WO2021238963A1 - 一种(s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸甲酯二酸盐的制备方法 - Google Patents
一种(s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸甲酯二酸盐的制备方法 Download PDFInfo
- Publication number
- WO2021238963A1 WO2021238963A1 PCT/CN2021/095965 CN2021095965W WO2021238963A1 WO 2021238963 A1 WO2021238963 A1 WO 2021238963A1 CN 2021095965 W CN2021095965 W CN 2021095965W WO 2021238963 A1 WO2021238963 A1 WO 2021238963A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- compound
- potassium
- added
- phenyl
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title abstract description 8
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 title abstract description 5
- 229940017219 methyl propionate Drugs 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000000746 purification Methods 0.000 claims abstract description 7
- FXSZGKYGUFCBQY-UHFFFAOYSA-N propanoic acid;dihydrochloride Chemical compound Cl.Cl.CCC(O)=O FXSZGKYGUFCBQY-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 239000000243 solution Substances 0.000 claims description 47
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 41
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 26
- 239000003054 catalyst Substances 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 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 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 229910000029 sodium carbonate Inorganic materials 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 16
- 239000012074 organic phase Substances 0.000 claims description 16
- PEMUHKUIQHFMTH-QMMMGPOBSA-N (2s)-2-amino-3-(4-bromophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(Br)C=C1 PEMUHKUIQHFMTH-QMMMGPOBSA-N 0.000 claims description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical group [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 14
- GMQUEDBQYNHEEM-UHFFFAOYSA-N [B].[B].CC(C)(O)C(C)(C)O.CC(C)(O)C(C)(C)O Chemical compound [B].[B].CC(C)(O)C(C)(C)O.CC(C)(O)C(C)(C)O GMQUEDBQYNHEEM-UHFFFAOYSA-N 0.000 claims description 13
- 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 13
- 229910052763 palladium Inorganic materials 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 101150003085 Pdcl gene Proteins 0.000 claims description 9
- 150000007522 mineralic acids Chemical class 0.000 claims description 9
- -1 organic acid salt Chemical class 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 8
- 235000006408 oxalic acid Nutrition 0.000 claims description 8
- 229910052698 phosphorus Inorganic materials 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 239000008346 aqueous phase Substances 0.000 claims description 7
- 235000011056 potassium acetate Nutrition 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 239000012458 free base Substances 0.000 claims description 6
- KHONQNXQXZDOFB-INIZCTEOSA-N methyl (2s)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(C)=C1C KHONQNXQXZDOFB-INIZCTEOSA-N 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 239000008096 xylene Substances 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 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
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical group OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical group OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 229940039748 oxalate Drugs 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical group [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Chemical group 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Chemical group OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 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
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 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
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 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
- 239000003513 alkali Substances 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 claims description 2
- SHPKCSFVQGSAJU-UAIGNFCESA-L dipotassium;(z)-but-2-enedioate Chemical compound [K+].[K+].[O-]C(=O)\C=C/C([O-])=O SHPKCSFVQGSAJU-UAIGNFCESA-L 0.000 claims description 2
- CVOQYKPWIVSMDC-UHFFFAOYSA-L dipotassium;butanedioate Chemical compound [K+].[K+].[O-]C(=O)CCC([O-])=O CVOQYKPWIVSMDC-UHFFFAOYSA-L 0.000 claims description 2
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 claims description 2
- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 claims description 2
- MSJMDZAOKORVFC-UAIGNFCESA-L disodium maleate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C/C([O-])=O MSJMDZAOKORVFC-UAIGNFCESA-L 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-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
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 claims description 2
- 239000001415 potassium malate Substances 0.000 claims description 2
- SVICABYXKQIXBM-UHFFFAOYSA-L potassium malate Chemical compound [K+].[K+].[O-]C(=O)C(O)CC([O-])=O SVICABYXKQIXBM-UHFFFAOYSA-L 0.000 claims description 2
- 235000011033 potassium malate Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 235000019265 sodium DL-malate Nutrition 0.000 claims description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 229960001790 sodium citrate Drugs 0.000 claims description 2
- 239000001394 sodium malate Substances 0.000 claims description 2
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 claims description 2
- 229940039790 sodium oxalate Drugs 0.000 claims description 2
- 229940074404 sodium succinate Drugs 0.000 claims description 2
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims 2
- NVGSFACCAOUJSD-HNNXBMFYSA-N (2S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoic acid Chemical compound N[C@H](C(=O)O)CC1=CC=C(C=C1)C1=C(C(=NC=C1)C)C NVGSFACCAOUJSD-HNNXBMFYSA-N 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical group [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- 244000248349 Citrus limon Species 0.000 claims 1
- 235000005979 Citrus limon Nutrition 0.000 claims 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical group Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical group [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical group [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 229940049920 malate Drugs 0.000 claims 1
- 150000003891 oxalate salts Chemical group 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 238000000638 solvent extraction Methods 0.000 claims 1
- 229940086735 succinate Drugs 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical group [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000000203 mixture Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 238000003756 stirring Methods 0.000 description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 10
- 239000011261 inert gas Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 7
- 229940126062 Compound A Drugs 0.000 description 6
- 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 6
- 239000010410 layer Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 2
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 238000007867 post-reaction treatment Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PHCLIPMSNVUELH-UHFFFAOYSA-N 4-bromo-2,3-dimethylpyridine Chemical compound CC1=NC=CC(Br)=C1C PHCLIPMSNVUELH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- TVGLTBPQUIEFBT-SQKCAUCHSA-N methyl (2s)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(C)=C1C TVGLTBPQUIEFBT-SQKCAUCHSA-N 0.000 description 1
- 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 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- 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
- C07D213/55—Acids; Esters
Definitions
- the invention belongs to the technical field of drug synthesis, and specifically relates to (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1- (Phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxeino[2,3-g]isoquinoline-8-carboxamido)
- S -2-amino-3-(4-(2,3 -The preparation method of dimethylpyridin-4-yl)phenyl)propionic acid methyl ester diacid salt.
- Compound A contains four chiral centers, of which (S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propionic acid methyl ester diacid salt is The synthesis introduces the last chiral center, which is a key intermediate in its preparation process.
- CN102378574B discloses a method for synthesizing the free base of compound A, which specifically discloses (S)-3-(4-bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester VI as a starting material, (S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propionic acid methyl ester di salt was prepared by Suzuki coupling, deprotection and other 3-step reactions Salt (IV).
- reaction step disclosed in the prior art is to add bis(pinacolyl) diboron (VII) to compound VI, stir at 75°C for 3 hours under the protection of nitrogen, and obtain (S)- after purification using a chromatographic column.
- the present invention provides a key intermediate of compound A (S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propionic acid methyl ester diacid salt Compared with the prior art, the method does not require separation and purification through a chromatographic column, has the advantages of low cost and high yield, and is more suitable for industrial production.
- the preparation method of the present invention is as follows:
- step (d) is further carried out: after compound IV is freed, it is mixed with an acid selected from organic acid or inorganic acid, and compound V can be obtained after purification by salt formation.
- the step (a) is carried out under the protection of inert gas.
- the compound I and the organic acid salt are added to the solvent first, and the temperature of the mixture is maintained at -10 to 10°C;
- the organic acid salt is selected from potassium acetate, sodium acetate, Potassium oxalate, sodium oxalate, sodium citrate, potassium citrate, potassium L-tartrate, sodium L-tartrate, potassium malate, sodium malate, potassium succinate, sodium succinate, potassium maleate, sodium maleate
- the solvent is selected from one or more of xylene, toluene or chlorobenzene.
- the bis(pinacol) diboron is added in two portions, and the reaction temperature is -10 ⁇ 10°C during the first addition, and the second time The reaction temperature during the addition is 20-30°C.
- catalyst a is added; the catalyst a is selected from a palladium catalyst alone, or a palladium catalyst and The organic phosphine ligand mixed system, wherein the palladium catalyst is selected from Pd 2 (dba) 3 , PdCl 2 (PPh 3 ) 2 , Pd(OAc) 2 , and the organic phosphorus ligand is selected from PCy 3 , PPh 3, n -Bu 3 P, one or more of P(OMe) 3 , preferably Pd 2 (dba) 3 and PCy 3 are mixed and used.
- the reaction temperature after adding the catalyst is 100-135°C, preferably 110-120°C.
- the molar ratio of the compound I, the organic acid salt and the bis(pinacol) diboron is 1:2:2 to 1:4:3
- the amount of the catalyst used is 0.1-1% by mole of the compound I.
- the post-reaction treatment method of step (a) is as follows: add heptane to dilute and stir, filter the insoluble matter, extract the filtrate with dilute hydrochloric acid, and wash the resulting aqueous layer with dichloromethane or ethyl acetate , Remove the organic layer, and concentrate the water layer to 2-5 times the volume of compound I to obtain compound II.
- the concentration of the dilute hydrochloric acid during the post-treatment is 1 to 2 mol/L.
- the step (b) is carried out under the protection of inert gas.
- step (b) water and an organic solvent are added to the compound II concentrate, and an alkaline reagent a is added to adjust the pH to about 7;
- the organic solvent is selected from ethanol, n-propyl One or more of alcohol, n-butanol, tetrahydrofuran, 1,4-dioxane, toluene, and xylene, preferably ethanol;
- the alkaline reagent a is selected from sodium carbonate, potassium carbonate, cesium carbonate, One or more of lithium carbonate is preferably sodium carbonate;
- the feeding ratio of 4-bromo-L-phenylalanine to compound II is 1:1.5 to 1:2.5, preferably 1:2.
- the alkaline reagent b and 4-bromo-L-phenylalanine are added in sequence, and the reaction temperature is adjusted to 30-40°C;
- the alkaline reagent is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, barium hydroxide, and potassium phosphate, preferably sodium carbonate.
- a catalyst b is added, and the catalyst b is selected from a palladium catalyst alone, or a mixed system of a palladium catalyst and an organophosphine ligand, wherein the palladium catalyst is selected from Pd( OAc) 2 , Pd 2 (dba) 3 , PdCl 2 (PPh 3 ) 2, PdCl 2 dppf, Pd(PPh 3 ) 4 , the organophosphine ligand is selected from Ph 2 P(CH 2 ) 2 PPh 2 (dppe ), Ph 2 P(CH 2 ) 3 PPh 2 (dppp), PCy 3 , n-Bu 3 P, P(OMe) 3 , one or more of PPh 3 , preferably Pd 2 (dba) 3 and PCy 3 is used in combination, the amount of the catalyst is 1 to 5% by mole of 4-bromo-L-phenylalanine; the reaction temperature is 60
- the post-reaction treatment method of step (b) is: concentration under reduced pressure, evaporate 4 times the volume of 4-bromo-L-phenylalanine solvent, and then add purified water to the original volume, Extract with ethyl acetate or dichloromethane to separate the organic phase; add acid dropwise to the aqueous phase to adjust the pH to 1-2, and filter; extract the filtrate with ethyl acetate or dichloromethane to separate the organic phase, and add hydroxide to the aqueous phase Adjust the pH of the sodium aqueous solution to 5-8, stir and crystallize to obtain compound III; the acid used for adjusting the pH is one of hydrochloric acid, sulfuric acid, and phosphoric acid, preferably hydrochloric acid.
- step (c) methanol is used as a solvent and a reagent at the same time, and oxalyl chloride or thionyl chloride is optionally added, and the reaction temperature is controlled at 40-70°C, preferably 55-65 °C.
- step (c) is concentrated to remove the solvent after the reaction is completed to obtain compound IV.
- step (d) an alkaline aqueous solution is added to the product of step (c) to adjust the pH, and then a solvent is used to extract 1 to 3 times, the water phase is separated, and the organic phase is concentrated to obtain compound IV
- the free base; the extraction solvent is selected from one of ethyl acetate, dichloromethane, isopropyl acetate, butyl acetate or 2-methyltetrahydrofuran.
- the free alkali solution of compound IV is uniformly mixed with the solvent, and then an organic acid or inorganic acid solution is added, and the mixture is stirred to form salt and crystallize to obtain compound V.
- the solvent is selected from one or more of dichloromethane, acetone, isopropanol, acetonitrile, and tetrahydrofuran, the organic acid or inorganic acid
- the organic acid or inorganic acid One selected from oxalic acid, L-tartaric acid, malic acid, succinic acid, maleic acid, citric acid, phosphoric acid, sulfuric acid, hydrobromic acid; preferably oxalic acid or phosphoric acid; the organic acid or inorganic acid is dissolved in acetone, methanol Or in ethanol.
- the (S)-2-amino-3-[4-(2) prepared through the steps (a) to (c), or through the steps (a) to (d) ,3-dimethylpyridin-4-yl)phenyl]propionic acid methyl ester diacid salt is a key intermediate in the preparation of compound A.
- di-acid salt means that the free base and the acid form a salt at a molar ratio of 1:2, and the acid includes organic acid and inorganic acid.
- the preparation method of (S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propionic acid methyl ester diacid salt of the present invention is relatively Technically speaking, the process route has low raw material cost and high yield, does not need to be purified by a chromatographic column, and is more suitable for industrial production.
- (S)-(S)-(S)-(S)-(S)-[4-(2,3-dimethylpyridin-4-yl)phenyl]propionic acid methyl ester dihydrochloride is further prepared from (S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propionic acid methyl ester dihydrochloride 2-Amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propionic acid methyl ester diacid salt has better storage stability.
- the experimental methods without specific conditions are usually conventional conditions, or according to the conditions recommended by the raw material or commodity manufacturers;
- the reagents without an indication of the source are usually conventional reagents that are commercially available.
- the detection equipment used in the present invention is:
- the content of phosphorus is 12.3%, which is measured in the four general rules 3103, which proves that it contains two molecules of phosphoric acid, that is, the molecular formula is C 17 H 20 N 2 O 2 ⁇ 2H 3 PO 4 .
- the properties of the prepared salt (oxalate, phosphate) and hydrochloride were compared, and the stability inspection experiment under 40°C/75% humidity was carried out.
- the chemical purity (HPLC) was tested and the product shape was observed.
- the chemical stability was evaluated, and the detailed experimental results are shown in Table 2. The results show that by changing the salt type, the moisture absorption of the solid can be improved, so as to prevent the product from deteriorating due to water absorption during storage.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种(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]丙酸甲基酯二酸盐的制备方法,该方法与现有技术相比,无需经过色谱柱分离纯化,具有成本低、收率高的优点,更适合于工业化生产。
Description
本发明属于药物合成技术领域,具体涉及(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)丙酸甲酯二酸盐的制备方法。
(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(化合物A),是非肽类小分子胰高血糖素样肽-1受体(GLP-1R)激动剂,其分子式为C
50H
49Cl
4N
3O
6,分子量为929.76,其化学结构式如下:
化合物A含有四个手性中心,其中,(S)-2-氨基-3-[4-(2,3-二甲基吡啶-4-基)苯基]丙酸甲基酯二酸盐为合成引入最后一个手性中心,是其制备过程中的关键中间体。
CN102378574B公开了合成化合物A游离碱的方法,其中具体公开了由(S)-3-(4-溴-苯基)-2-叔丁氧基羰基氨基-丙酸甲酯VI作为起始物料,通过Suzuki偶联,脱保护等3步反应制备得到(S)-2-氨基-3-[4-(2,3-二甲基吡啶-4-基)苯基]丙酸甲基酯二盐酸盐(IV)。
具体而言,现有技术公开的反应步骤是向化合物VI中加入二(频哪醇基)二硼(VII),在氮气保护下75℃搅拌3小时,使用色谱柱纯化后得到(S)-2-叔丁氧基羰基氨基-3-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-苯基]-丙酸甲基酯(VIII),然后加入4-溴-2,3-二甲基-吡啶(IX),在氮气保护下,于80℃搅拌18小时,使用色谱柱纯化后 得到(S)-2-叔丁氧基羰基氨基-3-[4-(2,3-二甲基-吡啶-4-基)-苯基]-丙酸甲基酯(X),最后脱保护得到(S)-2-氨基-3-[4-(2,3-二甲基吡啶-4-基)苯基]丙酸甲基酯二盐酸盐(IV)。
在上述反应中,需要多次用到色谱柱分离纯化,总收率仅49%,且原料化合物VI和化合物IX较为昂贵,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,不适合工业化生产。
因此,有必要优化化合物A的关键中间体(S)-2-氨基-3-[4-(2,3-二甲基吡啶-4-基)苯基]丙酸甲基酯二酸盐的制备方法,同时寻找可替换的盐型,提高收率,降低成本,以适用于工业化生产。
发明内容
本发明提供了一种化合物A的关键中间体(S)-2-氨基-3-[4-(2,3-二甲基吡啶-4-基)苯基]丙酸甲基酯二酸盐的制备方法,该方法与现有技术相比,无需经过色谱柱分离纯化,具有成本低、收率高的优点,更适合于工业化生产。
本发明的制备方法如下:
步骤(a):化合物I与二(频哪醇基)二硼反应制备化合物II;
步骤(b):化合物II与4-溴-L-苯丙氨酸反应制备化合物III;
步骤(c):化合物III经酯化反应制备化合物IV。
任选地,进一步进行步骤(d):化合物IV经游离后,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。
作为一种具体的实施方案,所述步骤(a)在惰性气体保护下进行。
作为一种具体的实施方案,所述步骤(a)中,化合物I和有机酸盐先加入溶剂中,保持混合物温度在-10~10℃;所述有机酸盐选自醋酸钾,醋酸钠,草酸钾,草酸钠,柠檬酸钠,柠檬酸钾,L-酒石酸钾,L-酒石酸钠,苹果酸钾,苹果酸钠,琥珀酸钾,琥珀酸钠,马来酸钾,马来酸钠的一种或两种以上,优选醋酸钾;所述溶剂选自二甲苯,甲苯或氯苯中的一种或两种以上。
作为一种具体的实施方案,所述步骤(a)中,所述的二(频哪醇基)二硼分两次加入,第一次加入时反应温度为-10~10℃,第二次加入时反应温度为20~30℃。
作为一种具体的实施方案,所述步骤(a)中,二(频哪醇基)二硼第二次反应完全后,加入催化剂a;所述催化剂a单独选自钯催化剂,或钯催化剂与有机膦配体混合 体系,其中所述钯催化剂选自Pd
2(dba)
3,PdCl
2(PPh
3)
2,Pd(OAc)
2,所述有机磷配体选自PCy
3,PPh
3,n-Bu
3P,P(OMe)
3中的一种或两种以上,优选Pd
2(dba)
3和PCy
3混合使用。
作为一种具体的实施方案,所述步骤(a)中,加入催化剂后的反应温度为100~135℃,优选110~120℃。
作为一种具体的实施方案,所述步骤(a)中,所述化合物I,有机酸盐和二(频哪醇基)二硼的投料摩尔比为1:2:2~1:4:3,所述催化剂用量为化合物I的0.1~1%倍摩尔量。
作为一种具体的实施方案,所述步骤(a)反应后处理方法为:加入庚烷稀释并搅拌,过滤不溶物,滤液用稀盐酸萃取,得到的水层用二氯甲烷或乙酸乙酯洗涤,除去有机层,并浓缩水层至化合物I的2~5倍体积,得到化合物II。
作为一种具体的实施方案,所述步骤(a)中,后处理过程中所述稀盐酸浓度为1~2mol/L。
作为一种具体的实施方案,所述步骤(b)在惰性气体保护下进行。
作为一种具体的实施方案,所述步骤(b)中,向化合物II浓缩液中加入水和有机溶剂,并加入碱性试剂a调节pH至7左右;所述有机溶剂选自乙醇,正丙醇,正丁醇,四氢呋喃,1,4-二氧六环,甲苯,二甲苯中的一种或两种以上,优选乙醇;所述碱性试剂a选自碳酸钠,碳酸钾,碳酸铯,碳酸锂中的一种或两种以上,优选碳酸钠;所述4-溴-L-苯丙氨酸与化合物II的投料比为1:1.5~1:2.5,优选1:2。
作为一种具体的实施方案,所述步骤(b)中,在调节pH后,再依次加入碱性试剂b和4-溴-L-苯丙氨酸,调整反应温度为30~40℃;所述碱性试剂选自碳酸钠,碳酸钾,碳酸铯,碳酸锂,氢氧化钡,磷酸钾中的一种或两种以上,优选碳酸钠。
作为一种具体的实施方案,所述步骤(b)中加入催化剂b,所述催化剂b单独选自钯催化剂,或钯催化剂与有机膦配体的混合体系,其中所述钯催化剂选自Pd(OAc)
2,Pd
2(dba)
3,PdCl
2(PPh
3)
2,PdCl
2dppf,Pd(PPh
3)
4,所述有机膦配体选自Ph
2P(CH
2)
2PPh
2(dppe),Ph
2P(CH
2)
3PPh
2(dppp),PCy
3,n-Bu
3P,P(OMe)
3,PPh
3中的一种或两种以上,优选Pd
2(dba)
3和PCy
3混合使用,所述催化剂用量为4-溴-L-苯丙氨酸的1~5%倍摩尔量;反应温度为60~90℃,优选75~85℃。
作为一种具体的实施方案,所述步骤(b)反应后处理方法为:减压浓缩,蒸除4-溴-L-苯丙氨酸4倍体积的溶剂,再加入纯化水至原体积,并用乙酸乙酯或二氯甲烷萃取,分除有机相;水相滴加酸调节pH至1~2,过滤;滤液用乙酸乙酯或二氯甲烷萃取,分除有机相,水相加入氢氧化钠水溶液调节pH至5~8,搅拌析晶,得到化合物III;调节pH所用酸为盐酸,硫酸,磷酸中的一种,优选盐酸。
作为一种具体的实施方案,所述步骤(c)中,甲醇同时作为溶剂和反应试剂,并任选地加入草酰氯或二氯亚砜,反应温度控制在40~70℃,优选55~65℃。
作为一种具体的实施方案,所述步骤(c)反应结束后浓缩除去溶剂,得到化合物IV。
作为一种具体的实施方案,所述步骤(d)中,对于步骤(c)的产物加入碱性水溶液调节pH,再使用溶剂萃取1~3次,分除水相,有机相浓缩得化合物IV的游离碱;所 述萃取溶剂选自乙酸乙酯,二氯甲烷,乙酸异丙酯,乙酸丁酯或2-甲基四氢呋喃中的一种。
作为一种具体的实施方案,所述步骤(d)中,将化合物IV的游离碱溶液与溶剂混合均匀,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。
作为一种具体的实施方案,所述步骤(d)中,所述溶剂选自二氯甲烷,丙酮,异丙醇,乙腈,四氢呋喃中的一种或两种以上,所述有机酸或无机酸选自草酸,L-酒石酸,苹果酸,琥珀酸,马来酸,柠檬酸,磷酸,硫酸,氢溴酸中的一种;优选草酸或磷酸;所述有机酸或无机酸溶解于丙酮,甲醇或乙醇中。
作为一种具体的实施方案,经由所述步骤(a)至(c),或经由所述步骤(a)至(d)制备得到的(S)-2-氨基-3-[4-(2,3-二甲基吡啶-4-基)苯基]丙酸甲基酯二酸盐是化合物A制备过程中的关键中间体。
术语“二酸盐”是指游离碱与酸以1:2的摩尔比成盐,所述的酸包括有机酸和无机酸。
本发明所述的(S)-2-氨基-3-[4-(2,3-二甲基吡啶-4-基)苯基]丙酸甲基酯二酸盐的制备方法,相对于现有技术来说,该工艺路线的原料成本低、收率高,无需经过色谱柱纯化,更适合于工业化生产。而且,由(S)-2-氨基-3-[4-(2,3-二甲基吡啶-4-基)苯基]丙酸甲基酯二盐酸盐进一步制备得到的(S)-2-氨基-3-[4-(2,3-二甲基吡啶-4-基)苯基]丙酸甲基酯二酸盐具有更好的储存稳定性。
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
2.质谱仪
仪器型号:Agilent 6460,测试条件:ESI源
实施例1-4反应投料量如表1所示。
表1 实施例1-4反应投料量表
实施例1
(a)惰性气体保护下,向化合物I中依次加入二甲苯和醋酸钾。将上述混合物降温至0℃左右,之后加入二(频哪醇基)二硼。该混合物在0℃左右搅拌1小时,然后维持反应液温度在0℃左右,加入二(频哪醇基)二硼。上述混合物保持温度于15℃左右搅拌1小时。得到的反应液继续在20℃左右搅拌至原料反应完全,再加入Pd
2(dba)
3和PCy
3,升温至110~120℃之间,反应8h,反应结束后,降温,加入庚烷稀释,搅拌0.5小时。将反应液中的不溶物过滤,滤液用稀HCl萃取。水层用二氯甲烷洗涤,除去有机层。溶液浓缩至化合物I的2.5倍体积,得到化合物II(收率99%)。
(b)在惰性气体保护下,将水和乙醇加入到化合物II溶液中,然后向反应液中加入碳酸钠,调节溶液pH到7左右。之后,依次将碳酸钠和4-溴-L-苯丙氨酸加入至上述反应液中。将该反应液升温至30~40℃范围内,在氮气氛围下加入Pd
2(dba)
3和PCy
3,升温至80℃左右反应12小时,反应结束后,减压浓缩,蒸除4-溴-L-苯丙氨酸4倍量的溶剂体积,再加入纯化水至原体积。加入二氯甲烷萃取3次,再分除有机相,水相滴加浓盐酸调节pH至1~2,过滤。滤液再用二氯甲烷萃取一次,分除有机相,水相加入 氢氧化钠水溶液调节pH至7左右,搅拌析晶,得到化合物III(收率84%)。
(c)将化合物III加入甲醇中,冷却至0℃。将草酰氯滴加入上述冷却的混合物中,之后将反应液升温至60℃左右反应1.5小时,反应结束后浓缩除去溶剂,得化合物IV。
(d)向化合物IV加入纯化水搅拌至完全溶解,控温20℃以下,滴加碳酸钠水溶液调节pH至8左右,再加入二氯甲烷萃取3次,分除水相,有机相降温至5℃以下,滴加草酸的丙酮溶液,搅拌析晶,得化合物V(收率80%)。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C
17H
20N
2O
2·2C
2H
2O
4。HRMS(ESI)C
17H
20N
2O
2(以游离碱计)的计算值:285.1598[M+H],实测值:285.1604。
实施例2
(a)在惰性气体保护下,向化合物I中依次加入甲苯和醋酸钾。将上述混合物降温至-5℃左右,之后加入二(频哪醇基)二硼。该混合物在0℃左右搅拌0.5小时,然后维持反应液温度在0℃左右,加入二(频哪醇基)二硼。上述混合物保持温度于10℃左右搅拌1.5小时。得到的反应液继续在25℃搅拌10小时至原料反应完全,再加入Pd
2(dba)
3和PCy
3,升温至110~120℃之间,反应8h,反应结束后,降温,加入正庚烷稀释,搅拌1小时。将反应液中的不溶物过滤,滤液用稀HCl萃取。水层用乙酸乙酯洗涤,除去有机层。溶液浓缩至化合物I的3倍体积,得到化合物II(收率98%)。
(b)在惰性气体保护下,将水和正丙醇加入到化合物II溶液中,然后向反应液中加入碳酸钠,调节溶液pH至7左右。之后,依次将碳酸钠和4-溴-L-苯丙氨酸加入至上述反应液中。将该反应液升温至30~40℃范围内,在氮气氛围下加入PdCl
2(PPh
3)
2和PCy
3,升温至80℃左右反应14小时,反应结束后,减压浓缩,蒸除4-溴-L-苯丙氨酸4倍体积的溶剂,再加入纯化水至原体积。加入乙酸乙酯萃取3次,再分除有机相,水相滴加浓盐酸调节pH至1.5左右,过滤。滤液再用乙酸乙酯萃取一次,分除有机相,水相加入25%的氢氧化钠水溶液调节pH至8,搅拌析晶,得到化合物III(收率85%)。
(c)将化合物III加入甲醇中,冷却至0℃。将二氯亚砜滴加入上述冷却的混合物中,之后将反应液升温至60℃左右反应3小时,反应结束后浓缩除去溶剂,得化合物IV。
(d)向化合物IV加入纯化水搅拌至完全溶解,控温20℃以下,滴加碳酸钠水溶液调节pH至9左右,再加入乙酸乙酯萃取3次,分除水相,有机相降温至5℃以下,滴加草酸的甲醇溶液,搅拌析晶,得化合物V(收率81%)。所得化合物的表征数据同实施例1。
实施例3
(a)在惰性气体保护下,向化合物I中依次加入氯苯和醋酸钾。将上述混合物降温至0℃左右,之后加入二(频哪醇基)二硼。该混合物在0℃左右搅拌1小时,然 后维持反应液温度在0℃左右,加入二(频哪醇基)二硼。上述混合物保持温度于10℃左右搅拌1.5小时。得到的反应液继续在30℃搅拌10小时至原料反应完全,再加入Pd
2(dba)
3和PCy
3,升温至110~120℃之间,反应8h,反应结束后,降温至70℃,用正庚烷稀释,搅拌1小时。将反应液中的不溶物过滤,滤液用稀HCl萃取。水层用二氯甲烷洗涤,除去有机层。溶液浓缩至化合物I的5倍体积,得到化合物II(收率95%)。
(b)在惰性气体保护下,将水和四氢呋喃加入到化合物II溶液中,然后向反应液中加入碳酸钠,调节溶液pH到7左右。之后,依次将碳酸钠和4-溴-L-苯丙氨酸加入至上述反应液中。将该反应液升温至30~40℃范围内,在氮气氛围下加入PdCl
2(PPh
3)
2,升温至80℃左右反应11小时,反应结束后,减压浓缩,蒸除4-溴-L-苯丙氨酸4倍体积的溶剂,再加入纯化水至原体积。加入乙酸乙酯萃取3次,再分除有机相,水相滴加浓盐酸调节pH至1.5左右,过滤。滤液再用乙酸乙酯萃取一次,分除有机相,水相加入氢氧化钠水溶液调节pH至7.5,搅拌析晶,得到化合物III(收率86%)。
(c)将化合物III加入甲醇中,冷却至0℃。将二氯亚砜滴加入上述冷却的混合物中,之后将反应液升温至60℃左右反应1.5小时,反应结束后浓缩除去溶剂,得化合物IV。
(d)向化合物IV加入纯化水搅拌至完全溶解,控温20℃以下,滴加20%碳酸钠水溶液调节pH至8.5,再加入二氯甲烷萃取3次,分除水相,有机相浓缩至干,加入丙酮搅拌降温至5℃以下,滴加磷酸的丙酮溶液,搅拌析晶,得化合物V(收率82%)。
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)C
17H
20N
2O
2(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C
17H
20N
2O
2·2H
3PO
4。
实施例4
(a)在惰性气体保护下,向化合物I中依次加入二甲苯和醋酸钾。将上述混合物降温至0℃,之后加入二(频哪醇基)二硼。该混合物在0℃左右搅拌1小时,然后维持反应液温度在0℃左右,加入二(频哪醇基)二硼。上述混合物保持温度于15℃左右搅拌1小时。得到的反应液继续在25℃左右搅拌至原料反应完全,再加入Pd
2(dba)
3和PCy
3,升温至110~120℃之间反应,反应结束后,降温至70℃,用正庚烷稀释,搅拌1小时。将反应液中的不溶物过滤,用正庚烷洗涤。滤液用稀HCl萃取。水层用二氯甲烷洗涤,除去有机层。溶液浓缩至化合物I的3倍体积,得到化合物II(收率100%)。
(b)在惰性气体保护下,将水和正丙醇加入到化合物II溶液中,然后向反应液中加入碳酸钠,调节溶液pH到7左右。之后,依次将碳酸钠和4-溴-L-苯丙氨酸加入至上述反应液中。将该反应液升温至30~40℃范围内,在氮气氛围下加入PdCl
2(PPh
3)
2,升温至80℃左右反应,反应结束后,减压浓缩,蒸除4-溴-L-苯丙氨酸4倍体积的溶剂,再加入纯化水至原体积。加入二氯甲烷萃取3次,再分除有机相,水相滴加浓盐酸调节pH至1~2,过滤。滤液再用二氯甲烷萃取一次,分除有机相,水相加入氢氧化钠水溶 液调节pH至6左右,搅拌析晶,得到化合物III(收率85%)。
(c)将化合物III加入甲醇中,冷却至0℃。将二氯亚砜滴加入上述冷却的混合物中,之后将反应液升温至60℃左右反应3小时,反应结束后浓缩除去溶剂,得化合物IV。
(d)向化合物IV加入纯化水搅拌至完全溶解,控温20℃以下,滴加碳酸钠水溶液调节pH至8左右,再加入二氯甲烷萃取3次,分除水相,有机相降温至5℃以下,滴加草酸的甲醇溶液,搅拌析晶,得化合物V(收率81%)。所得化合物的表征数据同实施例1。
实施例5:化合物V盐型的对比
将制备得到的盐型(草酸盐,磷酸盐)与盐酸盐进行性质对比,进行40℃/75%的湿度条件下的稳定性考察实验,通过测试化学纯度(HPLC)及观察产品形状来进行化学稳定性评估,详细实验结果如表2所示。结果显示,通过改变盐型种类,可改善固体的引湿性,从而避免产品因为储存中吸水变质。
表2 化合物V盐型稳定性数据
Claims (9)
- 根据权利要求1所述的方法,其特征在于,所述步骤(a)中加入催化剂a,所述催化剂a单独选自钯催化剂,或钯催化剂与有机膦配体混合体系,其中所述钯催化剂选自Pd 2(dba) 3,PdCl 2(PPh 3) 2,Pd(OAc) 2,所述有机磷配体选自PCy 3,PPh 3,n-Bu 3P,P(OMe) 3中的一种或两种以上;和/或所述步骤(b)中加入催化剂b,所述催化剂b单独选自钯催化剂,或钯催化剂与有机膦配体的混合体系,其中所述钯催化剂选自Pd(OAc) 2,Pd 2(dba) 3,PdCl 2(PPh 3) 2,PdCl 2dppf,Pd(PPh 3) 4,所述有机膦配体选自Ph 2P(CH 2) 2PPh 2(dppe),Ph 2P(CH 2) 3PPh 2(dppp),PCy 3,n-Bu 3P,P(OMe) 3,PPh 3中的一种或两种以上;和/或所述步骤(a)和(b)中合计使用的催化剂总量占总反应体系的0.1~5%倍摩尔量,其中步骤(a)催化剂用量为化合物I的0.1~1%倍摩尔量,步骤(b)催化剂用量为4-溴-L-苯基丙氨酸的1~5%倍摩尔量。
- 根据权利要求1所述的方法,其特征在于,所述步骤(a)中加入有机酸盐,所述的有机酸盐选自醋酸钾,醋酸钠,草酸钾,草酸钠,柠檬酸钠,柠檬酸钾,L-酒石酸钾,L-酒石酸钠,苹果酸钾,苹果酸钠,琥珀酸钾,琥珀酸钠,马来酸钾,马来酸钠中的一种或两种以上;和/或所述步骤(b)中在调节pH后,加入碱性试剂b,所述的碱性试剂b选自碳酸钠,碳酸钾,碳酸铯,碳酸锂,氢氧化钡,磷酸钾中的一种或两种以上;和/或所述步骤(b)中使用的溶剂选自乙醇,正丙醇,正丁醇,四氢呋喃,1,4-二氧六环,甲苯,二甲苯中的一种或两种以上。
- 根据权利要求3所述的方法,其特征在于,所述步骤(a)中,化合物I,有机酸盐和二(频哪醇基)二硼的投料摩尔比为1:2:2~1:4:3;和/或步骤(b)中,4-溴-L-苯丙氨酸与化合物II的投料摩尔比为1:1.5~1:2.5,优选1:2。
- 根据权利要求1所述的方法,其特征在于,所述步骤(c)中,甲醇同时作为溶剂和反应试剂;和/或加入草酰氯或二氯亚砜;和/或反应温度控制在40~70℃,优选55~65℃。
- 根据权利要求1所述的方法,其特征在于,对于步骤(c)的产物加入碱性水溶液调节pH,再使用溶剂萃取,分除水相,有机相浓缩得化合物IV的游离碱;和/或所述萃取溶剂选自乙酸乙酯,二氯甲烷,乙酸异丙酯,乙酸丁酯或2-甲基四氢呋喃中的一种。
- 根据权利要求1所述的方法,其特征在于,所述步骤(d)中,将化合物IV的游离碱溶液与溶剂混合均匀,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。
- 根据权利要求7所述的方法,其特征在于,所述步骤(d)中,所述溶剂选自二氯甲烷,丙酮,异丙醇,乙腈,四氢呋喃中的一种或两种以上;和/或所述有机酸或无机酸选自草酸,L-酒石酸,苹果酸,琥珀酸,马来酸,柠檬酸,磷酸,硫酸,氢溴酸中的一种,优选草酸或磷酸;和/或所述有机酸或无机酸溶解于丙酮,甲醇或乙醇中。
- 根据权利要求1-8中任一项所述的方法制备的(S)-2-氨基-3-[4-(2,3-二甲基吡啶-4-基)苯基]丙酸甲基酯二酸盐在制备(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)丙酸二盐酸盐中的应用。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/000,102 US20230348483A1 (en) | 2020-05-28 | 2021-05-26 | Preparation method for (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)methyl propionate diacid salt |
EP21812542.5A EP4159719A4 (en) | 2020-05-28 | 2021-05-26 | METHOD FOR PREPARING METHYL PROPANOATE DIACID SALT (S)-2-AMINO-3-(4-(2,3-DIMETHYLPYRIDINE-4-YL)PHENYL) |
CN202180038387.8A CN115667219A (zh) | 2020-05-28 | 2021-05-26 | 一种(s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸甲酯二酸盐的制备方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010481657.X | 2020-05-28 | ||
CN202010481657 | 2020-05-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021238963A1 true WO2021238963A1 (zh) | 2021-12-02 |
Family
ID=78745588
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/095965 WO2021238963A1 (zh) | 2020-05-28 | 2021-05-26 | 一种(s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸甲酯二酸盐的制备方法 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20230348483A1 (zh) |
EP (1) | EP4159719A4 (zh) |
CN (1) | CN115667219A (zh) |
TW (1) | TW202210461A (zh) |
WO (1) | WO2021238963A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115057845A (zh) * | 2022-06-14 | 2022-09-16 | 山东罗欣药业集团恒欣药业有限公司 | 一种阿贝西利的制备方法 |
WO2022262143A1 (zh) * | 2021-06-17 | 2022-12-22 | 杭州中美华东制药有限公司 | 一种吡啶硼酸酯的制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102378574A (zh) | 2009-03-30 | 2012-03-14 | 转化技术制药公司 | 取代的偶氮蒽衍生物、药物组合物及其使用方法 |
TW201925204A (zh) * | 2017-11-22 | 2019-07-01 | 日商第一三共股份有限公司 | 稠合三環化合物 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2716664C (en) * | 2008-03-07 | 2016-10-11 | Transtech Pharma, Inc. | Oxadiazoanthracene compounds |
EA028942B1 (ru) * | 2014-04-02 | 2018-01-31 | Бристол-Майерс Сквибб Компани | Биарильные ингибиторы киназы |
CN105884752B (zh) * | 2015-02-13 | 2018-08-31 | 山东轩竹医药科技有限公司 | 并环类回旋酶和拓扑异构酶iv抑制剂 |
-
2021
- 2021-05-26 US US18/000,102 patent/US20230348483A1/en active Pending
- 2021-05-26 WO PCT/CN2021/095965 patent/WO2021238963A1/zh unknown
- 2021-05-26 EP EP21812542.5A patent/EP4159719A4/en active Pending
- 2021-05-26 TW TW110119038A patent/TW202210461A/zh unknown
- 2021-05-26 CN CN202180038387.8A patent/CN115667219A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102378574A (zh) | 2009-03-30 | 2012-03-14 | 转化技术制药公司 | 取代的偶氮蒽衍生物、药物组合物及其使用方法 |
TW201925204A (zh) * | 2017-11-22 | 2019-07-01 | 日商第一三共股份有限公司 | 稠合三環化合物 |
Non-Patent Citations (1)
Title |
---|
See also references of EP4159719A4 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022262143A1 (zh) * | 2021-06-17 | 2022-12-22 | 杭州中美华东制药有限公司 | 一种吡啶硼酸酯的制备方法 |
CN115057845A (zh) * | 2022-06-14 | 2022-09-16 | 山东罗欣药业集团恒欣药业有限公司 | 一种阿贝西利的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
EP4159719A4 (en) | 2024-07-17 |
US20230348483A1 (en) | 2023-11-02 |
EP4159719A1 (en) | 2023-04-05 |
TW202210461A (zh) | 2022-03-16 |
CN115667219A (zh) | 2023-01-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6087284B2 (ja) | L−オルニチンフェニルアセテートを製造するための方法 | |
JP6447508B2 (ja) | 3−(イミダゾ[1,2−b]ピリダジン−3−イルエチニル)−4−メチル−N−{4−[(4−メチルピペラジン−1−イル)メチル]−3−(トリフルオロメチル)フェニル}ベンズアミドおよびその一塩酸塩の結晶形 | |
EP3610875B1 (en) | Opioid receptor (mor) agonist salt, fumarate salt i crystal form thereof and preparation method thereof | |
EP2791141B1 (en) | Tofacitinib mono-tartrate salt | |
WO2021238963A1 (zh) | 一种(s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸甲酯二酸盐的制备方法 | |
US20150166511A1 (en) | Crystalline form i of tyrosine kinase inhibitor dimaleate and preparation methods thereof | |
US8501960B2 (en) | Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof | |
US11465999B2 (en) | Process for preparing Alectinib or a pharmaceutically acceptable salt thereof | |
TW201321342A (zh) | 用於製備喹啉衍生物之方法 | |
EP3785713A1 (en) | Salt of cetagliptin, preparation method therefor, pharmaceutical composition, and use thereof | |
WO2016150283A1 (zh) | 2-异丙氧基-5-甲基-4-(4-哌啶基)苯胺二盐酸盐的水合物、其制备方法及用途 | |
KR20130132631A (ko) | Dpp-ⅳ 저해제의 신규한 염 | |
CN115697968B (zh) | (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 | |
JP2022500494A (ja) | 3−[(1S)−1−イミダゾ[1,2−a]ピリジン−6−イルエチル]−5−(1−メチルピラゾール−4−イル)トリアゾロ[4,5−b]ピラジン及びその多形相の改良製造法 | |
KR101557832B1 (ko) | (r)-3-플루오로페닐-3,4,5-트리플루오로벤질카르밤산 1-아자비시클로 [2.2.2]옥트-3-일 에스테르의 안정한 결정성 염 | |
WO2023001299A1 (zh) | 式i化合物的晶型及其制备和应用 | |
CN109956922B (zh) | 屈昔多巴关键中间体的拆分方法 | |
JP4109446B2 (ja) | ジアステレオ異性体として純粋なトランス−2−[(α−メチルベンジル)アミノ]シクロペンタノールの製造方法 | |
CN113382633A (zh) | (4-(2-氟-4-(1-甲基-1H-苯并[d]咪唑-5-基)苯甲酰基)哌嗪-1-基)(1-羟基环丙基)甲酮的固体形式 | |
CN118184660A (zh) | 一种苯并二氮杂䓬化合物的盐、盐的晶型、制备方法及用途 | |
CN115991678A (zh) | 一种二酮基哌嗪类化合物、制备方法及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21812542 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2021812542 Country of ref document: EP Effective date: 20230102 |