CN117105931A - 一种制备吡啶并嘧啶类化合物的方法及其中间体 - Google Patents
一种制备吡啶并嘧啶类化合物的方法及其中间体 Download PDFInfo
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- CN117105931A CN117105931A CN202310587353.5A CN202310587353A CN117105931A CN 117105931 A CN117105931 A CN 117105931A CN 202310587353 A CN202310587353 A CN 202310587353A CN 117105931 A CN117105931 A CN 117105931A
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 150000008518 pyridopyrimidines Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 56
- 238000006243 chemical reaction Methods 0.000 claims description 54
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- -1 di-tert-butylphosphino Chemical group 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 claims description 9
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 claims description 9
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims description 9
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Inorganic materials [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- 229940011051 isopropyl acetate Drugs 0.000 claims description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 8
- 238000004176 ammonification Methods 0.000 claims description 7
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 7
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 5
- DIWVBIXQCNRCFE-MRVPVSSYSA-N (2r)-2-methoxy-2-phenylacetic acid Chemical compound CO[C@@H](C(O)=O)C1=CC=CC=C1 DIWVBIXQCNRCFE-MRVPVSSYSA-N 0.000 claims description 4
- JJYKJUXBWFATTE-SECBINFHSA-N (2r)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid Chemical compound CO[C@](C(O)=O)(C(F)(F)F)C1=CC=CC=C1 JJYKJUXBWFATTE-SECBINFHSA-N 0.000 claims description 4
- QVADRSWDTZDDGR-GSVOUGTGSA-N (2r)-5-oxooxolane-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCC(=O)O1 QVADRSWDTZDDGR-GSVOUGTGSA-N 0.000 claims description 4
- OBCUSTCTKLTMBX-VIFPVBQESA-N (2s)-2-acetyloxy-2-phenylacetic acid Chemical compound CC(=O)O[C@H](C(O)=O)C1=CC=CC=C1 OBCUSTCTKLTMBX-VIFPVBQESA-N 0.000 claims description 4
- HMBHAQMOBKLWRX-MRVPVSSYSA-N (3r)-2,3-dihydro-1,4-benzodioxine-3-carboxylic acid Chemical compound C1=CC=C2O[C@@H](C(=O)O)COC2=C1 HMBHAQMOBKLWRX-MRVPVSSYSA-N 0.000 claims description 4
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 claims description 4
- LSPHULWDVZXLIL-LDWIPMOCSA-N (?)-Camphoric acid Chemical compound CC1(C)[C@@H](C(O)=O)CC[C@@]1(C)C(O)=O LSPHULWDVZXLIL-LDWIPMOCSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 claims description 4
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 4
- CILPHQCEVYJUDN-UHFFFAOYSA-N 2-(5-methyl-2-propan-2-ylcyclohexyl)oxyacetic acid Chemical compound CC(C)C1CCC(C)CC1OCC(O)=O CILPHQCEVYJUDN-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-SZSCBOSDSA-N 2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one Chemical compound OC[C@H](O)C1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-SZSCBOSDSA-N 0.000 claims description 4
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 claims description 4
- GNIBXNFOQQRJER-SNVBAGLBSA-N 2-carbamoyl-3-[(1r)-1-phenylethyl]benzoic acid Chemical compound C1([C@@H](C)C=2C(=C(C(O)=O)C=CC=2)C(N)=O)=CC=CC=C1 GNIBXNFOQQRJER-SNVBAGLBSA-N 0.000 claims description 4
- BTXXTMOWISPQSJ-UHFFFAOYSA-N 4,4,4-trifluorobutan-2-one Chemical compound CC(=O)CC(F)(F)F BTXXTMOWISPQSJ-UHFFFAOYSA-N 0.000 claims description 4
- QKZASAQBZATLAE-UHFFFAOYSA-N 4-bromo-2-nitro-n-propan-2-ylaniline Chemical compound CC(C)NC1=CC=C(Br)C=C1[N+]([O-])=O QKZASAQBZATLAE-UHFFFAOYSA-N 0.000 claims description 4
- BQACOLQNOUYJCE-FYZZASKESA-N Abietic acid Natural products CC(C)C1=CC2=CC[C@]3(C)[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1 BQACOLQNOUYJCE-FYZZASKESA-N 0.000 claims description 4
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 claims description 4
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 claims description 4
- 229930182847 D-glutamic acid Natural products 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 4
- 239000002211 L-ascorbic acid Substances 0.000 claims description 4
- 235000000069 L-ascorbic acid Nutrition 0.000 claims description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 229960005261 aspartic acid Drugs 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 claims description 4
- WDIIYWASEVHBBT-UHFFFAOYSA-N di(propan-2-yl)phosphane Chemical compound CC(C)PC(C)C WDIIYWASEVHBBT-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 3
- 150000003839 salts Chemical class 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 claims 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- VUYVXCJTTQJVKJ-UHFFFAOYSA-N palladium(2+);tricyclohexylphosphanium;dichloride Chemical compound Cl[Pd]Cl.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 VUYVXCJTTQJVKJ-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 23
- LOAMFRKPMNSMNJ-UHFFFAOYSA-N CC(C)C1=NC=CC(=C1N2C3=NC(=C(C=C3C(=O)NC2=O)Cl)Cl)SC Chemical compound CC(C)C1=NC=CC(=C1N2C3=NC(=C(C=C3C(=O)NC2=O)Cl)Cl)SC LOAMFRKPMNSMNJ-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229960003966 nicotinamide Drugs 0.000 description 4
- 235000005152 nicotinamide Nutrition 0.000 description 4
- 239000011570 nicotinamide Substances 0.000 description 4
- BFZUOEGHALWJQA-UHFFFAOYSA-N CC(C)C1=NC=CC(=C1N)SC Chemical compound CC(C)C1=NC=CC(=C1N)SC BFZUOEGHALWJQA-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
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- 238000004321 preservation Methods 0.000 description 3
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- 238000005406 washing Methods 0.000 description 3
- HNLNICWOZQXGGA-UHFFFAOYSA-N 4-chloro-2-propan-2-ylpyridin-3-amine Chemical compound CC(C)C1=NC=CC(Cl)=C1N HNLNICWOZQXGGA-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- ZSJYSZWQVCWDQO-UHFFFAOYSA-N 2,4-dichloropyridin-3-amine Chemical compound NC1=C(Cl)C=CN=C1Cl ZSJYSZWQVCWDQO-UHFFFAOYSA-N 0.000 description 1
- DBAVDGXPOXFHRC-UHFFFAOYSA-N 2,5,6-trichloropyridine-3-carboxamide Chemical compound NC(=O)C1=CC(Cl)=C(Cl)N=C1Cl DBAVDGXPOXFHRC-UHFFFAOYSA-N 0.000 description 1
- XMJRZCYSCMZVJQ-UHFFFAOYSA-N 2,5,6-trichloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(Cl)=C(Cl)N=C1Cl XMJRZCYSCMZVJQ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 150000001939 cyclooctenes Chemical class 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- AGCOMFFHXJMNLN-UHFFFAOYSA-N dichloromethane;dihydrochloride Chemical compound Cl.Cl.ClCCl AGCOMFFHXJMNLN-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- JGBZTJWQMWZVNX-UHFFFAOYSA-N palladium;tricyclohexylphosphane Chemical compound [Pd].C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 JGBZTJWQMWZVNX-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- ZCYHCMUUDWKVPN-UHFFFAOYSA-N potassium;bis(trimethylsilyl)azanide;oxolane Chemical compound [K+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C ZCYHCMUUDWKVPN-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/19—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/78—Benzoic acid esters
-
- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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Abstract
本发明属于化学医药领域,涉及一种制备吡啶并嘧啶类化合物的方法及其中间体,尤其涉及6,7‑二氯‑1‑(2‑异丙基‑4‑(甲硫基)吡啶‑3‑基)吡啶并[2,3‑d]嘧啶‑2,4(1H,3H)‑二酮的制备方法及其制备中间体。本发明方法克服了现有技术中轴手性化合物因本身理化性质等特点导致制备或分离比较局限、效率较低或收率不高,无法实现工业化生产的问题,通过选用新的中间体和改进的工艺路线,实现了所得产物纯度好、收率高、工艺可操作性强,工艺安全性高,且可工业化生产。
Description
技术领域
本发明属于化学医药领域,具体涉及一种制备吡啶并嘧啶类化合物的方法及其中间体。
背景技术
化合物6,7-二氯-1-(2-异丙基-4-(甲硫基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮作为一种化工原料,该化合物具有轴手性。手性化合物是指是指分子量、分子结构相同,但左右排列相反,如实物与其镜中的映体。人的左右手、结构相同,大姆至小指的次序也相同,但顺序不同,左手是由左向右,右手则是由右向左,所以叫做“手性”。也就是指一对分子。由于它们像人的两只手一样彼此不能重合,又称为手性化合物。手性有以下几类:①中心型手性.由于分子中有手征性碳或其他原子的不对称因素(见不对称原子),使分子具有手征中心.②轴型手性.通过分子中的一个轴来区别左右手征性,该轴即为手性轴.例如丙二烯型或联苯型旋光化合物分子.③面型手性.分子就一个平面来区别手征性,该面即为手性面,例如旋光性提篮型化合物或反环辛烯等。现有技术WO202023907公开了该化合物的制备方法,但并未公开该化合物的轴手性特性,也没有公开制备和分离轴手性化合物的方法。
在工业上或医药合成领域,往往需要制备和分离高纯度的化合物6,7-二氯-1-(2-异丙基-4-(甲硫基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的轴手性化合物,但是往往因为该化合物本身的理化性质或结构特点,导致制备或分离比较局限、效率较低或收率不高,无法实现工业化生产。因此如何通过可工业化的制备方法获得高纯度高收率的化合物6,7-二氯-1-(2-异丙基-4-(甲硫基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮及其轴手性异构体,是化工医药领域渴望解决的技术问题。
发明内容
为了解决现有技术中存在的问题,本发明提供一种6,7-二氯-1-(2-异丙基-4-(甲硫基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的轴手性化合物、其制备方法及其中间体。
具体而言,本发明提供式(I-a)或式(I-b)化合物及其药学上可接受的盐:
本发明还提供制备通式(II)所示制备式(I-a)或(I-b)化合物的中间体,:
R1选自:氢、氨基保护基,当为式(II)的轴手性化合物时,R1不为氢。
优选地,R1选自取代或未取代的烷氧羰基、酰基和烷基,
n选自0、1、2或3。
进一步地,本发明提供式(II)化合物的轴手性化合物,其结构如式(II-a)和式(II-b)所示:
进一步地,本发明还提供制备式(I-a)或(I-b)化合物的中间体,其结构如式(III-a)或式(III-b)所示:
m选自0.5,1,2或3;
Y选自L-酒石酸、D-苹果酸、L-樟脑磺酸、D-二苯甲酰酒石酸、松香酸、L-半胱氨酸、D-樟脑酸、(-)-二特戊酰基-L-酒石酸、D-(+)-二对甲基苯甲酰酒石酸、(S)-(+)-O-乙酰基-L-扁桃酸、(S)-扁桃酸、[(1R)-(内型,反式)]-(+)-3-溴樟脑-8-磺酸铵盐、L-天冬氨酸、D-谷氨酸、(R)-(-)-5-氧代-2-四氢呋喃羧酸、S-2-苯基丙酸、L-焦谷氨酸、D-(-)-奎尼酸、L(+)-抗坏血酸、(S)-(+)-苯基丁二酸、1S)-(-)-樟脑烷酸、(R)-1,4-苯并二恶烷-2-甲酸、(+)-薄荷氧基乙酸、(R)-(-)-α-甲氧基苯乙酸、R)-(+)-α-甲氧基-α-(三氟甲基)苯乙酸、(R)-(+)-N-(1-苯乙基)琥珀酰胺酸、N,N-双[(R)-(+)-1-苯基乙基]邻氨甲酰苯甲酸;
更优选:L-樟脑磺酸、D-二苯甲酰酒石酸、[(1R)-(内型,反式)]-(+)-3-溴樟脑-8-磺酸铵盐、L-焦谷氨酸、1S)-(-)-樟脑烷酸。
本发明具体实施例中,还提供式(III-a)或式(III-b)优选地结构,具体如下:
本发明还提供式(I-a)或式(I-b)化合物的制备方法,包括步骤a1:
式(III-A)或式(III-a)化合物经脱保护氨化后制得式(I-a)化合物;
或者步骤a2:
式(III-B)或式(III-b)化合物经脱保护氨化后制得式(I-b)化合物;
其中脱保护是通过酸解法或者氧化法的方式进行;
优选地,酸解法所用的酸选自乙酸、三氟乙酸、三氟甲磺酸、甲磺酸、三溴化硼中的一种或多种,更优选地选择其中两种,进一步优选地为三氟乙酸和三氟甲磺酸;三氟乙酸和甲磺酸;
优选地,所述氧化法所用的氧化剂选自2,3-二氯-5,6-二氰基苯醌或硝酸铈铵。
本发明还提供式(III-A)和式(III-B)或式(III-a)和式(III-b)的制备方法,所述方法由式(II)化合物与手性酸反应拆分制得式目标化合物;
优选地,所述手性酸选自:L-酒石酸、D-苹果酸、L-樟脑磺酸、D-二苯甲酰酒石酸、松香酸、L-半胱氨酸、D-樟脑酸、(-)-二特戊酰基-L-酒石酸、D-(+)-二对甲基苯甲酰酒石酸、(S)-(+)-O-乙酰基-L-扁桃酸、(S)-扁桃酸、[(1R)-(内型,反式)]-(+)-3-溴樟脑-8-磺酸铵盐、L-天冬氨酸、D-谷氨酸、(R)-(-)-5-氧代-2-四氢呋喃羧酸、S-2-苯基丙酸、L-焦谷氨酸、D-(-)-奎尼酸、L(+)-抗坏血酸、(S)-(+)-苯基丁二酸、1S)-(-)-樟脑烷酸、(R)-1,4-苯并二恶烷-2-甲酸、(+)-薄荷氧基乙酸、(R)-(-)-α-甲氧基苯乙酸、R)-(+)-α-甲氧基-α-(三氟甲基)苯乙酸、(R)-(+)-N-(1-苯乙基)琥珀酰胺酸、N,N-双[(R)-(+)-1-苯基乙基]邻氨甲酰苯甲酸,
更优选:L-樟脑磺酸、D-二苯甲酰酒石酸、[(1R)-(内型,反式)]-(+)-3-溴樟脑-8-磺酸铵盐、L-焦谷氨酸、1S)-(-)-樟脑烷酸。
进一步优选的,所述反应如步骤所示:
所述反应溶体系选自四氢呋喃/正庚烷、2-甲四氢呋喃/正庚烷、甲醇/二氯甲烷/正庚烷、四氢呋喃、2-甲四氢呋喃、甲醇、丙酮、醋酸异丙酯(IPAc)、乙酸异丙酯(IPA)、乙醇、异丙醇、水/乙腈、甲基叔丁基醚、甲苯、4-甲基-2-戊酮、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮;
优选地,所述溶剂体系至少包含四氢呋喃或2-甲四氢呋喃;
进一步优选四氢呋喃/正庚烷、2-甲四氢呋喃/正庚烷、四氢呋喃/甲苯、2-甲基四氢呋喃/甲苯、四氢呋喃/丙酮、2-甲基四氢呋喃/丙酮。
本发明还提供制备式(II)化合物的方法,由式D化合物与保护基试剂按照步骤c制得:
X为卤素,优选Cl;
优选地,步骤c是在碱性条件下进行的。
本发明还提供通过步骤d制备式D化合物的方法:
所述反应是在碱性条件下进行的;
优选地,所述碱选自氢氧化钠、氢氧化钾、KHMDS、NaHMDS、LiHNMDS、叔丁醇钾、叔丁醇钠、甲醇钠、乙醇钠、碳酸钠、碳酸钾、磷酸钾或三乙胺;
优选地,所述反应是在四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺或二甲基亚砜溶剂环境中进行的;
优选地,加碱反应后,再加酸调节PH值,所述酸优选醋酸或盐酸;
优选地,调PH值为7-8。
本发明还在于通过步骤e制备式C化合物的方法:
优选地,式A化合物是通过步骤f1制得:
优选地,所述步骤f1是在锌和氯化铁催化下反应的;
优选地,所述步骤f1是在氮气保护下进行的。
所述式A1化合物是由步骤g反应制得:
优选地,步骤g是在包含钯类催化剂的条件下进行的,进一步优选地钯类催化剂选自四(三苯基膦)钯、双(三苯基膦)二氯化钯、二(三叔丁基膦)钯、1,1'-双(二-叔丁基膦基)二茂铁二氯化钯、双(三邻甲苯基膦)二氯化钯、双-(三环己基磷基)二氯化钯、[1,3-双(2,6-二异丙基苯基)-2-咪唑亚基](3-氯吡啶基)二氯化钯(II)、[1,1'-双(二异丙基膦)二茂铁]二氯钯、醋酸钯/4,5-双二苯基膦-9,9-二甲基氧杂蒽、醋酸钯/2-双环己基膦-2',4',6'-三异丙基联苯、醋酸钯/2-双环己基膦-2',6'-二甲氧基联苯、醋酸钯/1,2-双(二苯基膦)乙烷、三(二亚苄基丙酮)二钯/4,5-双二苯基膦-9,9-二甲基氧杂蒽、三(二亚苄基丙酮)二钯/2-双环己基膦-2',4',6'-三异丙基联苯、三(二亚苄基丙酮)二钯/2-双环己基膦-2',6'-二甲氧基联苯;更优选催化剂包含[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷;
优选地,催化剂还包含氯化锌;
优选地,所述步骤f1是在氮气保护下进行的。
本发明还提供了经步骤f2制备式B化合物的方法,由SM2化合物经氨化反应制得:
优选地,所述氨化反应的氨化试剂是氨水或氨气;
优选地,所述氨化反应中还加入了活化试剂,进一步优选地,活化试剂选自碳酸酐二叔丁酯、草酰氯/N,N-二甲基甲酰胺、氯化亚砜/N,N-二甲基甲酰胺、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
通过本发明提供的中间体或制备工艺,可以高效地制备相应的目标产物。本发明的中间体原料简单易得,通过合适的中间体与反应条件选择,简化了反应步骤,提升了反应效率,同时高收率地获得了目标产物,从而使本发明工艺适用于工业化放大生产。
具体实施方式
下面结合实施例对本发明做进一步详细、完整地说明,但决非限制本发明,本发明的保护与公开范围并非仅局限于实施例的内容。
实施例1I-a化合物的制备
反应瓶中加入三氟乙酸(50.0mL),中间体III-a1(28.9g),再慢慢往反应体系中滴加三氟甲磺酸(37.0g),滴毕,室温搅拌过夜,反应完全。反应液降温至5-10℃,缓慢滴加NaOH水溶液调节反应液pH=7-8,再加入乙酸乙酯(300mL),搅拌。分液,水相再用乙酸乙酯萃取一次,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。向浓缩物中加入甲醇(300mL),升温至65-70℃,搅拌1小时,降至室温搅拌1小时。过滤,滤液浓缩,浓缩物中加入正庚烷(200mL),升温至50-55℃,搅拌1小时,再降至室温搅拌1小时。过滤,滤饼干燥,得到式(I-a)化合物15.0g,呈黄色固体,HPLC纯度:99.7%,收率89.9%。MSm/z(ESI):397[M+H]+;
1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),8.61(s,1H),8.55(d,J=5.2Hz,1H),7.28(d,J=5.2Hz 1H),3.00-2.93(m,1H),2.43(s,3H),1.11-1.03(dd,J=22.4,6.4Hz,6H)。
实施例2中间体III-a1的制备
反应瓶中加入II-a(6,7-二氯-1-(2-异丙基-4-(甲硫基)吡啶-3-基)-3-(4-甲氧基苄基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮)(50.0g),D-二苯甲酰酒石酸(138.5g)和2-甲基四氢呋喃(1000mL),升温至70-75℃,搅拌溶清后,缓慢滴加正庚烷(700mL)。滴毕,保温搅拌1小时,慢慢降至室温,继续搅拌8小时。过滤,滤饼干燥,得到式(III-a1)27.7g,呈类白色固体,化学纯度99.2%,手性纯度98.6%,收率41.2%。
MS m/z(ESI):517[M+H]+;357[M-H]-;
1H NMR(400MHz,DMSO-d6)δ13.91(s,1H),8.68(s,1H),8.56(d,J=5.2Hz,1H),8.03(d,J=7.2Hz,2H),7.74(t,J=7.2Hz,1H),7.61(t,J=7.6Hz 2H),7.32-7.27(m,3H),6.89(d,J=8.8Hz,2H),5.87(s,1H),5.09(s,2H),3.72(s,3H),2.98-2.91(m,1H),2.42(s,3H),1.08-1.03(dd,J=14.8,6.4Hz,6H)。
实施例3中间体III-a1-2的制备:
反应瓶中加入II-a(6,7-二氯-1-(2-异丙基-4-(甲硫基)吡啶-3-基)-3-(4-甲氧基苄基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮)(18.0g),L-樟脑磺酸(16.2g)和2-甲基四氢呋喃(450mL),升温至75-80℃,搅拌溶清后,缓慢滴加正庚烷(450mL)。滴毕,保温搅拌1小时,慢慢降至室温,继续搅拌16小时。过滤,滤饼干燥,得到式(III-a1-2)9.1g,呈类白色固体,化学纯度98.9%,手性纯度94.8%,收率35.0%。
MS m/z(ESI):517[M+H]+;231[M-H]-;
实施例4中间体III-a1-3的制备
反应瓶中加入II-a(6,7-二氯-1-(2-异丙基-4-(甲硫基)吡啶-3-基)-3-(4-甲氧基苄基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮)(15.0g),L-焦谷氨酸(15.0g)和四氢呋喃(600mL),升温至70-75℃,搅拌溶清后,缓慢滴加正庚烷(400mL)。滴毕,保温搅拌1小时,慢慢降至室温,继续搅拌16小时。过滤,滤饼干燥,得到式(III-a1-3)5.8g,呈类白色固体,化学纯度98.7%,手性纯度92.6%,收率31.2%。
MS m/z(ESI):517[M+H]+;130[M+H]+;
实施例5中间体II-a的制备
反应瓶中加入D(6,7-二氯-1-(2-异丙基-4-(甲硫基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮)(28.0g),碳酸钾(19.5g),对甲氧基苄氯(11.6g),THF(280mL),搅拌,升温至50℃,搅拌过夜,原料反应完全。反应液减压浓缩,浓缩液中缓慢滴加水(560mL),搅拌2小时。过滤,水洗,滤饼干燥,得到固体II-a化合物35.5g,纯度94.5%,收率97.3%。
MS m/z(ESI):517[M+H]+;
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.56(d,J=5.2Hz,1H),7.32-7.27(m,3H),6.89(d,J=8.4Hz,2H),5.09(s,2H),3.72(s,3H),2.98-2.91(m,1H),2.42(s,3H),1.08-1.03(dd,J=14.4,6.8Hz,6H)。
实施例6中间体D的制备
方法1:反应瓶中加入水(200mL),氢氧化钠(7.0g),搅拌溶清,室温下加入THF(100mL)和中间体C(2,5,6-三氯-N-((2-异丙基-4-(甲硫基)吡啶-3-基)氨基甲酰)尼克酰胺)(31.7g),搅拌5小时,反应完全。滴加醋酸(6.0g),调到pH=7-8,再加入水(300mL),搅拌2小时。过滤,水洗,滤饼干燥,得到目标产物6,7-二氯-1-(2-异丙基-4-(甲硫基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮28.0g,为白色固体,纯度:97.7%,收率96.4%。
方法2:室温下反应瓶中加入THF(400mL)和中间体C(2,5,6-三氯-N-((2-异丙基-4-(甲硫基)吡啶-3-基)氨基甲酰)尼克酰胺)(20.0g),搅拌溶清,冷却到-70℃,滴加1.0MKHMDS THF溶液(92.2mL),并搅拌2小时,反应完全。加入水(200mL)淬灭,升到室温,滴加醋酸(2.8g),调到pH=7-8。分液,水相用乙酸乙酯(200mL)萃取,合并有机相,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩干,浓缩物用正庚烷(100mL)和乙酸乙酯(100mL)混合溶剂打浆16h,过滤,滤饼干燥,得到目标产物6,7-二氯-1-(2-异丙基-4-(甲硫基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮12.3g,为类白色固体,纯度:96.7%,收率67.4%。
实施例7中间体C的制备
方法1:将化合物B(2,5,6-三氯尼克酰胺)(27.5g),THF(250.0mL)加入三口瓶中,搅拌溶清。氮气保护下,降至0-5℃,将草酰氯(18.6g)溶于DCM(40mL)滴入反应瓶中。反应液升温至50℃,搅拌2h,再降温至-70℃,往反应体系中滴加吡啶(28.9g),滴完,搅拌10分钟。再往反应体系中滴加化合物A(2-异丙基-4-(甲硫基)吡啶-3-胺)的THF溶液(22.2g,30mLTHF稀释),滴完,继续搅拌30分钟,撤去干冰浴,升至室温,搅拌2小时,反应完全。反应体系中加入饱和碳酸氢钠水溶液,搅拌,分液,水相用乙酸乙酯(300mL)萃取,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。向浓缩物中加入EA(80mL),加热至回流,滴加正庚烷(200mL),降至室温,搅拌3h,过滤,滤饼干燥,得目标产物2,5,6-三氯-N-((2-异丙基-4-(甲硫基)吡啶-3-基)氨基甲酰)尼克酰胺42.9g,类白色固体,HPLC纯度:95%,收率81.1%。
方法2:将化合物B(2,5,6-三氯尼克酰胺)(110.0g),THF(880mL)加入三口瓶中,搅拌溶清。氮气保护下,降至0-5℃,将草酰氯(74.3g)溶于DCM(150mL)滴入反应瓶中。反应液升温至50℃,搅拌2h。减压蒸馏,内温28-33℃。蒸馏至约剩3体积溶剂时,补加THF(220mL),继续蒸馏。蒸馏至约剩3体积溶剂时,停止蒸馏,补加THF(700mL)。降至0-5℃,往反应体系中滴加化合物A(2-异丙基-4-(甲硫基)吡啶-3-胺)的THF溶液(86.3g,200mL THF稀释),滴完,升至25℃搅拌2小时,反应完全。反应体系中加入饱和碳酸氢钠水溶液(700mL),分液。用乙酸乙酯(1L)萃取水相,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩剩235.8g褐色固体。向浓缩物中加入乙酸乙酯(330mL),加热至回流,滴加正庚烷(330mL),降至室温,搅拌3小时。过滤,滤饼干燥,得目标产物C(2,5,6-三氯-N-((2-异丙基-4-(甲硫基)吡啶-3-基)氨基甲酰)尼克酰胺)157.6g,类白色固体,HPLC纯度:97%,收率74.5%。
实施例8中间体B的制备
将SM2(2,5,6-三氯烟酸)(150.0g)、乙酸乙酯(2.0L)加入到反应瓶中,搅拌溶清,再将(Boc)2O(260.2g)加入反应瓶中,慢慢往反应瓶中滴加吡啶(104.8g),搅拌2h。将反应液冷却至10℃,滴加氨水(90.3g),升至室温搅拌2h,反应完全。反应液中加入THF(1.0L),分层,有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。往浓缩物中加入到乙酸乙酯(600mL),加热至回流,滴加正庚烷(900mL),冷却至10℃搅拌2h,过滤,得类白色固体B(2,5,6-三氯烟酰胺)135.1g,HPLC纯度:99.0%,收率:90.5%。
实施例9中间体A的制备
向反应瓶中加入二甲基二硫(44.2g),锌粉(76.5g),乙腈(800mL)和水(200mL),开启搅拌。氮气保护下降温至0-5℃,分批加入氯化铁(95.3g),再升温至20-30℃,搅拌4小时。向反应瓶中加入A1(4-氯-2-异丙基吡啶-3-胺)(100g),搅拌1小时,升温至60-65℃,搅拌过夜,反应完全。反应液降温至20-30℃,过滤,滤液浓缩。浓缩液中加入乙酸乙酯(1000mL),缓慢滴加饱和碳酸钠水溶液调节pH=9,体系中有黄色固体析出。过滤,用乙酸乙酯洗涤滤饼,滤液分层,水相用乙酸乙酯萃取一次,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩,得到棕红色油状物2-异丙基-4-(甲硫基)吡啶-3-胺93.6g,放置后部分固化。HPLC纯度:95.3%,收率:87.3%。
实施例10中间体A1的制备
向反应瓶中依次加入原料SM1(2,4-二氯吡啶-3-胺)(70.0g)和THF(350mL),开启搅拌,溶清。向反应瓶中分批加入氯化锌(87.8g),氮气置换3次,加入[1,1'-双(二苯基膦)二茂铁]二氯化钯-二氯甲烷(3.5g),升温至40-45℃,向反应瓶中缓慢滴加异丙基氯化镁溶液(300mL),滴加完毕,保温1小时,反应完全。反应液降温至15℃,向反应瓶中缓慢加入水(700mL)和乙酸乙酯(700mL),分液,水相再用乙酸乙酯(700mL)萃取一次,合并有机相。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩,得到棕红色油状物A1(4-氯-2-异丙基吡啶-3-胺)70.6g,HPLC纯度:93.2%,收率:97.0%。
Claims (15)
1.一种式(I-a)或式(I-b)化合物及其药学上可接受的盐:
2.制备权利要求1所述化合物及其药学上可接受的盐的中间体,其特征在于中间体如式(II)所示或其轴手性化合物:
R1选自:氢、氨基保护基,当为式(II)的轴手性化合物时,R1不为氢。
3.根据权利要求2所述中间体,其特征在于:
R1选自取代或未取代的烷氧羰基、酰基和烷基,
优选:
更优选:
n选自0、1、2或3。
4.根据权利要求2所述的中间体,其特征在于,所述式(II)的轴手性化合物结构如下:
5.制备权利要求1所述化合物及其药学上可接受的盐的中间体,其特征在于,所述中间体结构如下:
m选自0.5,1,2或3;
Y选自L-酒石酸、D-苹果酸、L-樟脑磺酸、D-二苯甲酰酒石酸、松香酸、L-半胱氨酸、D-樟脑酸、(-)-二特戊酰基-L-酒石酸、D-(+)-二对甲基苯甲酰酒石酸、(S)-(+)-O-乙酰基-L-扁桃酸、(S)-扁桃酸、[(1R)-(内型,反式)]-(+)-3-溴樟脑-8-磺酸铵盐、L-天冬氨酸、D-谷氨酸、(R)-(-)-5-氧代-2-四氢呋喃羧酸、S-2-苯基丙酸、L-焦谷氨酸、D-(-)-奎尼酸、L(+)-抗坏血酸、(S)-(+)-苯基丁二酸、1S)-(-)-樟脑烷酸、(R)-1,4-苯并二恶烷-2-甲酸、(+)-薄荷氧基乙酸、(R)-(-)-α-甲氧基苯乙酸、R)-(+)-α-甲氧基-α-(三氟甲基)苯乙酸、(R)-(+)-N-(1-苯乙基)琥珀酰胺酸、N,N-双[(R)-(+)-1-苯基乙基]邻氨甲酰苯甲酸;
更优选:L-樟脑磺酸、D-二苯甲酰酒石酸、[(1R)-(内型,反式)]-(+)-3-溴樟脑-8-磺酸铵盐、L-焦谷氨酸、1S)-(-)-樟脑烷酸;
优选地,结构如下:
6.制备权利要求1所述式(I-a)或式(I-b)化合物的方法,其特征在于包括步骤a1:
式(III-A)或式(III-a)化合物经脱保护氨化后制得式(I-a)化合物;
或者步骤a2:
式(III-B)或式(III-b)化合物经脱保护氨化后制得式(I-b)化合物。
7.根据权利要求6所述的制备方法,其特征在于:
所述脱保护是通过酸解法或者氧化法的方式进行;
优选地,酸解法所用的酸选自乙酸、三氟乙酸、三氟甲磺酸、甲磺酸、三溴化硼中的一种或多种,更优选地选择其中两种,进一步优选地为三氟乙酸/三氟甲磺酸、三氟乙酸/甲磺酸;
优选地,所述氧化法所用的氧化剂选自2,3-二氯-5,6-二氰基苯醌或硝酸铈铵。
8.制备权利要求5所述中间体的制备方法,其特征在于,所述中间体由式(II)化合物与手性酸反应拆分制得:
优选地,所述手性酸选自:L-酒石酸、D-苹果酸、L-樟脑磺酸、D-二苯甲酰酒石酸、松香酸、L-半胱氨酸、D-樟脑酸、(-)-二特戊酰基-L-酒石酸、D-(+)-二对甲基苯甲酰酒石酸、(S)-(+)-O-乙酰基-L-扁桃酸、(S)-扁桃酸、[(1R)-(内型,反式)]-(+)-3-溴樟脑-8-磺酸铵盐、L-天冬氨酸、D-谷氨酸、(R)-(-)-5-氧代-2-四氢呋喃羧酸、S-2-苯基丙酸、L-焦谷氨酸、D-(-)-奎尼酸、L(+)-抗坏血酸、(S)-(+)-苯基丁二酸、1S)-(-)-樟脑烷酸、(R)-1,4-苯并二恶烷-2-甲酸、(+)-薄荷氧基乙酸、(R)-(-)-α-甲氧基苯乙酸、R)-(+)-α-甲氧基-α-(三氟甲基)苯乙酸、(R)-(+)-N-(1-苯乙基)琥珀酰胺酸、N,N-双[(R)-(+)-1-苯基乙基]邻氨甲酰苯甲酸,
更优选地:L-樟脑磺酸、D-二苯甲酰酒石酸、[(1R)-(内型,反式)]-(+)-3-溴樟脑-8-磺酸铵盐、L-焦谷氨酸、1S)-(-)-樟脑烷酸;
进一步优选地,所述反应是按步骤b进行的:
9.根据权利要求8所述的制备方法,其特征在于:
所述反应溶剂体系选自四氢呋喃/正庚烷、2-甲四氢呋喃/正庚烷、甲醇/二氯甲烷/正庚烷、四氢呋喃、2-甲四氢呋喃、甲醇、丙酮、醋酸异丙酯(IPAc)、乙酸异丙酯(IPA)、乙醇、异丙醇、水/乙腈、甲基叔丁基醚、甲苯、4-甲基-2-戊酮、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮;
优选地,反应溶剂体系至少包含四氢呋喃或2-甲基四氢呋喃;
进一步优选四氢呋喃/正庚烷、2-甲基四氢呋喃/正庚烷、四氢呋喃/甲苯、2-甲基四氢呋喃/甲苯、四氢呋喃/丙酮、2-甲基四氢呋喃/丙酮。
10.制备权利要求2所述式(II)化合物的制备方法,其特征在于由式D化合物与保护基试剂按照步骤c制得:
优选地,所述保护基试剂选自
更优选:
X为卤素,优选Cl;
优选地,步骤c是在碱性条件下进行的。
11.根据权利要求10所述的制备方法,其特征在于,式D化合物是通过步骤d制得:
所述反应是在碱性条件下进行的;
优选地,所述碱选自氢氧化钠、氢氧化钾、KHMDS、NaHMDS、LiHNMDS、叔丁醇钾、叔丁醇钠、甲醇钠、乙醇钠、碳酸钠、碳酸钾、磷酸钾、三乙胺;
优选地,所述反应是在四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺或二甲基亚砜溶剂环境中进行的;
优选地,加碱反应后,再加酸调节PH值,所述酸优选醋酸或盐酸;
优选地,调PH值为7-8。
12.根据权利要求11所述的制备方法,其特征在于,式C化合物是通过步骤e制得:
优选地,式A化合物是通过步骤f1制得:
优选地,所述步骤f1是在锌和氯化铁催化下进行的;
优选地,所述步骤f1是在氮气保护下进行的。
13.根据权利要求12所述的制备方法,其特征在于步骤e的反应溶剂中还添加了吡啶。
14.根据权利要求12~13所述的制备方法,其特征在于,式A1化合物是由步骤g反应制得:
优选地,步骤g是在包含钯类催化剂的条件下进行的,进一步优选地钯类催化剂选自四(三苯基膦)钯、双(三苯基膦)二氯化钯、二(三叔丁基膦)钯、1,1'-双(二-叔丁基膦基)二茂铁二氯化钯、双(三邻甲苯基膦)二氯化钯、双-(三环己基磷基)二氯化钯、[1,3-双(2,6-二异丙基苯基)-2-咪唑亚基](3-氯吡啶基)二氯化钯(II)、[1,1'-双(二异丙基膦)二茂铁]二氯钯、醋酸钯/4,5-双二苯基膦-9,9-二甲基氧杂蒽、醋酸钯/2-双环己基膦-2',4',6'-三异丙基联苯、醋酸钯/2-双环己基膦-2',6'-二甲氧基联苯、醋酸钯/1,2-双(二苯基膦)乙烷、三(二亚苄基丙酮)二钯/4,5-双二苯基膦-9,9-二甲基氧杂蒽、三(二亚苄基丙酮)二钯/2-双环己基膦-2',4',6'-三异丙基联苯、三(二亚苄基丙酮)二钯/2-双环己基膦-2',6'-二甲氧基联苯,更优选地催化剂包含[1,1'-双(二苯基膦)二茂铁]二氯化钯-二氯甲烷;
优选地,催化剂还包含氯化锌;
优选地,步骤g是在氮气保护下进行的。
15.根据权利要求12~13所述的制备方法,其特征在于,式B化合物经步骤f2由SM2化合物经氨化反应制得:
优选地,所述氨化反应的氨化试剂是氨水或氨气;
优选地,所述氨化反应中还加入了活化试剂,进一步优选地,活化试剂选自碳酸酐二叔丁酯、草酰氯/N,N-二甲基甲酰胺、氯化亚砜/N,N-二甲基甲酰胺、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
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