WO2023116707A1 - 噻吩衍生物的制备 - Google Patents
噻吩衍生物的制备 Download PDFInfo
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- WO2023116707A1 WO2023116707A1 PCT/CN2022/140411 CN2022140411W WO2023116707A1 WO 2023116707 A1 WO2023116707 A1 WO 2023116707A1 CN 2022140411 W CN2022140411 W CN 2022140411W WO 2023116707 A1 WO2023116707 A1 WO 2023116707A1
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- compound represented
- condensation reaction
- present disclosure
- compound shown
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- 238000002360 preparation method Methods 0.000 title claims description 66
- 150000003577 thiophenes Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 436
- 238000006482 condensation reaction Methods 0.000 claims abstract description 143
- 238000000034 method Methods 0.000 claims abstract description 126
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 190
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 147
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 99
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 94
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 87
- 239000000203 mixture Substances 0.000 claims description 85
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 78
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 58
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 56
- 239000002904 solvent Substances 0.000 claims description 55
- -1 urea cation Chemical class 0.000 claims description 55
- 238000006460 hydrolysis reaction Methods 0.000 claims description 53
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 48
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 48
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 47
- 239000012346 acetyl chloride Substances 0.000 claims description 47
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 239000003795 chemical substances by application Substances 0.000 claims description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 41
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 39
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 32
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 31
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 29
- 239000003153 chemical reaction reagent Substances 0.000 claims description 29
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 26
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 13
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 13
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 claims description 10
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 claims description 10
- 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 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- 239000004202 carbamide Substances 0.000 claims description 9
- TZCYLJGNWDVJRA-UHFFFAOYSA-N 6-chloro-1-hydroxybenzotriazole Chemical compound C1=C(Cl)C=C2N(O)N=NC2=C1 TZCYLJGNWDVJRA-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 6
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-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
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 5
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 claims description 5
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 claims description 5
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 5
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 5
- 229910003002 lithium salt Inorganic materials 0.000 claims description 5
- 159000000002 lithium salts Chemical class 0.000 claims description 5
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- 159000000000 sodium salts Chemical class 0.000 claims description 5
- 150000001718 carbodiimides Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims 2
- 239000012964 benzotriazole Substances 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 20
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 150000007942 carboxylates Chemical class 0.000 description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
- 244000025254 Cannabis sativa Species 0.000 description 4
- 125000005110 aryl thio group Chemical group 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 159000000001 potassium salts Chemical class 0.000 description 4
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 description 4
- 125000005152 trihalomethanesulfonyl group Chemical group 0.000 description 4
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- DDFGTVSLZJLQEV-UHFFFAOYSA-N [C](C1CCCCC1)C1CCCCC1 Chemical compound [C](C1CCCCC1)C1CCCCC1 DDFGTVSLZJLQEV-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 125000002355 alkine group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 3
- 229910000071 diazene Inorganic materials 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- YNVOMSDITJMNET-UHFFFAOYSA-M thiophene-3-carboxylate Chemical compound [O-]C(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-M 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 125000005631 S-sulfonamido group Chemical group 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
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- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
Definitions
- the present disclosure relates generally to the field of medicinal chemistry, and more specifically the present disclosure relates to the preparation of thiophene derivatives.
- Phosphodiesterase refers to enzymes that catalyze the hydrolysis of oligonucleotides, that is, double-formulated phosphate molecules in polynucleotides, which have the ability to hydrolyze intracellular second messengers (cAMP, cyclic adenosine monophosphate or cGMP, phosphate The function of guanosine) degrades intracellular cAMP or cGMP, thereby terminating the biochemical effects transmitted by these second messengers.
- cAMP cyclic adenosine monophosphate
- cGMP cyclic adenosine monophosphate
- phosphate phosphate The function of guanosine
- the disclosure relates to a method for preparing a compound represented by formula (VII),
- the method comprises carrying out condensation reaction with the compound shown in formula (VI) or formula (VIII)
- the present disclosure relates to a method for preparing a compound represented by formula (VI),
- the method includes subjecting the compound represented by formula (V) to a hydrolysis reaction.
- the present disclosure relates to a method for preparing a compound represented by formula (V),
- the method includes subjecting the compound represented by formula (IV) to condensation reaction.
- the present disclosure relates to a method for preparing a compound represented by formula (IV),
- the method comprises performing condensation reaction on the compound represented by formula (III) and the compound represented by formula (II) to obtain the compound represented by formula (IV).
- the present disclosure relates to a method for preparing a compound represented by formula (III),
- the method comprises reacting a compound of general formula (I),
- R 1 ⁇ R 2 , R 1 and R 2 are selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl.
- the present disclosure relates to a method for preparing a compound represented by formula (VII), comprising
- the compound represented by the formula (IV) is subjected to condensation reaction to obtain the compound represented by the formula (V);
- the compound represented by the formula (VI) or formula (VIII) is subjected to condensation reaction to obtain the compound represented by the formula (VII).
- the disclosure relates to a method for preparing a compound represented by formula (VII),
- the method comprises carrying out condensation reaction of the compound shown in formula (VIII)
- the present disclosure relates to a method for preparing a compound represented by formula (VIII),
- the method comprises carrying out the hydrolysis reaction of the compound shown in formula (IX)
- the present disclosure relates to a method for preparing a compound represented by formula (IX),
- the method comprises carrying out condensation reaction of the compound shown in formula (X)
- the present disclosure relates to a method for preparing a compound represented by formula (X),
- the method comprises carrying out condensation reaction of the compound shown in formula (XI) and the compound shown in formula (II) to obtain the compound shown in the formula (X),
- the present disclosure relates to a method for preparing a compound represented by formula (XI),
- the method comprises reacting a compound of general formula (I),
- R 1 ⁇ R 2 , R 1 and R 2 are selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl.
- the present disclosure relates to a method for preparing a compound represented by formula (VII), comprising
- the compound represented by the formula (X) is subjected to condensation reaction to obtain the compound represented by the formula (IX);
- the compound represented by the formula (VIII) is subjected to condensation reaction to obtain the compound represented by the formula (VII).
- the present disclosure relates to a method for preparing a compound represented by formula (VII'),
- Said method comprises carrying out condensation reaction with the compound shown in formula (VI '),
- the present disclosure relates to a method for preparing a compound represented by formula (VI'),
- the method comprises carrying out a hydrolysis reaction of the compound shown in formula (V'),
- the present disclosure relates to a method for preparing a compound represented by formula (V'),
- the method comprises carrying out a condensation reaction of the compound shown in formula (IV'),
- the present disclosure relates to a method for preparing a compound represented by formula (IV'),
- the method comprises carrying out a condensation reaction between the compound shown in formula (III) and the compound shown in formula (II') to obtain the compound shown in the formula (IV'),
- the present disclosure relates to a method for preparing a compound represented by formula (VII'), comprising
- the compound represented by the formula (VI') is subjected to condensation reaction to obtain the compound represented by the formula (VII').
- the present disclosure relates to a method for preparing a compound represented by formula (VII"),
- Said method comprises carrying out condensation reaction with the compound shown in formula (VI ").
- the present disclosure relates to a method for preparing a compound represented by formula (VI"),
- the method comprises carrying out a hydrolysis reaction of the compound shown in formula (V"),
- the present disclosure relates to a method for preparing a compound represented by formula (V"),
- the method comprises carrying out a condensation reaction of the compound shown in formula (IV"),
- the present disclosure relates to a method for preparing a compound represented by formula (IV"),
- the method comprises carrying out a condensation reaction between the compound shown in formula (III) and the compound shown in formula (II") to obtain the compound shown in formula (IV"),
- the present disclosure relates to a method for preparing a compound represented by formula (VII), which comprises
- the compound represented by the formula (VI) is subjected to condensation reaction to obtain the compound represented by the formula (VII").
- references throughout the specification to "an embodiment,” “an embodiment,” “in another embodiment,” or “in certain embodiments” mean that in at least one embodiment include relevant specific reference elements, structures or features. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” or “in another embodiment” or “in certain embodiments” in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, particular elements, structures or characteristics may be combined in any suitable manner in one or more embodiments.
- C 1 -C 4 alkyl describes an alkyl group as defined below having a total of 1 to 4 carbon atoms
- a C 3 -C 10 cycloalkyl describes an alkyl group as defined below having a total of 3 to 10 carbon atoms cycloalkyl.
- the total number of carbons in the shorthand notation does not include carbons that may be present in substituents of the stated group.
- hydrocarbyl refers to an aliphatic hydrocarbon group.
- the hydrocarbyl moiety may be a "saturated hydrocarbyl” group, meaning that it does not contain any alkene or alkyne moieties, ie, an alkyl group.
- the hydrocarbyl moiety may also be an "unsaturated hydrocarbyl” moiety, meaning that it contains at least one alkene or alkyne moiety.
- alkene also known as alkenyl
- alkenyl means a group consisting of two to eight carbon atoms and at least one carbon-carbon double bond, and a straight or branched hydrocarbon chain connected by a single bond to the rest of the molecule Groups such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc.
- alkyne means from two to eight A group consisting of two carbon atoms and at least one carbon-carbon triple bond, and a straight or branched hydrocarbon chain group connected to the rest of the molecule by a single bond.
- Hydrocarbyl moieties, whether saturated or unsaturated, can be branched or straight chain.
- Hydrocarbyl groups may have from 1 to 8 carbon atoms (in this disclosure, each time a numerical range such as “1 to 8” refers to each integer in the given range; as “1 to 8” means all Said hydrocarbyl groups may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. up to and including 8 carbon atoms, although this definition also covers occurrences of the term "hydrocarbyl" where no numerical range is specified) .
- Hydrocarbyl groups may be optionally substituted, ie substituted or unsubstituted.
- the substituent is one or more groups individually and independently selected from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy, aryloxy, Mercapto, thiol, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxy, isocyanato (isocyanato), thiocyanate, isothiocyanato ( isothiocyanato), nitro, silyl, trihalomethanesulfonyl,
- Typical hydrocarbyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
- substituents described above Whenever a substituent is described as being “optionally substituted", the substituent may be substituted with one of the substituents described above.
- aryl refers to a carbocyclic ring (full carbon) or two or more fused rings (rings that share two adjacent carbon atoms) with a fully delocalized Pi electron system.
- Aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. An aryl group may, for example, have five to twelve carbon atoms. The aryl groups of the present disclosure can be substituted or unsubstituted.
- the hydrogen atom is replaced by one or more groups independently selected from the following substituents: hydrocarbyl, cyclohydrocarbyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, protected hydroxyl, hydrocarbyloxy Base, aryloxy, mercapto, alkylthio, arylthio, cyano, halogenated, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N- Thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, Thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarby
- heteroaryl refers to a 5- to 18-membered aromatic ring group consisting of one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen and sulfur.
- a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can be Optionally oxidized; nitrogen atoms may be optionally quaternized.
- heteroaryl examples include, but are not limited to, azepinenyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuryl , benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepyl, 1,4-benzodioxanyl, benzonaphthalene Furyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuryl, benzofuran Keto, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzo Thienyl, furyl, furanone, iso
- heteroaryl groups of the present disclosure can be substituted or unsubstituted.
- the hydrogen atom is replaced by one or more groups independently selected from the following substituents: hydrocarbyl, cyclohydrocarbyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, protected hydroxyl, hydrocarbyloxy Base, aryloxy, mercapto, alkylthio, arylthio, cyano, halogenated, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N- Thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, Thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulful
- cycloalkyl refers to a group consisting solely of carbon and hydrogen atoms, having three to fifteen carbon atoms, and in certain embodiments three to twelve carbon atoms, and which is A stable non-aromatic monocyclic or bicyclic hydrocarbon group, saturated or unsaturated, attached to the rest of the molecule by a single bond, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl, etc.
- cycloalkyl is intended to include cycloalkyl as defined above optionally substituted with one or more groups selected from the group consisting of: cycloalkyl, aryl, heteroaryl , heteroalicyclic, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogenated, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfinylamino, N-sulfinylamino, C-carboxy, O-carboxy, isocyan Acido, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (
- the term "substantially complete” reaction means that the reactants contain more than about 80% (% yield), more preferably more than about 90% (% yield), even more preferably more than about 95% (% yield) ) and most preferably over about 97% (% yield) of the desired product.
- the term "about” is used to make it clear that the numerical values given are approximate.
- the term “about” means that the referenced temperature includes deviations in the range of 30%, 25%, 20%, 15%, 10%, or 5%.
- the term “about” means that the referenced time includes a deviation within 30%, 25%, 20%, 15%, 10%, or 5%.
- Class 1 solvents refers to Class 1 solvents in ICH Q3C (R8), which is a class of solvents that should be avoided in pharmaceutical production.
- solvents are known human carcinogens and are strongly suspected to be Carcinogens, and environmental hazards, more specifically: benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, 1,1,1-trichloroethane.
- Class 2 solvents refers to Class 2 solvents in ICH Q3C (R8), which is a class of solvents whose use should be restricted in pharmaceutical production.
- solvents are non-genotoxic animal carcinogens, or may cause other Solvents with irreversible toxicity such as neurotoxicity or teratogenicity, and possibly other severe but reversible toxicity, more specifically: acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, cyclopentylmethyl ether, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-di Oxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N- Meth
- Class 3 solvents refers to Class 3 solvents in ICH Q3C (R8), which is a class of solvents with low potential toxicity in pharmaceutical production. Exposure, more specifically: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, Methyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, 2 - Methyltetrahydrofuran, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, triethylamine.
- the described structure should be favored. Additionally, if the stereochemistry of a structure or a portion of a structure is not marked with, for example, bold or dashed lines, the structure or the portion of the structure should be construed to include all stereoisomers of the structure.
- the disclosure relates to a method for preparing a compound represented by formula (VII),
- Said method comprises carrying out condensation reaction with the compound shown in formula (VI) or formula (VIII),
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII) include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexyl carbon Diimine (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC ⁇ HCl), thionyl chloride (SOCl 2 ), oxalyl chloride ((COCl) 2 ), acetyl chloride (AcCl), acetic anhydride (Ac 2 O), N,N-dimethylformamide (DMF) and any mixture thereof.
- CDI N,N'-carbonyldiimidazole
- DCC dicyclohexyl carbon Diimine
- EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
- EDC
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare the compound represented by formula (VII) include, but are not limited to, thionyl chloride (SOCl 2 )/N,N-dimethyl Combinations of formamide (DMF), oxalyl chloride ((COCl) 2 )/N,N-dimethylformamide (DMF) or acetyl chloride (AcCl)/N,N-dimethylformamide (DMF).
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII) include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexyl carbon Diimine (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC ⁇ HCl), thionyl chloride (SOCl 2 ), oxalyl chloride ((COCl) 2 ), acetyl chloride (AcCl), acetic anhydride (Ac 2 O), N,N-dimethylformamide (DMF), thionyl chloride (SOCl 2 )/N,N-dimethyl Combination of formamide (DMF), oxalyl chloride ((COCl) 2 )/N,N-dimethylformamide (DMF) or acetyl
- CDI
- illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII) include, but are not limited to, tetrahydrofuran, dichloromethane (DCM), acetic anhydride (Ac 2 O) and any mixture thereof.
- condensation reaction to produce the compound of formula (VII) is carried out at about -5 to about 150°C.
- condensation reaction to produce the compound of formula (VII) is carried out at about -10 to about 40°C.
- condensation reaction to produce the compound of formula (VII) is carried out at about 20 to about 30°C.
- the compound of formula (VII) is recrystallized.
- illustrative examples of solvents that can be used in the present disclosure to recrystallize the compound represented by formula (VII) include, but are not limited to, acetonitrile/isopropanol, ethyl acetate, acetonitrile/water, tetrahydrofuran/ Water and any mixture thereof.
- the present disclosure relates to a method for preparing a compound represented by formula (VI),
- the method comprises subjecting the compound represented by formula (V) to a hydrolysis reaction
- the hydrolysis reaction to prepare the compound represented by formula (VI) is carried out under basic conditions.
- illustrative examples of salts that can be used in the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI) include, but are not limited to, potassium salts, sodium salts, lithium salts, and any mixtures thereof.
- illustrative examples of salts that can be used in the hydrolysis reactions of the present disclosure to prepare compounds represented by formula (VI) include, but are not limited to, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, carbonic acid Sodium, lithium hydroxide, lithium carbonate and any mixture thereof.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI) is carried out at about -5 to about 35°C.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI) is carried out at about 0 to about 35°C.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI) is carried out at about 20 to about 30°C.
- illustrative examples of solvents that can be used for the compound represented by formula (VI) of the present disclosure include, but are not limited to, ethanol/water, methanol/water, isopropanol/water, acetonitrile/acetone/water, Acetonitrile/acetone, ethyl acetate, tetrahydrofuran, tetrahydrofuran/water, acetone/water and any mixture thereof.
- the compound shown in formula (V) that can be used in the preparation of the compound shown in formula (VI) of the present disclosure and the salt that can be used in the hydrolysis reaction of the compound shown in the preparation formula (VI) of the present disclosure The molar ratio is from about 1:1 to about 1:10.
- the compound shown in formula (V) that can be used in the preparation of the compound shown in formula (VI) of the present disclosure and the salt that can be used in the hydrolysis reaction of the compound shown in the preparation formula (VI) of the present disclosure The molar ratio is about 1:1 to 1:6.
- the compound shown in formula (V) that can be used in the preparation of the compound shown in formula (VI) of the present disclosure and the salt that can be used in the hydrolysis reaction of the compound shown in the preparation formula (VI) of the present disclosure The molar ratio is about 1:5.
- the present disclosure relates to a method for preparing a compound represented by formula (V),
- the method comprises carrying out condensation reaction of the compound shown in formula (IV),
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (V) include, but are not limited to, acetyl chloride (AcCl), acetic anhydride (Ac 2 O) and any mixture.
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (V) include, but are not limited to, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), triethylamine (TEA), pyridine (Py), N,N-diisopropylethylamine (DIEA), pyridine (Py) and any mixture thereof.
- DMAP 4-dimethylaminopyridine
- NMM N-methylmorpholine
- TAA triethylamine
- Py N,N-diisopropylethylamine
- DIEA N,N-diisopropylethylamine
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare the compound represented by formula (V) include, but are not limited to, Ac 2 O, Ac 2 O/DMAP, Ac 2 O/DMAP/ NMM, CH 3 COCl/TEA/DCM/DMAP or CH 3 COCl/Py to prepare the compound represented by formula (V).
- illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (V) include, but are not limited to, acetic anhydride, dichloromethane (DCM), pyridine (Py), tetrahydrofuran , acetonitrile, acetone, ethyl acetate and any mixture thereof.
- condensation reaction of the present disclosure to prepare the compound represented by formula (V) is carried out at about 0 to about 150°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (V) is carried out at about 90 to about 150°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (V) is carried out at about 125 to about 140°C.
- solvents that can be used to purify compounds represented by formula (V) of the present disclosure include, but are not limited to, ethanol, methyl tert-butyl ether (MTBE), methanol, ethyl acetate, n-hexane alkanes, diethyl ether, tetrahydrofuran (THF) and any mixture thereof.
- MTBE methyl tert-butyl ether
- methanol ethyl acetate
- n-hexane alkanes diethyl ether
- THF tetrahydrofuran
- the present disclosure relates to a method for preparing a compound represented by formula (IV),
- the method comprises carrying out condensation reaction of the compound shown in formula (II) and the compound shown in formula (III) to obtain the compound shown in the formula (IV),
- condensing agents that can be used in the preparation of compounds represented by formula (IV) in the present disclosure include, but are not limited to, carbodiimide condensing agents, phosphorus cation condensing agents, urea cations type condensing agents, other suitable condensing agents, and any mixture thereof.
- carbodiimide-type condensing agents that can be used in the present disclosure to prepare compounds represented by formula (IV) include, but are not limited to, 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide (EDC), EDCI (the hydrochloride salt of EDC) and dicyclohexylcarbodiimide (DCC).
- EDC 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide
- EDCI the hydrochloride salt of EDC
- DCC dicyclohexylcarbodiimide
- an illustrative example of a phosphorus cationic condensing agent that can be used in the preparation of the compound represented by formula (IV) of the present disclosure includes, but is not limited to, 1H-benzotriazol-1-yloxytripyrrolidine benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) ).
- urea cationic condensing agents that can be used in the preparation of compounds represented by formula (IV) in the present disclosure include, but are not limited to, N,N,N',N'-tetramethyl- O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU).
- HBTU N,N,N',N'-tetramethyl- O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate
- HATU 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea Hexafluorophosphate
- illustrative examples of other suitable condensing agents that can be used in the present disclosure to prepare compounds of formula (IV) include, but are not limited to, 1-hydroxybenzotriazole (HOBt), 6-chloro -1-hydroxybenzotriazole (Cl-HOBt), N-hydroxy-7-azabenzotriazole (HOAt), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride ( BOP-Cl), 3-diethoxyphosphoryl-1,2,3-benzoxazol-4(3H)-one (DEPBT), N-hydroxysuccinimide (HOSu) and pentafluorophenol.
- HOBt 1-hydroxybenzotriazole
- Cl-HOBt 6-chloro -1-hydroxybenzotriazole
- HOAt N-hydroxy-7-azabenzotriazole
- BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphoryl chloride
- DEPBT 3-diethoxyphosphoryl-1,2,
- illustrative examples of solvents that can be used in the preparation of compounds represented by formula (IV) in the present disclosure include, but are not limited to, dichloromethane, chloroform, acetonitrile, toluene, tetrahydrofuran, dioxane, and any mixture thereof.
- condensation reaction of the present disclosure to prepare the compound represented by formula (IV) is carried out at about 0 to about 50°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (IV) is carried out at about 25 to about 35°C.
- the weight ratio of the feed amount of formula (III) to formula (II) is about 1:1.3 to about 1:1.4.
- the weight ratio of the feed amount of formula (III) to formula (II) is about 1:1.35-about 1:1.4.
- the weight ratio of the feed amount of formula (III) to formula (II) is about 1:1.36.
- the present disclosure relates to a method for preparing a compound represented by formula (III),
- the method comprises reacting a compound of general formula (I),
- R 1 ⁇ R 2 , R 1 and R 2 are selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl.
- R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 6 -C 12 aryl.
- R and R are each independently selected from methyl, ethyl, propyl, tert-butyl, benzyl, or allyl.
- illustrative examples of compounds of formula (III) that can be used in the present disclosure include, but are not limited to, trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrathree Phenylphosphine palladium or any mixture thereof.
- TFA trifluoroacetic acid
- hydrochloric acid hydrochloric acid
- hydrobromic acid hydrobromic acid
- sulfonic acid palladium on carbon
- tetrathree Phenylphosphine palladium tetrathree Phenylphosphine palladium or any mixture thereof.
- the illustrative examples that can be used in the present disclosure to prepare the compound represented by formula (III) are trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium Or the weight ratio of any mixture thereof to the compound represented by formula (I) is about 1.5:1 to about 1:1.
- the illustrative examples that can be used in the present disclosure to prepare the compound represented by formula (III) are trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium Or the weight ratio of any mixture thereof to the compound represented by formula (I) is about 1.1:1 to about 1:1.
- the illustrative examples that can be used in the present disclosure to prepare the compound represented by formula (III) are trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium Or the weight ratio of any mixture thereof to the compound represented by formula (I) is about 1.02:1.
- illustrative examples of solvents that can be used in the preparation of compounds represented by formula (III) in the present disclosure include, but are not limited to, dichloromethane, toluene, dichloroethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, methanol, ethanol or any mixture thereof.
- reaction for preparing the compound represented by formula (III) of the present disclosure is carried out at -20 to 0°C.
- reaction for preparing the compound represented by formula (III) of the present disclosure is carried out at -15 to -5°C.
- illustrative examples of compounds of formula (III) that can be used in the present disclosure include, but are not limited to, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof.
- the present disclosure relates to a method for preparing a compound represented by formula (VII), comprising
- the compound represented by the formula (IV) is subjected to condensation reaction to obtain the compound represented by the formula (V);
- the compound represented by the formula (VI) is subjected to condensation reaction to obtain the compound represented by the formula (VII).
- the disclosure relates to a method for preparing a compound represented by formula (VII),
- the method includes subjecting the compound represented by formula (VIII) to condensation reaction.
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII) include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexyl carbon Diimine (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC ⁇ HCl), thionyl chloride (SOCl 2 ), oxalyl chloride ((COCl) 2 ), acetyl chloride (AcCl), acetic anhydride (Ac 2 O), N,N-dimethylformamide (DMF) and any mixture thereof.
- CDI N,N'-carbonyldiimidazole
- DCC dicyclohexyl carbon Diimine
- EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
- EDC
- thionyl chloride SOCl 2
- oxalyl chloride (COCl) 2
- acetyl chloride (AcCl)/N,N-dimethylformamide (DMF) for the condensation reaction of the compound shown in the preparation formula (VII).
- the combination of N-dimethylformamide (DMF) carries out the condensation reaction of the compound shown in the preparation formula (VII), the weight ratio of the above-mentioned reaction reagent and the compound shown in the formula (VIII) is About 1:1 to about 3:1.
- illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII) include, but are not limited to, tetrahydrofuran, dichloromethane (DCM), acetic anhydride (Ac 2 O) and any mixture thereof.
- condensation reaction to produce the compound of formula (VII) is carried out at about -5 to about 150°C.
- condensation reaction to produce the compound of formula (VII) is carried out at about -10 to about 40°C.
- condensation reaction to produce the compound of formula (VII) is carried out at about 20 to about 30°C.
- the compound of formula (VII) is recrystallized.
- illustrative examples of solvents that can be used in the present disclosure to recrystallize the compound represented by formula (VII) include, but are not limited to, acetonitrile/isopropanol, ethyl acetate, acetonitrile/water, tetrahydrofuran/ Water and any mixture thereof.
- the present disclosure relates to a method for preparing a compound represented by formula (VIII),
- the method comprises carrying out a hydrolysis reaction of the compound represented by formula (IX),
- the hydrolysis reaction to prepare the compound represented by formula (VIII) is carried out under basic conditions.
- illustrative examples of salts that can be used in the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VIII) include, but are not limited to, potassium salts, sodium salts, lithium salts, and any mixtures thereof.
- illustrative examples of salts that can be used in the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VIII) include, but are not limited to, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, carbonic acid Sodium, lithium hydroxide, lithium carbonate and any mixture thereof.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VIII) is carried out at about -5 to about 35°C.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VIII) is carried out at about 0 to about 35°C.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VIII) is carried out at about 20 to about 30°C.
- illustrative examples of solvents that can be used to purify compounds of formula (VIII) of the present disclosure include, but are not limited to, ethanol/water, methanol/water, isopropanol/water, acetonitrile/acetone/water , acetonitrile/acetone, ethyl acetate, tetrahydrofuran, tetrahydrofuran/water and any mixture thereof.
- the compound shown in formula (V) that can be used in the preparation of the compound shown in formula (VIII) of the present disclosure and the salt that can be used in the hydrolysis reaction of the compound shown in the preparation formula (VIII) of the present disclosure The molar ratio is from about 1:1 to about 1:10.
- the compound shown in formula (V) that can be used in the preparation of the compound shown in formula (VIII) of the present disclosure and the salt that can be used in the hydrolysis reaction of the compound shown in the preparation formula (VIII) of the present disclosure The molar ratio is from about 1:1 to about 1:6.
- the compound shown in formula (V) that can be used in the preparation of the compound shown in formula (VIII) of the present disclosure and the salt that can be used in the hydrolysis reaction of the compound shown in the preparation formula (VIII) of the present disclosure The molar ratio is about 1:5.
- the present disclosure relates to a method for preparing a compound represented by formula (IX),
- the method comprises subjecting the compound represented by formula (X) to a condensation reaction
- illustrative examples of reagents that can be used in the condensation reactions of the present disclosure to prepare compounds represented by formula (IX) include, but are not limited to, acetyl chloride (AcCl), acetic anhydride (Ac 2 O) and any mixture.
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (IX) include, but are not limited to, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), triethylamine (TEA), pyridine (Py), N,N-diisopropylethylamine (DIEA), pyridine (Py) and any mixture thereof.
- DMAP 4-dimethylaminopyridine
- NMM N-methylmorpholine
- TAA triethylamine
- Py N,N-diisopropylethylamine
- DIEA N,N-diisopropylethylamine
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare the compound represented by formula (IX) include, but are not limited to, Ac 2 O, Ac 2 O/DMAP, Ac 2 O/DMAP/ NMM, CH3COCl /TEA/DCM/DMAP or CH3COCl /Py.
- illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (IX) include, but are not limited to, acetic anhydride, dichloromethane (DCM), pyridine (Py), tetrahydrofuran , acetonitrile, acetone, ethyl acetate and any mixture thereof.
- condensation reaction of the present disclosure to prepare the compound represented by formula (IX) is carried out at about 0 to about 150°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (IX) is carried out at about 90 to about 150°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (IX) is carried out at about 125 to about 140°C.
- MTBE methyl tert-butyl ether
- methanol ethyl acetate
- n-hexane alkanes diethyl ether
- THF tetrahydrofuran
- the present disclosure relates to a method for preparing a compound represented by formula (X),
- the method comprises carrying out condensation reaction of the compound shown in formula (II) and the compound shown in formula (XI) to obtain the compound shown in the formula (X),
- condensing agents that can be used in the preparation of compounds represented by formula (X) in the present disclosure include, but are not limited to, carbodiimide-type condensing agents, phosphorus-cation-type condensing agents, urea-cation type condensing agents, other suitable condensing agents, and any mixture thereof.
- carbodiimide-type condensing agents that can be used in the present disclosure to prepare compounds represented by formula (X) include, but are not limited to, 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide (EDC), EDCI (the hydrochloride salt of EDC) and dicyclohexylcarbodiimide (DCC).
- EDC 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide
- EDCI the hydrochloride salt of EDC
- DCC dicyclohexylcarbodiimide
- illustrative examples of phosphorus cationic condensing agents that can be used in the preparation of compounds represented by formula (X) in the present disclosure include, but are not limited to, 1H-benzotriazol-1-yloxytripyrrolidine benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) ).
- illustrative examples of urea cationic condensing agents that can be used in the present disclosure to prepare compounds represented by formula (X) include, but are not limited to, N,N,N',N'-tetramethyl- O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU).
- HBTU N,N,N',N'-tetramethyl- O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate
- HATU 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea Hexafluorophosphate
- illustrative examples of other suitable condensing agents that can be used in the present disclosure to prepare compounds of formula (X) include, but are not limited to, 1-hydroxybenzotriazole (HOBt), 6-chloro -1-hydroxybenzotriazole (Cl-HOBt), N-hydroxy-7-azabenzotriazole (HOAt), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride ( BOP-Cl), 3-diethoxyphosphoryl-1,2,3-benzoxazol-4(3H)-one (DEPBT), N-hydroxysuccinimide (HOSu) and pentafluorophenol.
- HOBt 1-hydroxybenzotriazole
- Cl-HOBt 6-chloro -1-hydroxybenzotriazole
- HOAt N-hydroxy-7-azabenzotriazole
- BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphoryl chloride
- DEPBT 3-diethoxyphosphoryl-1,2,
- illustrative examples of solvents that can be used in the preparation of compounds represented by formula (X) in the present disclosure include, but are not limited to, dichloromethane, chloroform, toluene, tetrahydrofuran, dioxane, and any mixture.
- condensation reaction of the present disclosure to prepare the compound represented by formula (X) is carried out at about 0 to about 50°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (X) is carried out at about 25 to about 35°C.
- the weight ratio of the feed amount of formula (XI) to formula (II) is about 1:1.3 to about 1:1.4.
- the weight ratio of the feed amount of formula (XI) to formula (II) is about 1:1.35 to about 1:1.4.
- the weight ratio of the feed amount of the formula (XI) to the formula (II) is about 1:1.36.
- the present disclosure relates to a method for preparing a compound represented by formula (XI),
- the method comprises reacting a compound of general formula (I),
- R 1 ⁇ R 2 , R 1 and R 2 are selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl.
- R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 6 -C 12 aryl.
- R and R are each independently selected from methyl, ethyl, propyl, tert-butyl, benzyl, or allyl.
- illustrative examples of compounds of formula (XI) that can be used in the present disclosure include, but are not limited to, trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrathree Phenylphosphine palladium or any mixture thereof.
- TFA trifluoroacetic acid
- hydrochloric acid hydrochloric acid
- hydrobromic acid hydrobromic acid
- sulfonic acid palladium on carbon
- tetrathree Phenylphosphine palladium tetrathree Phenylphosphine palladium or any mixture thereof.
- the illustrative examples of compounds of formula (XI) that can be used in the present disclosure are trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium Or the weight ratio of any mixture thereof to the compound represented by formula (I) is about 1.5:1 to about 1:1.
- the illustrative examples of compounds of formula (XI) that can be used in the present disclosure are trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium Or the weight ratio of any mixture thereof to the compound represented by formula (I) is about 1.1:1 to about 1:1.
- the illustrative examples of compounds of formula (XI) that can be used in the present disclosure are trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium Or the weight ratio of any mixture thereof to the compound represented by formula (I) is about 1.02:1.
- illustrative examples of solvents that can be used in the preparation of compounds represented by formula (XI) in the present disclosure include, but are not limited to, dichloromethane, benzene, toluene, dichloroethane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, methanol, ethanol or any mixture thereof.
- reaction of the present disclosure to prepare the compound represented by formula (XI) is carried out at about -20 to about 0°C.
- reaction of the present disclosure to prepare the compound represented by formula (XI) is carried out at about -15 to about -5°C.
- illustrative examples of compounds of formula (XI) that can be used in the present disclosure include, but are not limited to, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof.
- the present disclosure relates to a method for preparing a compound represented by formula (VII), comprising
- the compound represented by the formula (X) is subjected to condensation reaction to obtain the compound represented by the formula (IX);
- the compound represented by the formula (VIII) is subjected to condensation reaction to obtain the compound represented by the formula (VII).
- the present disclosure relates to a method for preparing a compound represented by formula (VII'),
- Said method comprises carrying out condensation reaction with the compound shown in formula (VI '),
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII') include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexyl Carbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC ⁇ HCl), thionyl chloride (SOCl 2 ), grass Acid chloride ((COCl) 2 ), acetyl chloride (AcCl), acetic anhydride (Ac 2 O), N,N-dimethylformamide (DMF) and any mixture thereof.
- CDI N,N'-carbonyldiimidazole
- DCC dicyclohexyl Carbodiimide
- EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
- EDC ED
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare the compound represented by formula (VII') include, but are not limited to, thionyl chloride (SOCl 2 )/N,N-dimethyl Dimethylformamide (DMF), oxalyl chloride ((COCl) 2 )/N,N-dimethylformamide (DMF) or acetyl chloride (AcCl)/N,N-dimethylformamide (DMF) Condensation reactions for the preparation of compounds represented by formula (VII').
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII') include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexyl Carbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC ⁇ HCl), thionyl chloride (SOCl 2 ), grass Acid chloride ((COCl) 2 ), acetyl chloride (AcCl), acetic anhydride (Ac 2 O), N,N-dimethylformamide (DMF), thionyl chloride (SOCl 2 )/N,N-dimethyl Dimethylformamide (DMF), oxalyl chloride ((COCl) 2 )/N,N-dimethylformamide (DMF) or acetyl chloride (CDI), di
- illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII') include, but are not limited to, tetrahydrofuran, dichloromethane (DCM), acetic anhydride (Ac 2 O ) and any mixture thereof.
- condensation reaction to produce the compound of formula (VII') is carried out at about -5 to about 150°C.
- condensation reaction to produce the compound of formula (VII') is carried out at about -10 to about 40°C.
- condensation reaction to produce the compound of formula (VII') is carried out at about 20 to about 30°C.
- the compound of formula (VII') is recrystallized.
- illustrative examples of solvents that can be used in the recrystallization of compounds represented by formula (VII') of the present disclosure include, but are not limited to, acetonitrile/isopropanol, ethyl acetate, acetonitrile/water, tetrahydrofuran / water and any mixture thereof.
- the present disclosure relates to a method for preparing a compound represented by formula (VI'),
- the method comprises carrying out a hydrolysis reaction of the compound shown in formula (V'),
- the hydrolysis reaction to prepare the compound represented by formula (VI') is carried out under basic conditions.
- illustrative examples of salts that can be used in the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI') include, but are not limited to, potassium salts, sodium salts, lithium salts, and any mixtures thereof.
- illustrative examples of salts that can be used in the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI') include, but are not limited to, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, Sodium carbonate, lithium hydroxide, lithium carbonate and any mixture thereof.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI') is carried out at about -5 to about 35°C.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI') is carried out at about 0 to about 35°C.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI') is carried out at about 20 to about 30°C.
- illustrative examples of solvents that can be used for the compound represented by formula (VI') of the present disclosure include, but are not limited to, ethanol/water, methanol/water, isopropanol/water, acetonitrile/acetone/water , acetonitrile/acetone, ethyl acetate, tetrahydrofuran, tetrahydrofuran/water, acetone/water and any mixture thereof.
- the compound shown in formula (V') that can be used in the preparation of the compound shown in formula (VI') of the present disclosure and the hydrolysis reaction that can be used in the compound shown in the preparation formula (VI') of the present disclosure The molar ratio of the salts is from about 1:1 to about 1:10.
- the compound shown in formula (V') that can be used in the preparation of the compound shown in formula (VI') of the present disclosure and the hydrolysis reaction that can be used in the compound shown in the preparation formula (VI') of the present disclosure The molar ratio of the salts is from about 1:1 to about 1:6.
- the compound shown in formula (V') that can be used in the preparation of the compound shown in formula (VI') of the present disclosure and the hydrolysis reaction that can be used in the compound shown in the preparation formula (VI') of the present disclosure The molar ratio of salt to salt is about 1:5.
- the present disclosure relates to a method for preparing a compound represented by formula (V'),
- the method comprises carrying out a condensation reaction of the compound shown in formula (IV'),
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (V') include, but are not limited to, acetyl chloride (AcCl), acetic anhydride (Ac 2 O) and any mixture.
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (V') include, but are not limited to, 4-dimethylaminopyridine (DMAP), N-methyl phenoline (NMM), triethylamine (TEA), dichloromethane (DCM), pyridine (Py), N,N-diisopropylethylamine (DIEA) and any mixture thereof.
- DMAP 4-dimethylaminopyridine
- NMM N-methyl phenoline
- TAA triethylamine
- DCM dichloromethane
- Py pyridine
- DIEA N,N-diisopropylethylamine
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare the compound represented by formula (V') include, but are not limited to, Ac 2 O, Ac 2 O/DMAP, Ac 2 O/DMAP/ NMM, CH 3 COCl/TEA/DCM/DMAP or CH 3 COCl/Py to prepare the compound represented by formula (V').
- illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (V') include, but are not limited to, acetic anhydride, dichloromethane (DCM), pyridine (Py), Tetrahydrofuran, acetonitrile, acetone, ethyl acetate and any mixture thereof.
- condensation reaction of the present disclosure to prepare the compound represented by formula (V') is carried out at about 0 to about 150°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (V') is carried out at about 90 to about 150°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (V') is carried out at about 125 to about 140°C.
- illustrative examples of solvents that can be used to purify compounds represented by formula (V') of the present disclosure include, but are not limited to, ethanol, methyl tert-butyl ether (MTBE), methanol, ethyl acetate, n-hexane, diethyl ether, tetrahydrofuran (THF) and any mixture thereof.
- MTBE methyl tert-butyl ether
- methanol ethyl acetate
- n-hexane diethyl ether
- THF tetrahydrofuran
- the present disclosure relates to a method for preparing a compound represented by formula (IV'),
- the method comprises carrying out a condensation reaction between the compound shown in formula (III) and the compound shown in formula (II') to obtain the compound shown in the formula (IV'),
- condensing agents that can be used in the preparation of compounds represented by formula (IV') in the present disclosure include, but are not limited to, carbodiimide condensing agents, phosphorus cation condensing agents, urea cations Ionic condensing agents, other suitable condensing agents, and any mixtures thereof.
- carbodiimide-type condensing agents that can be used in the preparation of compounds represented by formula (IV') in the present disclosure include, but are not limited to, 1-(3-dimethylaminopropyl) - 3-Ethylcarbodiimide (EDC), EDCI (the hydrochloride salt of EDC) and dicyclohexylcarbodiimide (DCC).
- EDC 1-(3-dimethylaminopropyl) - 3-Ethylcarbodiimide
- EDCI the hydrochloride salt of EDC
- DCC dicyclohexylcarbodiimide
- an illustrative example of a phosphorus cationic condensing agent that can be used in the preparation of the compound represented by formula (IV') in the present disclosure includes, but is not limited to, 1H-benzotriazol-1-yloxytripyrrole Alkyl hexafluorophosphate (PyBOP), tripyrrolidinylphosphonium bromide hexafluorophosphate (PyBrOP), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate ( BOP).
- 1H-benzotriazol-1-yloxytripyrrole Alkyl hexafluorophosphate PyBOP
- tripyrrolidinylphosphonium bromide hexafluorophosphate PyBrOP
- benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate BOP
- urea cationic condensing agents that can be used in the preparation of compounds represented by formula (IV') in the present disclosure include, but are not limited to, N,N,N',N'-tetramethyl -O-(1H-Benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (HATU).
- HBTU N,N,N',N'-tetramethyl -O-(1H-Benzotriazol-1-yl)uronium hexafluorophosphate
- HATU 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate
- illustrative examples of other suitable condensing agents that can be used in the preparation of compounds represented by formula (IV') of the present disclosure include, but are not limited to, 1-hydroxybenzotriazole (HOBt), 6- Chloro-1-hydroxybenzotriazole (Cl-HOBt), N-hydroxy-7-azabenzotriazole (HOAt), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl), 3-diethoxyphosphoryl-1,2,3-benzoxazol-4(3H)-one (DEPBT), N-hydroxysuccinimide (HOSu) and pentafluorophenol.
- HOBt 1-hydroxybenzotriazole
- Cl-HOBt 6- Chloro-1-hydroxybenzotriazole
- HOAt N-hydroxy-7-azabenzotriazole
- BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphoryl chloride
- DEPBT 3-diethoxyphosphoryl-1
- illustrative examples of solvents that can be used in the preparation of compounds represented by formula (IV') in the present disclosure include, but are not limited to, dichloromethane, chloroform, acetonitrile, toluene, tetrahydrofuran, dioxane and any mixture thereof.
- condensation reaction of the present disclosure to prepare the compound represented by formula (IV') is carried out at about 0 to about 50°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (IV') is carried out at about 25 to about 35°C.
- the weight ratio of the feed amount of the formula (III) to the formula (II') is about 1:1.3 to about 1:1.4.
- the weight ratio of the feed amount of formula (III) to formula (II') is about 1:1.35 to about 1:1.4.
- the weight ratio of the feed amount of the formula (III) to the formula (II') is about 1:1.36.
- the present disclosure relates to a method for preparing a compound represented by formula (VII'), comprising
- the compound represented by the formula (VI') is subjected to condensation reaction to obtain the compound represented by the formula (VII').
- the present disclosure relates to a method for preparing a compound represented by formula (VII"),
- Said method comprises carrying out condensation reaction with the compound shown in formula (VI ").
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII") include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexyl Carbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC ⁇ HCl), thionyl chloride (SOCl 2 ), grass Acid chloride ((COCl) 2 ), acetyl chloride (AcCl), acetic anhydride (Ac 2 O), N,N-dimethylformamide (DMF) and any mixture thereof.
- CDI N,N'-carbonyldiimidazole
- DCC dicyclohexyl Carbodiimide
- EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
- EDC EDCI
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII") include, but are not limited to, thionyl chloride (SOCl 2 )/N,N-dimethyl Dimethylformamide (DMF), oxalyl chloride ((COCl) 2 )/N,N-dimethylformamide (DMF) or acetyl chloride (AcCl)/N,N-dimethylformamide (DMF) Condensation reactions for the preparation of compounds represented by formula (VII").
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII") include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexyl Carbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC ⁇ HCl), thionyl chloride (SOCl 2 ), grass Acid chloride ((COCl) 2 ), acetyl chloride (AcCl), acetic anhydride (Ac 2 O), N,N-dimethylformamide (DMF), thionyl chloride (SOCl 2 )/N,N-dimethyl Dimethylformamide (DMF), oxalyl chloride ((COCl) 2 )/N,N-dimethylformamide (DMF) or acetyl chloride (A
- illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (VII") include, but are not limited to, tetrahydrofuran, dichloromethane (DCM), acetic anhydride (Ac 2 O ) and any mixture thereof.
- condensation reaction to produce the compound of formula (VII") is carried out at about -5 to about 150°C.
- condensation reaction to produce the compound of formula (VII") is carried out at about -10 to about 40°C.
- condensation reaction to produce the compound of formula (VII) is carried out at about 20 to about 30°C.
- the compound of formula (VII) is recrystallized.
- illustrative examples of solvents that can be used in the present disclosure to recrystallize the compound represented by formula (VII") include, but are not limited to, acetonitrile/isopropanol, ethyl acetate, acetonitrile/water, tetrahydrofuran / water and any mixture thereof.
- the present disclosure relates to a method for preparing a compound represented by formula (VI"),
- the method comprises carrying out a hydrolysis reaction of the compound shown in formula (V"),
- the hydrolysis reaction to prepare the compound represented by formula (VI") is carried out under basic conditions.
- illustrative examples of salts that can be used in the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI") include, but are not limited to, potassium salts, sodium salts, lithium salts, and any mixtures thereof.
- illustrative examples of salts that can be used in the hydrolysis reaction of the present disclosure to prepare compounds represented by formula (VI") include, but are not limited to, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, Sodium carbonate, lithium hydroxide, lithium carbonate and any mixture thereof.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI") is carried out at about -5 to about 35°C.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI") is carried out at about 0 to about 35°C.
- the hydrolysis reaction of the present disclosure to prepare the compound represented by formula (VI") is carried out at about 20 to about 30°C.
- illustrative examples of solvents that can be used to purify compounds of formula (VI") of the present disclosure include, but are not limited to, ethanol/water, methanol/water, isopropanol/water, acetonitrile/acetone/ Water, acetonitrile/acetone, ethyl acetate, tetrahydrofuran, tetrahydrofuran/water and any mixture thereof.
- the compound shown in formula (V") that can be used to prepare the compound shown in formula (VI') of the present disclosure and the hydrolysis reaction that can be used to prepare the compound shown in formula (VI") of the present disclosure The molar ratio of the salts is from about 1:1 to about 1:10.
- the compound shown in formula (V") that can be used in the preparation of the compound shown in formula (VI") of the present disclosure and the hydrolysis reaction that can be used in the preparation of the compound shown in formula (VI") of the present disclosure The molar ratio of the salts is about 1:1 to 1:6.
- the compound shown in formula (V") that can be used in the preparation of the compound shown in formula (VI") of the present disclosure and the hydrolysis reaction that can be used in the preparation of the compound shown in formula (VI") of the present disclosure The molar ratio of salt to salt is about 1:5.
- the present disclosure relates to a method for preparing a compound represented by formula (V"),
- the method comprises carrying out a condensation reaction of the compound shown in formula (IV"),
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (V") include, but are not limited to, acetyl chloride (AcCl), acetic anhydride (Ac 2 O) and any mixture.
- illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (V") include, but are not limited to, 4-dimethylaminopyridine (DMAP), N-methyl phenoline (NMM), triethylamine (TEA), dichloromethane (DCM), pyridine (Py), N,N-diisopropylethylamine (DIEA) and any mixture thereof.
- DMAP 4-dimethylaminopyridine
- NMM N-methyl phenoline
- TAA triethylamine
- DCM dichloromethane
- Py pyridine
- DIEA N,N-diisopropylethylamine
- illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (V") include, but are not limited to, Ac 2 O, Ac 2 O/DMAP, Ac 2 O/DMAP /NMM, CH 3 COCl/TEA/DCM/DMAP or CH 3 COCl/Py to prepare the compound represented by formula (V").
- illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare compounds represented by formula (V") include, but are not limited to, acetic anhydride, dichloromethane (DCM), pyridine (Py), Tetrahydrofuran, acetonitrile, acetone, ethyl acetate and any mixture thereof.
- condensation reaction of the present disclosure to prepare the compound represented by formula (V") is carried out at about 0 to about 150°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (V") is carried out at about 90 to about 150°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (V") is carried out at about 125 to about 140°C.
- illustrative examples of solvents that can be used to purify compounds represented by formula (V") of the present disclosure include, but are not limited to, ethanol, methyl tert-butyl ether (MTBE), methanol, ethyl acetate, n-hexane, diethyl ether, tetrahydrofuran (THF) and any mixture thereof.
- MTBE methyl tert-butyl ether
- methanol ethyl acetate
- n-hexane diethyl ether
- THF tetrahydrofuran
- the present disclosure relates to a method for preparing a compound represented by formula (IV"),
- the method comprises carrying out a condensation reaction between the compound shown in formula (III) and the compound shown in formula (II") to obtain the compound shown in formula (IV"),
- condensing agents that can be used in the preparation of compounds represented by formula (IV") in the present disclosure include, but are not limited to, carbodiimide condensing agents, phosphorous cation condensing agents, urea positive Ionic condensing agents, other suitable condensing agents, and any mixtures thereof.
- carbodiimide-type condensing agents that can be used in the present disclosure include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ( EDC), EDCI (the hydrochloride salt of EDC) and dicyclohexylcarbodiimide (DCC).
- EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
- EDCI the hydrochloride salt of EDC
- DCC dicyclohexylcarbodiimide
- illustrative examples of phosphocation-type condensing agents that can be used in the present disclosure include, but are not limited to, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP), Tripyrrolidinylphosphonium bromide hexafluorophosphate (PyBrOP) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP).
- PyBOP 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate
- PyBrOP Tripyrrolidinylphosphonium bromide hexafluorophosphate
- BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
- urea cationic condensing agents that can be used in the present disclosure include, but are not limited to, N,N,N',N'-tetramethyl-O-(1H-benzotriazole -1-yl)uronium hexafluorophosphate (HBTU) and 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).
- illustrative examples of other suitable condensing agents include, but are not limited to, 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), N-hydroxy-7-azabenzotriazole (HOAt), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl), 3-diethyl Oxyphosphoryl-1,2,3-benzoxazol 4(3H)-one (DEPBT), N-hydroxysuccinimide (HOSu) and pentafluorophenol.
- HOBt 1-hydroxybenzotriazole
- Cl-HOBt 6-chloro-1-hydroxybenzotriazole
- HOAt N-hydroxy-7-azabenzotriazole
- BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphoryl chloride
- DEPBT 3-diethyl Oxyphosphoryl-1,2,3-benzoxazol 4(3H)
- condensation reaction of the present disclosure to prepare the compound represented by formula (IV") is carried out at about 0 to about 50°C.
- condensation reaction of the present disclosure to prepare the compound represented by formula (IV") is carried out at about 25 to about 35°C.
- the weight ratio of the feed amount of the formula (III) to the formula (II") is about 1:1.3 to about 1:1.4.
- the weight ratio of the feed amount of the formula (III) to the formula (II") is about 1:1.35 to about 1:1.4.
- the weight ratio of the feed amount of the formula (III) to the formula (II") is about 1:1.36.
- the present disclosure relates to a method for preparing a compound represented by formula (VII), which comprises
- the compound represented by the formula (VI) is subjected to condensation reaction to obtain the compound represented by the formula (VII").
- the preparation method of the present disclosure does not require chromatographic purification, and is easier to scale up production.
- the reaction conditions of the present disclosure are easy to control, easier to scale up production, and easier to produce stability and repeatability.
- the preparation method of the present disclosure is more effective than the existing disclosure methods, and unexpectedly, the compound meeting the clinical quality standard can be directly obtained through the preparation method and route of the present disclosure, thereby eliminating the need for complicated purification steps.
- Clinical specification means a substance of sufficient purity to be suitable for human administration.
- the preparation method of the present disclosure does not use Class 1 solvents, and has better safety to the human body in terms of residual solvents.
- the preparation methods of the present disclosure are economical and use readily available starting materials.
- the preparation method of the present disclosure has better single-step yield and better overall yield.
- the concentrate was dissolved in dichloromethane, washed with water and brine, and dried over anhydrous sodium sulfate. Removal of solvent gave a residue.
- the residue was added into acetonitrile (5ml), heated to reflux until dissolved, and isopropanol (30ml) was added to reflux for 2 hours. Heating was stopped, and the mixture was stirred at room temperature. Filter with suction to obtain a filter cake, and dry in vacuo to obtain 3.7 g of the title compound (purity: 99.32%, yield: 77.1%).
- reaction solution was raised to room temperature, stirred for 3 to 6 hours, monitored by HPLC, and stopped until the reaction was basically completed.
- 4 mol/L hydrochloric acid was added dropwise to adjust the pH to 5 to 6, and the mixture was concentrated in vacuo to obtain an oil. Dissolve the oil in water, add dropwise 4mol/L hydrochloric acid to adjust the pH to 1 to 2, and a solid precipitates out.
- Acetonitrile (120ml) and acetone (40ml) were added to the mixture and stirred for 3 hours, filtered with suction to obtain a filter cake, dried in vacuo to obtain 11.3g of the title compound (purity: 98%, yield: 73%).
- (S)-methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl) was prepared according to the method described in Example 12 or 13 above )-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate, just use N-hydroxysuccinimide (HOSu), N-hydroxyl-7-azobenzotriazole ( HOAt) or HOBt instead of Cl-HOBt, to obtain a similar reaction effect.
- HOSu N-hydroxysuccinimide
- HOAt N-hydroxyl-7-azobenzotriazole
- HOBt HOBt
- (S)-methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl) was prepared according to the method described in Example 12 or 13 above )-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate, just replace dichloromethane with tetrahydrofuran, N,N-dimethylformamide, chloroform, obtain similar reaction effect .
- (S)-methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl) was prepared according to the method described in Example 12 or 13 above )-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate, but the reaction temperature is from about 15°C to about 35°C, and a similar reaction effect is obtained.
- reaction liquid was added to methyl tert-butyl ether (78.3g) and stirred for 2 hours, filtered with suction to obtain a filter cake, and dried in vacuum to obtain 3.7g of the title compound (yield: 86%, sample purity: 97.4%).
- the hydrogenation bottle was replaced with nitrogen gas twice, and then replaced with hydrogen gas twice, and reacted with hydrogen gas (pressure 15 psi) until the reaction was basically completed.
- the feed liquid was passed through diatomaceous earth to remove Pd/C.
- the filtrate was concentrated under reduced pressure to remove the solvent to obtain a residue.
- the residue was added to methyl tert-butyl ether (300ml) and stirred for 2 hours, filtered with suction to obtain a filter cake, and dried in vacuo to obtain 20.3g of the title compound (yield: 59%, purity 95.4%).
- 1 H NMR 600MHz, Acetone-d 6 ) ⁇ 7.75(s,1H),7.53(s,H),3.96(s,3H).LCMS:202.1([M+H] + ).
- relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, without necessarily requiring or implying any relationship between these entities or operations. an actual relationship or order.
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Abstract
一种制备式(VII)所示化合物的方法,所述方法包括将式(VI)所示的化合物进行缩合反应。
Description
领域
本公开大体上涉及药物化学领域,更具体地本公开涉及噻吩衍生物的制备。
背景
磷酸二酯酶(PDE)系指催化寡核苷酸即多核苷酸中双重制化的磷酸分子进行水解的酶类,其具有水解细胞内第二信使(cAMP,环磷酸腺苷或cGMP,磷酸鸟苷)的功能,降解细胞内cAMP或cGMP,从而终结这些第二信使所传导的生化作用。
概述
一方面,本公开涉及制备式(VII)所示化合物的方法,
所述方法包括将式(VI)或式(VIII)所示的化合物进行缩合反应
另一方面,本公开涉及制备式(VI)所示化合物的方法,
所述方法包括将式(V)所示化合物进行水解反应。
再一方面,本公开涉及制备式(V)所示化合物的方法,
所述方法包括将式(IV)所示化合物进行缩合反应。
又一方面,本公开涉及制备式(IV)所示化合物的方法,
所述方法包括将式(III)所示化合物与式(II)所示化合物进行缩合反应,得到所述式(IV)所示化合物。
另一方面,本公开涉及制备式(III)所示化合物的方法,
所述方法包括将通式(I)化合物进行反应,
其中R
1≠R
2,R
1和R
2选自取代或未取代的烷基、取代或未取代的烯基、取代或未取代的芳基。
再一方面,本公开涉及制备式(VII)所示化合物的方法,其包括
将通式(I)化合物进行反应,得到式(III)所示化合物;
将式(III)所示化合物与所述式(II)所示化合物进行缩合反应,得到式(IV)所示化合物;
将所述式(IV)所示化合物进行缩合反应,得到式(V)所示化合物;
将所述式(V)所示化合物进行水解反应,得到式(VI)所示化合物;以及
将所述式(VI)或式(VIII)所示的化合物进行缩合反应,得到所述式(VII)所示化合物。
一方面,本公开涉及制备式(VII)所示化合物的方法,
所述方法包括将式(VIII)所示的化合物进行缩合反应
另一方面,本公开涉及制备式(VIII)所示化合物的方法,
所述方法包括将式(IX)所示化合物进行水解反应
再一方面,本公开涉及制备式(IX)所示化合物的方法,
所述方法包括将式(X)所示化合物进行缩合反应
又一方面,本公开涉及制备式(X)所示化合物的方法,
所述方法包括将式(XI)所示化合物与式(II)所示化合物进行缩合反应,得到所述式(X)所示化合物,
另一方面,本公开涉及制备式(XI)所示化合物的方法,
所述方法包括将通式(I)化合物进行反应,
其中R
1≠R
2,R
1和R
2选自取代或未取代的烷基、取代或未取代的烯基、取代或未取代的芳基。
再一方面,本公开涉及制备式(VII)所示化合物的方法,其包括
将通式(I)化合物进行反应,得到式(XI)所示化合物;
将式(II)所示化合物与所述式(XI)所示化合物进行缩合反应,得到式(X)所示化合物;
将所述式(X)所示化合物进行缩合反应,得到式(IX)所示化合物;
将所述式(IX)所示化合物进行水解反应,得到式(VIII)所示化合物;以及
将所述式(VIII)所示的化合物进行缩合反应,得到所述式(VII)所示化合物。
一方面,本公开涉及制备式(VII’)所示化合物的方法,
所述方法包括将式(VI’)所示的化合物进行缩合反应,
另一方面,本公开涉及制备式(VI’)所示化合物的方法,
所述方法包括将式(V’)所示化合物进行水解反应,
再一方面,本公开涉及制备式(V’)所示化合物的方法,
所述方法包括将式(IV’)所示化合物进行缩合反应,
又一方面,本公开涉及制备式(IV’)所示化合物的方法,
所述方法包括将式(III)所示化合物与式(II’)所示化合物进行缩合反应,得到所述式(IV’)所示化合物,
再一方面,本公开涉及制备式(VII’)所示化合物的方法,其包括
将通式(I)化合物进行反应,得到式(III)所示化合物;
将式(III)所示化合物与所述式(II’)所示化合物进行缩合反应,得到式(IV’)所示化合物;
将所述式(IV’)所示化合物进行缩合反应,得到式(V’)所示化合物;
将所述式(V’)所示化合物进行水解反应,得到式(VI’)所示化合物;以及
将所述式(VI’)所示的化合物进行缩合反应,得到所述式(VII’)所示化合物。
一方面,本公开涉及制备式(VII”)所示化合物的方法,
所述方法包括将式(VI”)所示的化合物进行缩合反应.
另一方面,本公开涉及制备式(VI”)所示化合物的方法,
所述方法包括将式(V”)所示化合物进行水解反应,
再一方面,本公开涉及制备式(V”)所示化合物的方法,
所述方法包括将式(IV”)所示化合物进行缩合反应,
又一方面,本公开涉及制备式(IV”)所示化合物的方法,
所述方法包括将式(III)所示化合物与式(II”)所示化合物进行缩合反应,得到所述式(IV”)所示化合物,
再一方面,本公开涉及制备式(VII”)所示化合物的方法,其包括
将通式(I)化合物进行反应,得到式(III)所示化合物;
将式(III)所示化合物与所述式(II”)所示化合物进行缩合反应,得到式(IV”)所示化合物;
将所述式(IV”)所示化合物进行缩合反应,得到式(V”)所示化合物;
将所述式(V”)所示化合物进行水解反应,得到式(VI”)所示化合 物;以及
将所述式(VI”)所示的化合物进行缩合反应,得到所述式(VII”)所示化合物。
详述
在以下的说明中,包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而,相关领域的技术人员会认识到,不采用一个或多个这些具体的细节,而采用其它方法、部件、材料等的情况下仍实现实施方案。
除非本申请中另有要求,在整个说明书和所附的权利要求书中,词语“包括”、“包含”、“含有”和“具有”应解释为开放式的、含括式的意义,即“包括但不限于”。
在本公开和所附权利要求书中使用时,除非上下文另有明确规定,否则不带数量指示的单数指称物包括复数指称物。
在整个说明书中提到的“一实施方案”、“实施方案”、“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此,在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外,具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解,在本公开的说明书和所附的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象,除非文中另外明确地规定。
定义
因此,除非另有相反的说明,否则说明书及所附权利要求中所用的下列术语具有以下的意思:
本公开中命名的某些化学基团前面所置的简写符号表示在所指示的化学基团存在的碳原子总数。例如,C
1-C
4烷基描述如下文所定义的 具有总共1至4个碳原子的烷基,而C
3-C
10环烷基描述如下文所定义的具有总共3至10个碳原子的环烷基。简写符号中的碳总数不包含可能存在于所述基团的取代基中的碳。
在本公开中,术语“烃基”系指脂肪族烃基团。烃基部分可以是“饱和的烃基”基团,意为其不包含任何烯或炔部分,也即烷基。烃基部分还可以是“不饱和的烃基”部分,意为其包含至少一个烯或炔部分。“烯”部分,也即烯基,是指由两至八个碳原子和至少一个碳-碳双键组成的基团,并且由单键与分子的其余部分连接的直链或支链烃链基团,例如乙烯基、丙-1-烯基、丁-1-烯基、戊-1-烯基、戊-1,4-二烯基等,并且“炔”部分是指由两至八个碳原子和至少一个碳-碳三键组成的基团,并且由单键与分子的其余部分连接的直链或支链烃链基团。烃基部分,无论饱和的或不饱和的,可以是支链的或直链的。
烃基基团可具有1至8个碳原子(在本公开中每次出现时,诸如“1至8”的数值范围是指给定范围中的每一整数;如“1至8”意为所述烃基基团可由1个碳原子、2个碳原子、3个碳原子、4个碳原子等直至并包括8个碳原子,尽管本定义还涵盖未指定数值范围的术语“烃基”的出现)。
烃基基团可以是任意取代的,亦即取代或未取代的。当被取代时,取代基团是单独地并且独立地选自下列的一个或多个基团:环烃基、芳基、杂芳基、杂脂环基、羟基、烃氧基、芳氧基、巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合(isocyanato)、氰硫基、异硫氰酸根合(isothiocyanato)、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或包括单-和二-取代的氨基基团在内的氨基,及其被保护的衍生物。通常烃基基团包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、乙烯基、丙烯基、丁烯基、乙炔基、丙炔基和丁炔基。每当取代基被描述为被“任意取代的”时,取代基可被上述取代基之一取代。
在本公开中,术语“芳基”是指具有完全离域的Pi电子体系的碳环(全碳)或两个或多个稠合环(共享两个相邻碳原子的环)。芳基基团包括但不限于芴基、苯基及萘基。芳基基团例如可以具有五至十二个碳原子。本公开的芳基基团可以是取代的或未取代的。当被取代时,氢原子被一个或多个独立地选自下列取代基的基团取代:烃基、环烃基、芳基、杂芳基、杂脂环基、羟基、被保护的羟基、烃氧基、芳氧基、巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、Ν-硫代氨基甲酰基、C-酰氨基、Ν-酰氨基、S-亚磺酰氨基、Ν-亚磺酰氨基、C-羧基、被保护的C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或被保护的氨基。每当取代基被描述为被“任意取代的”时,取代基可被上述取代基之一取代。
在本公开中,术语“杂芳基”系指是指由一至十七个碳原子和一至十个选自氮、氧及硫的杂原子组成的5元至18元芳族环基。在某些实施方案中,杂芳基可为单环、双环、三环或四环环系统,其可包含经稠合或桥接的环系统;且杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。杂芳基的示例性实例包括但不限于氮杂卓基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并二氧杂环戊烯基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、苯并[b][1,4]二氧杂环庚基、1,4-苯并二噁烷基、苯并萘呋喃基、苯并噁唑基、苯并二氧杂环戊烯基、苯并二氧杂环己烯基、苯并吡喃基、苯并吡喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、噌啉基、二苯并呋喃基、二苯并噻吩基、呋喃基、呋喃酮基、异噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、异吲哚基、吲哚啉基、异吲哚啉基、异喹啉基、吲哚嗪基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂卓基、噁唑基、环氧乙基、1-苯基-1H-吡咯基、菲嗪基、菲噻嗪基、菲噁嗪基、酞嗪基、喋啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、喹唑啉基、喹噁啉基、喹啉基、奎宁环基、异喹啉基、 四氢喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基和噻吩基。本公开的杂芳基基团可以是取代的或未取代的。当被取代时,氢原子被一个或多个独立地选自下列取代基的基团取代:烃基、环烃基、芳基、杂芳基、杂脂环基、羟基、被保护的羟基、烃氧基、芳氧基、巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、Ν-硫代氨基甲酰基、C-酰氨基、Ν-酰氨基、S-亚磺酰氨基、Ν-亚磺酰氨基、C-羧基、被保护的C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或被保护的氨基。每当取代基被描述为被“任意取代的”时,取代基可被上述取代基之一取代。
在本公开中,术语“环烃基”系指仅由碳和氢原子组成的,具有三至十五个碳原子的,在某些实施方案中具有三至十二个碳原子的,并且其为饱和或不饱和的,并且通过单键与分子的其余部分相连的稳定的非芳香族单环或双环烃基团,例如环丙基、环丁基、环戊基、环己基、环癸基等。除非本公开中另有明确说明,否则术语“环烃基”旨在包括被一个或多个选自如下取代基的基团所任意取代的上述定义的环烃基:环烃基、芳基、杂芳基、杂脂环基、羟基、烃氧基、芳氧基、巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰基氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或包括单-和二-取代的氨基基团在内的氨基,及其被保护的衍生物。
在本公开中,术语“基本完成”的反应是指反应物含有超过约80%(%收率)、更优选超过约90%(%收率)、甚至更优选超过约95%(%收率)和最优选超过约97%(%收率)的所需产物。
在本公开中,术语“约”用于明确所给数值是近似的。例如,在表示反应温度时,术语“约”表示所指温度包括偏差在30%、25%、20%、15%、10%或5%范围内的温度。同样,在表示反应时间时,术 语“约”表示所指时间包括偏差在30%、25%、20%、15%、10%或5%范围内的时间。
在本公开中,术语1类溶剂是指,ICH Q3C(R8)中的1类溶剂,是一类在医药生产中应避免使用的溶剂,该类溶剂是已知的人体致癌物,强疑似人体致癌物,以及环境危害物,更具体的是指:苯、四氯化碳、1,2-二氯乙烷、1,1-二氯乙烯、1,1,1-三氯乙烷。
在本公开中,术语2类溶剂是指,ICH Q3C(R8)中的2类溶剂,是一类在医药生产中应限制使用的溶剂,该类溶剂是非遗传毒性动物致癌物,或可能导致其他不可逆毒性如神经毒性或致畸性的溶剂,可能有其他严重但可逆的毒性的溶剂,更具体的是指:乙腈、氯苯、氯仿、异丙基苯、环己烷、环戊基甲基醚、1,2-二氯乙烯、二氯甲烷、1,2-二甲氧基乙烷、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、1,4-二噁烷、2-乙氧基乙醇、乙二醇、甲酰胺、己烷、甲醇、2-甲氧基乙醇、甲基丁基酮、甲基环己烷、甲基异丁基酮、N-甲基吡咯烷酮、硝基甲烷、吡啶、环丁砜、叔丁醇、四氢呋喃、四氢萘、甲苯、1,1,2-三氯乙烯、二甲苯。
在本公开中,术语3类溶剂是指,ICH Q3C(R8)中的3类溶剂,是一类在医药生产中低潜在毒性的溶剂,该类溶剂对人体低潜在毒性,无须制定基于健康的暴露程度,更具体的是指:乙酸、丙酮、苯甲醚、1-丁醇、2-丁醇、乙酸丁酯、叔丁基甲基醚、二甲基亚砜、乙醇、乙酸乙酯、乙醚、甲酸甲酯、甲酸、庚烷、乙酸异丁酯、乙酸异丙酯、乙酸甲酯、3-甲基-1-丁醇、甲基乙基酮、2-甲基-1-丙醇、2-甲基四氢呋喃、戊烷、1-戊醇、1-丙醇、2-丙醇、乙酸丙酯、三乙胺。
如果在描绘的结构和给出的该结构的名称之间有出入,则应该偏重于该描述的结构。另外,如果结构或结构的一部分的立体化学没有用例如加粗或虚线标出,则该结构或该结构的一部分应该被解释为包括该结构的所有立体异构体。
一方面,本公开涉及制备式(VII)所示化合物的方法,
所述方法包括将式(VI)或式(VIII)所示的化合物进行缩合反应,
在某些实施方案中,能够用于本公开的制备式(VII)所示化合物的缩合反应的试剂的示例性实例包括但不限于N,N’-羰基二咪唑(CDI)、二环己基碳二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC·HCl)、二氯亚砜(SOCl
2)、草酰氯((COCl)
2)、乙酰氯(AcCl)、乙酸酐(Ac
2O)、N,N-二甲基甲酰胺(DMF)及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VII)所示化合物的缩合反应的试剂的示例性实例包括但不限于二氯亚砜(SOCl
2)/N,N-二甲基甲酰胺(DMF)、草酰氯((COCl)
2)/N,N-二甲基甲酰胺(DMF)或乙酰氯(AcCl)/N,N-二甲基甲酰胺(DMF)的组合。
在某些实施方案中,能够用于本公开的制备式(VII)所示化合物的缩合反应的试剂的示例性实例包括但不限于N,N’-羰基二咪唑(CDI)、二环己基碳二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC·HCl)、二氯亚砜(SOCl
2)、草酰氯((COCl)
2)、乙酰氯(AcCl)、乙酸酐(Ac
2O)、N,N-二甲基甲酰胺(DMF)、二氯亚砜(SOCl
2)/N,N-二甲基甲酰胺(DMF)、草酰氯((COCl)
2)/N,N-二甲基甲酰胺(DMF)或乙酰氯 (AcCl)/N,N-二甲基甲酰胺(DMF)的组合进行制备式(VII)所示化合物的缩合反应,上述反应试剂与式(VI)所示化合物或式(VIII)所示的化合物的重量比为约1:1至约3:1。
在某些实施方案中,能够用于本公开的制备式(VII)所示化合物的缩合反应的溶剂的示例性实例包括但不限于四氢呋喃、二氯甲烷(DCM)、乙酸酐(Ac
2O)及其任意混合物。
在某些实施方案中,在约-5至约150℃进行制备式(VII)所示化合物的缩合反应。
在某些实施方案中,在约-10至约40℃进行制备式(VII)所示化合物的缩合反应。
在某些实施方案中,在约20至约30℃进行制备式(VII)所示化合物的缩合反应。
在某些实施方案中,对式(VII)所示化合物进行重结晶。
在某些实施方案中,能够用于本公开的对式(VII)所示化合物进行重结晶的溶剂的示例性实例包括但不限于乙腈/异丙醇、乙酸乙酯、乙腈/水、四氢呋喃/水及其任意混合物。
另一方面,本公开涉及制备式(VI)所示化合物的方法,
所述方法包括将式(V)所示化合物进行水解反应,
在某些实施方案中,在碱性条件下进行制备式(VI)所示化合物的水解反应。
在某些实施方案中,能够用于本公开的制备式(VI)所示化合物的水解反应的盐的示例性实例例包括但不限于钾盐、钠盐、锂盐及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VI)所示化合物的水解反应的盐的示例性实例包括但不限于氢氧化钾、碳酸钾、碳酸氢钾、氢氧化钠、碳酸钠、氢氧化锂、碳酸锂及其任意混合物。
在某些实施方案中,在约-5至约35℃进行本公开的制备式(VI)所示化合物的水解反应。
在某些实施方案中,在约0至约35℃进行本公开的制备式(VI)所示化合物的水解反应。
在某些实施方案中,在约20至约30℃进行本公开的制备式(VI)所示化合物的水解反应。
在某些实施方案中,能够用于本公开的式(VI)所示化合物的溶剂的示例性实例包括但不限于乙醇/水、甲醇/水、异丙醇/水、乙腈/丙酮/水、乙腈/丙酮、乙酸乙酯、四氢呋喃、四氢呋喃/水、丙酮/水及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VI)所示化合物的式(V)所示化合物与能够用于本公开的制备式(VI)所示化合物的水解反应的盐的摩尔比为约1:1至约1:10。
在某些实施方案中,能够用于本公开的制备式(VI)所示化合物的式(V)所示化合物与能够用于本公开的制备式(VI)所示化合物的水解 反应的盐的摩尔比为约1:1至1:6。
在某些实施方案中,能够用于本公开的制备式(VI)所示化合物的式(V)所示化合物与能够用于本公开的制备式(VI)所示化合物的水解反应的盐的摩尔比为约1:5。
再一方面,本公开涉及制备式(V)所示化合物的方法,
所述方法包括将式(IV)所示化合物进行缩合反应,
在某些实施方案中,能够用于本公开的制备式(V)所示化合物的缩合反应的试剂的示例性实例包括但不限于乙酰氯(AcCl)、乙酸酐(Ac
2O)及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(V)所示化合物的缩合反应的试剂的示例性实例包括但不限于4-二甲氨基吡啶(DMAP)、N-甲基吗啉(NMM)、三乙胺(TEA)、吡啶(Py)、N,N-二异丙基乙胺(DIEA)、吡啶(Py)及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(V)所示化合物的缩 合反应的试剂的示例性实例包括但不限于Ac
2O、Ac
2O/DMAP、Ac
2O/DMAP/NMM、CH
3COCl/TEA/DCM/DMAP或CH
3COCl/Py制备式(V)所示化合物。
在某些实施方案中,能够用于本公开的制备式(V)所示化合物的缩合反应的溶剂的示例性实例包括但不限于乙酸酐、二氯甲烷(DCM)、吡啶(Py)、四氢呋喃、乙腈、丙酮、乙酸乙酯及其任意混合物。
在某些实施方案中,在约0至约150℃进行本公开的制备式(V)所示化合物的缩合反应。
在某些实施方案中,在约90至约150℃进行本公开的制备式(V)所示化合物的缩合反应。
在某些实施方案中,在约125至约140℃进行本公开的制备式(V)所示化合物的缩合反应。
在某些实施方案中,能够用于纯化本公开的式(V)所示化合物的溶剂的示例性实例包括但不限于乙醇、甲基叔丁基醚(MTBE)、甲醇、乙酸乙酯、正己烷、乙醚、四氢呋喃(THF)及其任意混合物。
又一方面,本公开涉及制备式(IV)所示化合物的方法,
所述方法包括将式(II)所示化合物与式(III)所示化合物进行缩合反应,得到所述式(IV)所示化合物,
在某些实施方案中,能够用于本公开的制备式(IV)所示化合物的缩合剂的示例性实例包括但不限于碳二亚胺型缩合剂、磷正离子型缩合剂、脲正离子型缩合剂、其他合适的缩合剂及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(IV)所示化合物的碳二亚胺型缩合剂的示例性实例包括但不限于1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC的盐酸盐)和二环己基碳二亚胺(DCC)。
在某些实施方案中,能够用于本公开的制备式(IV)所示化合物的磷正离子型缩合剂的示例性实例包括但不限于1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PyBOP)、三吡咯烷基溴化鏻六氟磷酸盐(PyBrOP)和苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)。
在某些实施方案中,能够用于本公开的制备式(IV)所示化合物的脲正离子型缩合剂的示例性实例包括但不限于N,N,N’,N’-四甲基-O-(1H-苯并三唑-1-基)脲六氟磷酸盐(HBTU)和2-(7-氧化苯并三氮 唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)。
在某些实施方案中,能够用于本公开的制备式(IV)所示化合物的其他合适的缩合剂的示例性实例包括但不限于1-羟基苯并三氮唑(HOBt)、6-氯-1-羟基苯并三氮唑(Cl-HOBt)、N-羟基-7-氮杂苯并三氮唑(HOAt)、双(2-氧代-3-噁唑烷基)次磷酰氯(BOP-Cl)、3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮(DEPBT)、N-羟基琥珀酰亚胺(HOSu)和五氟苯酚。
在某些实施方案中,能够用于本公开的制备式(IV)所示化合物的溶剂的示例性实例包括但不限于二氯甲烷、三氯甲烷、乙腈、甲苯、四氢呋喃、二氧六环及其任意混合物。
在某些实施方案中,在约0至约50℃进行本公开的制备式(IV)所示化合物的缩合反应。
在某些实施方案中,在约25至约35℃进行本公开的制备式(IV)所示化合物的缩合反应。
在某些实施方案中,制备本公开的式(IV)所示化合物的缩合反应,式(III)与式(II)的投料量重量比为约1:1.3-约1:1.4。
在某些实施方案中,制备本公开的式(IV)所示化合物的缩合反应,式(III)与式(II)的投料量重量比为约1:1.35-约1:1.4。
在某些实施方案中,制备本公开的式(IV)所示化合物的缩合反应,式(III)与式(II)的投料量重量比为约1:1.36。
另一方面,本公开涉及制备式(III)所示化合物的方法,
所述方法包括将通式(I)化合物进行反应,
其中R
1≠R
2,R
1和R
2选自取代或未取代的烷基、取代或未取代的烯基、取代或未取代的芳基。
在某些实施方案中,R
1和R
2各自独立的选自取代或未取代的C
1-C
6烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
6-C
12芳基。
在某些实施方案中,R
1和R
2各自独立的选自甲基、乙基、丙基、叔丁基、苄基或烯丙基。
在某些实施方案中,能够用于本公开的制备式(III)所示化合物的示例性实例包括但不限于三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(III)所示化合物的示例性实例三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或及其任意混合物与式(I)所示化合物的重量比为约1.5:1-约1:1。
在某些实施方案中,能够用于本公开的制备式(III)所示化合物的示例性实例三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或及其任意混合物与式(I)所示化合物的重量比为约1.1:1至约1:1。
在某些实施方案中,能够用于本公开的制备式(III)所示化合物的示例性实例三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或及其任意混合物与式(I)所示化合物的重量比为约1.02:1。
在某些实施方案中,能够用于本公开的制备式(III)所示化合物的溶剂的示例性实例包括但不限于二氯甲烷、甲苯、二氯乙烷、乙酸乙酯、四氢呋喃、1,4-二氧六环、甲醇、乙醇或及其任意混合物。
在某些实施方案中,在-20至0℃进行本公开的制备式(III)所示化合物的反应。
在某些实施方案中,在-15至-5℃进行本公开的制备式(III)所示化合物的反应。
在某些实施方案中,能够用于本公开的制备式(III)所示化合物的示例性实例包括但不限于钯碳、四三苯基膦钯或及其任意混合物。
再一方面,本公开涉及制备式(VII)所示化合物的方法,其包括
将通式(I)化合物进行反应,得到式(III)所示化合物;
将式(III)所示化合物与所述式(II)所示化合物进行缩合反应,得到式(IV)所示化合物;
将所述式(IV)所示化合物进行缩合反应,得到式(V)所示化合物;
将所述式(V)所示化合物进行水解反应,得到式(VI)所示化合物;以及
将所述式(VI)所示的化合物进行缩合反应,得到所述式(VII)所示化合物。
一方面,本公开涉及制备式(VII)所示化合物的方法,
所述方法包括将式(VIII)所示的化合物进行缩合反应。
在某些实施方案中,能够用于本公开的制备式(VII)所示化合物的缩合反应的试剂的示例性实例包括但不限于N,N’-羰基二咪唑(CDI)、二环己基碳二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、 EDCI(EDC·HCl)、二氯亚砜(SOCl
2)、草酰氯((COCl)
2)、乙酰氯(AcCl)、乙酸酐(Ac
2O)、N,N-二甲基甲酰胺(DMF)及其任意混合物。
在某些实施方案中,使用二氯亚砜(SOCl
2)/N,N-二甲基甲酰胺(DMF)、草酰氯((COCl)
2)/N,N-二甲基甲酰胺(DMF)或乙酰氯(AcCl)/N,N-二甲基甲酰胺(DMF)的组合进行制备式(VII)所示化合物的缩合反应。
在某些实施方案中,使用二氯亚砜(SOCl
2)/N,N-二甲基甲酰胺(DMF)、草酰氯((COCl)
2)/N,N-二甲基甲酰胺(DMF)或乙酰氯(AcCl)/N,N-二甲基甲酰胺(DMF)的组合进行制备式(VII)所示化合物的缩合反应,上述反应试剂与式(VIII)所示化合物的重量比为约1:1至约3:1。
在某些实施方案中,能够用于本公开的制备式(VII)所示化合物的缩合反应的溶剂的示例性实例包括但不限于四氢呋喃、二氯甲烷(DCM)、乙酸酐(Ac
2O)及其任意混合物。
在某些实施方案中,在约-5至约150℃进行制备式(VII)所示化合物的缩合反应。
在某些实施方案中,在约-10至约40℃进行制备式(VII)所示化合物的缩合反应。
在某些实施方案中,在约20至约30℃进行制备式(VII)所示化合物的缩合反应。
在某些实施方案中,对式(VII)所示化合物进行重结晶。
在某些实施方案中,能够用于本公开的对式(VII)所示化合物进行重结晶的溶剂的示例性实例包括但不限于乙腈/异丙醇、乙酸乙酯、乙腈/水、四氢呋喃/水及其任意混合物。
另一方面,本公开涉及制备式(VIII)所示化合物的方法,
所述方法包括将式(IX)所示化合物进行水解反应,
在某些实施方案中,在碱性条件下进行制备式(VIII)所示化合物的水解反应。
在某些实施方案中,能够用于本公开的制备式(VIII)所示化合物的水解反应的盐的示例性实例包括但不限于钾盐、钠盐、锂盐及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VIII)所示化合物的水解反应的盐的示例性实例包括但不限于氢氧化钾、碳酸钾、碳酸氢钾、氢氧化钠、碳酸钠、氢氧化锂、碳酸锂及其任意混合物。
在某些实施方案中,在约-5至约35℃进行本公开的制备式(VIII)所示化合物的水解反应。
在某些实施方案中,在约0至约35℃进行本公开的制备式(VIII)所示化合物的水解反应。
在某些实施方案中,在约20至约30℃进行本公开的制备式(VIII)所示化合物的水解反应。
在某些实施方案中,能够用于纯化本公开的式(VIII)所示化合物的溶剂的示例性实例包括但不限于乙醇/水、甲醇/水、异丙醇/水、乙腈/丙酮/水、乙腈/丙酮、乙酸乙酯、四氢呋喃、四氢呋喃/水及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VIII)所示化合物的式(V)所示化合物与能够用于本公开的制备式(VIII)所示化合物的水解反应的盐的摩尔比为约1:1至约1:10。
在某些实施方案中,能够用于本公开的制备式(VIII)所示化合物的式(V)所示化合物与能够用于本公开的制备式(VIII)所示化合物的水解反应的盐的摩尔比为约1:1至约1:6。
在某些实施方案中,能够用于本公开的制备式(VIII)所示化合物的式(V)所示化合物与能够用于本公开的制备式(VIII)所示化合物的水解反应的盐的摩尔比为约1:5。
再一方面,本公开涉及制备式(IX)所示化合物的方法,
所述方法包括将式(X)所示化合物进行缩合反应,
在某些实施方案中,能够用于本公开的制备式(IX)所示化合物的缩合反应的试剂的示例性实例包括但不限于乙酰氯(AcCl)、乙酸酐(Ac
2O)及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(IX)所示化合物的缩合反应的试剂的示例性实例包括但不限于4-二甲氨基吡啶(DMAP)、N-甲基吗啉(NMM)、三乙胺(TEA)、吡啶(Py)、N,N-二异丙基乙胺(DIEA)、吡啶(Py)及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(IX)所示化合物的缩合反应的试剂的示例性实例包括但不限于Ac
2O、Ac
2O/DMAP、Ac
2O/DMAP/NMM、CH
3COCl/TEA/DCM/DMAP或CH
3COCl/Py。
在某些实施方案中,能够用于本公开的制备式(IX)所示化合物的缩合反应的溶剂的示例性实例包括但不限于乙酸酐、二氯甲烷(DCM)、吡啶(Py)、四氢呋喃、乙腈、丙酮、乙酸乙酯及其任意混合物。
在某些实施方案中,在约0至约150℃进行本公开的制备式(IX)所示化合物的缩合反应。
在某些实施方案中,在约90至约150℃进行本公开的制备式(IX)所示化合物的缩合反应。
在某些实施方案中,在约125至约140℃进行本公开的制备式(IX)所示化合物的缩合反应。
在某些实施方案中,能够用于纯化本公开的式(IX)所示化合物的溶剂的示例性实例包括但不限于乙醇、甲基叔丁基醚(MTBE)、甲醇、乙酸乙酯、正己烷、乙醚、四氢呋喃(THF)及其任意混合物。
又一方面,本公开涉及制备式(X)所示化合物的方法,
所述方法包括将式(II)所示化合物与式(XI)所示化合物进行缩合反应,得到所述式(X)所示化合物,
在某些实施方案中,能够用于本公开的制备式(X)所示化合物的缩合剂的示例性实例包括但不限于碳二亚胺型缩合剂、磷正离子型缩合剂、脲正离子型缩合剂、其他合适的缩合剂及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(X)所示化合物的碳 二亚胺型缩合剂的示例性实例包括但不限于1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC的盐酸盐)和二环己基碳二亚胺(DCC)。
在某些实施方案中,能够用于本公开的制备式(X)所示化合物的磷正离子型缩合剂的示例性实例包括但不限于1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PyBOP)、三吡咯烷基溴化鏻六氟磷酸盐(PyBrOP)和苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)。
在某些实施方案中,能够用于本公开的制备式(X)所示化合物的脲正离子型缩合剂的示例性实例包括但不限于N,N,N’,N’-四甲基-O-(1H-苯并三唑-1-基)脲六氟磷酸盐(HBTU)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)。
在某些实施方案中,能够用于本公开的制备式(X)所示化合物的其他合适的缩合剂的示例性实例包括但不限于1-羟基苯并三氮唑(HOBt)、6-氯-1-羟基苯并三氮唑(Cl-HOBt)、N-羟基-7-氮杂苯并三氮唑(HOAt)、双(2-氧代-3-噁唑烷基)次磷酰氯(BOP-Cl)、3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮(DEPBT)、N-羟基琥珀酰亚胺(HOSu)和五氟苯酚。
在某些实施方案中,能够用于本公开的制备式(X)所示化合物的溶剂的示例性实例包括但不限于二氯甲烷、三氯甲烷、甲苯、四氢呋喃、二氧六环及其任意混合物。
在某些实施方案中,在约0至约50℃进行本公开的制备式(X)所示化合物的缩合反应。
在某些实施方案中,在约25至约35℃进行本公开的制备式(X)所示化合物的缩合反应。
在某些实施方案中,制备本公开的式(X)所示化合物的缩合反应,式(XI)与式(II)的投料量重量比为约1:1.3至约1:1.4。
在某些实施方案中,制备本公开的式(X)所示化合物的缩合反应,式(XI)与式(II)的投料量重量比为约1:1.35至约1:1.4。
在某些实施方案中,制备本公开的式(X)所示化合物的缩合反应,式(XI)与式(II)的投料量重量比为约1:1.36。
另一方面,本公开涉及制备式(XI)所示化合物的方法,
所述方法包括将通式(I)化合物进行反应,
其中R
1≠R
2,R
1和R
2选自取代或未取代的烷基、取代或未取代的烯基、取代或未取代的芳基。
在某些实施方案中,R
1和R
2各自独立的选自取代或未取代的C
1-C
6烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
6-C
12芳基。
在某些实施方案中,R
1和R
2各自独立的选自甲基、乙基、丙基、叔丁基、苄基或烯丙基。
在某些实施方案中,能够用于本公开的制备式(XI)所示化合物的示例性实例包括但不限于三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(XI)所示化合物的示例性实例三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或及其任意混合物与式(I)所示化合物的重量比为约1.5:1至约1:1。
在某些实施方案中,能够用于本公开的制备式(XI)所示化合物的示例性实例三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或及其任意混合物与式(I)所示化合物的重量比为约1.1:1至约1:1。
在某些实施方案中,能够用于本公开的制备式(XI)所示化合物的示例性实例三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或及其任意混合物与式(I)所示化合物的重量比为约1.02:1。
在某些实施方案中,能够用于本公开的制备式(XI)所示化合物的 溶剂的示例性实例包括但不限于二氯甲烷、苯、甲苯、二氯乙烷、乙酸乙酯、四氢呋喃、1,4-二氧六环、甲醇、乙醇或及其任意混合物。
在某些实施方案中,在约-20至约0℃进行本公开的制备式(XI)所示化合物的反应。
在某些实施方案中,在约-15至约-5℃进行本公开的制备式(XI)所示化合物的反应。
在某些实施方案中,能够用于本公开的制备式(XI)所示化合物的示例性实例包括但不限于钯碳、四三苯基膦钯或及其任意混合物。
再一方面,本公开涉及制备式(VII)所示化合物的方法,其包括
将通式(I)化合物进行反应,得到式(XI)所示化合物;
将式(XI)所示化合物与所述式(II)所示化合物进行缩合反应,得到式(X)所示化合物;
将所述式(X)所示化合物进行缩合反应,得到式(IX)所示化合物;
将所述式(IX)所示化合物进行水解反应,得到式(VIII)所示化合物;以及
将所述式(VIII)所示的化合物进行缩合反应,得到所述式(VII)所示化合物。
一方面,本公开涉及制备式(VII’)所示化合物的方法,
所述方法包括将式(VI’)所示的化合物进行缩合反应,
在某些实施方案中,能够用于本公开的制备式(VII’)所示化合物的缩合反应的试剂的示例性实例包括但不限于N,N’-羰基二咪唑(CDI)、二环己基碳二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC·HCl)、二氯亚砜(SOCl
2)、草酰氯((COCl)
2)、乙酰氯(AcCl)、乙酸酐(Ac
2O)、N,N-二甲基甲酰胺(DMF)及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VII’)所示化合物的缩合反应的试剂的示例性实例包括但不限于二氯亚砜(SOCl
2)/N,N-二甲基甲酰胺(DMF)、草酰氯((COCl)
2)/N,N-二甲基甲酰胺(DMF)或乙酰氯(AcCl)/N,N-二甲基甲酰胺(DMF)的组合进行制备式(VII’)所示化合物的缩合反应。
在某些实施方案中,能够用于本公开的制备式(VII’)所示化合物的缩合反应的试剂的示例性实例包括但不限于N,N’-羰基二咪唑(CDI)、二环己基碳二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC·HCl)、二氯亚砜(SOCl
2)、草酰氯((COCl)
2)、乙酰氯(AcCl)、乙酸酐(Ac
2O)、N,N-二甲基甲酰胺(DMF)、二氯亚砜(SOCl
2)/N,N-二甲基甲酰胺(DMF)、草酰氯((COCl)
2)/N,N-二甲基甲酰胺(DMF)或乙酰氯(AcCl)/N,N-二甲基甲酰胺(DMF)的组合进行制备式(VII’)所示化合物的缩合反应,上述反应试剂与式(VI’)所示化合物的重量比为约1:1至约3:1。
在某些实施方案中,能够用于本公开的制备式(VII’)所示化合物的缩合反应的溶剂的示例性实例包括但不限于四氢呋喃、二氯甲烷(DCM)、乙酸酐(Ac
2O)及其任意混合物。
在某些实施方案中,在约-5至约150℃进行制备式(VII’)所示化合物的缩合反应。
在某些实施方案中,在约-10至约40℃进行制备式(VII’)所示化合物的缩合反应。
在某些实施方案中,在约20至约30℃进行制备式(VII’)所示化合物的缩合反应。
在某些实施方案中,对式(VII’)所示化合物进行重结晶。
在某些实施方案中,能够用于本公开的对式(VII’)所示化合物进行重结晶的溶剂的示例性实例包括但不限于乙腈/异丙醇、乙酸乙酯、乙腈/水、四氢呋喃/水及其任意混合物。
另一方面,本公开涉及制备式(VI’)所示化合物的方法,
所述方法包括将式(V’)所示化合物进行水解反应,
在某些实施方案中,在碱性条件下进行制备式(VI’)所示化合物的水解反应。
在某些实施方案中,能够用于本公开的制备式(VI’)所示化合物的水解反应的盐的示例性实例包括但不限于钾盐、钠盐、锂盐及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VI’)所示化合物的水解反应的盐的示例性实例包括但不限于氢氧化钾、碳酸钾、碳酸氢钾、氢氧化钠、碳酸钠、氢氧化锂、碳酸锂及其任意混合物。
在某些实施方案中,在约-5至约35℃进行本公开的制备式(VI’)所示化合物的水解反应。
在某些实施方案中,在约0至约35℃进行本公开的制备式(VI’)所示化合物的水解反应。
在某些实施方案中,在约20至约30℃进行本公开的制备式(VI’)所示化合物的水解反应。
在某些实施方案中,能够用于本公开的式(VI’)所示化合物的溶剂的示例性实例包括但不限于乙醇/水、甲醇/水、异丙醇/水、乙腈/丙酮/水、乙腈/丙酮、乙酸乙酯、四氢呋喃、四氢呋喃/水、、丙酮/水及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VI’)所示化合物的式(V’)所示化合物与能够用于本公开的制备式(VI’)所示化合物的水解反应的盐的摩尔比为约1:1至约1:10。
在某些实施方案中,能够用于本公开的制备式(VI’)所示化合物的式(V’)所示化合物与能够用于本公开的制备式(VI’)所示化合物的水解反应的盐的摩尔比为约1:1至约1:6。
在某些实施方案中,能够用于本公开的制备式(VI’)所示化合物的式(V’)所示化合物与能够用于本公开的制备式(VI’)所示化合物的水解反应的盐的摩尔比为约1:5。
再一方面,本公开涉及制备式(V’)所示化合物的方法,
所述方法包括将式(IV’)所示化合物进行缩合反应,
在某些实施方案中,能够用于本公开的制备式(V’)所示化合物的缩合反应的试剂的示例性实例包括但不限于乙酰氯(AcCl)、乙酸酐(Ac
2O)及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(V’)所示化合物的缩合反应的试剂的示例性实例包括但不限于4-二甲氨基吡啶(DMAP)、N-甲基吗啉(NMM)、三乙胺(TEA)、二氯甲烷(DCM)、吡啶(Py)、N,N-二异丙基乙胺(DIEA)及其任意混合物。
某些实施方案中,能够用于本公开的制备式(V’)所示化合物的缩合反应的试剂的示例性实例包括但不限于Ac
2O、Ac
2O/DMAP、Ac
2O/DMAP/NMM、CH
3COCl/TEA/DCM/DMAP或CH
3COCl/Py制备式(V’)所示化合物。
在某些实施方案中,能够用于本公开的制备式(V’)所示化合物的 缩合反应的溶剂的示例性实例包括但不限于乙酸酐、二氯甲烷(DCM)、吡啶(Py)、四氢呋喃、乙腈、丙酮、乙酸乙酯及其任意混合物。
在某些实施方案中,在约0至约150℃进行本公开的制备式(V’)所示化合物的缩合反应。
在某些实施方案中,在约90至约150℃进行本公开的制备式(V’)所示化合物的缩合反应。
在某些实施方案中,在约125至约140℃进行本公开的制备式(V’)所示化合物的缩合反应。
在某些实施方案中,能够用于纯化本公开的式(V’)所示化合物的溶剂的示例性实例包括但不限于乙醇、甲基叔丁基醚(MTBE)、甲醇、乙酸乙酯、正己烷、乙醚、四氢呋喃(THF)及其任意混合物。
又一方面,本公开涉及制备式(IV’)所示化合物的方法,
所述方法包括将式(III)所示化合物与式(II’)所示化合物进行缩合反应,得到所述式(IV’)所示化合物,
在某些实施方案中,能够用于本公开的制备式(IV’)所示化合物的缩合剂的示例性实例包括但不限于碳二亚胺型缩合剂、磷正离子型缩合剂、脲正离子型缩合剂、其他合适的缩合剂及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(IV’)所示化合物的碳二亚胺型缩合剂的示例性实例包括但不限于1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC的盐酸盐)和二环己基碳二亚胺(DCC)。
在某些实施方案中,能够用于本公开的制备式(IV’)所示化合物的磷正离子型缩合剂的示例性实例包括但不限于1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PyBOP)、三吡咯烷基溴化鏻六氟磷酸盐(PyBrOP)和苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)。
在某些实施方案中,能够用于本公开的制备式(IV’)所示化合物的脲正离子型缩合剂的示例性实例包括但不限于N,N,N’,N’-四甲基-O-(1H-苯并三唑-1-基)脲六氟磷酸盐(HBTU)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)。
在某些实施方案中,能够用于本公开的制备式(IV’)所示化合物的其他合适的缩合剂的示例性实例包括但不限于1-羟基苯并三氮唑(HOBt)、6-氯-1-羟基苯并三氮唑(Cl-HOBt)、N-羟基-7-氮杂苯并三氮唑(HOAt)、双(2-氧代-3-噁唑烷基)次磷酰氯(BOP-Cl)、3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮(DEPBT)、N-羟基琥珀酰亚胺(HOSu)和五氟苯酚。
在某些实施方案中,能够用于本公开的制备式(IV’)所示化合物的 溶剂的示例性实例包括但不限于二氯甲烷、三氯甲烷、乙腈、甲苯、四氢呋喃、二氧六环及其任意混合物。
在某些实施方案中,在约0至约50℃进行本公开的制备式(IV’)所示化合物的缩合反应。
在某些实施方案中,在约25至约35℃进行本公开的制备式(IV’)所示化合物的缩合反应。
在某些实施方案中,制备本公开的式(IV’)所示化合物的缩合反应,式(III)与式(II’)的投料量重量比为约1:1.3-约1:1.4。
在某些实施方案中,制备本公开的式(IV’)所示化合物的缩合反应,式(III)与式(II’)的投料量重量比为约1:1.35至约1:1.4。
在某些实施方案中,制备本公开的式(IV’)所示化合物的缩合反应,式(III)与式(II’)的投料量重量比为约1:1.36。
再一方面,本公开涉及制备式(VII’)所示化合物的方法,其包括
将通式(I)化合物进行反应,得到式(III)所示化合物;
将式(III)所示化合物与所述式(II’)所示化合物进行缩合反应,得到式(IV’)所示化合物;
将所述式(IV’)所示化合物进行缩合反应,得到式(V’)所示化合物;
将所述式(V’)所示化合物进行水解反应,得到式(VI’)所示化合物;以及
将所述式(VI’)所示的化合物进行缩合反应,得到所述式(VII’)所示化合物。
一方面,本公开涉及制备式(VII”)所示化合物的方法,
所述方法包括将式(VI”)所示的化合物进行缩合反应.
在某些实施方案中,能够用于本公开的制备式(VII”)所示化合物的缩合反应的试剂的示例性实例包括但不限于N,N’-羰基二咪唑(CDI)、二环己基碳二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC·HCl)、二氯亚砜(SOCl
2)、草酰氯((COCl)
2)、乙酰氯(AcCl)、乙酸酐(Ac
2O)、N,N-二甲基甲酰胺(DMF)及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VII”)所示化合物的缩合反应的试剂的示例性实例包括但不限于二氯亚砜(SOCl
2)/N,N-二甲基甲酰胺(DMF)、草酰氯((COCl)
2)/N,N-二甲基甲酰胺(DMF)或乙酰氯(AcCl)/N,N-二甲基甲酰胺(DMF)的组合进行制备式(VII”)所示化合物的缩合反应。
在某些实施方案中,能够用于本公开的制备式(VII”)所示化合物的缩合反应的试剂的示例性实例包括但不限于N,N’-羰基二咪唑(CDI)、二环己基碳二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC·HCl)、二氯亚砜(SOCl
2)、草酰氯((COCl)
2)、乙酰氯(AcCl)、乙酸酐(Ac
2O)、N,N-二甲基甲酰胺(DMF)、二氯亚砜(SOCl
2)/N,N-二甲基甲酰胺(DMF)、草酰氯((COCl)
2)/N,N-二甲基甲酰胺(DMF)或乙酰氯(AcCl)/N,N-二甲基甲酰胺(DMF)的组合进行制备式(VII”)所示化合物的缩合反应,上述反应试剂与式(VI”)所示化合物的重量比为约1:1至约3:1。
在某些实施方案中,能够用于本公开的制备式(VII”)所示化合物的缩合反应的溶剂的示例性实例包括但不限于四氢呋喃、二氯甲烷(DCM)、乙酸酐(Ac
2O)及其任意混合物。
在某些实施方案中,在约-5至约150℃进行制备式(VII”)所示化合物的缩合反应。
在某些实施方案中,在约-10至约40℃进行制备式(VII”)所示化合物的缩合反应。
在某些实施方案中,在约20至约30℃进行制备式(VII”)所示化合物的缩合反应。
在某些实施方案中,对式(VII”)所示化合物进行重结晶。
在某些实施方案中,能够用于本公开的对式(VII”)所示化合物进行重结晶的溶剂的示例性实例包括但不限于乙腈/异丙醇、乙酸乙酯、乙腈/水、四氢呋喃/水及其任意混合物。
另一方面,本公开涉及制备式(VI”)所示化合物的方法,
所述方法包括将式(V”)所示化合物进行水解反应,
在某些实施方案中,在碱性条件下进行制备式(VI”)所示化合物的水解反应。
在某些实施方案中,能够用于本公开的制备式(VI”)所示化合物的水解反应的盐的示例性实例包括但不限于钾盐、钠盐、锂盐及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VI”)所示化合物的水解反应的盐的示例性实例包括但不限于氢氧化钾、碳酸钾、碳酸氢钾、氢氧化钠、碳酸钠、氢氧化锂、碳酸锂及其任意混合物。
在某些实施方案中,在约-5至约35℃进行本公开的制备式(VI”)所示化合物的水解反应。
在某些实施方案中,在约0至约35℃进行本公开的制备式(VI”)所示化合物的水解反应。
在某些实施方案中,在约20至约30℃进行本公开的制备式(VI”)所示化合物的水解反应。
在某些实施方案中,能够用于纯化本公开的式(VI”)所示化合物的溶剂的示例性实例包括但不限于乙醇/水、甲醇/水、异丙醇/水、乙腈/丙酮/水、乙腈/丙酮、乙酸乙酯、四氢呋喃、四氢呋喃/水及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(VI’)所示化合物的式(V”)所示化合物与能够用于本公开的制备式(VI”)所示化合物的水解反应的盐的摩尔比为约1:1至约1:10。
在某些实施方案中,能够用于本公开的制备式(VI”)所示化合物的式(V”)所示化合物与能够用于本公开的制备式(VI”)所示化合物的水解反应的盐的摩尔比为约1:1至1:6。
在某些实施方案中,能够用于本公开的制备式(VI”)所示化合物的式(V”)所示化合物与能够用于本公开的制备式(VI”)所示化合物的水解反应的盐的摩尔比为约1:5。
再一方面,本公开涉及制备式(V”)所示化合物的方法,
所述方法包括将式(IV”)所示化合物进行缩合反应,
在某些实施方案中,能够用于本公开的制备式(V”)所示化合物的缩合反应的试剂的示例性实例包括但不限于乙酰氯(AcCl)、乙酸酐(Ac
2O)及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(V”)所示化合物的缩合反应的溶剂的示例性实例包括但不限于4-二甲氨基吡啶(DMAP)、N-甲基吗啉(NMM)、三乙胺(TEA)、二氯甲烷(DCM)、吡啶(Py)、N,N-二异丙基乙胺(DIEA)及其任意混合物。
在某些实施方案中,能够用于本公开的制备式(V”)所示化合物的缩合反应的试剂的示例性实例包括但不限于Ac
2O、Ac
2O/DMAP、Ac
2O/DMAP/NMM、CH
3COCl/TEA/DCM/DMAP或CH
3COCl/Py制备式(V”)所示化合物。
在某些实施方案中,能够用于本公开的制备式(V”)所示化合物的 缩合反应的溶剂的示例性实例包括但不限于乙酸酐、二氯甲烷(DCM)、吡啶(Py)、四氢呋喃、乙腈、丙酮、乙酸乙酯及其任意混合物。
在某些实施方案中,在约0至约150℃进行本公开的制备式(V”)所示化合物的缩合反应。
在某些实施方案中,在约90至约150℃进行本公开的制备式(V”)所示化合物的缩合反应。
在某些实施方案中,在约125至约140℃进行本公开的制备式(V”)所示化合物的缩合反应。
在某些实施方案中,能够用于纯化本公开的式(V”)所示化合物的溶剂的示例性实例包括但不限于乙醇、甲基叔丁基醚(MTBE)、甲醇、乙酸乙酯、正己烷、乙醚、四氢呋喃(THF)及其任意混合物。
又一方面,本公开涉及制备式(IV”)所示化合物的方法,
所述方法包括将式(III)所示化合物与式(II”)所示化合物进行缩合反应,得到所述式(IV”)所示化合物,
在某些实施方案中,能够用于本公开的制备式(IV”)所示化合物的缩合剂的示例性实例包括但不限于碳二亚胺型缩合剂、磷正离子型缩合剂、脲正离子型缩合剂、其他合适的缩合剂及其任意混合物。
在某些实施方案中,能够用于本公开的碳二亚胺型缩合剂的示例性实例包括但不限于1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC的盐酸盐)和二环己基碳二亚胺(DCC)。
在某些实施方案中,能够用于本公开的磷正离子型缩合剂的示例性实例包括但不限于1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PyBOP)、三吡咯烷基溴化鏻六氟磷酸盐(PyBrOP)和苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)。
在某些实施方案中,能够用于本公开的脲正离子型缩合剂的示例性实例包括但不限于N,N,N’,N’-四甲基-O-(1H-苯并三唑-1-基)脲六氟磷酸盐(HBTU)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)。
在某些实施方案中,能够用于本公开的其他合适的缩合剂的示例性实例包括但不限于1-羟基苯并三氮唑(HOBt)、6-氯-1-羟基苯并三氮唑(Cl-HOBt)、N-羟基-7-氮杂苯并三氮唑(HOAt)、双(2-氧代-3-噁唑烷基)次磷酰氯(BOP-Cl)、3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮(DEPBT)、N-羟基琥珀酰亚胺(HOSu)和五氟苯酚。
在某些实施方案中,能够用于本公开的溶剂的示例性实例包括但不限于二氯甲烷、三氯甲烷、甲苯、四氢呋喃、二氧六环及其任意混合物。
在某些实施方案中,在约0至约50℃进行本公开的制备式(IV”)所示化合物的缩合反应。
在某些实施方案中,在约25至约35℃进行本公开的制备式(IV”)所示化合物的缩合反应。
在某些实施方案中,制备本公开的式(IV”)所示化合物的缩合反应,式(III)与式(II”)的投料量重量比为约1:1.3至约1:1.4。
在某些实施方案中,制备本公开的式(IV”)所示化合物的缩合反应,式(III)与式(II”)的投料量重量比为约1:1.35至约1:1.4。
在某些实施方案中,制备本公开的式(IV”)所示化合物的缩合反应,式(III)与式(II”)的投料量重量比为约1:1.36。
再一方面,本公开涉及制备式(VII”)所示化合物的方法,其包括
将通式(I)化合物进行反应,得到式(III)所示化合物;
将式(III)所示化合物与所述式(II”)所示化合物进行缩合反应,得到式(IV”)所示化合物;
将所述式(IV”)所示化合物进行缩合反应,得到式(V”)所示化合物;
将所述式(V”)所示化合物进行水解反应,得到式(VI”)所示化合物;以及
将所述式(VI”)所示的化合物进行缩合反应,得到所述式(VII”)所示化合物。
1H核磁共振(NMR)波谱与推测的结构相一致。特征化学位移(δ)为从三甲基硅烷向低场移动的百万分之一,并用常规缩写表示特征峰:例如,s表示单峰,dd表示双二重峰,d表示二重峰,t表示三重峰,q表示四重峰,h表示六重峰,m表示多重峰,br表示宽峰。
本公开的制备方法不需要色谱纯化,更易于放大规模生产。本公开的反应条件易于控制,更易于放大规模生产,也更易于生产的稳定性和重复性。本公开的制备方法比现有公开方法更有效,并且通过本公开的制备方法和路线可以意外的直接得到符合临床质量标准的化合物,从而无需复杂的纯化步骤。临床质量标准指适于对人类给药的有足够纯度的物质。本公开的制备方法没有使用1类溶剂,在残留溶剂 方面对人体有更好的安全性。本公开的制备方法经济、使用容易得到的原料。本公开的制备方法具有更好的单步收率,也具有更好的综合收率。
下文中,本公开将通过如下实施例进行详细解释以便更好地理解本公开的各个方面及其优点。然而,应当理解,以下的实施例是非限制性的而且仅用于说明本公开的某些实施方案。本领域技术人员可根据反应设备,反应设备的规模、反应设备的原理等进行适当调整实现本公开方案。
实施例
缩略语:
实施例1
(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的制备
将(S)-5-乙酰氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸(5g,10.3mmol)和四氢呋喃(25ml)加入100ml单口瓶中,室温(25℃)搅拌溶解。将CDI(5g,31.0mol)分批加入单口瓶,室温搅拌2至5小时,HPLC监测,停止反应。加水淬灭,真空浓缩混合物,得到浓缩物。浓缩物溶解在二氯甲烷中,用水和盐水洗涤,用无水硫酸钠干燥。除去溶剂,得到残渣。将残渣加入乙腈(5ml),加热回流至溶清,加入异丙醇(30ml)回流2小时。停止加热,降至室温搅拌。抽滤,得到滤饼,真空干燥得到3.7g标题化合物(纯度99.32%,收率:77.1%)。
1H NMR(500MHz,DMSO-d
6)δ11.71(s,1H),7.73(s,1H),7.04(s,1H), 6.91-6.94(m,2H),5.71(dd,1H),4.33(dd,1H),4.09(dd,1H),3.99(q,2H),3.72(s,3H),3.00(s,3H),2.23(s,3H),1.31(t,3H).
13C NMR(100MHz,DMSO-d
6)δ170.03,162.69,162.30,149.53,148.54,141.70,131.45,130.60,120.42,120.23,115.00,113.08,112.47,64.55,56.20,53.74,47.99,41.74,23.07,15.39.LCMS:489.1([M+Na]
+)、465.0([M-H]
-).元素分析结果[C
20H
22N
2O
7S
2]:C,50.78;H,4.80;N,5.93;Found:C,50.33;H,4.70;N,5.69.
实施例2
(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的制备
将(S)-5-乙酰氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸(4.47g)和四氢呋喃(23.5ml)加入反应釜中,室温搅拌溶解。将CDI(7.83g)分批加入反应釜,25℃反应6小时,HPLC监测停止反应。加水淬灭,真空浓缩混合物,得到油。油溶解在二氯甲烷中,用水和盐水洗涤,用无水硫酸钠干燥。除去溶剂,得到残渣。将残渣加入乙腈(15ml),加热回流至溶清,加入异丙醇(90ml)回流2小时。停止加热,降至室温搅拌过夜。抽滤,得到滤饼,真空干燥得到2.58g标题化合物(收率:60%,纯度98.3%)。
实施例3
(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的制备
将(S)-5-乙酰氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸(5g)和乙酸酐(15ml)加入50ml单口瓶中,加热回流2至3小时,HPLC监测,至反应基本完成停止反应。降至室温,反应液用二氯甲烷稀释,用水和盐水洗涤,用无水硫酸钠干燥。除去溶剂,得到残渣。将残渣加入乙腈(5ml),加热回流至溶清,加入异丙醇(30ml)回流2小时。停止加热,降至室温搅拌。抽滤,得到滤饼,真空干燥得到3.4g标题化合物(纯度89%,收率:71%)。
1H NMR(600MHz,CDCl
3-d
1) δ9.39(s,1H),7.33(s,1H),7.07-7.09(m,2H),6.84(d,1H),5.83(dd,1H),4.57(dd,1H),4.11(q,2H),3.86(s,3H),3.76(dd,1H),2.89(s,3H),2.30(s,3H),1.47(t,3H).LCMS:489.3([M+Na]
+)、465.4([M-H]
-).
实施例4
(S)-5-乙酰氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸的制备
将(S)-甲基-5-乙酰氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯(16g,0.0321mol)和乙醇(160ml)加入500ml三口瓶中搅拌溶解,冷却至0℃以下。滴加160ml 4.2%的氢氧化锂水溶液,滴加过程中,控制三口瓶内温度小于0℃。滴加完毕后,反应液升至室温,搅拌3至6小时,HPLC监测,至反应基本完成停止反应。反应结束后,滴加4mol/L盐酸调节pH至5至6,真空浓缩混合物,得到油状物。将油状物溶解在水中,滴加4mol/L盐酸调节pH至1至2,有固体析出。向混合物中加入乙腈(120ml)和丙酮(40ml)搅拌3小时,抽滤,得到滤饼,真空干燥得到11.3g标题化合物(纯度98%,收率:73%)。
1H NMR(600MHz,DMSO-d
6)δ11.41(s,1H),10.09(d,1H),7.85(s,1H),7.09(d,1H),6.98(dd,1H),6.93(d,1H),5.55(dd,1H),4.05(q,2H),3.80(dd,1H),3.75(s,3H),3.65(dd,1H),2.90(s,3H),2.19(s,3H),1.34(t,3H).LCMS:507.4([M+Na]
+)、483.4([M-H]
-)
实施例5
(S)-甲基-5-乙酰氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯的制备
将(S)-甲基-5-氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯(20g)和乙酸酐(70ml)加入250ml三口瓶中,加热回流至溶清,搅拌0.5小时。降温至80至90℃,反应液加入乙醇(210ml)搅拌析出固体,继续降至室温搅拌。抽滤,得到滤饼,真空干燥得到17.8g标题化合物(收率:82%,纯度99%)。
1H NMR(600MHz,CDCl3-d
1)δ12.97(s,1H),11.04(d,1H),7.85(s,1H),7.03-7.04(m,2H), 6.91(d,1H),5.67(dd,1H),4.18(q,2H),3.93(s,3H),3.89(s,3H),3.74(dd,1H),3.49(dd,1H),2.70(s,3H),2.29(s,3H),1.50(t,3H).LCMS:521.3([M+Na]
+)、497.5([M-H]
-).
实施例6
(S)-甲基-5-乙酰氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯的制备
将(S)-甲基-5-氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯(3.63g)和乙酸酐(12.7ml)加入反应釜中,加热125-140℃,搅拌0.5小时。降温至80至90℃,反应液加入乙醇(38ml)搅拌析出固体,继续降至室温搅拌5小时。抽滤,得到滤饼,真空干燥得到3.52g标题化合物(收率:89%,纯度99.50%)。
实施例7
(S)-甲基-5-乙酰氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯的制备
将(S)-甲基-5-氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯(12g,0.0263mol)、乙酰氯(2.5g,0.0318mol)和吡啶(30ml)加入100ml单口瓶中,室温搅拌过夜。真空浓缩混合物,得到浓缩物。浓缩物溶解在二氯甲烷中,用2mol/L盐酸、水和盐水洗涤,用无水硫酸钠干燥。除去溶剂,得到残渣。纯化残渣,得到10.1g标题化合物(收率:77.1%,纯度:96%)。
1H NMR(600MHz,CDCl
3-d
1)δ12.98(s,1H),11.05(d,1H),7.86(s,1H),7.03-7.05(m,2H),6.91(d,1H),5.67(dd,1H),4.17(q,2H),3.93(s,3H),3.89(s,3H),3.74(dd,1H),3.49(dd,1H),2.70(s,3H),2.29(s,3H),1.51(t,3H).LCMS:521.3([M+Na]
+)、497.5([M-H]
-)。
实施例8
(S)-甲基-5-氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯的制备
将2-氨基-4-(甲氧羰基)噻吩-3-羧酸(25g,0.124mol)、(S)-1-(3-乙氧基-4-甲氧基苯基)-2-甲砜基乙胺(34g,0.125mol)(参照专利CN104245668B制备、Cl-HOBt(25.3g,0.150mol)和二氯甲烷(300ml)加入500ml三口瓶中搅拌10至20分钟。将EDC·HCl(28.5g,0.149mol)加入三口瓶中。加料完毕后,加热至内温25至35℃,反应3至6小时,停止反应。反应结束后,将1mol/L盐酸加入三口瓶中,有固体析出,抽滤,滤液分出有机层,用水和盐水洗涤,用无水硫酸钠干燥。除去溶剂,将残渣加入乙酸乙酯(250ml),加热至回流2小时。停止加热,降至室温。抽滤,得到滤饼,真空干燥得到36.2g标题化合物(收率:64%,纯度99%)。
1H NMR(500MHz,DMSO-d
6)δ9.31(d,1H),7.31(s,1H),7.26(s,2H),36.2/7.06(s,1H),6.92(s,2H),5.45(dd,1H),4.05(q,2H),3.73(s,3H),3.69(s,3H),3.57-3.66(m,2H),2.79(s,3H),1.33(t,3H).
13C NMR(100MHz,DMSO-d
6)δ165.12,164.63,162.16,149.03,148.63,133.52,128.90,119.81,119.79,112.45,112.29,106.52,64.34,59.53,56.15,52.94,48.47,41.94,15.42.LCMS:457.1([M+H]
+)、455.0([M-H]
-).
实施例9
(S)-甲基-5-氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯的制备
将2-氨基-4-(甲氧羰基)噻吩-3-羧酸(7.5g)、(S)-1-(3-乙氧基-4-甲氧基苯基)-2-甲砜基乙胺(9.3g)、Cl-HOBt(7.6g)和二氯甲烷(102ml)搅拌10至20分钟。将EDC·HCl(8.6g)加入上述反应液中。加料完毕后,加热至内温25至35℃,反应3至6小时,HPLC监测,反应结束后,将1mol/L盐酸(1.6g)加入反应容器中,有固体析出,抽滤,滤液分出有机层,用水和盐水洗涤,用无水硫酸钠干燥。除去溶剂,将残渣加入乙酸乙酯(6.7g),加热至回流2小时。停止加热,降至室温。抽滤,得到滤饼,真空干燥得到14.6g标题化合物(收率:60%,纯度97%)。
可选择性的,根据上面实施例12或13中描述的方法类似的制备(S)-甲基-5-氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯,只是用N-羟基琥珀酰亚胺(HOSu)、N-羟基-7-偶 氮苯并三氮唑(HOAt)或HOBt代替Cl-HOBt,获得类似的反应效果。
可选择性的,根据上面实施例12或13中描述的方法类似的制备(S)-甲基-5-氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯,只是用四氢呋喃、N,N-二甲基甲酰胺、三氯甲烷代替二氯甲烷,获得类似的反应效果。
可选择性的,根据上面实施例12或13中描述的方法类似的制备(S)-甲基-5-氨基-4-[[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]氨基羰基]噻吩-3-羧酸酯,只是反应温度在约15℃到约35℃,获得类似的反应效果。
实施例10
2-氨基-4-(甲氧羰基)噻吩-3-羧酸的制备
将3-叔丁基-4-甲基2-氨基噻吩-3,4-二羧酸酯(47g,0.183mol,参考Organic Letters,13(1),38-41;2011公开的方法制备)和二氯甲烷(60ml)加入250ml三口瓶中搅拌溶解,冷却至-10℃。将三氟乙酸(48g,0.421mol)加入二氯甲烷(30ml)中配制成溶液A。将溶液A滴加入三口瓶中,滴加过程中,控制三口瓶内温度低于-5℃。滴加完毕后,控制内温小于0℃反应10至30分钟。将反应液加入甲基叔丁基醚(300ml)搅拌2小时,抽滤,得到滤饼,真空干燥得到28.2g标题化合物(收率:77%,纯度97.4%)。
1H NMR(600MHz,Acetone-d
6)δ7.75(s,1H),7.52(s,H),3.96(s,3H).LCMS:202.1([M+H]
+).
实施例11
2-氨基-4-(甲氧羰基)噻吩-3-羧酸的制备
将3-叔丁基-4-甲基2-氨基噻吩-3,4-二羧酸酯(5.5g)和二氯甲烷(9.6g)搅拌溶解,冷却至-10℃。将所得溶液记为A。将三氟乙酸(5.6g)加入二氯甲烷(4.8g)中配制成溶液B。将B溶液冷却至0℃以下,将溶液B滴加入A中,滴加过程中,控制温度低于-10±5℃。滴加完毕后反应10至30分钟。反应结束后,将反应液加入甲基叔丁基醚(78.3g)搅拌2小时,抽滤,得到滤饼,真空干燥得到3.7g标题化合物(收率:86%, 样品纯度97.4%)。
实施例12
2-氨基-4-(甲氧羰基)噻吩-3-羧酸的制备
将3-苄基-4-甲基2-氨基噻吩-3,4-二羧酸酯(50g,0.172mol,参考Organic Letters,13(1),38-41;2011公开的方法制备)加入乙酸乙酯(900ml)中搅拌溶解,记为溶液A。将2L氢化瓶用氮气惰化后,加入10%湿Pd/C(12.5g),再向氢化瓶中加入乙酸乙酯(100ml)没过催化剂。将溶液A和冰乙酸(150ml)依次加入氢化瓶中,拧紧瓶盖。氢化瓶氮气置换2次,再氢气置换2次,通氢气(压力15psi)反应,至反应基本完成。反应结束后,料液过硅藻土除Pd/C。滤液减压浓缩除去溶剂,得到残渣。将残渣加入甲基叔丁基醚(300ml)搅拌2小时,抽滤,得到滤饼,真空干燥得到20.3g标题化合物(收率:59%,纯度95.4%)。
1H NMR(600MHz,Acetone-d
6)δ7.75(s,1H),7.53(s,H),3.96(s,3H).LCMS:202.1([M+H]
+).
在本公开中,诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来,而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。
从前述中可以理解,尽管为了示例性说明的目的描述了本公开的具体实施方案,但是在不偏离本公开的精神和范围的条件下,本领域所述技术人员可以作出各种变形或改进。这些变形或修改都应落入本公开所附权利要求的范围。
Claims (31)
- 如权利要求1所述的方法,其中使用选自N,N’-羰基二咪唑(CDI)、二环己基碳二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC·HCl)、二氯亚砜(SOCl 2)、草酰氯((COCl) 2)、乙酰氯(AcCl)、乙酸酐(Ac 2O)、N,N-二甲基甲酰胺(DMF)或其任意混合物的试剂进行所述缩合反应,优选使用选自N,N’-羰基二咪唑(CDI)、二环己基碳二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)或其盐(1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐)、草酰氯((COCl) 2)、乙酰氯(AcCl)、乙酸酐(Ac 2O)、N,N-二甲基甲酰胺(DMF)的组合或其任意混合物的试剂进行所述缩合反应。
- 如权利要求1或2所述的方法,其中反应试剂与式(VI)或式(VIII) 所示化合物的重量比为约1:1至约3:1。
- 如权利要求1至3所述的方法,其中在选自四氢呋喃、二氯甲烷(DCM)、乙酸酐(Ac 2O)或其任意混合物的溶剂中进行所述缩合反应。
- 如权利要求1至4中任一权利要求所述的方法,其中在约-5至约150℃进行所述缩合反应。
- 如权利要求1至5中任一权利要求所述的方法,其中在约20至约30℃进行所述缩合反应。
- 如权利要求1至6中任一权利要求所述的方法,其还包括对所得的式(VII)所示化合物进行重结晶。
- 如权利要求7中所述的方法,其中重结晶的溶剂选自乙腈/异丙醇、乙酸乙酯、乙腈/水、四氢呋喃/水及其任意混合物。
- 如权利要求9所述的方法,其中在碱性条件下进行所述水解反应,优选使用钾盐、钠盐、锂盐或其任意混合物进行所述水解反应,更优选使用氢氧化钾、碳酸钾、碳酸氢钾、氢氧化钠、碳酸钠、氢氧化锂、碳酸锂或其任意混合物进行所述水解反应。
- 如权利要求9或10所述的方法,其中在约-5至约35℃进行所述水解反应,优选在约0至约35℃进行所述水解反应,更优选在约20至约30℃进行所述水解反应。
- 如权利要求9至11中任一权利要求所述的方法,其中在选自乙醇/水、甲醇/水、异丙醇/水、乙腈/丙酮/水、乙腈/丙酮、乙酸乙酯、四氢呋喃、四氢呋喃/水、丙酮/水或其任意混合物的溶剂中进行所述水解反应。
- 如权利要求9至12中任一权利要求所述的方法,其中式(V)所示化合物与权利要求10的反应试剂的摩尔比为约1:1至约1:10,优选为约1:1至约1:6,更优选为约1:5。
- 如权利要求14所述的方法,其中使用选自乙酰氯(AcCl)、乙酸酐(Ac 2O)或其任意混合物的试剂进行所述缩合反应。
- 如权利要求14或15所述的方法,其中在选自4-二甲氨基吡啶(DMAP)、N-甲基吗啉(NMM)、三乙胺(TEA)、N,N-二异丙基乙胺(DIEA)、吡啶(Py)或其任意混合物的试剂进行所述缩合反应。
- 如权利要求14至16中任一权利要求所述的方法,其中在选 自Ac 2O、Ac 2O/DMAP、Ac 2O/DMAP/NMM、CH 3COCl/TEA/DCM/DMAP或CH 3COCl/Py的试剂中进行所述缩合反应。
- 如权利要求14至17中任一权利要求所述的方法,其中在选自乙酸酐、二氯甲烷(DCM)、吡啶(Py)、四氢呋喃、乙腈、丙酮、乙酸乙酯或其任意混合物的溶剂中进行所述缩合反应。
- 如权利要求14至18中任一权利要求所述的方法,其中在约0至约150℃进行所述缩合反应,优选在约90至约150℃进行所述缩合反应,更优选在约125至约140℃进行所述缩合反应。
- 如权利要求14至19中任一权利要求所述的方法,其中用于纯化本公开的式(V)所示化合物的溶剂在选自乙醇、甲基叔丁基醚(MTBE)、甲醇、乙酸乙酯、正己烷、乙醚、四氢呋喃(THF)及其任意混合物的溶剂。
- 如权利要求21所述的方法,其中使用选自碳二亚胺型缩合剂、磷正离子型缩合剂、脲正离子型缩合剂、其他合适的缩合剂或其任意混合物进行所述缩合反应,所述碳二亚胺型缩合剂优选选自1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)、EDCI(EDC·HCl)或二环己基碳二亚胺(DCC),所述磷正离子型缩合剂优选选自1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PyBOP)、三吡咯烷基溴化鏻六氟磷酸盐(PyBrOP)和/或苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP),所述脲正离子型缩合剂优选选自N,N,N’,N’-四甲基-O-(1H-苯并三唑-1-基)脲六氟磷酸盐(HBTU)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU),所述其他合适的缩合剂优选选自1-羟基苯并三氮唑(HOBt)、6-氯-1-羟基苯并三氮唑(Cl-HOBt)、N-羟基-7-氮杂苯并三氮唑(HOAt)、双(2-氧代-3-噁唑烷基)次磷酰氯(BOP-Cl)、3-二乙氧基磷酰基-1,2,3-苯唑4(3H)-酮(DEPBT)、N-羟基琥珀酰亚胺(HOSu)和/或 五氟苯酚。
- 如权利要求21或22所述的方法,其中进行所述缩合反应的溶剂选自在二氯甲烷、三氯甲烷、乙腈、甲苯、四氢呋喃、二氧六环、及其任意混合物中进行所述缩合反应。
- 如权利要求21至23中任一权利要求所述的方法,其中在约0至约50℃进行所述缩合反应,优选在约25至约35℃进行所述缩合反应。
- 如权利要求21至24中任一权利要求所述的方法,其中式(III)所示化合物与式(II)所示化合物的投料量重量比为约1:1.3至约1:1.4。
- 如权利要求26所述的方法,其中在三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或其任意混合物的存在下进行所述反应。
- 如权利要求26或27所述的方法,其中在选自三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或其任意混合物与式(I)的重量比为约1.5:1至约1:1下进行反应,优选选自三氟乙酸(TFA)、盐酸、氢溴酸、磺酸、钯碳、四三苯基膦钯或其任意混合物与式(I)所示化合物的重量比为约1.1:1至约1:1下进行反应。
- 如权利要求26或28所述的方法,其中所述溶剂选自二氯甲烷、甲苯、二氯乙烷、乙酸乙酯、四氢呋喃、1,4-二氧六环、甲醇、乙醇或其任意混合物。
- 如权利要求26至29中任一权利要求所述的方法,其中在约-20至约0℃进行所述水解反应,优选在约-15至约-5℃进行所述反应。
- 制备式(VII)所示化合物的方法,其包括将通式(I)化合物进行反应,得到式(III)所示化合物;将式(III)所示化合物与所述式(II)所示化合物进行缩合反应,得到式(IV)所示化合物;将所述式(IV)所示化合物进行缩合反应,得到式(V)所示化合物;将所述式(V)所示化合物进行水解反应,得到式(VI)所示化合物;以及将所述式(VI)或式(VIII)所示的化合物进行缩合反应,得到所述式(VII)所示化合物。
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CN101186612A (zh) * | 2006-11-15 | 2008-05-28 | 天津和美生物技术有限公司 | 可抑制细胞释放肿瘤坏死因子的吡咯啉衍生物及其制备和应用 |
CN101885731A (zh) * | 2009-05-14 | 2010-11-17 | 天津和美生物技术有限公司 | 噻吩衍生物 |
CN104245668A (zh) | 2012-02-21 | 2014-12-24 | 细胞基因公司 | 用于制备(s)-1-(3-乙氧基-4-甲氧基苯基)-2-甲烷磺酰基乙胺的工艺 |
CN110997679A (zh) * | 2017-06-13 | 2020-04-10 | 拜欧赛里克斯公司 | 双环化合物和使用方法 |
WO2021119571A1 (en) * | 2019-12-12 | 2021-06-17 | Biotheryx, Inc. | Pde4 inhibitors, pharmaceutical compositions, and therapeutic applications |
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CN101186612A (zh) * | 2006-11-15 | 2008-05-28 | 天津和美生物技术有限公司 | 可抑制细胞释放肿瘤坏死因子的吡咯啉衍生物及其制备和应用 |
CN101885731A (zh) * | 2009-05-14 | 2010-11-17 | 天津和美生物技术有限公司 | 噻吩衍生物 |
CN104245668A (zh) | 2012-02-21 | 2014-12-24 | 细胞基因公司 | 用于制备(s)-1-(3-乙氧基-4-甲氧基苯基)-2-甲烷磺酰基乙胺的工艺 |
CN110997679A (zh) * | 2017-06-13 | 2020-04-10 | 拜欧赛里克斯公司 | 双环化合物和使用方法 |
WO2021119571A1 (en) * | 2019-12-12 | 2021-06-17 | Biotheryx, Inc. | Pde4 inhibitors, pharmaceutical compositions, and therapeutic applications |
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