CN115697968B - (s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯及其盐的制备方法 - Google Patents
(s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯及其盐的制备方法 Download PDFInfo
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- CN115697968B CN115697968B CN202180038252.1A CN202180038252A CN115697968B CN 115697968 B CN115697968 B CN 115697968B CN 202180038252 A CN202180038252 A CN 202180038252A CN 115697968 B CN115697968 B CN 115697968B
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- trifluoromethanesulfonyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000003839 salts Chemical class 0.000 title claims abstract description 13
- KUPMNJJKVPAVQU-UHFFFAOYSA-N methyl 2-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoate Chemical compound COC(C(C)C1=CC=C(C=C1)C1=C(C(=NC=C1)C)C)=O KUPMNJJKVPAVQU-UHFFFAOYSA-N 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 22
- 230000008569 process Effects 0.000 claims abstract description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 18
- 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 17
- 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 13
- 239000003054 catalyst Substances 0.000 claims description 11
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 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 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 150000007522 mineralic acids Chemical class 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 5
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 5
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 101150003085 Pdcl gene Proteins 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-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
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 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 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 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
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- IMNIECVIVJOTBH-UHFFFAOYSA-N trifluoromethanesulfonyl bromide Chemical compound FC(F)(F)S(Br)(=O)=O IMNIECVIVJOTBH-UHFFFAOYSA-N 0.000 claims description 2
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000013078 crystal Substances 0.000 claims 1
- 238000005755 formation reaction Methods 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- -1 4- (2, 3-dimethylpyridin-4-yl) phenyl methyl Chemical group 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 229940017219 methyl propionate Drugs 0.000 abstract 2
- 238000003908 quality control method Methods 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 2
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
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- 239000003513 alkali Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
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- 238000002474 experimental method Methods 0.000 description 2
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- FDFQRJWLHKSHPZ-LBPRGKRZSA-N methyl (2s)-3-(4-bromophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=C(Br)C=C1 FDFQRJWLHKSHPZ-LBPRGKRZSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MCUYHRNUDDANSO-UHFFFAOYSA-N 4-chloro-2,3-dimethyl-1-oxidopyridin-1-ium Chemical compound CC1=C(C)[N+]([O-])=CC=C1Cl MCUYHRNUDDANSO-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical compound Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
本发明提供了(S)‑2‑(3S,8S)‑3‑(4‑(3,4‑二氯苄氧基)苯基‑7‑((S)‑1‑苯丙基)‑2,3,6,7,8,9‑六氢‑[1,4]‑二氧杂环己烯并[2,3‑g]异喹啉‑8‑甲酰氨基)‑3‑(4‑(2,3‑二甲基吡啶‑4‑基)苯基)丙酸二盐酸盐合成工艺中的关键中间体(S)‑2‑氨基‑3‑(4‑(2,3‑二甲基吡啶‑4‑基)苯基丙酸甲酯及其盐的制备方法,其采用连续投料的方式,无需柱层析纯化,简化操作,减少损失,提高收率;进一步的,通过成盐纯化的方式获得可稳定储存的高纯度(S)‑2‑氨基‑3‑(4‑(2,3‑二甲基吡啶‑4‑基)苯基丙酸甲酯盐。本发明的制备方法总收率可达到85%以上,目标产物纯度98%以上,异构体含量在0.5%以下,具有工艺稳定性好,产品质量可控的优点,能够应用于工业化生产。
Description
技术领域
本发明属于医药技术领域,具体涉及一种(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸二盐酸盐合成工艺中间体(S)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯及其盐的制备方法。
背景技术
(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸二盐酸盐,是非肽类、高选择性口服胰高血糖素样肽-1受体(GLP-1R)激动剂,也具有作为糖尿病药物良好的前景。
(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸为二盐酸盐,其分子式为C50H49Cl4N3O6,分子量929.76。化学结构式如下所示:
发明专利CN102378574B公开了(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸及其制备方法,其中涉及关键中间体:(S)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯(化合物IV);该关键中间体由(S)-3-(4-溴-苯基)-2-叔丁氧基羰基氨基-丙酸甲酯(化合物VI)作为起始原料,通过Suzuki偶联、脱保护等3步反应制备得到,其反应过程如下:
但是,上述制备方法中需使用柱层析分离纯化,总收率仅有49%,且化合物IX价格较昂贵,市场上只有克级原料供应,此外,经实验发现,化合物IV极易吸湿变质,较难通过常规的溶剂析晶方式获得固体化合物,储存和运输难度大,较难实现工业化应用。因此,有必要重新开发一条适合工业化的合成路线。
发明内容
本发明提供了(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸二盐酸盐的关键中间体(S)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯及其盐的制备方法,该方法的生产成本低,可实现较大规模制备,能够应用于工业化生产。
本发明采取的技术方案为:以化合物I为起始原料,经酯化形成反应活性更高的化合物II,化合物II再与预先制备的化合物III发生偶联反应生成化合物X,化合物X再经脱保护,碱性条件下游离形成化合物IV,如有必要,化合物IV可重新成盐制备化合物V。
根据本发明的(S)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯(化合物IV)及其盐的制备方法包括如下步骤:
(a)化合物I与三氟甲磺酰化试剂发生酯化反应,生成化合物II;
(b)化合物II与化合物III发生偶联反应生成化合物X;
(c)化合物X在酸性条件下脱保护生成化合物IV;
(d)化合物IV再与选自有机酸或无机酸的酸混合,经成盐纯化后可获得化合物V,其中x为0.5~3;
作为一种具体的实施方案,所述步骤(a)中反应溶剂选自二氯甲烷,2-甲基四氢呋喃,四氢呋喃,甲苯,二甲苯中的一种或两种以上,优选二氯甲烷。
作为一种具体的实施方案,所述步骤(a)中加入缚酸剂,所述缚酸剂选自吡啶,三乙胺,二甲氨基吡啶,DBU,N-甲基吗啉,异丙胺中的一种,优选二甲氨基吡啶。
作为一种具体的实施方案,所述步骤(a)中三氟甲磺酰化试剂选自三氟甲磺酸酐、三氟甲磺酰氯、三氟甲磺酰溴中的一种,优选三氟甲磺酸酐。
作为一种具体的实施方案,所述步骤(a)中化合物I与三氟甲磺酰化试剂及缚酸剂的投料摩尔比为1:1.1:1.5~1:2:3。
作为一种具体的实施方案,所述步骤(a)反应温度为-10~40℃,优选0~20℃。
作为一种具体的实施方案,所述步骤(a)的反应后处理方式为:反应结束后加水搅拌,再加入稀盐酸,调节体系pH至酸性,分除水相,有机相浓缩除去溶剂,加入非极性溶剂搅拌析晶。
作为一种具体的实施方案,所述步骤(a)的后处理中使用的非极性溶剂选自石油醚,正庚烷,正戊烷,环己烷,正己烷中的一种或两种以上,优选正己烷。
作为一种具体的实施方案,所述步骤(b)中反应是在催化剂及碱作用下进行的,所述催化剂单独选自钯催化剂,或钯催化剂与有机膦配体的混合物,其中所述钯催化剂选自Pd(OAc)2,Pd2(dba)3,PdCl2(PPh3)2,PdCl2dppf,Pd(PPh3)4,所述有机膦配体选自Ph2P(CH2)2PPh2(dppe),Ph2P(CH2)3PPh2(dppp),PCy3,n-Bu3P,P(OMe)3,PPh3中的一种或两种以上,所述催化剂优选Pd2(dba)3与PCy3的混合体系,所述碱选自碳酸钾,碳酸钠,碳酸铯中的一种,优选碳酸钾。
作为一种具体的实施方案,所述步骤(b)中反应溶剂为选自甲苯,二甲苯,正丁醇中一种或两种以上与水的混合体系,优选甲苯与水的混合体系。
作为一种具体的实施方案,所述步骤(b)中催化剂用量为化合物II的1~5%倍摩尔数,所述反应温度为60~120℃,优选75~115℃。
作为一种具体的实施方案,所述步骤(b)中化合物II与化合物III的投料比为1:1.1~1:3,优选1:1.2~1:2。
作为一种具体的实施方案,所述步骤(b)的后处理方式为:反应结束后,加硅藻土滤除固体不溶物,分液,有机相再用稀盐酸调节pH至弱酸性,分除水相,有机相浓缩至干,加入溶剂稀释,直接投入下一步反应,收率按照100%计。
作为一种具体的实施方案,所述步骤(b)中使用的稀释溶剂为步骤(c)的反应溶剂。
作为一种具体的实施方案,所述步骤(c)中反应溶剂选自四氢呋喃,二氯甲烷/甲醇,二氧六环中的一种,优选二氯甲烷/甲醇溶液。
作为一种具体的实施方案,所述步骤(c)中的酸性条件指加入6~12mol/L盐酸溶液。
作为一种具体的实施方案,所述步骤(c)的后处理方式为反应结束后加入二氯甲烷及纯化水,搅拌,用稀碱溶液调节pH至8~10,分除水相,有机相浓缩或作为溶液直接投入下一步反应,收率按照100%计。
作为一种具体的实施方案,所述步骤(d)中的酸选自有机酸和无机酸,其中所述有机酸选自草酸,酒石酸,柠檬酸,琥珀酸,马来酸,苹果酸,富马酸,乙醇酸,马尿酸,对甲苯磺酸,苯甲酸,己二酸中的一种,优选酒石酸;所述无机酸选自磷酸,硫酸,氢溴酸中的一种,优选磷酸。
作为一种具体的实施方案,所述步骤(d)中的反应溶剂为选自二氯甲烷,丙酮,乙腈,异丙醇,四氢呋喃中的一种,优选丙酮。
作为一种具体的实施方案,所述步骤(d)中酸的加入方式为:将酸溶于适宜溶剂中,所述的适宜溶剂包括但不限于以下几种:甲醇,乙醇,丙酮,四氢呋喃等,并进一步将其加入到化合物IV的溶液中,搅拌反应。
作为一种具体的实施方案,所述步骤(d)成盐反应投料摩尔比为游离碱IV:酸=1:0.5~1:3.5,优选1:2.0~1:2.5。
作为一种具体的实施方案,所述步骤(d)的成盐反应温度为-10~25℃,优选5~20℃。
作为一种具体的实施方案,所述步骤(d)中加酸后的搅拌析晶时间为2~15小时。
本发明的有益效果
本发明提供了(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸二盐酸盐的合成工艺中的关键中间体(S)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯及其盐的制备方法。相对于专利公开的路线,本发明的制备方法采用的原料成本较低,制备获得(S)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯的2步反应过程采用连续投料的方式,无需在每步反应后进行柱层析纯化,可以简化操作,减少损失,提高收率;进一步的,成盐纯化的方式获得纯度更高的(S)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯盐,便于稳定储存。本发明的制备方法总收率可达到85%以上,目标产物纯度98%以上,异构体含量在0.5%以下,具有工艺稳定性好,产品质量可控的优点,能够应用于工业化生产。
具体实施方式
下面结合具体实施例对本发明作进一步的详细说明。以下实施例用于理解本发明的方法和核心思想,对于本领域的技术人员来说,在不脱离本发明构思的前提下,进行任何可能的变化或替换,均属于本发明的保护范围。
本发明实施例中未注明具体条件的实验方法,通常为常规条件,或按照原料或商品制造厂商所建议的条件;未注明来源的试剂,通常为通过商业途径可购得的常规试剂。
本发明所使用的检测仪器为:
1.核磁共振仪
仪器型号:Bruker DMX-500核磁共振仪
2.质谱仪
仪器型号:Agilent 6460,测试条件:ESI源
实施例1:化合物III的制备
在反应瓶中加入30克2,3-二甲基-4-氯吡啶-1-氧化物,300毫升甲苯和50克醋酸钾,搅拌混合均匀,氮气保护,降温到-5℃,加入46.5克二(频哪醇基)二硼,搅拌1小时,再加入49.8克二(频哪醇基)二硼,室温搅拌反应18小时,再加入300毫克Pd2dba3和400毫克PCy3,升温至110~120℃,反应8~12小时,反应结束后降温至30℃,加入420毫升正庚烷,搅拌1小时,过滤得滤液,滤液升温至35℃,加入150毫升稀盐酸,搅拌10分钟,再用二氯甲烷或乙酸乙酯萃取,减压浓缩得化合物III 44克,收率98%。
实施例2:化合物II的制备
在反应瓶中加入250毫升二氯甲烷和55克化合物I,搅拌溶解,加入28.6克2-甲基吡啶,降温至-5℃,滴加57.7克三氟甲烷磺酸酐,加完后反应1小时,反应完全后,用1N稀盐酸调节PH=2-3,分除水相,有机相浓缩除去溶剂,加入正己烷搅拌析晶,过滤得化合物II71g,收率90%。
实施例3:化合物X的制备
反应瓶中加入17克碳酸钾和100毫升去离子水,搅拌溶解,加入15.3克化合物III、19.1克化合物II和300毫升甲苯,搅拌溶解得到澄清溶液,氮气保护下,加入304毫克Pd2dba3和387毫克PCy3。升温至80℃反应16小时,反应结束后,降温至50℃,垫硅藻土过滤,滤液分层得有机相,有机相再用稀盐酸洗涤至pH为6~7,分除水层,有机层浓缩至干,加入下一步反应溶剂稀释,直接投入下一步反应。收率按100%计,得约18.1g化合物X。
实施例4:化合物IV的制备
在反应釜中加入18.1克化合物X和100毫升二氯甲烷,搅拌溶解,滴加65毫升6NHCl/甲醇,室温反应2小时,反应结束后,加入200毫升二氯甲烷,饱和碳酸氢钠调节pH至约为8,分液,得有机相,备用,收率按照100%计,得约13.4g化合物IV。
实施例5:化合物V的制备
取上一步骤制备的化合物IV(13.4g)的二氯甲烷溶液,加入含11.5克二水合草酸和27毫升乙醇的溶液,加完后室温搅拌析晶3小时,过滤,得白色固体化合物V(二草酸盐)20g,收率95%,纯度:99.1%,ee%:98.2%。1H NMR(500MHz,d6-DMSO)δ8.37(d,J=5.0Hz,1H),7.38-7.16(m,4H),7.15(s,1H),4.35-4.32(m,1H),3.26-3.15(m,2H),3.70(s,3H),2.56(s,3H),2.53(s,3H);13C NMR(100MHz,d6-DMSO)δ169.5,163.4(4C),158.5,157.8,148.9,145.9,142.0,141.8,140.9,138.7,156.6,149.7,144.1,137.6,134.8,129.5(2C),129.4,128.9(2C),122.6,53.2,52.6,35.7,22.2,15.8;经碳谱证实结构中含2分子草酸,分子式为C17H20N2O2·2C2H2O4。HRMS(ESI)C17H20N2O2(以游离碱计)的计算值:285.1598[M+H],实测值:285.1604。
实施例6:化合物V的制备
取上一步骤制备的化合物IV(13.4g)的二氯甲烷溶液,浓缩至干,加入70g丙酮,搅拌溶解,5℃下滴入磷酸(10.32g)的丙酮溶液,搅拌至有固体产生,15℃析晶3小时,过滤,得类白色固体化合物V(二磷酸盐)19.9g,收率90%,纯度98.5%,ee%:98.0%。1H NMR(500MHz,d6-DMSO)δ8.30(d,J=5.0Hz,1H),7.36-7.30(m,4H),7.04(s,1H),4.25-4.23(m,1H),3.24-3.11(m,2H),3.68(s,3H),2.51(s,3H),2.16(s,3H);13C NMR(100MHz,d6-DMSO)δ170.0,157.3,148.3,145.4,138.0,134.7,129.5(2C),128.9(2C),128.4,122.1,53.4,52.5,36.1,23.0,15.8;HRMS(ESI)C17H20N2O2(以游离碱计)的计算值:285.1598[M+H],实测值:285.1604。参照《中国药典》2015版四部通则3103测得磷含量为12.3%,证明含两分子磷酸,即分子式为C17H20N2O2·2H3PO4。
Claims (14)
1.一种(S)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯(化合物IV)及其盐的制备方法,其特征在于,包括如下步骤:
(a)化合物I与三氟甲磺酰化试剂反应,制备化合物II;
(b)化合物II与化合物III反应制备化合物X;
(c)化合物X脱除保护,制备化合物IV;
其中:
在步骤(a)中加入缚酸剂,所述缚酸剂选自吡啶、三乙胺、二甲氨基吡啶、二异丙基乙胺、DBU、N-甲基吗啉、异丙胺中的一种或两种以上;
步骤(b)中的反应是在催化剂及碱作用下进行的,所述催化剂单独选自钯催化剂,或钯催化剂与有机膦配体的混合物,其中所述钯催化剂选自Pd(OAc)2、Pd2(dba)3、PdCl2(PPh3)2、PdCl2dppf和Pd(PPh3)4,所述有机膦配体选自Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp)、PCy3、n-Bu3P、P(OMe)3和PPh3中的一种或两种以上,所述催化剂的用量为化合物II的1~5%倍摩尔量;以及所述碱选自碳酸钾,碳酸钠和碳酸铯中的一种;以及
步骤(b)中的反应溶剂选自甲苯、二甲苯和正丁醇中的一种或两种以上与水的混合体系。
2.根据权利要求1所述的方法,其特征在于,任选地包括步骤(d):化合物IV与选自有机酸或无机酸的酸混合,经成盐纯化后可获得化合物V,
其中x为0.5~3。
3.根据权利要求1或2所述的方法,其特征在于,步骤(a)中三氟甲磺酰化试剂选自三氟甲磺酸酐、三氟甲磺酰氯、三氟甲磺酰溴中的一种;和/或
步骤(a)中反应溶剂选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯中的一种或两种以上。
4.根据权利要求1或2所述的方法,其特征在于,步骤(a)中化合物I与三氟甲磺酰化试剂及缚酸剂的投料摩尔比为1:1.1:1.5~1:2:3,和/或
所述步骤(a)反应温度为-10~40℃。
5.根据权利要求1或2所述的方法,其特征在于,步骤(b)中的所述碱为碳酸钾。
6.根据权利要求1或2所述的方法,其特征在于,所述步骤(b)的反应温度为60~120℃;和/或
步骤(b)中化合物II与化合物III的投料摩尔比为1:1.1~1:3。
7.根据权利要求6所述的方法,其中步骤(b)中化合物II与化合物III的投料摩尔比为1:1.2~1:2。
8.根据权利要求2所述的方法,其特征在于,所述步骤(d)中,将化合物IV与溶剂混合均匀,再加入有机酸或无机酸的溶液,搅拌成盐析晶,得到化合物V。
9.根据权利要求2或8所述的方法,其特征在于,所述步骤(d)中的酸选自有机酸和无机酸,其中所述有机酸选自草酸、酒石酸、柠檬酸、琥珀酸、马来酸、苹果酸、富马酸、乙醇酸、马尿酸、对甲苯磺酸、苯甲酸和己二酸中的一种;所述无机酸选自磷酸、硫酸和氢溴酸中的一种。
10.根据权利要求9所述的方法,其中所述有机酸为酒石酸。
11.根据权利要求9所述的方法,其中所述无机酸为磷酸。
12.根据权利要求2或8所述的方法,其特征在于,所述步骤(d)中化合物IV与酸摩尔比为1:1.1~1:3。
13.根据权利要求12所述的方法,其中所述步骤(d)中化合物IV与酸摩尔比为1:2.0~1:2.5。
14.根据权利要求2或8所述的方法,其特征在于成盐反应温度为-10~25℃。
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