetyl group, trimethylsilyl ethoxycarbonyl, p-toluenesulfonyl, trityl, 2,4- diformazans
Oxy-benzyl, to methoxy-benzyl, benzyl；R1As defined above；R2For hydroxyl, fluorine, chlorine, bromine, iodine, mesyloxy, to first
Phenylsulfonyloxy or p-nitrophenyl sulfonyloxy；LG2Selected from hydrogen, chlorine, bromine, p-toluenesulfonyl, benzenesulfonyl, mesyl；Indicate singly-bound or double bond.
In above compound (1), compound (2), compound (3), it is respectively present a chiral carbon, in order to obtain single structure
The target compound of type, can use single configuration raw material be reacted, can also use containing two kinds of configurations mixture into
Row reaction, then splits mixture to obtain the compound of single configuration.
The alkali B3 is triethylamine, diisopropyl ethyl amine, n-BuLi, tetrabutylammonium hydroxide, ammonium hydroxide, pyridine, 4-
Dimethylamino naphthyridine, N-methylmorpholine, potassium hydroxide, potassium carbonate, saleratus, potassium tert-butoxide, potassium phosphate, hydrofining, hydrogen-oxygen
Change sodium, sodium carbonate, sodium bicarbonate, sodium hydride, sodium borohydride, cesium carbonate, or combinations thereof.
In some embodiments, the alkali B3 be triethylamine, diisopropyl ethyl amine, ammonium hydroxide, 4-dimethylaminopyridine,
Potassium carbonate, cesium carbonate, or combinations thereof.In some embodiments, the alkali B3 is potassium carbonate.In some embodiments, institute
State alkali B3 be triethylamine, diisopropyl ethyl amine, or combinations thereof.
The temperature T3 is -10 DEG C -40 DEG C.In some embodiments, temperature T3 is 0 DEG C -30 DEG C.
The organic solvent S3 is dichloromethane, toluene, ethyl acetate, acetonitrile, 2- methyltetrahydrofurans, N, N- dimethyl
Acetamide, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), or combinations thereof.In some embodiments, the organic solvent S3 is
Dichloromethane, toluene, ethyl acetate, acetonitrile, or combinations thereof.
In some embodiments, R2For chlorine, LG2For hydrogen, compound (4) is acryloyl chloride.
In some embodiments, R2For hydroxyl, LG2For hydrogen, compound (4) is acrylic acid.
In some embodiments, R2For hydroxyl, LG2For chlorine, compound (4) is 1- chloropropionic acids.
In some embodiments, R2For chlorine, LG2For chlorine, compound (4) is 1- chlorpromazine chlorides.
In some embodiments, R2For hydroxyl, LG2For p-toluenesulfonyl, compound (4) is 1- p-toluenesulfonyls
Propionic acid.
In some embodiments, R1For p-toluenesulfonyl, compound (4) is acryloyl chloride.
In some embodiments, R1For p-toluenesulfonyl, compound (4) is acrylic acid.
In some embodiments, R1For t-Butyldimethylsilyl, compound (4) is acryloyl chloride.
In some embodiments, LG1For tertbutyloxycarbonyl；R1For p-toluenesulfonyl.
In some embodiments, LG1For tertbutyloxycarbonyl；R1For 4- tnBuoromethyl-benzenesulfonyls.
In some embodiments, the preparation method of compound (3) includes：3- tolysulfonyl oxygroup piperidines is in triethylamine
In the presence of, in methylene chloride, is reacted at 20 DEG C -25 DEG C with acryloyl chloride, compound (3) is prepared, i.e. 3- is to toluene sulphur
Acyloxy-N- propenecarbonyl piperidines.
In some embodiments, the preparation method of compound (3) includes：N- tertbutyloxycarbonyl -3- tolysulfonyl oxygen
Phenylpiperidines pass through deprotection reaction, obtain 3- tolysulfonyl oxygroup piperidines；3- tolysulfonyl oxygroup piperidines and acryloyl
Chlorine is acylated, and compound (3) i.e. 3- tolysulfonyl oxygroup-N- propenecarbonyl piperidines is prepared.
In some embodiments, the preparation method of compound (3) includes：N- tertbutyloxycarbonyl -3- hydroxy piperidines with it is right
In the presence of a base, in organic solvent, by esterification, N- tertbutyloxycarbonyl -3- are prepared to toluene in toluene sulfochloride
Sulfonyloxy piperidines；Then pass through deprotection reaction, obtain 3- tolysulfonyl oxygroup piperidines；3- tolysulfonyl oxygroup piperazines
Pyridine is acylated with acryloyl chloride, and compound (3) i.e. 3- tolysulfonyl oxygroup-N- propenecarbonyl piperidines is prepared.
In some embodiments, the preparation method of compound (3) includes：(S) -1- tertbutyloxycarbonyls -3- hydroxy piperidines
In the presence of a base with paratoluensulfonyl chloride, in organic solvent, by esterification, (S) -1- tertbutyloxycarbonyls-are prepared
3- tolysulfonyl oxygroup piperidines；Then pass through deprotection reaction, obtain (S) -3- tolysulfonyl oxygroup piperidines；(S)-3-
Tolysulfonyl oxygroup piperidines is acylated with acryloyl chloride, and compound (3) i.e. (S) -3- tolysulfonyl oxygroups-N- third is prepared
Alkene carbonyl piperidines.
The third aspect, the present invention provides a kind of methods for replacing Buddhist nun according to Shandong shown in new formula (1) comprising：Chemical combination
Object (3) in the presence of alkali B4, in organic solvent S4, is reacted in temperature T4, is prepared into compound (5) shown in formula (5)
Buddhist nun is replaced to according to Shandong：
Wherein, R1As defined above.Above compound (3) can be single S configurations, or R configurations and S configurations
Mixture.
The alkali B4 is selected from：Potassium carbonate, triethylamine, diisopropyl ethyl amine, tetrabutyl ammonium fluoride, pyridine, tetrabutylammonium hydrogen
Amine-oxides, 4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butoxide, cesium carbonate, or combinations thereof.
The organic solvent S4 be selected from n,N-dimethylacetamide, n,N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
Or combinations thereof.
The temperature T4 is 50 DEG C -100 DEG C.In some embodiments, the temperature T4 is 50 DEG C -80 DEG C.
In some embodiments, R1For p-toluenesulfonyl.
In some embodiments, the alkali B4 is selected from：Potassium carbonate, triethylamine, tetrabutyl ammonium fluoride, cesium carbonate or its
Combination.In some embodiments, the alkali B4 is selected from potassium carbonate.In some embodiments, the alkali B4 is selected from the tetrabutyl
Ammonium fluoride.
In some embodiments, the organic solvent S4 is selected from n,N-Dimethylformamide.
In some embodiments, described to include for the preparation method of Buddhist nun according to Shandong：Compound (5) shown in formula (5) and (S)-
3- tolysulfonyl oxygroup-N- propenecarbonyls piperidines is in the presence of potassium carbonate, in n,N-Dimethylformamide, at 55 DEG C -65
DEG C reaction, be prepared according to Shandong replace Buddhist nun, be shown below：
The method of aforementioned prepare compound (3) can be used for preparing according to Shandong in the method for Buddhist nun.
In some embodiments, it prepares and includes for the method for Buddhist nun according to Shandong：Compound (2) is deposited with compound (4) in alkali B3
Under, in organic solvent S3, amidation process is carried out in temperature T3, compound (3) is made；Compound (3) and compound (5)
It in the presence of alkali B4, at temperature T4, is reacted in organic solvent S4, compound (1) is prepared and replaces Buddhist nun according to Shandong.
In some embodiments, it prepares and includes for the method for Buddhist nun according to Shandong：Compound (0) carries out protection group reaction, system
It is standby to obtain compound (1)；Compound (1) carries out deprotection reaction, and compound (2) is prepared；Compound (2) and compound
(4) in the presence of alkali B3, in organic solvent S3, amidation process is carried out in temperature T3, compound (3) is made；Compound (3)
It with compound (5) in the presence of alkali B4, in organic solvent S4, is reacted in temperature T4, compound (1) is prepared according to Shandong
For Buddhist nun.
Specific implementation mode
In order to make those skilled in the art more fully understand technical scheme of the present invention, it is non-that some are disclosed further below
Limiting embodiment, the present invention is described in further detail.
Reagent used in the present invention can be bought or can described method system through the invention from the market
It is standby and obtain.
In the present invention, g expressions gram, mL indicates that milliliter, h indicate hour.
Embodiment 1：Prepare compound (S) -3- tolysulfonyl oxygroup-N- propenecarbonyl piperidines
Step 1：Prepare (S) -1- tertbutyloxycarbonyl -3- tolysulfonyl oxygroup piperidines
In reactor, (S) -1- tertbutyloxycarbonyl -3- hydroxy piperidine 30.00g, triethylamine 30.17g, 4- diformazan ammonia is added
Yl pyridines 1.82g, dichloromethane 70mL, is stirred, and mixed liquor is cooled to 0 DEG C；It is molten that paratoluensulfonyl chloride 31.26g is added
In the mixed liquor of 40mL dichloromethane, drop finishes within 30 minutes, then 0 DEG C of insulated and stirred 0.5h is moved at 28 DEG C of room temperature and continued to stir
3h.Reaction solution washs 3 times (100mL/ times) with saturated sodium bicarbonate, and organic layer is evaporated, and then uses 450mL mixed solvent acetic acid second
Ester：Hexamethylene=1:8 crystallizations, compound as white solid (S) -1- tertbutyloxycarbonyl -3- tolysulfonyl is obtained after removing solvent
Oxygroup piperidines 45.36g；Mass spectrum MS data：733.0,378.0,302.0,300.0；Nuclear magnetic data：1H NMR(600MHz,
CDCl3) δ 7.82 (d, J=8.3Hz, 2H), 7.36 (d, J=8.0Hz, 2H), 4.46 (s, 1H), 3.57 (d, J=12.4Hz,
1H), 3.46-3.20 (m, 3H), 2.46 (s, 3H), 1.91-1.71 (m, 3H), 1.44 (d, J=7.4Hz, 10H).
Step 2：Prepare compound (S) -3- tolysulfonyl oxygroup piperidines
In reactor, (S) -1- tertbutyloxycarbonyl -3- tolysulfonyl oxygroup piperidines 20.00g, ethyl acetate is added
The hydrochloric acid 100mL of 100mL, 4mol/L are stirred overnight at 24 DEG C, thin-layer chromatography detection reaction (EA:MeOH=1:2, Rf=
0.57) after, liquid separation, water phase is extracted 2 times respectively with ethyl acetate 50mL, is spin-dried for after ethyl acetate layer is merged, and is obtained white
Solid.Solid 50mL ethyl acetate：Petroleum ether=1:4 mixed liquor is beaten 0.5h, filters, and 45 DEG C of dry 4h obtain solid
13.12g；Mass spectrum MS data：257.00,256.00；Nuclear magnetic data：1H NMR(600MHz,D2O) δ 7.77 (d, J=8.4Hz,
2H), 7.41 (d, J=8.2Hz, 2H), 4.87 (s, 1H), 3.32 (ddd, J=13.6,7.6,6.0Hz, 1H), 3.27 (d, J=
13.0Hz, 1H), 3.20 (dd, J=13.9,2.1Hz, 1H), 2.98 (td, J=12.6,3.2Hz, 1H), 2.36 (s, 3H),
1.92–1.82(m,1H),1.79–1.63(m,3H)。
Step 3：Prepare compound (S) -3- tolysulfonyl oxygroup-N- propenecarbonyl piperidines
In reactor, (S) -3- tolysulfonyl oxygroups piperidinyl-1 0.00g, triethylamine 11.90g and dichloromethane is added
100mL after mixing, is stirred at 24 DEG C, and acryloyl chloride 3.95g is added dropwise thereto, stirs 17h；Reaction solution be washed with water (50mL ×
3) after, by dichloromethane layer evaporated under reduced pressure, oily (S) -3- tolysulfonyl oxygroup-N- propenecarbonyl piperidinyl-1s 0.09g is obtained；Matter
Compose MS data：311.20,310.20；Nuclear magnetic data：1H NMR(600MHz,CDCl3)δ7.88–7.76(m,2H),7.37(d,J
=8.0Hz, 2H), 6.59-6.35 (m, 1H), 6.25 (dd, J=16.8,1.8Hz, 1H), 5.69 (dd, J=15.6,6.1Hz,
1H), 4.52 (s, 1H), 3.81-3.60 (m, 2H), 3.43 (d, J=52.3Hz, 2H), 2.46 (s, 3H), 2.04-1.73 (m,
5H),1.52(s,1H)。
Embodiment 2：Prepare compound (S) -3- tolysulfonyl oxygroup-N- propenecarbonyl piperidines
In reactor, (S) -3- tolysulfonyl oxygroups piperidinyl-1 0.00g, diisopropyl ethyl amine 15.25g and first is added
Benzene 100mL after mixing, is stirred at 20 DEG C, and acrylic acid 3.50g is added dropwise thereto, stirs 17h；Reaction solution is washed with water 3 times
After (50mL/ times), toluene layer is spin-dried for, obtains oily (S) -3- tolysulfonyl oxygroup-N- propenecarbonyl piperidinyl-1s 0.04g.
Embodiment 3：It prepares and replaces Buddhist nun according to Shandong
By (S) -3- tolysulfonyl oxygroup-N- propenecarbonyl piperidines 5.00g, 4- amino -3- (4- Phenoxyphenyls) -
1H- pyrazolos [3,4-d] pyrimidine 2.45g, potassium carbonate 3.35g and n,N-Dimethylformamide 50mL, stirring, mixed liquor are warming up to
It 60 DEG C, is stirred overnight.Reaction solution is cooled to room temperature, water 50mL is added dropwise thereto, there are a large amount of white solids to be precipitated, is filtered, filter
Cake uses 10mL methanol to be beaten 1h at room temperature, filters, and filter cake vacuum drying, get Yi Lu replaces Buddhist nun 2.71g；Mass spectrum MS data：
442.20,441.20；Nuclear magnetic data：1H NMR (400MHz, DMSO) δ 8.25 (s, 1H), 7.66 (d, J=7.2Hz, 2H),
7.43 (t, J=7.6Hz, 2H), 7.34-7.04 (m, 5H), 6.98-6.56 (m, 2H), 6.09 (dd, J=27.2,17.1Hz,
1H), 5.64 (dd, J=48.8,9.4Hz, 1H), 4.70 (s, 1H), 4.55 (d, J=10.9Hz, 1H), 4.18 (d, J=
10.0Hz, 1H), 4.06 (d, J=13.1Hz, 1H), 3.70 (s, 1H), 3.20 (d, J=11.4Hz, 1H), 3.02 (s, 1H),
2.26 (d, J=9.6Hz, 1H), 2.13 (s, 1H), 1.93 (d, J=12.6Hz, 1H), 1.57 (s, 1H).
Embodiment 4：It prepares and replaces Buddhist nun according to Shandong
(S) -3- (p-nitrophenyl sulfonyloxy)-N- propenecarbonyl piperidines is prepared using the method for embodiment 1；It takes
(S) -3- (p-nitrophenyl sulfonyloxy)-N- propenecarbonyl piperidines 5.00g, 4- amino -3- (4- Phenoxyphenyls) -1H- pyrazoles
And [3,4-d] pyrimidine 2.15g, potassium carbonate 3.00g and DMF50mL, stirring, mixed liquor are warming up to 60 DEG C, are stirred overnight.It will reaction
Liquid is cooled to room temperature, and water 50mL is added dropwise thereto, has a large amount of white solids to be precipitated, and is filtered, and filter cake uses 10mL methanol at room temperature
It is beaten 1h, is filtered, filter cake vacuum drying, get Yi Lu replaces Buddhist nun 2.31g.
Embodiment 5
With reference to the method for embodiment 1, paratoluensulfonyl chloride is substituted using tert-butyl chloro-silicane, is prepared (S)-
3- t-Butyldimethylsilyl epoxide-N- propenecarbonyl piperidines；Referring next to the method for embodiment 3, it is prepared and replaces Buddhist nun according to Shandong.
The method of the present invention is described by preferred embodiment, related personnel can obviously hold within the present invention,
Method described herein and application are modified or are suitably changed and combined in spirit and scope, to realize and apply the present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular, it should be pointed out that institute
There are similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (7)
1. a kind of method for replacing Buddhist nun according to Shandong shown in formula (1), including：
In the presence of alkali B3, in organic solvent S3, amidation process, system are carried out in temperature T3 with compound (4) for compound (2)
Obtain compound (3)：
Compound (3) in the presence of alkali B4, in organic solvent S4, is reacted in temperature T4, is prepared with compound (5)
Buddhist nun is replaced according to Shandong：
Wherein, R1For p-toluenesulfonyl, 4- tnBuoromethyl-benzenesulfonyls, brosyl, 2- nitrobenzenesulfonyls, 4- nitre
Base benzenesulfonyl, benzenesulfonyl, mesyl, trifyl, t-Butyldimethylsilyl or triethyl group silicon substrate；Chemical combination
Object (3) is the mixture of S configurations or R configurations and S configurations；R2For hydroxyl, fluorine, chlorine, bromine, iodine, mesyloxy, to toluene sulphur
Acyloxy or p-nitrophenyl sulfonyloxy；LG2Selected from hydrogen, chlorine, bromine, p-toluenesulfonyl, benzenesulfonyl, mesyl；Indicate singly-bound or double bond.
2. according to the method described in claim 1, further including：Compound (0) carries out protection group reaction, and compound is prepared
(1)；Compound (1) carries out deprotection reaction, and compound (2) is prepared：
Wherein, LG1Selected from C1-C4 alkoxy carbonyls, benzyloxycarbonyl, trifluoroacetyl group, acetyl group, allyloxycarbonyl, trimethyl
Silicon carbethoxyl group, p-toluenesulfonyl, trityl, 2,4- dimethoxy-benzyls, to methoxy-benzyl, benzyl.
3. according to the method described in claim 1, the alkali B3 be triethylamine, diisopropyl ethyl amine, ammonium hydroxide, 4- dimethylaminos
Pyridine, potassium carbonate, cesium carbonate, or combinations thereof.
4. according to the method described in claim 1, the temperature T3 is -10 DEG C -40 DEG C；The organic solvent S3 is dichloromethane
Alkane, toluene, ethyl acetate, acetonitrile, or combinations thereof.
5. according to the method described in claim 1, the alkali B4 be potassium carbonate, triethylamine, diisopropyl ethyl amine, tetrabutyl fluorine
Change ammonium, pyridine, tetrabutylammonium hydroxide, 4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butoxide, cesium carbonate, or combinations thereof.
6. according to the method described in claim 1, the organic solvent S4 be n,N-dimethylacetamide, N, N- dimethyl formyls
Amine, dimethyl sulfoxide (DMSO), or combinations thereof；The temperature T4 is 50 DEG C -80 DEG C.
7. according to the method described in claim 1, including：Compound (5) and (S) -3- tolysulfonyl oxygroup-N- propenecarbonyls
Piperidines is in the presence of potassium carbonate, in DMF, in 55 DEG C of -65 DEG C of reactions, is prepared and replaces Buddhist nun according to Shandong：
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