WO2023206874A1 - 沙库必曲中间体、其制备方法及其应用 - Google Patents
沙库必曲中间体、其制备方法及其应用 Download PDFInfo
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- WO2023206874A1 WO2023206874A1 PCT/CN2022/114100 CN2022114100W WO2023206874A1 WO 2023206874 A1 WO2023206874 A1 WO 2023206874A1 CN 2022114100 W CN2022114100 W CN 2022114100W WO 2023206874 A1 WO2023206874 A1 WO 2023206874A1
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 title claims abstract description 14
- 229960003953 sacubitril Drugs 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 86
- 230000008569 process Effects 0.000 claims abstract description 66
- 239000002253 acid Substances 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 419
- 238000006243 chemical reaction Methods 0.000 claims description 189
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 84
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 claims description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 68
- 239000003153 chemical reaction reagent Substances 0.000 claims description 62
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 43
- 239000002585 base Substances 0.000 claims description 38
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 33
- 230000035484 reaction time Effects 0.000 claims description 32
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 30
- -1 trimethylsilyl ethoxycarbonyl Chemical group 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 238000010438 heat treatment Methods 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 25
- 230000009471 action Effects 0.000 claims description 21
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 15
- 235000011181 potassium carbonates Nutrition 0.000 claims description 15
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 11
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 9
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 claims description 9
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 9
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 239000007983 Tris buffer Substances 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 3
- 239000000543 intermediate Substances 0.000 abstract description 25
- 239000002994 raw material Substances 0.000 abstract description 20
- DRDVJQOGFWAVLH-UHFFFAOYSA-N tert-butyl n-hydroxycarbamate Chemical compound CC(C)(C)OC(=O)NO DRDVJQOGFWAVLH-UHFFFAOYSA-N 0.000 abstract description 19
- 102000003729 Neprilysin Human genes 0.000 abstract description 10
- 108090000028 Neprilysin Proteins 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000003112 inhibitor Substances 0.000 abstract description 6
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 14
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- 108010092674 Enkephalins Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- JAZNSOPOXXXZQO-UHFFFAOYSA-N [N].CCO Chemical compound [N].CCO JAZNSOPOXXXZQO-UHFFFAOYSA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000003413 degradative effect Effects 0.000 description 1
- VIYPAVOOGIVLDA-UHFFFAOYSA-N dichloromethane N,N-diethylethanamine methanesulfonyl chloride Chemical compound C(Cl)Cl.C(C)N(CC)CC.CS(=O)(=O)Cl VIYPAVOOGIVLDA-UHFFFAOYSA-N 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- QGEFGPVWRJCFQP-UHFFFAOYSA-M magnesium;methanidylbenzene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C1=CC=CC=C1 QGEFGPVWRJCFQP-UHFFFAOYSA-M 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001452 natriuretic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 229940051537 valsartan and sacubitril Drugs 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/14—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/02—Preparation by ring-closure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/16—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with acylated ring nitrogen atoms
- C07D203/20—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with acylated ring nitrogen atoms by carbonic acid, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention belongs to the field of medicine and relates to pharmaceutical intermediates, specifically to sacubitril intermediates, their preparation methods and their applications.
- ANF Mammalian endogenous atrial natriuretic peptide
- NEP atrial natriuretic peptide
- Natural ANF peptides are metabolically inactivated, specifically by degradative enzymes thought to be equivalent to NEP, which also cause metabolic inactivation of enkephalins.
- Sacubitril (AHU-377) is one of the main components of LCZ696 (CAS: 936623-90-4), an anti-heart failure drug developed by Novartis.
- This anti-heart failure drug is a supramolecular complex (complex) composed of valsartan and sacubitril (AHU-377) through non-covalent bonding. It has angiotensin receptor blocking and neutral endogenous peptides.
- Enzyme inhibition has the dual effect of reducing the risk of cardiovascular disease. It is mainly used to treat heart failure and can also be used to treat high blood pressure.
- Sacubitril (AHU-377) is usually prepared through the key intermediate N-Boc aminoalcohol [formula (10-a)].
- the chemical name of this intermediate is: N-[(1R)-2-[1,1 '-Biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamic acid tert-butyl ester (CAS: 1426129-50-1); its structural formula is:
- the D-tyrosine used in this method is an unnatural amino acid and is expensive; the reaction process also uses the expensive trifluoromethanesulfonic anhydride reagent, and the reagent is very active and corrosive, and requires high production equipment and operation. Conducive to industrial applications.
- Patent WO2014032627 and patent CN 105026361 disclose the preparation method of N-Boc aminoalcohol.
- the synthesis route is as follows:
- triphenylphosphine is used, and a large amount of triphenylphosphine compounds are generated after the reaction, which makes separation and purification difficult and leads to a lot of solid waste; azodicarboxylate compounds are also used, and these compounds are harmful to light. , sensitive to heat and vibration, and there are potential dangers in the heating process. These problems will lead to an increase in the entire production cost.
- patent CN 105985225 discloses a preparation method of Sacubitril intermediate, as follows:
- This method is similar to the methods disclosed in patent WO2014/032627 and patent CN 105026361.
- the main change is that a hydroxyl protecting agent is used instead of epichlorohydrin.
- the reaction process is basically similar, and the same reaction type uses basically the same reagents.
- the final step Since the hydroxyl group is protected by a benzyl group, additional palladium-catalyzed hydrogenolysis is required to remove the protecting group.
- the patent reports that the yield of preparing N-Boc aminoalcohol has been improved, considering the cost of reagents and finally adding the step of noble metal catalytic hydrogenation to remove the benzyl group, the cost will increase significantly.
- Patents WO 2013/026773 and CN 103764624 disclose a method for preparing sacubitril intermediate aminoalcohol using p-phenylbenzaldehyde as raw material.
- the synthesis route is as follows:
- This process includes a catalytic hydrogenation step, but its disadvantage is that the precious metals Rh and Pd are used in large amounts, resulting in high production costs.
- this intermediate can also be prepared by enzymatic methods.
- patent CN 105884656 discloses a method for preparing this intermediate through enzyme-catalyzed asymmetric reductive amination, as follows:
- benzyl magnesium bromide is used as raw material and reacts with oxalyl chloride monomethyl ester to generate ketoacid ester; then under the action of bromination reagent, the 4-position of the benzene ring is brominated; copper catalysis is used with phenylboronic acid.
- the ketone acid ester is obtained; in the system of glucose, NADP + and reductase CGKR2 and GDH, the ketoacid ester is catalyzed asymmetric reductive amination to obtain the chiral amino acid methyl ester; after Boc protection of the amino group, Under the action of sodium borohydride and Lewis acid, carboxylic acid methyl ester is reduced to alcohol to obtain the key intermediate N-Boc aminoalcohol.
- the present invention relates to a preparation process of sacubitril intermediates.
- the key intermediate N-Boc aminoalcohol [formula (10) and formula (10-a)] can be efficiently prepared.
- the intermediates can be used for neutral endopeptidase (NEP) inhibitors or prodrugs thereof, in particular, NEP inhibitors containing the skeleton of ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid or ester, Such as Shakubi Qu and so on.
- NEP neutral endopeptidase
- This process route has cheap raw materials, easy operation, no special requirements for equipment, and low production cost. It is suitable for industrial production and has great application potential and commercial value.
- the present invention also provides intermediates for preparing compound (10-a).
- the present invention provides a preparation process of compound (10), which includes the following steps:
- Step a Compound (6) and compound (M) react under the action of a catalyst to obtain compound (7), wherein,
- R 1 is F, Cl, Br, I or -OR 3 , R 3 represents C 1-6 alkyl or C 1-6 heteroalkyl;
- R 2 is Where X is Cl, Br or I;
- Pg 1 is an amino protecting group
- Compound (10) has the structure: Wherein, “*” indicates that compound (10) is in R configuration or S configuration. Preferably, “*” indicates that compound (10) is in R configuration.
- step a in the process of the present invention, in step a,
- the catalyst is a cuprous salt, preferably CuI, CuBr, CuCl or CuCN; the amino protecting group is benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl or
- the reaction is carried out under dry anaerobic conditions.
- the reaction is carried out under dry anaerobic conditions with nitrogen protection; or
- the reaction temperature of the reaction is -60°C ⁇ 0°C, the preferred reaction temperature is -45°C ⁇ 0°C, the more preferred reaction temperature is -30°C ⁇ -10°C, the most preferred reaction temperature is -20°C ⁇ -15°C ;or
- the reaction time of the reaction is 0.5h ⁇ 3h; the preferred reaction time is 0.8h ⁇ 2h; the more preferred reaction time is 1h ⁇ 1.5h; the most preferred reaction time is 1h.
- the reaction solvent of the reaction is a first solvent
- the first solvent is an organic aprotic solvent
- the organic aprotic solvent is tetrahydrofuran , 2-methyltetrahydrofuran, toluene, cyclopentane methyl ether, methylene chloride, methyl tert-butyl ether or diethyl ether, or any combination thereof.
- the molar ratio of compound (6) to compound (M) is 1:0.7 ⁇ 2, preferably 1:1 ⁇ 2, more preferably 1: 1 to 1.5, most preferably 1:1.
- the process of the present invention further includes the following steps:
- “*” indicates that compound (7), compound (8) and compound (9) are all in R configuration or S configuration.
- “*” indicates compound (7), compound (8) and compound (9). ) are all R configuration;
- Step b Compound (7) is reacted in a second solvent and under a first heating condition to obtain compound (8), wherein,
- the reaction time is 0.3h ⁇ 2h, more preferably, the reaction time is 0.3h ⁇ 1h, most preferably, the reaction time is 0.5h;
- Step c Compound (8) is hydrolyzed with a base in a third solvent and under a second heating condition to obtain compound (9), wherein,
- the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate or sodium methoxide or any combination thereof;
- the feeding molar ratio of the compound (8) and the base is 1: (0.9-5), and more preferably, the feeding molar ratio of the compound (8) and the base is 1: (1-5). 4), further preferably, the feeding molar ratio of the compound (8) and the base is 1: (2-4), most preferably, the feeding molar ratio of the compound (8) and the base is 1:3.75;
- the reaction time is 1h to 5h, more preferably, the reaction time is 2h to 4h, and most preferably, the reaction time is 3h.
- the heating temperatures under the first heating condition and the second heating condition are each independently 80°C to 150°C, preferably 100°C. ⁇ 150°C, further preferably 110°C ⁇ 130°C, most preferably 120°C; preferably, the heating temperature under the first heating condition and the second heating condition is the same temperature; or,
- the second solvent and the third solvent are each independently n-butanol, benzene, toluene, ethylene glycol dimethyl ether, N, N-dimethylformamide, N.N-dimethylacetamide; preferably, the The second solvent and the third solvent are the same solvent.
- a base is added directly without post-treatment to carry out the reaction in step c.
- the process of the present invention further includes the following steps:
- Step d Compound (9) is subjected to amino protection reaction to obtain compound (10).
- step a the compound (6) is prepared by the following steps:
- “*” on compound (2), compound (3), compound (4a), compound (4) and compound (5) means compound (2), compound (3), compound (4a), compound (4) ) and compound (5) are both in S configuration, and the “*” on compound (6) indicates that compound (6) is in R configuration; or, compound (2), compound (3), compound (4a), compound ( The “*” on 4) and compound (5) indicates that compound (2), compound (3), compound (4a), compound (4) and compound (5) are all in R configuration, and the “*” on compound (6) *” indicates that compound (6) is in S configuration;
- Pg 2 is a hydroxyl protecting group, preferably methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl or nitrosulfonyl; R 1 and Pg 1 have the definitions described in the present invention;
- Step a' Compound (2) and a hydroxyl protecting reagent are reacted with a hydroxyl protecting reagent to obtain compound (3); preferably, the molar ratio of compound (2) to hydroxyl protecting reagent is 1: (1-3), more preferably Preferably, the feeding molar ratio of the compound (2) to the hydroxyl protecting reagent is 1: (1-2). More preferably, the feeding molar ratio of the compound (2) to the hydroxyl protecting reagent is 1: (1.2-2). 1.5), most preferably, the molar ratio of the compound (2) to the hydroxyl protecting reagent is 1:1.3;
- Step b' compound (3) reacts with acid HY to obtain compound (4a); preferably, the acid HY is hydrochloric acid, hydrobromic acid, formic acid, hydroiodic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid;
- Step c' Compound (4a) obtains compound (4) under the action of a base; preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate or potassium carbonate;
- Step d’ Compound (4) and amino-protecting reagent are reacted with amino-protecting reagent to obtain compound (5); preferably, the molar ratio of compound (4) to amino-protecting reagent is 1:1 to 1.5;
- Step e' Compound (5) is reacted in a fourth solvent under the action of an alkaline reagent to obtain compound (6); preferably, the alkaline reagent is sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, tert.
- the alkaline reagent is sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, tert.
- the reaction temperature is -10°C to 50 °C, further preferably, the reaction temperature is -10°C to 15°C, even more preferably, the reaction temperature is -5°C to 10°C, and most preferably, the reaction temperature is 0°C to 10°C.
- step a the compound (6) is prepared by the following steps:
- the "*" on compound (4-1-a) and compound (5-1) indicates that both compound (4-1-a) and compound (5-1) are in S configuration, and the "*” on compound (6) “*” indicates that compound (6) is in R configuration; or, “*” on compound (4-1-a) and compound (5-1) indicates compound (4-1-a) and compound (5-1 ) are all in R configuration, and the “*” on compound (6) indicates that compound (6) is in S configuration;
- Step a" Compound (4-1-a) undergoes an amino protection reaction with an amino protecting reagent under the action of a base to obtain compound (5-1); preferably, the reaction between the compound (4-1-a) and the amino protecting reagent
- the feeding molar ratio is 1: (0.7-2); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate;
- Step b" Compound (5-1) is reacted under the action of triphenylphosphine and ethyl azodicarboxylate at low temperature under nitrogen protection to obtain compound (6), wherein the low temperature is -40°C to 0°C, preferably The temperature range is -30°C to -10°C, and more preferably -20°C to -10°C.
- step a the compound (6) is prepared by the following steps:
- Step a"' compound (4a) reacts under the action of a base to obtain compound (5-2); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; preferably, the compound ( The molar ratio of 4a) to alkali is 1: (1-3), more preferably 1 : (1.2-2.5), most preferably 1 : 1.5; preferably, the reaction temperature is 10°C to 100°C, more preferably Preferably, the reaction temperature is 30°C to 80°C, more preferably, the reaction temperature is 40°C to 60°C, and most preferably, the reaction temperature is 50°C;
- Step b"' Compound (5-2) continues to perform an amino protection reaction with an amino protecting reagent to obtain compound (6); preferably, the molar ratio of the compound (5-2) to the amino protecting reagent is 1:(0.7 ⁇ 2);
- the reaction is a low-temperature reaction, and the low temperature is -5°C to 15°C, and more preferably, the low temperature is 0°C to 10°C.
- the present invention provides a compound having the following structure of formula (7a) or (7b):
- R 1a is F, Cl, Br, I or -OR 3
- R 3 represents a C 1-6 alkyl group or a heteroatom-substituted C 1-6 alkyl group
- Pg 1a is an amino protecting group, preferably benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl or tris Methylsilylethoxycarbonyl;
- R 1a is Br or I
- Pg 1a is not tert-butoxycarbonyl.
- compound (7a) or compound (7b) of the present invention has one of the following structures:
- the present invention provides a compound having the following structure of formula (6a) or (6b):
- X is F, Cl, Br or I
- Pg 1 is an amino protecting group, preferably benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl or tris Methylsilylethoxycarbonyl.
- compound (6a) or compound (6b) of the present invention has one of the following structures:
- the present invention provides a compound having the following structure of formula (8-a) or (8-b):
- the present invention provides the use of the process of the present invention or the compound of the present invention in the preparation of sacubitril.
- C q1-q2 represents the number of carbon atoms in the described group.
- C 1-6 alkyl represents an alkyl group containing 1-6 carbon atoms.
- alkyl means a saturated straight or branched chain monovalent hydrocarbon group containing 1 to 20 carbon atoms. In another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl (s-Bu, -CH( CH3 )CH 2 CH 3 ), tert-butyl, n-pentyl, 2-pentyl, etc.
- heteroalkyl means that one carbon atom in the alkyl group is replaced by a heteroatom, where the heteroatom is O, S, N, or Si.
- the heteroalkyl group contains 1-6 carbon atoms; in yet another embodiment, the heteroalkyl group contains 1-4 carbon atoms; in yet another embodiment, the heteroalkyl group Groups contain 1-3 carbon atoms.
- Examples of heteroalkyl groups include, but are not limited to , -CH2OCH3 , -CH2OCH2CH3 , -CH2SCH3 , -CH2SiH2CH3 , -CH2NHCH3 , and the like .
- halogen means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).
- amino protecting group refers to a substituent connected to an amino group to block or protect the functionality of the amino group in a compound.
- amino protecting groups include but are not limited to benzyloxycarbonyl (-Cbz), tert-butoxycarbonyl ( -Boc), methoxycarbonyl (-COOMe or -CO 2 Me), ethoxycarbonyl (-COOEt or -CO 2 Et), isobutyloxycarbonyl (-COO i Bu or -CO 2 i Bu), isopropyl Carbonyloxycarbonyl (-COO i Pr or -CO 2 i Pr), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc).
- hydroxyl protecting group refers to a substituent of a hydroxyl group used to block or protect the functionality of a hydroxyl group.
- hydroxyl protecting groups include, but are not limited to, methanesulfonyl-(Ms), trifluoromethanesulfonyl-(- Tf), p-toluenesulfonyl (-Ts) or nitrosulfonyl (-Ns)
- first or “second” or “third” do not indicate a sequence, but are only used to distinguish the modifiers after the first, second or third, such as the first solvent, the second solvent or the third solvent respectively. represents the solvent used in the corresponding reaction; similarly, the first heating condition and the second heating condition also represent the heating conditions in the corresponding reaction.
- N-Boc aminoalcohol [formula (10) or formula (10-a)]
- the intermediates can be used for neutral endopeptidase (NEP) inhibitors or prodrugs thereof, in particular, NEP inhibitors containing the skeleton of ⁇ -amino- ⁇ -biphenyl- ⁇ -methylalkanoic acid or ester, Such as Shakubi Qu and so on.
- NEP neutral endopeptidase
- the present invention also provides intermediates for preparing compound (10) or compound (10-a).
- the present invention provides a preparation process of compound (10), which includes the following steps:
- R 1 , R 2 , Pg 1 and compound (10) each have the definitions as described in the present invention.
- Step a Compound (6) and compound (M) react under the action of a catalyst to obtain compound (7), wherein,
- step a "*" indicates that both compound (6) and compound (7) are in R configuration, then step a is expressed as:
- R 1 is F, Cl, Br, I or -OR 3
- R 3 represents C 1-6 alkyl or C 1-6 heteroalkyl
- R2 is Where X is Cl, Br or I.
- Pg 1 is an amino protecting group.
- compound (10) is of the structure: Among them, “*” indicates that compound (10) is in R configuration or S configuration.
- compound (10) has the structure: Among them, “*” indicates that compound (10) has the R configuration, that is, compound (10) is compound (10-a):
- the catalyst in step a of the process of the present invention, is a cuprous salt, preferably CuI, CuBr, CuCl or CuCN.
- the amino protecting group is benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, watmethoxycarbonyl, allyloxycarbonyl or trimethylsilylethoxycarbonyl.
- step a the reaction is carried out under dry anaerobic conditions; in some preferred embodiments, in the process of the present invention, in step a, the reaction is carried out under dry anaerobic conditions.
- the above reaction was carried out under dry anaerobic conditions with nitrogen protection.
- the reaction temperature of the reaction in step a, is -60°C to 0°C; in some preferred embodiments, in the process of the present invention, in step a, The reaction temperature is -45°C ⁇ 0°C. In some more preferred embodiments, in the process of the present invention, in step a, the reaction temperature is -30°C ⁇ -10°C; in some most preferred embodiments, the reaction temperature is -30°C ⁇ -10°C. In an embodiment, in the process of the present invention, in step a, the reaction temperature is -20°C to -15°C.
- the reaction time of the reaction is 0.5h to 3h; in some preferred embodiments, in the process of the present invention, in step a, the reaction time of The reaction time is 0.8h ⁇ 2h; in some more preferred embodiments, the process of the present invention, in step a, the reaction time is 1h ⁇ 1.5h; in some most preferred embodiments, the reaction time of the present invention is In the above-mentioned process, in step a, the reaction time is 1 h.
- the reaction solvent of the reaction is a first solvent
- the first solvent is an organic aprotic solvent
- the organic aprotic solvent is tetrahydrofuran. , 2-methyltetrahydrofuran, toluene, cyclopentane methyl ether, methylene chloride, methyl tert-butyl ether or diethyl ether, or any combination thereof.
- step a the molar ratio of the compound (6) to the compound (M) is 1:0.7-2; in some preferred embodiments, the molar ratio of the compound (6) to the compound (M) is 1:0.7-2.
- the molar ratio of compound (6) to compound (M) is 1:1 to 2; in some more preferred embodiments, in the process described in the present invention, in step a, The feeding molar ratio of compound (6) to compound (M) is 1:1 to 1.5; in some more preferred embodiments, in the process of the present invention, in step a, the compound (6) and compound The feeding molar ratio of (M) is 1:1.
- the process of the present invention further includes the following steps:
- R 1 , R 2 , Pg 1 and compound (10) each have the definitions as described in the present invention.
- “*” indicates that compound (7), compound (8) and compound (9) are all in R configuration or S configuration; preferably, “*” indicates that compound (7), compound (8) and compound (9) are all in R configuration or S configuration; It is R configuration;
- Step b Compound (7) is reacted in the second solvent and under the first heating condition to obtain compound (8);
- the reaction time is 0.3h-2h, more preferably, the reaction time is 0.3h-1h, and most preferably, the reaction time is 0.5h;
- Step c Compound (8) is hydrolyzed with a base in a third solvent and under a second heating condition to obtain compound (9), wherein,
- the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate or sodium methoxide or any combination thereof;
- the feeding molar ratio of the compound (8) and the base is 1: (0.9-5), and more preferably, the feeding molar ratio of the compound (8) and the base is 1: (1-5). 4), further preferably, the feeding molar ratio of the compound (8) and the base is 1: (2-4), most preferably, the feeding molar ratio of the compound (8) and the base is 1:3.75;
- the reaction time is 1h to 5h, more preferably, the reaction time is 2h to 4h, and most preferably, the reaction time is 3h.
- the heating temperatures under the first heating condition and the second heating condition are each independently 80°C to 150°C, preferably 100°C to 150°C, further preferably 110°C to 130°C, Most preferably, in some embodiments, the process of the present invention, in step b and step c, is 120°C; preferably, the heating temperature under the first heating condition and the second heating condition is the same temperature.
- the second solvent and the third solvent are each independently n-butanol, benzene, toluene, ethylene glycol dimethyl ether, N, N-dimethylformamide or N,N-dimethylacetamide, or any combination thereof; preferably, the second solvent and the third solvent are the same solvent.
- a base is added directly without post-treatment to carry out the reaction in step c.
- the process of the present invention further includes the following steps:
- Step d Compound (9) is subjected to amino protection reaction to obtain compound (10).
- step a the compound (6) is prepared by the following steps:
- “*” on compound (2), compound (3), compound (4a), compound (4) and compound (5) means compound (2), compound (3), compound (4a), compound (4) ) and compound (5) are both in S configuration, and the “*” on compound (6) indicates that compound (6) is in R configuration; or, compound (2), compound (3), compound (4a), compound ( The “*” on 4) and compound (5) indicates that compound (2), compound (3), compound (4a), compound (4) and compound (5) are all in R configuration, and the “*” on compound (6) *” indicates that compound (6) is in S configuration;
- Pg 2 is a hydroxyl protecting group, preferably methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl or nitrosulfonyl; R 1 and Pg 1 have the definitions as claimed in claim 1;
- Step a' Compound (2) and a hydroxyl protecting reagent are reacted with a hydroxyl protecting reagent to obtain compound (3); preferably, the molar ratio of compound (2) to hydroxyl protecting reagent is 1: (1-3), more preferably Preferably, the feeding molar ratio of the compound (2) to the hydroxyl protecting reagent is 1: (1-2). More preferably, the feeding molar ratio of the compound (2) to the hydroxyl protecting reagent is 1: (1.2-2). 1.5), most preferably, the molar ratio of the compound (2) to the hydroxyl protecting reagent is 1:1.3;
- Step b' compound (3) reacts with acid HY to obtain compound (4a); preferably, the acid HY is hydrochloric acid, hydrobromic acid, formic acid, hydroiodic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid;
- Step c' Compound (4a) obtains compound (4) under the action of a base; preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate;
- Step d’ Compound (4) and amino-protecting reagent are reacted with amino-protecting reagent to obtain compound (5); preferably, the molar ratio of compound (4) to amino-protecting reagent is 1:1 to 1.5;
- Step e' Compound (5) is reacted in a fourth solvent under the action of an alkaline reagent to obtain compound (6); preferably, the alkaline reagent is sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, tert.
- the alkaline reagent is sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, tert.
- the reaction temperature is -10°C to 50 °C, further preferably, the reaction temperature is -10°C to 15°C, even more preferably, the reaction temperature is -5°C to 10°C, and most preferably, the reaction temperature is 0°C to 10°C.
- step a the compound (6) is prepared by the following steps:
- the "*" on compound (4-1-a) and compound (5-1) indicates that both compound (4-1-a) and compound (5-1) are in S configuration, and the "*” on compound (6) “*” indicates that compound (6) is in R configuration; or, “*” on compound (4-1-a) and compound (5-1) indicates compound (4-1-a) and compound (5-1 ) are all in R configuration, and the “*” on compound (6) indicates that compound (6) is in S configuration;
- Step a" Compound (4-1-a) undergoes an amino protection reaction with an amino protecting reagent under the action of a base to obtain compound (5-1);
- the reaction between the compound (4-1-a) and the amino protecting reagent The feeding molar ratio is 1: (0.7-2); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate;
- Step b" Compound (5-1) is reacted under the action of triphenylphosphine and ethyl azodicarboxylate at low temperature under nitrogen protection to obtain compound (6), wherein the low temperature is -40°C to 0°C, preferably The temperature range is -30°C to -10°C, and more preferably -20°C to -10°C.
- step a the compound (6) is prepared by the following steps:
- Step a"' compound (4a) reacts under the action of a base to obtain compound (5-2); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; preferably, the compound ( The molar ratio of 4a) to alkali is 1: (1-3), more preferably 1: (1.2-2.5), most preferably 1:1.5; preferably, the reaction temperature is 10°C-100°C, more preferably Preferably, the reaction temperature is 30°C to 80°C, more preferably, the reaction temperature is 40°C to 60°C, and most preferably, the reaction temperature is 50°C;
- Step b"' Compound (5-2) continues to perform an amino protection reaction with an amino protecting reagent to obtain compound (6); preferably, the molar ratio of the compound (4-1-a) to the amino protecting reagent is 1: (0.7 ⁇ 2);
- the reaction is a low-temperature reaction, and the low temperature is -5°C to 15°C, and more preferably, the low temperature is 0°C to 10°C.
- the present invention provides a compound having the following structure of formula (7a) or (7b):
- R 1a is F, Cl, Br, I or -OR 3
- R 3 represents a C 1-6 alkyl group or a heteroatom-substituted C 1-6 alkyl group
- Pg 1a is an amino protecting group, preferably benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl or tris Methylsilylethoxycarbonyl;
- R 1a is Br or I
- Pg 1a is not tert-butoxycarbonyl.
- compound (7a) or compound (7b) of the present invention has one of the following structures:
- the present invention provides a compound having the following structure of formula (6a) or (6b):
- X is F, Cl, Br or I
- Pg 1 is an amino protecting group, preferably benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl or tris Methylsilylethoxycarbonyl.
- compound (6a) or compound (6b) of the present invention has one of the following structures:
- the present invention provides a compound having the following structure of formula (8-a) or (8-b):
- the present invention provides the use of the process of the present invention or the compound of the present invention in the preparation of Sacubitril.
- the route of the present application has high yield, simple operation, can realize continuous operation, facilitates process amplification and production, and the raw materials used are cheap and easy to obtain, and the cost is low. specifically,
- auxiliary materials used in the process route of this application such as sodium hydroxide, hydrochloric acid, methanesulfonyl chloride, etc., are all commonly used materials in industrial large-scale production. They are cheap and easy to obtain, are extremely economical, and have low production costs.
- Example 2 Multiple intermediates in the process route of this application can be continuously fed and produced without separation and purification, which can effectively reduce the energy consumption and labor costs of industrial production.
- Example 2 can be carried out directly.
- the organic phase separated in step 2 of Example 1 can be directly subjected to a salt-forming operation, and the product obtained can be directly transferred to the aqueous phase for Example 3.
- Step 6 of Example 7 contains a three-step reaction, and a one-pot operation can be realized using toluene as the solvent.
- the purification of product (10-a) is completed.
- the compounds of the present invention can be prepared by the methods described herein.
- the following reaction schemes and examples serve to further illustrate the present invention. Those skilled in the art should understand that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.
- the examples described below all temperatures are in degrees Celsius unless otherwise indicated.
- the room temperature of the present invention is 10°C to 30°C or 15°C to 25°C.
- the reagents are conventional reagents and can be purchased from the market.
- the chromatographic column uses a silica gel column.
- the NMR spectrum uses CDC1 3 or DMSO-d 6 as the solvent (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard.
- the coupling constant J is expressed in Hertz (Hz).
- aqueous solution of crude compound (4-a) in step 2 (0.374 mol, 1.0 eq) was added into the 2L reaction bottle, the internal temperature was lowered to 0-10°C, and then the aqueous sodium hydroxide solution was added dropwise (17 g of sodium hydroxide was dissolved in 100 mL of water, 1.1 eq ) Adjust the pH value to between 8 and 9, and the system gradually turns into a white turbid state. After the dropwise addition, the system is maintained at 0 to 10°C. Dilute 82g (1eq) di-tert-butyl dicarbonate with 100mL dichloromethane and drop it into the reaction system.
- the system will produce gas and exothermic, and the internal temperature will rise to 10 ⁇ 15°C.
- the reaction will be incubated for 2 hours and then LC-MS Monitor that the reaction raw materials disappear and the reaction ends.
- Leave to stand for separation add 137g of methylene chloride to the water phase for extraction, separate the organic phase, combine the organic phases, and wash the organic phase with water.
- the organic phase was dried, filtered and concentrated under reduced pressure to obtain a light yellow oily liquid, which turned into 126g of white waxy solid after standing, which was the crude compound (5-a).
- step 3 Take 126g of the crude compound (5-a) obtained in step 3, add 500mL of tetrahydrofuran at room temperature, stir and dissolve, lower the temperature by 0 to 10°C, add 60% sodium hydride solid (20g, 0.83mol, 2eq) to the reaction, and the system will generate gas bubbles. After returning to room temperature to 25-30°C and reacting for 1 hour, the reaction was monitored by LC-MS and the raw materials disappeared. Dichloromethane and water were added to the residue after recovering tetrahydrofuran under reduced pressure for extraction. The organic phase was dried and desolvated to obtain 85g of light yellow oily liquid, which was purified by vacuum distillation to obtain 51.6g of colorless oily liquid, which was compound (6-a). The GC purity was 92%, and the total yield from the start of the reaction of compound PhCHO in step 1 to the final synthesis of compound (6-a) in step 4 was 58.3%.
- Step 1 of Example 4 Screening of different process conditions in Step 1 of Example 4: According to the input amount of the reagents shown in Table 5, and the other operations are the same as Step 1 of Example 4, compound (7-a) is obtained, and the results are shown in Table 5.
- Cuprous iodide is expensive. Research has found that cuprous iodide can still effectively catalyze the reaction when the dosage is 0.01eq. At the same time, the reaction effect after initial amplification of the reaction is almost the same as that in the small test.
- reaction After the addition is completed, the reaction will be incubated for 2 hours and monitored by LC-MS. The reaction raw materials disappear and the reaction ends. Leave to stand for separation, add 137g of methylene chloride to the water phase for extraction, separate the organic phase, combine the organic phases, and wash the organic phase with water. The organic phase was dried, filtered and concentrated under reduced pressure to obtain a light yellow oily liquid, which turned into 105g of white waxy solid after standing, which was the crude compound (5-2-a).
- step 3 Add 70g of compound (7-2-a) obtained in step 3 into a 500mL reaction bottle, add 200mL of toluene, heat to 110°C and stir until refluxing for 2 to 3 hours.
- LC-MS monitors the disappearance of reaction compound (7-2-a).
- Compound (8-a) was generated, and toluene was recovered under reduced pressure to obtain 59.5 g of a light yellow solid, which could be directly used in the next reaction.
- the reaction will be incubated for 2 hours before LC-MS Monitor that the reaction raw materials disappear and the reaction ends. Leave to stand for separation, add methylene chloride to the water phase for extraction, separate the organic phase, and combine the organic phases. The organic phase was dried, filtered and concentrated under reduced pressure to obtain a light yellow oily liquid, which turned into 112g of white waxy solid after standing, which was the crude compound (5-3-a).
- This embodiment is a kilogram-scale amplification reaction, and the process room temperature is between 25°C and 35°C.
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Abstract
一种沙库必曲中间体、其制备方法及其应用。可以高效制备关键中间体N-Boc氨基醇:式(10)或式(10-a)。中间体可用于制备中性内肽酶(NEP)抑制剂或其前药,尤其是包含γ-氨基-δ-联苯-α-甲基烷酸或酯的骨架的NEP抑制剂,如沙库必曲。还提供了制备式(10)或式(10-a)的中间体。工艺路线的原料便宜、操作简便、生产成本低,适用于工业化生产。
Description
本发明属于医药领域,涉及医药中间体,具体涉及沙库必曲中间体、其制备方法及其应用。
哺乳动物内源性心钠肽(ANP)也称为心纳素(ANF),具有利尿、排钠和血管舒张功能。天然ANF肽经代谢引起失活,特别是通过被认为相当于NEP的降解酶失活,该酶还会引起脑啡肽的代谢失活。
沙库必曲(AHU-377)是由诺华公司研发的一种用于抗心衰的药物LCZ696(CAS:936623-90-4)的主要成分之一。该抗心衰药物由缬沙坦和沙库必曲(AHU-377)通过非共价键结合而成的超分子络合物(复合物),具有血管紧张素受体阻断和中性内肽酶抑制双重作用,降低心血管疾病的危险,主要用于治疗心脏衰竭,也可以用于高血压。
沙库必曲(AHU-377)通常经过关键中间体N-Boc氨基醇[式(10-a)]进行制备,该中间体化学名称为:N-[(1R)-2-[1,1′-联苯]-4-基-1-(羟基甲基)乙基]氨基甲酸叔丁酯(CAS:1426129-50-1);其结构式为:
现有技术中关于沙库必曲中间体N-Boc氨基醇合成方法的专利文献有很多,如文献J.Med.Chem.1995,38,1689-1700,报道了一种以D-酪氨酸为原料,制备沙库必曲中间体的方法。合成路线如下:
该方法使用的D-酪氨酸为非天然氨基酸,价格昂贵;反应过程还使用到昂贵的三氟甲磺酸酐试剂,并且该试剂很活泼,腐蚀性强,对生产设备和操作要求高,不利于工业应用。
专利WO2014032627和专利CN 105026361公开了N-Boc氨基醇的制备方法,合成路线如下所示:
该方法主要存在的问题有:使用到三苯基膦,反应后生成大量的三苯氧膦化合物,导致分离纯化困难,固体废料多;还使用了偶氮二甲酸酯类化合物,这些化合物对光、热和震动敏感,加热过程存在潜在的危险,这些问题将会导致整个生产成本的提高。
类似的,专利CN 105985225公开了一种沙库必曲中间体的制备方法,具体如下:
该方法与专利WO2014/032627和专利CN 105026361公开的方法类似,主要改变在于使用羟基保护剂代替了环氧氯丙烷,反应过程基本类似,并且相同反应类型都采用了基本一致的试剂,最后步骤,由于羟基使用苄基进行保护,还需要额外的钯催化氢解脱去保护基。虽然该专利报道称制备N-Boc氨基醇的产率得到了提高,但是考虑试剂成本,最后增加贵金属催化氢解脱除苄基的步骤,成本上会大幅提高。
专利WO 2013/026773和CN 103764624公开了一种通过对苯基苯甲醛为原料制备沙库必曲中间体氨基醇的方法,其合成路线如下:
该工艺中包括催化氢化步骤,其缺点是使用了贵金属Rh和Pd,用量较大,导致生产成本高。
除了上述例举的一些化学合成法可以制备N-Boc氨基醇中间体外,还可以通过酶方法制 备该中间体。如专利CN 105884656公开了通过酶催化的不对称还原氨化制备该中间体的方法,具体如下:
在该方法中,以苄基溴化镁为原料,与草酰氯单甲酯反应生成酮酸酯;接着在溴代试剂作用下,苯环4-位发生溴化;使用铜催化与苯硼酸进行偶联,得到联苯酮酸酯;在葡萄糖、NADP
+和还原酶CGKR2与GDH体系中,对酮酸酯进行催化不对称还原胺化,获得手性氨基酸甲酯;经过Boc保护氨基后,在硼氢化钠和路易斯酸作用下,将羧酸甲酯还原为醇,得到关键中间体N-Boc氨基醇。
该方法存在合成路线较长的问题,其次酰氯、溴代试剂使用上不方便,铜催化偶联和不对称还原胺化步骤中,需要使用到较多的金属铜、还原酶;此外,该专利中并未指出经过还原胺化后,产物的对映体过量情况。
综上所述,现有报道的制备工艺中,沙库必曲关键手性中间体N-Boc氨基醇(10-a)的制备,一方面受到原料、反应试剂、后处理工艺等方面的限制,另外一方面合成路线长、非对映异构体比例低、环境不友好等问题,导致了生产成本高,操作繁琐,不利于工业化。因此,开发出关键手性中间体N-Boc氨基醇(10-a)更简便、经济和便于工业化的生产路线,具有重要意义。
发明内容
本发明涉及沙库必曲中间体的制备工艺,通过本发明所公开方法的实施,可以高效制备关键中间体N-Boc氨基醇[式(10)和式(10-a)]。所述的中间体可用于中性内肽酶(NEP)抑制剂或其前药,尤其地,包含γ-氨基-δ-联苯-α-甲基烷酸或酯的骨架的NEP抑制剂,如沙库必曲等。该工艺路线原料便宜、操作简便、对设备无特殊要求、生产成本低,适用于工业化生产,具有极大的应用潜力和商业化价值。并且本发还提供了制备化合物(10-a)的中间体。
具体地,一方面,本发明提供一种化合物(10)的制备工艺,其包括以下步骤:
步骤a:化合物(6)与化合物(M)在催化剂作用下反应得到化合物(7),其中,
“*”表示化合物(6)和化合物(7)均为R构型或S构型;优选地,“*”表示化合物(6)和化合物(7)均为R构型;
R
1为F、Cl、Br、I或-OR
3,R
3表示C
1-6烷基或C
1-6杂烷基;
Pg
1为氨基保护基;
在一些实施方案中,本发明所述的工艺,步骤a中,
所述催化剂为亚铜盐,优选地为CuI、CuBr、CuCl或CuCN;所述氨基保护基为苄氧羰基、叔丁氧羰基、甲氧羰基、乙氧羰基、异丙基氧羰基、异丁基氧羰基、笏甲氧基羰基、烯丙氧羰基或三甲基硅乙氧羰基;或
所述反应是在干燥无氧条件下进行的,优选地,所述反应是在干燥无氧条件下通入氮气保护进行的;或
所述反应的反应温度为-60℃~0℃,优选反应温度为-45℃~0℃,更优选反应温度为-30℃~-10℃,最优选反应温度为-20℃~-15℃;或
所述反应的反应时间为0.5h~3h;优选反应时间为0.8h~2h;更优选反应时间为1h~1.5h;最优选反应时间为1h。
在一些实施方案中,本发明所述的工艺,步骤a中,所述反应的反应溶剂为第一溶剂,所述第一溶剂为有机非质子溶剂;优选地,所述有机非质子溶剂为四氢呋喃、2-甲基四氢呋 喃、甲苯、环戊烷甲醚、二氯甲烷、甲基叔丁基醚或乙醚,或其任意组合。
在一些实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)与化合物(M)的投料摩尔比为1∶0.7~2,优选1∶1~2,更优选1∶1~1.5,最优选1∶1。
在一些实施方案中,本发明所述的工艺,还包括以下步骤:
其中,“*”表示化合物(7)、化合物(8)和化合物(9)均为R构型或S构型,优选地,“*”表示化合物(7)、化合物(8)和化合物(9)均为R构型;
步骤b:化合物(7)在第二溶剂中和第一加热条件下反应得到化合物(8),其中,
优选地,所述反应时间为0.3h~2h,更选地,所述反应时间为0.3h~1h,最优选地,所述反应时间为0.5h;
步骤c:化合物(8)在第三溶剂中和第二加热条件下与碱进行水解反应得到化合物(9),其中,
优选地,所述碱为氢氧化钠、氢氧化钾、氢氧化锂、叔丁醇钾、叔丁醇钠、碳酸钠、碳酸钾或甲醇钠或其任意组合;
优选地,所述化合物(8)和所述碱的投料摩尔比为1∶(0.9~5),更优选地,所述化合物(8)和所述碱的投料摩尔比为1∶(1~4),更进一步优选地,所述化合物(8)和所述碱的投料摩尔比为1∶(2~4),最优选地,所述化合物(8)和所述碱的投料摩尔比为1∶3.75;
优选地,所述反应时间为1h~5h,更选地,所述反应时间为2h~4h,最优选地,所述反应时间为3h。
在一些实施方案中,本发明所述的工艺,步骤b和步骤c中,所述第一加热条件和第二加热条件下的加热温度各自独立地为80℃~150℃,优选地为100℃~150℃,进一步优选地为110℃~130℃,最优选地为120℃;优选地,所述第一加热条件和第二加热条件下的加热温度为相同温度;或,
所述第二溶剂和第三溶剂各自独立地为正丁醇、苯、甲苯、乙二醇二甲醚、N,N-二甲基甲酰胺、N.N-二甲基乙酰胺;优选地,所述第二溶剂和第三溶剂为相同溶剂。
在一些实施方案中,本发明所述的工艺,所述步骤b反应结束后不经后处理直接加入碱进行步骤c的反应。
在一些实施方案中,本发明所述的工艺,还包括以下步骤:
其中,“*”表示化合物(9)和化合物(10)均为R构型或S构型,优选地,“*”表示化合物(9)和化合物(10)均为R构型;
步骤d:化合物(9)通过氨基保护反应得到化合物(10)。
在一些实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)由以下步骤制备而成:
其中,化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)上的“*”表示化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)均为S构型,化合物(6)上的“*”表示化合物(6)为R构型;或,化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)上的“*”表示化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)均为R构型,化合物(6)上的“*”表示化合物(6)为S构型;
Pg
2为羟基保护基,优选为甲磺酰基、三氟甲磺酰基、对甲苯磺酰基或硝基磺酰基;R
1和Pg
1具有本发明所述的定义;
步骤a’:化合物(2)与羟基保护试剂通过羟基保护反应得到化合物(3);优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶(1~3),更优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶(1~2),更进一步优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶(1.2~1.5),最优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶1.3;
步骤b’:化合物(3)与酸HY反应得到化合物(4a);优选地,所述酸HY为盐酸、氢溴酸、甲酸、氢碘酸、对甲苯磺酸或三氟甲磺酸;
步骤c’:化合物(4a)在碱作用下得到化合物(4);优选地,所述碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、碳酸氢钾或碳酸钾;
步骤d’:化合物(4)与氨基保护试剂通过氨基保护反应得到化合物(5);优选地,所述化合物(4)与氨基保护试剂的投料摩尔比为1∶1~1.5;
步骤e’:化合物(5)在碱性试剂作用下在第四溶剂中反应得到化合物(6);优选地,所述碱性试剂为氢化钠、甲醇钠、氢氧化钠、氢氧化钾、叔丁醇钾、叔丁醇钠、碳酸钾、碳酸钠或乙醇钠;优选地,所述化合物(5)与碱性试剂的投料摩尔比为1∶(1~3),更优选为1∶(1.5~2.5),最优选为1∶2.2;优选地,所述第四溶剂为四氢呋喃或N,N-二甲基甲酰胺,或其组合;优选地,所述反应温度为-10℃~50℃,进一步优选地,所述反应温度为-10℃~15℃,更进一步优选地,所述反应温度为-5℃~10℃,最优选地,所述反应温度为0℃~10℃。
在一些实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)由以下步骤制备而成:
其中,化合物(4-1-a)和化合物(5-1)上的“*”表示化合物(4-1-a)和化合物(5-1)均为S构型,化合物(6)上的“*”表示化合物(6)为R构型;或,化合物(4-1-a)和化合物(5-1)上的“*”表示化合物(4-1-a)和化合物(5-1)均为R构型,化合物(6)上的“*”表示化合物(6)为S构型;
步骤a”:化合物(4-1-a)在碱作用下与氨基保护试剂进行氨基保护反应得到化合物(5-1);优选地,所述化合物(4-1-a)与氨基保护试剂的投料摩尔比为1∶(0.7~2);优选地,所述碱为氢氧化钠、氢氧化钾、碳酸钠或碳酸钾;
步骤b”:化合物(5-1)在三苯基膦和偶氮二甲酸乙酯作用下和氮气保护下低温反应得到化合物(6),其中,所述低温为-40℃~0℃,优选为-30℃~-10℃,更优选为-20℃~-10℃。
在一些实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)由以下步骤制备而成:
化合物(4a)上的“*”表示化合物(4a)为S构型,化合物(5-2)和化合物(6)上的“*”表示化合物(5-2)和化合物(6)均为R构型;或,化合物(4a)上的“*”表示化合物(4a)和R构型,化合物(5-2)和化合物(6)上的“*”表示化合物(5-2)和化合物(6)均为S构型;
步骤a”’:化合物(4a)在碱作用下反应得到化合物(5-2);优选地,所述碱为氢氧化钠、氢氧化钾、碳酸钠或碳酸钾;优选地,所述化合物(4a)与碱的投料摩尔比为1∶(1~3),更优选为1
∶(1.2~2.5),最优选为1
∶1.5;优选地,所述反应温度为10℃~100℃,更优选地,所述反应温度为30℃~80℃,更进一步优选地,所述反应温度为40℃~60℃,最优选地,所述反应温度为50℃;
步骤b”’:化合物(5-2)继续与氨基保护试剂进行氨基保护反应得到化合物(6);优选地,所述化合物(5-2)与氨基保护试剂的投料摩尔比为1∶(0.7~2);优选地,所述反应为低温反应,所述低温为为-5℃~15℃,更优选所述低温为0℃~10℃。
另一方面,本发明提供一种化合物,其具有如下式(7a)或(7b)结构:
其中,R
1a为F、Cl、Br、I或-OR
3,R
3表示C
1-6烷基或含杂原子取代的C
1-6烷基;
Pg
1a为氨基保护基,优选为苄氧羰基、叔丁氧羰基、甲氧羰基、乙氧羰基、异丙基氧羰基、异丁基氧羰基、笏甲氧基羰基、烯丙氧羰基或三甲基硅乙氧羰基;
且当R
1a为Br或I时,Pg
1a不为叔丁氧羰基。
在一些实施方案中,本发明化合物(7a)或化合物(7b)具有如下其中之一结构:
另一方面,本发明提供一种化合物,其具有如下式(6a)或(6b)结构:
其中,X为F、Cl、Br或I;
Pg
1为氨基保护基,优选为苄氧羰基、叔丁氧羰基、甲氧羰基、乙氧羰基、异丙基氧羰基、异丁基氧羰基、笏甲氧基羰基、烯丙氧羰基或三甲基硅乙氧羰基。
在一些实施方案中,本发明化合物(6a)或化合物(6b)具有如下其中之一结构:
另一方面,本发明提供一种化合物,其具有如下式(8-a)或(8-b)结构:
另一方面,本发明提供本发明所述的工艺或本发明所述的化合物在制备沙库必曲中的应用。
本发明的详细说明书
术语定义
现在详细描述本发明的某些实施方案,其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案,它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到,许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术,等等),以本申请为准。
除非另外说明,本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
在本发明中所采用的描述方式“各...独立地为”与“...各自独立地为”和“...独立地为”可以互换,均应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
本发明中“C
q1-q2”表示所描述的基团的碳原子个数,例如,C
1-6烷基表示含有1-6个碳原子的烷基。
术语“烷基”表示含有1至20个碳原子,饱和的直链或支链一价烃基基团。在另一实施方案中,烷基基团含有1-6个碳原子;在又一实施方案中,烷基基团含有1-4个碳原子;还在一实施方案中,烷基基团含有1-3个碳原子。烷基基团的实例包含,但并不限于,甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基(s-Bu、-CH(CH
3)CH
2CH
3),叔丁基、正戊基、2-戊基,等。
术语“杂烷基”表示烷基基团中一个碳原子被杂原子所取代,其中杂原子为O、S、N、Si。在一实施方案中,杂烷基基团含有1-6个碳原子;在又一实施方案中,杂烷基基团含有1-4个碳原子;还在一实施方案中,杂烷基基团含有1-3个碳原子。杂烷基基团的实例包含,但并不限于,-CH
2OCH
3、-CH
2OCH
2CH
3、-CH
2SCH
3、-CH
2SiH
2CH
3、-CH
2NHCH
3,等。
术语“卤素”表示F(氟)、Cl(氯)、Br(溴)或I(碘)。
术语“氨基保护基”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性,氨基保护基的实例包括但不限于苄氧羰基(-Cbz)、叔丁氧羰基(-Boc)、甲氧羰基(-COOMe或-CO
2Me)、乙氧羰基(-COOEt或-CO
2Et)、异丁基氧羰基(-COO
iBu或-CO
2
iBu)、异丙基氧羰基(-COO
iPr或-CO
2
iPr)、笏甲氧基羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)。
术语“羟基基保护基”,是指羟基的取代基用来阻断或保护羟基的功能性,羟基保护基的实例包括但不限于,甲磺酰基-(Ms)、三氟甲磺酰基(-Tf)、对甲苯磺酰基(-Ts)或硝基磺酰基(-Ns)
术语“第一”或“第二”或“第三”不表示先后顺序,仅是为了区分第一或第二或第三后面的修饰词,如第一溶剂、第二溶剂或第三溶剂分别表示对应反应中所用的溶剂;同样,第一加热条件和第二加热条件也是分别表示对应反应中的加热条件。
本发明的详细描述。
通过本发明所公开方法的实施,可以高效制备关键中间体N-Boc氨基醇[式(10)或式(10-a)]。所述的中间体可用于中性内肽酶(NEP)抑制剂或其前药,尤其地,包含γ-氨基-δ-联苯-α-甲基烷酸或酯的骨架的NEP抑制剂,如沙库必曲等。并且本发还提供了制备化合物(10)或化合物(10-a)的中间体。
具体地,一方面,本发明提供一种化合物(10)的制备工艺,其包括以下步骤:
其中,R
1、R
2、Pg
1和化合物(10)各自具有如本发明所述的定义;
步骤a:化合物(6)与化合物(M)在催化剂作用下反应得到化合物(7),其中,
“*”表示化合物(6)和化合物(7)均为R构型或S构型。
在一些优选的实施方案中,步骤a中,“*”表示化合物(6)和化合物(7)均为R构型,则步骤a表示为:
步骤[a]:化合物(6a’)与化合物(M)在催化剂作用下反应得到化合物(7a’),其中R
1、R
2和Pg
1各自具有如本发明所述的定义。
在一些实施方案中,R
1为F、Cl、Br、I或-OR
3,R
3表示C
1-6烷基或C
1-6杂烷基;
在一些实施方案中,Pg
1为氨基保护基。
在一些实施方案中,本发明所述的工艺,步骤a中,所述催化剂为亚铜盐,优选地为CuI、CuBr、CuCl或CuCN。
在一些实施方案中,本发明所述的工艺,步骤a中,所述氨基保护基为苄氧羰基、叔丁氧羰基、甲氧羰基、乙氧羰基、笏甲氧基羰基、烯丙氧羰基或三甲基硅乙氧羰基。
在一些实施方案中,本发明所述的工艺,步骤a中,所述反应是在干燥无氧条件下进行的;在一些优选的实施方案中,本发明所述的工艺,步骤a中,所述反应是在干燥无氧条件下通入氮气保护进行的。
在一些实施方案中,本发明所述的工艺,步骤a中,所述反应的反应温度为-60℃~0℃;在一些优选的实施方案中,本发明所述的工艺,步骤a中,所述反应温度为-45℃~0℃,在一些更优选的实施方案中,本发明所述的工艺,步骤a中,所述反应温度为-30℃~-10℃;在一些最优选的实施方案中,本发明所述的工艺,步骤a中,所述反应温度为-20℃~-15℃。
在一些实施方案中,本发明所述的工艺,步骤a中,所述反应的反应时间为0.5h~3h;在一些优选的实施方案中,本发明所述的工艺,步骤a中,所述反应时间为0.8h~2h;在一些更优选的实施方案中,本发明所述的工艺,步骤a中,所述反应时间为1h~1.5h;在一些最优选的实施方案中,本发明所述的工艺,步骤a中,所述反应时间为1h。
在一些实施方案中,本发明所述的工艺,步骤a中,所述反应的反应溶剂为第一溶剂, 所述第一溶剂为有机非质子溶剂;优选地,所述有机非质子溶剂为四氢呋喃、2-甲基四氢呋喃、甲苯、环戊烷甲醚、二氯甲烷、甲基叔丁基醚或乙醚,或其任意组合。
在一些实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)与化合物(M)的投料摩尔比为1∶0.7~2;在一些优选的实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)与化合物(M)的投料摩尔比为1∶1~2;在一些更优选的实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)与化合物(M)的投料摩尔比为1∶1~1.5;在一些更优选的实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)与化合物(M)的投料摩尔比为1∶1。
在一些实施方案中,本发明所述的工艺,还包括以下步骤:
其中,R
1、R
2、Pg
1和化合物(10)各自具有如本发明所述的定义;
“*”表示化合物(7)、化合物(8)和化合物(9)均为R构型或S构型;优选地,“*”表示化合物(7)、化合物(8)和化合物(9)均为R构型;
步骤b:化合物(7)在第二溶剂中和第一加热条件下反应得到化合物(8);
其中优选地,所述反应时间为0.3h~2h,更选地,所述反应时间为0.3h~1h,最优选地,所述反应时间为0.5h;
步骤c:化合物(8)在第三溶剂中和第二加热条件下与碱进行水解反应得到化合物(9),其中,
优选地,所述碱为氢氧化钠、氢氧化钾、氢氧化锂、叔丁醇钾、叔丁醇钠、碳酸钠、碳酸钾或甲醇钠或其任意组合;
优选地,所述化合物(8)和所述碱的投料摩尔比为1∶(0.9~5),更优选地,所述化合物(8)和所述碱的投料摩尔比为1∶(1~4),更进一步优选地,所述化合物(8)和所述碱的投料摩尔比为1∶(2~4),最优选地,所述化合物(8)和所述碱的投料摩尔比为1∶3.75;
优选地,所述反应时间为1h~5h,更选地,所述反应时间为2h~4h,最优选地,所述反应时间为3h。
在一些实施方案中,所述第一加热条件和第二加热条件下的加热温度各自独立地为80℃ ~150℃,优选地为100℃~150℃,进一步优选地为110℃~130℃,最优选地在一些实施方案中,本发明所述的工艺,步骤b和步骤c中,为120℃;优选地,所述第一加热条件和第二加热条件下的加热温度为相同温度。
在一些实施方案中,本发明所述的工艺,步骤b和步骤c中,所述第二溶剂和第三溶剂各自独立地为正丁醇、苯、甲苯、乙二醇二甲醚、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺,或其任意组合;优选地,所述第二溶剂和第三溶剂为相同溶剂。
在一些实施方案中,本发明所述的工艺,所述步骤b反应结束后不经后处理直接加入碱进行步骤c的反应。
在一些实施方案中,本发明所述的工艺,还包括以下步骤:
其中,“*”表示化合物(9)和化合物(10)均为R构型或S构型,优选地,“*”表示化合物(9)和化合物(10)均为R构型;
步骤d:化合物(9)通过氨基保护反应得到化合物(10)。
在一些实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)由以下步骤制备而成:
其中,化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)上的“*”表示化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)均为S构型,化合物(6)上的“*”表示化合物(6)为R构型;或,化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)上的“*”表示化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)均为R构型,化合物(6)上的“*”表示化合物(6)为S构型;
Pg
2为羟基保护基,优选为甲磺酰基、三氟甲磺酰基、对甲苯磺酰基或硝基磺酰基;R
1 和Pg
1具有如权利要求1所述的定义;
步骤a’:化合物(2)与羟基保护试剂通过羟基保护反应得到化合物(3);优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶(1~3),更优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶(1~2),更进一步优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶(1.2~1.5),最优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶1.3;
步骤b’:化合物(3)与酸HY反应得到化合物(4a);优选地,所述酸HY为盐酸、氢溴酸、甲酸、氢碘酸、对甲苯磺酸或三氟甲磺酸;
步骤c’:化合物(4a)在碱作用下得到化合物(4);优选地,所述碱为氢氧化钠、氢氧化钾、碳酸钠或碳酸钾;
步骤d’:化合物(4)与氨基保护试剂通过氨基保护反应得到化合物(5);优选地,所述化合物(4)与氨基保护试剂的投料摩尔比为1∶1~1.5;
步骤e’:化合物(5)在碱性试剂作用下在第四溶剂中反应得到化合物(6);优选地,所述碱性试剂为氢化钠、甲醇钠、氢氧化钠、氢氧化钾、叔丁醇钾、叔丁醇钠、碳酸钾、碳酸钠或乙醇钠;优选地,所述化合物(5)与碱性试剂的投料摩尔比为1∶(1~3),更优选为1∶(1.5~2.5),最优选为1∶2.2;优选地,所述第四溶剂为四氢呋喃或N,N-二甲基甲酰胺,或其组合;优选地,所述反应温度为-10℃~50℃,进一步优选地,所述反应温度为-10℃~15℃,更进一步优选地,所述反应温度为-5℃~10℃,最优选地,所述反应温度为0℃~10℃。
在一些实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)由以下步骤制备而成:
其中,化合物(4-1-a)和化合物(5-1)上的“*”表示化合物(4-1-a)和化合物(5-1)均为S构型,化合物(6)上的“*”表示化合物(6)为R构型;或,化合物(4-1-a)和化合物(5-1)上的“*”表示化合物(4-1-a)和化合物(5-1)均为R构型,化合物(6)上的“*”表示化合物(6)为S构型;
步骤a”:化合物(4-1-a)在碱作用下与氨基保护试剂进行氨基保护反应得到化合物(5-1); 优选地,所述化合物(4-1-a)与氨基保护试剂的投料摩尔比为1∶(0.7~2);优选地,所述碱为氢氧化钠、氢氧化钾、碳酸钠或碳酸钾;
步骤b”:化合物(5-1)在三苯基膦和偶氮二甲酸乙酯作用下和氮气保护下低温反应得到化合物(6),其中,所述低温为-40℃~0℃,优选为-30℃~-10℃,更优选为-20℃~-10℃。
在一些实施方案中,本发明所述的工艺,步骤a中,所述化合物(6)由以下步骤制备而成:
化合物(4a)上的“*”表示化合物(4a)为S构型,化合物(5-2)和化合物(6)上的“*”表示化合物(5-2)和化合物(6)均为R构型;或,化合物(4a)上的“*”表示化合物(4a)为R构型,化合物(5-2)和化合物(6)上的“*”表示化合物(5-2)和化合物(6)均为S构型;
步骤a”’:化合物(4a)在碱作用下反应得到化合物(5-2);优选地,所述碱为氢氧化钠、氢氧化钾、碳酸钠或碳酸钾;优选地,所述化合物(4a)与碱的投料摩尔比为1∶(1~3),更优选为1∶(1.2~2.5),最优选为1∶1.5;优选地,所述反应温度为10℃~100℃,更优选地,所述反应温度为30℃~80℃,更进一步优选地,所述反应温度为40℃~60℃,最优选地,所述反应温度为50℃;
步骤b”’:化合物(5-2)继续与氨基保护试剂进行氨基保护反应得到化合物(6);优选地,所述化合物(4-1-a)与氨基保护试剂的投料摩尔比为1∶(0.7~2);优选地,所述反应为低温反应,所述低温为为-5℃~15℃,更优选所述低温为0℃~10℃。
另一方面,本发明提供一种化合物,其具有如下式(7a)或(7b)结构:
其中,R
1a为F、Cl、Br、I或-OR
3,R
3表示C
1-6烷基或含杂原子取代的C
1-6烷基;
Pg
1a为氨基保护基,优选为苄氧羰基、叔丁氧羰基、甲氧羰基、乙氧羰基、异丙基氧羰基、异丁基氧羰基、笏甲氧基羰基、烯丙氧羰基或三甲基硅乙氧羰基;
且当R
1a为Br或I时,Pg
1a不为叔丁氧羰基。
在一些实施方案中,本发明化合物(7a)或化合物(7b)具有如下其中之一结构:
另一方面,本发明提供一种化合物,其具有如下式(6a)或(6b)结构:
其中,X为F、Cl、Br或I;
Pg
1为氨基保护基,优选为苄氧羰基、叔丁氧羰基、甲氧羰基、乙氧羰基、异丙基氧羰基、异丁基氧羰基、笏甲氧基羰基、烯丙氧羰基或三甲基硅乙氧羰基。
在一些实施方案中,本发明化合物(6a)或化合物(6b)具有如下其中之一结构:
另一方面,本发明提供一种化合物,其具有如下式(8-a)或(8-b)结构:
另一方面,本发明提供本发明所述的工艺或本发明所述的化合物在制备沙库必曲中的应 用。
相对于目前已报道路线,本申请路线具有收率高,操作简便,可实现连续化操作,便于工艺放大生产,所用原料价格低廉易得,成本低等。具体地,
1、本申请工艺路线所用的辅料如氢氧化钠,盐酸,甲磺酰氯等均为工业化大生产常用物料,价格便宜易得,经济型极好生产成本低廉。
2、本申请工艺路线中多个中间体无需分离纯化可进行连续化投料生产,可有效降低工业生产的能耗及人工成本,如实施例1减压回收溶剂后可直接进行实施例2,实施例1步骤2中分出的有机相可直接进行成盐操作得到的产物进入水相直接进行实施例3,实施例7步骤6中包含三步反应以甲苯为溶剂可实现一锅法操作,同时完成产物(10-a)的纯化。
一般地,本发明的化合物可以通过本发明所描述的方法制备得到。下面的反应方案和实施例用于进一步举例说明本发明的内容。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
下面所描述的实施例,除非其他方面表明所有的温度定为摄氏度。本发明的室温为10℃~30℃或15℃~25℃。若无其他说明,试剂均为常规试剂,可从市场上购买得到。色谱柱是使用硅胶柱。核磁共振光谱以CDC1
3或DMSO-d
6为溶剂(报导以ppm为单位),用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。偶合常数J,用赫兹(Hz)表示。
下面简写词的使用贯穿本发明:
苄氧羰基-Cbz | 叔丁氧羰基-Boc |
甲氧羰基-COOMe或-CO 2Me | 乙氧羰基-COOEt或-CO 2Et |
异丁基氧羰基-COO iBu或-CO 2 iBu | 笏甲氧基羰基-Fmoc |
异丙基氧羰基-COO iPr或-CO 2 iPr | 三甲基硅乙氧羰基-Teoc |
烯丙氧羰基-Alloc | 三氟甲磺酰基-OTf |
甲磺酰基-OMs | 硝基磺酰基-Ns |
对甲苯磺酰基-Ts | 乙酸乙酯EA,EtOAc |
石油醚PE | 四氢呋喃THF |
Chloroform-d氘代氯仿 | DMSO-d 6氘代二甲亚砜 |
M,mol/L摩尔/升 |
实施例
实施例1:化合物(6-a)的合成
步骤1:化合物(2-a)的合成
取苯甲醛50g(0.47mol)加入乙醇300mL室温搅拌,取氨水(25%)50mL在温度15~20℃下滴入反应体系,滴加完毕恢复室温搅拌20min后,取(S)-环氧氯丙烷52g(0.56mol,1.2eq)在氮气保护下用50mL乙醇稀释后缓慢滴入反应体系,滴加完毕体系室温25~30℃搅拌反应12h。GC监测反应,环氧氯丙烷消失,反应结束。减压蒸馏回收乙醇得到黄色油状产品,加入100mL乙醇再次蒸馏后得到浅黄色油状液体113g为粗品化合物(2-a)。
实施例1步骤1不同工艺条件筛选:按表一所示各试剂投料量,其余操作同上述步骤1操作,得到化合物(2-a),检测所得化合物(2-a)的GC含量,结果如表一所示。
表一:实施例1步骤1不同工艺条件筛选
苯甲醛 | 环氧氯丙烷 | 氨水(25%) | 乙醇 | 氮气 | GC含量 | |
01 | 18.7g | 24g(1.5eq) | 14.7g | 50mL | 无 | 79% |
02 | 18.7g | 24g(1.5eq) | 14.7g | 50mL | 有 | 92% |
03 | 18.7g | 24g(1.2eq) | 14.7g | 50mL | 有 | 91% |
04 | 100g | 104g(1.2eq) | 120g | 400mL | 有 | 94% |
对反应进行条件筛选优化发现,在其他条件与表一上一段落一致的情况下,在滴加环氧氯丙烷过程中氮气保护可有效降低产生的杂质,提高产率。同时反应放大后与小试结果类似,反应稳定性较好。
步骤2:化合物(4-a)的合成
取上步(步骤1)粗品化合物(2-a)(113g,0.42mol,1.0eq)加入400mL二氯甲烷中,室温搅拌有少量白色不溶物,过滤,滤液加入三乙胺63.7g(0.629mol,1.5eq),降温至內温0~10℃,滴加用100mL二氯甲烷稀释的甲磺酰氯62.5g(0.545mol,1.3eq),体系內温升至12℃,有白色物质析出。滴加完毕体系降温至4℃,保温搅拌1h后正相HPLC监测反 应,原料消失。体系加入400mL水充分搅拌30min,萃取,有机相用水(400mL×2)洗涤两次。取120g浓盐酸用240mL水稀释后加入有机相中,室温充分搅拌3~4h,静置分层,有机相用50mL水洗涤后合并水相得到粗品化合物(4-a)水溶液,直接用于下步反应。
实施例1步骤2不同工艺条件筛选:按表二所示试剂投料量,其余操作同上述实施例1步骤2的操作,得到化合物(4-a)水溶液,检测化合物(2-a)的转化率,结果见表二。
表二:实施例1步骤2不同工艺条件筛选
2-a(粗品) | 甲磺酰氯 | 三乙胺 | 二氯甲烷 | 转化率 | |
01 | 113g(0.4mol) | 67g(1.4eq) | 63.7g(1.5eq) | 500mL | 100% |
02 | 113g(0.4mol) | 62g(1.3eq) | 63.7g(1.5eq) | 500mL | 100% |
03 | 113g(0.4mol) | 57g(1.2eq) | 63.7g(1.5eq) | 500mL | 98% |
04 | 113g(0.4mol) | 48g(1eq) | 63.7g(1.5eq) | 500mL | 80% |
在与表二上一段落相似的反应条件下,对于同一批次的(2-a)进行羟基保护反应,发现反应转化率与甲璜酰氯使用量相关。使用当量为1.3eq时,可以使反应转化完全。
步骤3:化合物(5-a)的合成
步骤2的粗品化合物(4-a)水溶液(0.374mol,1.0eq)加入2L反应瓶内,降温內温0-10℃后滴入氢氧化钠水溶液(17g氢氧化钠加入100mL水溶解,1.1eq)调节pH值为8~9之间,体系逐渐变为白色浑浊状态,滴加完毕,体系维持0~10℃。取82g(1eq)二碳酸二叔丁酯用100mL二氯甲烷稀释后滴入反应体系,体系产生气体并放热,內温升至10~15℃,滴加完毕后保温反应2h后LC-MS监测反应原料消失,反应结束。静置分层,水相加入137g二氯甲烷萃取,分出有机相,合并有机相,水洗有机相。有机相干燥过滤后减压浓缩得到淡黄色油状液体,静置后变为白色蜡状固体126g,为粗品化合物(5-a)。
(5-a)的表征数据:
1H NMR(600MHz,Chloroform-d)δ5.09(s,1H),4.89(s,1H),3.81-3.76(m,1H),3.70(dd,J=12.4,6.1Hz,1H),3.55(dq,J=10.2,5.2Hz,1H),3.45(dt,J=14.2,6.2Hz,1H),3.13(s,3H),1.45(s,9H).
13C NMR(151MHz,CDCl
3)δ155.92,80.16,79.85,43.58,42.36,38.38,28.22.
实施例1步骤3不同工艺条件筛选:按表三所示试剂投料量,其余操作同上述实施例1步骤3的操作,得到粗品化合物(5-a),检测化合物(4-a)转化率,结果见表三。
表三:实施例1步骤3不同工艺条件筛选
4-a(粗品) | 氢氧化钠 | 二碳酸二叔丁酯 | 二氯甲烷 | 转化率 | |
01 | 水溶液(0.34mol) | 15g(1.1eq) | 74g(1eq) | 500mL | 100% |
02 | 水溶液(0.34mol) | 15g(1.1eq) | 140g(1.5eq) | 500mL | 100% |
在与表三上一段落相似的反应条件下,当二碳酸二叔丁酯的用量为1~1.5eq时,反应均可以完全转化。
步骤4:化合物(6-a)的合成
取步骤3所得的126g粗品化合物(5-a)加入500mL四氢呋喃室温搅拌溶清,降温0~10℃,取60%的氢化钠固体(20g,0.83mol,2eq)加入反应,体系产生气体泡沫,恢复室温25~30℃反应1h后LC-MS监测反应,原料消失。减压回收四氢呋喃后残留物中加入二氯甲烷和水进行萃取,有机相干燥脱溶,得到85g淡黄色油状液体,减压蒸馏纯化得51.6g无色油状液体,为化合物(6-a),GC纯度92%,从步骤1的化合物PhCHO开始反应到最终合成步骤4的化合物(6-a)的合计收率为58.3%。
(6-a)的表征数据:
1H NMR(600MHz,Chloroform-d)δ3.63(dd,J=10.0,4.1Hz,1H),3.46(dd,J=11.3,5.9Hz,1H),2.78-2.70(m,1H),2.38(d,J=4.0Hz,1H),2.12(s,1H),1.46(s,9H).
13C NMR(151MHz,CDCl
3)δ160.96,81.15,44.50,37.12,30.92,27.43.
实施例1步骤4不同工艺条件筛选:按表四所示试剂投料量,其余操作同上述实施例1步骤4的操作,得到化合物(6-a),收率结果见表四。
表四:实施例1步骤4不同工艺条件筛选
在与表四上一段落相似的反应条件下,当碱选用NaH,且溶剂选用THF时,反应收率最高。
实施例2:化合物(6-a)的合成
步骤1:化合物(5-1-a)的合成
取实施例1步骤1制备的的113g粗品(2-a)(0.4mol,1.0eq)加入200mL二氯甲烷为溶剂,86g浓盐酸(1.0eq)用100mL水稀释后滴入反应,滴加完毕室温25~30℃充分搅拌1h后,静置分相,有机相用50mL水洗涤后合并水相,水相降温至内温0~10℃,取17g氢氧化钠用50mL水溶解后缓慢滴入反应,滴加完毕取65g二碳酸二叔丁酯(0.417mol,1eq)用100mL二氯甲烷稀释后缓慢滴入反应体系,体系放热并有气体产生,滴加完毕恢复室温搅拌2h后,LC-MS检测原料转化完全,静置分相,水相加入100mL二氯甲烷洗涤,合并有机相,干燥过滤减压脱溶后得到白色固体98g为粗品化合物(5-1-a)。
步骤2:化合物(6-a)的合成
取上步(实施例2步骤1)所得粗品化合物(5-1-a)98g(0.376mol,1eq)加入300mL甲苯室温搅拌溶清,氮气保护下加入三苯基膦108g(0.413mol,1.1eq)降至内温-10~-20℃,取68.7g偶氮二甲酸二乙酯(0.394mol,1.05eq)缓慢滴入反应体系,体系逐渐由无色变为黄色有固体析出,滴加完毕,保温反应2h后,LC-MS监测反应,原料消失。后处理取150mL水加入反应,室温搅拌后静置分相,有机相减压脱溶后得到黄色油状液体115g,减压蒸馏纯化得到无色油状液体64g为纯品化合物(6-a)。GC纯度93%;从实施例1步骤1开始计算到最终合成实施例2的化合物(6-a)的反应合计收率73%。
实施例3:化合物(6-a)的合成
将实施例1步骤2中所得粗品化合物(4-a)水溶液(0.356mol,1eq)降温至5~10℃,取15g氢氧化钠(0.392mol,1.1eq)用50mL水稀释后缓慢滴入反应体系,滴加完毕体系补加甲苯200mL加热升温至50℃反应1~2h后,LC-MS监测反应原料转化完毕。体系降温至0~10℃,取二碳酸二叔丁酯71.5g(0.327mol,1eq)滴入反应体系,滴加完毕恢复室温反应2~3h后LC-MS显示原料消失有目标产物生成。静置分层,水相用100mL甲苯洗涤后合并有机相,减压脱溶后得到黄色油状物85g。减压蒸馏纯化得到化合物(6-a),为无色油状液体60g,GC纯度为95%;从实施例1步骤1开始计算到最终合成实施例3的化合物(6-a)的反应合计收率68%。
实施例4:化合物(10-a)的合成
步骤1:化合物(7-a)的合成
取实施例1步骤4所得的51.6g的化合物(6-a)(0.27mol,1.0eq)用200mL四氢呋喃溶解,得化合物(6-a)的四氢呋喃溶液,备用。干燥除氧反应瓶内加入碘化亚铜0.5g(0.003mol,0.01eq),氮气保护下取联苯基溴化镁134mL(2.0M,1.0eq)加入反应体系,內温降至-15~-20℃后,取化合物(6-a)的四氢呋喃溶液滴入反应体系,体系逐渐变为绿色,滴加完毕保持温度-5℃~-10℃反应1h。GC监测反应完毕,取50mL水淬灭反应,减压回收四氢呋喃后,加入二氯甲烷300mL和400mL水萃取,分液,有机相干燥脱溶得白色絮状固体,正庚烷打浆得到74g纯品化合物(7-a),收率79%。
(7-a)的表征数据:
1H NMR(600MHz,Chloroform-d)δ7.56(dd,J=19.0,7.5Hz,4H),7.43(t,J=7.4Hz,2H),7.33(dd,J=15.2,7.4Hz,3H),4.85(d,J=6.8Hz,1H),4.17(s,1H),3.65(d,J=10.0Hz,1H),3.54(d,J=11.1Hz,1H),2.94(dt,J=21.5,8.7Hz,2H),1.44(s,9H).
13C NMR(151MHz,CDCl
3)δ155.03,140.75,139.72,136.13,129.71,128.76,127.36,127.23,126.98,79.84,51.98,46.96,37.41,28.33.
实施例4步骤1不同工艺条件筛选:按表五所示试剂的投料量,其余操作同实施例4步骤1,得到化合物(7-a),结果如表五所示。
表五:实施例4步骤1不同工艺条件筛选
碘化亚铜价格高,研究发现,碘化亚铜使用量为0.01eq时仍可有效催化反应,同时反应初步放大后反应效果与小试几乎一致。
步骤2:化合物(10-a)的合成
取70g(0.2mol,1eq)的化合物(7-a)加入200mL的甲苯,加热升温至110℃回流反应0.5h后,LC-MS监测(7-a)消失生成化合物(8-a)。
化合物(8-a)的表征数据:
1H NMR(400MHz,DMSO-d
6)δ7.83(s,1H),7.69-7.64(m,2H),7.61(d,J=8.2Hz,2H),7.46(t,J=7.6Hz,2H),7.40-7.31(m,3H),4.30(t,J=8.2Hz,1H),4.15-4.05(m,1H),4.03(dd,J=8.2,5.4Hz,1H),2.84(qd,J=13.6,6.1Hz,2H);
13C NMR(101MHz,DMSO)δ159.11,140.35,138.87,136.34,130.49,129.40,127.79,127.14,127.00,68.57,52.95,40.35.
取氢氧化钠24g(0.6mol,3eq)加入反应,保温80℃反应3h后LC-MS监测反应化合物(8-a)消失生成化合物(9-a);
体系降温至25~30℃加入100mL水后滴加二碳酸二叔丁酯44g(0.2mol,1eq),体系逐渐变浑浊析出白色固体,滴加完毕后保温反应2h后HPLC显示化合物(9-a)消失生成化合物(10-a),体系补加甲苯200mL加热升温至60℃搅拌30min,保温静置分层,弃去水相后有机相缓慢降温至0℃析出白色固体,过滤干燥得53g化合物(10-a)(白色固体),纯度99.5%,三步合计收率85.5%。
实施例5:化合物(8-a)的合成
步骤1:化合物(5-2-a)合成
将实施例1步骤2所得的粗品化合物(4-a)水溶液(0.374mol,1.0eq)加入2L反应瓶内,降温內温低于10℃后滴入氢氧化钠水溶液(17g氢氧化钠加入100mL水溶解,1.1eq)调节pH值为8~9之间,体系逐渐变为白色浑浊状态,滴加完毕,体系降温至0~10℃。取37g(1.1eq)氯甲酸甲酯用100mL二氯甲烷稀释后滴入反应体系,体系产生气体并放热,內温升至10~15℃,滴加完毕后保温反应2h后LC-MS监测反应原料消失,反应结束。静置分层,水相加入137g二氯甲烷萃取,分出有机相,合并有机相,并用水洗有机相。有机相干燥过滤后减压浓缩得到淡黄色油状液体,静置后变为白色蜡状固体105g,为粗品化合物(5-2-a)。
化合物(5-2-a)的表征数据:
1H NMR(600MHz,Chloroform-d)δ5.79(s,1H),4.89(s,1H),3.81(d,J=11.6Hz,1H),3.73(dd,J=11.9,6.0Hz,1H),3.68(s,3H),3.58(d,J=14.4Hz,1H),3.54-3.47(m,1H),3.14(s,3H);
13C NMR(151MHz,CDCl
3)δ157.12,79.40,52.15,43.36,42.30,38.04.
步骤2:化合物(6-2-a)的合成
取实施例5步骤2所得的105g粗品化合物(5-2-a)(0.32mol,1eq)加入400mL四氢呋喃室温搅拌溶清,降温0~10℃,取60%的氢化钠固体(19.2g,0.48mol,1.5eq)加入反应,体系产生气体泡沫,恢复室温25~30℃反应1h后LC-MS监测反应,原料消失。减压回收四氢呋喃后加入二氯甲烷,水萃取,有机相干燥脱溶,得到58g淡黄色油状液体。减压蒸馏纯化得43.5g无色油状液体,为化合物(6-2-a),GC纯度95%,从实施例1开始计算前五步合计收率62.5%。
化合物(6-2-a)的表征数据:
1H NMR(600MHz,Chloroform-d)δ3.74(s,3H),3.65(dd,J=11.6,6.0Hz,1H),3.51(dd,J=11.6,5.7Hz,1H),2.82(dt,J=5.4,2.5Hz,1H),2.47(d,J=6.0Hz,1H),2.20(s,1H).
13C NMR(151MHz,CDCl
3)δ162.60,53.39,44.35,37.17,30.93.
步骤3:化合物(7-2-a)的合成
取步骤2所得的43g的化合物(6-2-a)(0.287mol,1.0eq)用200mL四氢呋喃溶解,得到 化合物(6-a)的四氢呋喃溶液,备用。
干燥除氧反应瓶内加入碘化亚铜0.5g(0.0028mol,0.01eq),氮气保护下取联苯基溴化镁158mL(2.0M,1.1eq)加入反应体系,內温降至-15~-20℃后,取化合物(6-a)的四氢呋喃溶液滴入反应体系,滴加完毕保持温度-10~-5℃反应1h。GC监测反应完毕,取50mL水淬灭反应,减压回收四氢呋喃后,加入二氯甲烷300mL和400mL水萃取,分液,有机相干燥脱溶得白色絮状固体,正庚烷打浆得到70g纯品化合物(7-2-a),收率80%。
化合物(7-2-a)的表征数据:
1H NMR(400MHz,Chloroform-d)δ7.60-7.51(m,4H),7.43(t,J=7.6Hz,2H),7.37-7.27(m,3H),5.03(d,J=7.4Hz,1H),4.22(s,1H),3.68(s,3H),3.64(d,J=3.5Hz,1H),3.54(dd,J=11.2,3.2Hz,1H),2.96(t,J=6.4Hz,2H);
13C NMR(101MHz,CDCl
3)δ156.19,140.63,139.81,135.82,129.63,128.75,127.40,127.25,126.95,52.48,52.24,46.71,37.30.
步骤4:化合物(8-a)的合成
取步骤3中所得的化合物(7-2-a)70g加入500mL反应瓶内,加入甲苯200mL加热升温110℃搅拌至回流2~3h,LC-MS监测反应化合物(7-2-a)消失,生成化合物(8-a),减压回收甲苯后得到浅黄色固体59.5g可直接用于下步反应。
实施例6:化合物(8-a)的合成
步骤1:化合物(5-3-a)的合成
将实施例1步骤2的粗品化合物(4-a)水溶液(0.374mol,1.0eq)加入2L反应瓶内,降温內温低于10℃后滴入氢氧化钠水溶液(17g氢氧化钠加入100mL水溶解,1.1eq)调节PH值为8~9之间,体系逐渐变为白色浑浊状态,滴加完毕,体系降温至0~10℃。取43.9g(1.1eq)氯甲酸乙酯用100mL二氯甲烷稀释后滴入反应体系,体系产生气体并放热,內温升至10~15℃,滴加完毕后保温反应2h后LC-MS监测反应原料消失,反应结束。静置分层,水相加入二氯甲烷萃取,分出有机相,合并有机相。有机相干燥过滤后减压浓缩得到淡黄色油状液体,静置后变为白色蜡状固体112g,为粗品化合物(5-3-a)。
化合物(5-3-a)的表征数据:
1H NMR(600MHz,Chloroform-d)δ5.44(s,1H),4.90(s,1H), 4.13(d,J=6.7Hz,2H),3.80(d,J=12.2Hz,1H),3.72(dd,J=12.2,6.0Hz,1H),3.60(d,J=14.5Hz,1H),3.51(dt,J=13.7,6.0Hz,1H),3.13(s,3H),1.25(t,J=6.4Hz,3H);
13C NMR(151MHz,CDCl
3)δ156.76,79.63,61.21,43.47,42.50,38.28,14.39.
步骤2:化合物(6-3-a)的合成
取步骤3的112g粗品化合物(5-3-a)(0.32mol,1eq)加入400mL四氢呋喃室温搅拌溶清,降温0~10℃,取60%的氢化钠固体(26.18g,0.65mol,2eq)加入反应,体系产生气体泡沫,恢复室温25~30℃反应1h后LC-MS监测反应,原料消失。减压回收四氢呋喃后加入二氯甲烷,水萃取,有机相干燥脱溶得到54g淡黄色油状液体。减压蒸馏纯化得47.6g无色油状液体,为化合物(6-3-a),GC纯度94%,从实施例1开始计算前五步合计收率63%。
步骤3:化合物(7-3-a)的合成
取步骤2所得的47g的化合物(6-3-a)(0.287mol,1.0eq)用200mL四氢呋喃溶解,得化合物(6-3-a)的四氢呋喃溶液,备用。
干燥除氧反应瓶内加入碘化亚铜0.5g(0.0028mol,0.01eq),氮气保护下取联苯基溴化镁158mL(2.0M,1.1eq)加入反应体系,內温降至-15~-20℃后,取化合物(6-3-a)的四氢呋喃溶液滴入反应体系,滴加完毕保持温度-5~-10℃反应1h。GC监测反应完毕,取50mL水淬灭反应,减压回收四氢呋喃后,加入二氯甲烷300mL和400mL水萃取,分液,有机相干燥脱溶得白色絮状固体,正庚烷打浆得到77g纯品化合物(7-3-a),收率85%。
化合物(7-3-a)的表征数据:
1H NMR(400MHz,Chloroform-d)δ7.60-7.51(m,4H),7.42(t,J=7.6Hz,2H),7.32(dd,J=14.0,7.6Hz,3H),5.01(d,J=7.7Hz,1H),4.21(s,1H),4.12(q,J=7.1Hz,2H),3.65(dd,J=10.8,3.8Hz,1H),3.53(dt,J=11.1,3.6Hz,1H),2.95(tt,J=13.4,6.4Hz,2H),1.24(t,J=7.1Hz,3H);
13C NMR(101MHz,CDCl
3)δ155.78,140.64,139.76,135.89,129.63,128.73,127.36,127.22,126.93,61.04,52.35,46.75,28.29,14.51.
步骤4:化合物(8-a)的合成
取步骤3中所得的化合物(7-3-a)70g加入500mL反应瓶内,加入甲苯200mL加热升温110℃搅拌至回流2~3h,LC-MS监测反应(7-3-a)消失,生成化合物(8-a),减压回甲苯后得到浅黄色固体63g可直接用于下步反应。
实施例7:化合物(10-a)的合成
此实施例为公斤级放大反应,工艺室温均为25~35℃之间。
步骤1:化合物(2-a)的合成
取苯甲醛1.0kg(9.42mol)加入乙醇4L室温搅拌,取氨水(25%)1L在温度15~20℃下滴入反应体系,滴加完毕恢复室温搅拌20min后,取(S)-环氧氯丙烷1.05kg(11.3mol,1.2eq)在氮气保护下用2L乙醇稀释后缓慢滴入反应体系,滴加完毕体系室温25~30℃搅拌反应12h。GC监测反应,环氧氯丙烷消失,反应结束。减压蒸馏回收乙醇得到黄色油状产品加入1L乙醇再次蒸馏后得到浅黄色油状液体2.3kg为粗品化合物(2-a)。
步骤2:化合物(4-a)的合成
取上步(实施例7步骤1)所得粗品化合物(2-a)(2.3kg,8.5mol)加入8L二氯甲烷中,室温搅拌有少量白色不溶物,过滤,滤液加入三乙胺1.29kg(12.75mol,1.5eq),降温至內温0~10℃,滴加甲磺酰氯1.27kg(11.05mol,1.3eq),体系內温升至12~20℃,有白色物质析出。滴加完毕恢复室温搅拌1h后正相HPLC监测反应,原料消失。体系加入2L水充分搅拌30min,萃取,有机相用水(2L×2)洗涤两次。
取1.2kg浓盐酸用2.4L水稀释后加入上步处理的有机相中,室温充分搅拌3~4h,静置分层,有机相用500mL水洗涤后合并水相得到粗品化合物(4-a)水溶液直接用于下步反应。
步骤3:化合物(5-a)的合成
将实施例7步骤2所得粗品化合物(4-a)水溶液(7.63mol)加入反应釜内,降温內温低于10℃后滴入氢氧化钠水溶液(460g氢氧化钠加入2L水溶解),体系逐渐变为白色浑浊状态,滴加完毕,体系降温至0~10℃。取1.7kg(7.63mol,1eq)二碳酸二叔丁酯滴入反应 体系,体系产生气体并放热,內温升至10~15℃,滴加完毕后保温反应2h后LC-MS监测反应原料消失,反应结束。静置分层,反应加入2.7kg二氯甲烷萃取,静置分出有机相,2kg水洗有机相后,有机相干燥过滤后减压蒸馏回收溶剂后得到淡黄色油状液体,静置后变为白色蜡状固体2.5kg,为粗品化合物(5-a)。
步骤4:化合物(6-a)的合成
取实施例7步骤3所得2.5kg的粗品化合物(5-a)(7.65mol)加入5L四氢呋喃室温搅拌溶清,得化合物(5-a)的四氢呋喃溶液,备用。
反应釜加入2L四氢呋喃,降温0~10℃,取60%的氢化钠固体(460g,11.47mol,1.5eq)加入反应釜,保温搅拌30min后滴加化合物(5-a)的四氢呋喃溶液,2~3h滴加完毕。升温至50℃反应5h后LC-MS监测反应,原料消失。500mL水淬灭反应后减压回收四氢呋喃,加入二氯甲烷4L,水2.5L萃取,有机相干燥脱溶得到1.75kg淡黄色油状液体。减压蒸馏纯化得1.1kg无色油状液体,为化合物(6-a),GC纯度96%,前五步合计收率60%。
步骤5:化合物(7-a)的合成
取实施例7步骤4所得的1.1kg的化合物(6-a)用4.5L四氢呋喃溶解,得化合物(6-a)的四氢呋喃溶液,备用,干燥除氧反应釜内加入碘化亚铜11g,氮气保护下取2.0M的联苯基溴化镁3L(6mol)加入反应体系,內温降至-15~-20℃后,取化合物(6-a)的四氢呋喃溶液滴入反应体系,体系逐渐变为灰绿色,2h滴加完毕,保持温度反应1~2h。GC监测反应完毕,取2L水淬灭反应,减压回收四氢呋喃后,加入二氯甲烷5L和6L水萃取,分液,有机相干燥脱溶得白色絮状固体2.1kg,正庚烷打浆得到1.6kg纯品化合物(7-a),收率79%。
步骤6:化合物(10-a)的合成
取实施例7步骤5所得1.6kg的化合物(7-a)加入8L的甲苯,加热升温至100~110℃回流反应1~2h后,LC-MS监测反应化合物(7-a)消失生成化合物(8-a)。降温补加甲苯2L后取氢氧化钠740g加入反应,回流反应3h后LC-MS监测反应化合物(8-a)消失生成化合物 (9-a)。体系降温至25~30℃滴加二碳酸二叔丁酯1.1kg,体系逐渐变浑浊析出白色固体,滴加完毕后保温反应2h后HPLC显示化合物(9-a)消失生成化合物(10-a),体系补加水2L后加热升温至50~60℃搅拌30min,保温静置分层,分出有机相并缓慢降温至0℃析出白色固体,过滤干燥得1.25kg化合物(10-a)(白色固体),纯度99.3%,三步合计收率87%。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (17)
- 根据权利要求1所述的工艺,其特征在于,所述催化剂为亚铜盐,优选地为CuI、CuBr、CuCl或CuCN;所述氨基保护基为苄氧羰基、叔丁氧羰基、甲氧羰基、乙氧羰基、异丙基氧羰基、异丁基氧羰基、笏甲氧基羰基、烯丙氧羰基或三甲基硅乙氧羰基;或所述反应是在干燥无氧条件下进行的,优选地,所述反应是在干燥无氧条件下通入氮气保护进行的;或所述反应的反应温度为-60℃~0℃,优选反应温度为-45℃~0℃,更优选反应温度为-30℃~-10℃,最优选反应温度为-20℃~-15℃;或所述反应的反应时间为0.5h~3h;优选反应时间为0.8h~2h;更优选反应时间为1h~ 1.5h;最优选反应时间为1h。
- 根据权利要求1-2任意一项所述的工艺,其特征在于,所述反应的反应溶剂为第一溶剂,所述第一溶剂为有机非质子溶剂;优选地,所述有机非质子溶剂为四氢呋喃、2-甲基四氢呋喃、甲苯、环戊烷甲醚、二氯甲烷、甲基叔丁基醚或乙醚,或其任意组合。
- 根据权利要求1-3任意一项所述的工艺,所述化合物(6)与化合物(M)的投料摩尔比为1∶0.7~2,优选1∶1~2,更优选1∶1~1.5,最优选1∶1。
- 根据权利要求1-4任意一项所述的工艺,其特征在于,还包括以下步骤:其中,“*”表示化合物(7)、化合物(8)和化合物(9)均为R构型或S构型,优选地,“*”表示化合物(7)、化合物(8)和化合物(9)均为R构型;步骤b:化合物(7)在第二溶剂中和第一加热条件下反应得到化合物(8),其中,优选地,所述反应时间为0.3h~2h,更选地,所述反应时间为0.3h~1h,最优选地,所述反应时间为0.5h;步骤c:化合物(8)在第三溶剂中和第二加热条件下与碱进行水解反应得到化合物(9),其中,优选地,所述碱为氢氧化钠、氢氧化钾、氢氧化锂、叔丁醇钾、叔丁醇钠、碳酸钠、碳酸钾或甲醇钠,或其任意组合;优选地,所述化合物(8)和所述碱的投料摩尔比为1∶(0.9~5),更优选地,所述化合物(8)和所述碱的投料摩尔比为1∶(1~4),更进一步优选地,所述化合物(8)和所述碱的投料摩尔比为1∶(2~4),最优选地,所述化合物(8)和所述碱的投料投料摩尔比为1∶3.75;优选地,所述反应时间为1h~5h,更选地,所述反应时间为2h~4h,最优选地,所述反应时间为3h。
- 根据权利要求5所述的工艺,其特征在于,所述第一加热条件和第二加热条件下的加热温度各自独立地为80℃~150℃,优选地为100℃~150℃,进一步优选地为110℃~130℃, 最优选地为120℃;优选地,所述第一加热条件和第二加热条件下的加热温度为相同温度;或,所述第二溶剂和第三溶剂各自独立地为正丁醇、苯、甲苯、乙二醇二甲醚、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺,或其任意组合;优选地,所述第二溶剂和第三溶剂为相同溶剂。
- 根据权利要求5或6所述的工艺,其特征在于,所述步骤b反应结束后不经后处理直接加入碱进行步骤c的反应。
- 根据权利要求1-8任意一项所述的工艺,其特征在于,所述化合物(6)由以下步骤制备而成:其中,化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)上的“*”表示化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)均为S构型,化合物(6)上的“*”表示化合物(6)为R构型;或,化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)上的“*”表示化合物(2)、化合物(3)、化合物(4a)、化合物(4)和化合物(5)均为R构型,化合物(6)上的“*”表示化合物(6)为S构型;Pg 2为羟基保护基,优选为甲磺酰基、三氟甲磺酰基、对甲苯磺酰基或硝基磺酰基;R 1 和Pg 1具有如权利要求1所述的定义;步骤a’:化合物(2)与羟基保护试剂通过羟基保护反应得到化合物(3);优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶(1~3),更优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶(1~2),更进一步优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶(1.2~1.5),最优选地,所述化合物(2)与羟基保护试剂的投料摩尔比为1∶1.3;步骤b’:化合物(3)与酸HY反应得到化合物(4a);优选地,所述酸HY为盐酸、氢溴酸、甲酸、氢碘酸、对甲苯磺酸或三氟甲磺酸;步骤c’:化合物(4a)在碱作用下得到化合物(4);优选地,所述碱为氢氧化钠、氢氧化钾、碳酸钠或碳酸钾;步骤d’:化合物(4)与氨基保护试剂通过氨基保护反应得到化合物(5);优选地,所述化合物(4)与氨基保护试剂的投料摩尔比为1∶1~1.5;步骤e’:化合物(5)在碱性试剂作用下在第四溶剂中反应得到化合物(6);优选地,所述碱性试剂为氢化钠、甲醇钠、氢氧化钠、氢氧化钾、叔丁醇钾、叔丁醇钠、碳酸钾、碳酸钠或乙醇钠;优选地,所述化合物(5)与碱性试剂的投料摩尔比为1∶(1~3),更优选为1∶(1.5~2.5),最优选为1∶2.2;优选地,所述第四溶剂为四氢呋喃或N,N-二甲基甲酰胺,或其组合;优选地,所述反应温度为-10℃~50℃,进一步优选地,所述反应温度为-10℃~15℃,更进一步优选地,所述反应温度为-5℃~10℃,最优选地,所述反应温度为0℃~10℃。
- 根据权利要求1-8任意一项所述的工艺,其特征在于,所述化合物(6)由以下步骤制备而成:化合物(4-1-a)和化合物(5-1)上的“*”表示化合物(4-1-a)和化合物(5-1)均为S构型,化合物(6)上的“*”表示化合物(6)为R构型;或,化合物(4-1-a)和化合物(5-1)上的“*”表示化合物(4-1-a)和化合物(5-1)均为R构型,化合物(6)上的“*”表示化合物(6)为S构型;步骤a”:化合物(4-1-a)在碱作用下与氨基保护试剂进行氨基保护反应得到化合物(5-1);优选地,所述化合物(4-1-a)与氨基保护试剂的投料摩尔比为1∶(0.7~2);优选地,所述碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、碳酸氢钾或碳酸钾;步骤b”:化合物(5-1)在三苯基膦和偶氮二甲酸乙酯作用下和氮气保护下低温反应得到化合物(6),其中,所述低温为-40℃~0℃,优选为-30℃~-10℃,更优选为-20℃~-10℃。
- 根据权利要求1-8任意一项所述的工艺,其特征在于,所述化合物(6)由以下步骤制备而成:其中,化合物(4a)上的“*”表示化合物(4a)为S构型,化合物(5-2)和化合物(6)上的“*”表示化合物(5-2)和化合物(6)均为R构型;或,化合物(4a)上的“*”表示化合物(4a)为R构型,化合物(5-2)和化合物(6)上的“*”表示化合物(5-2)和化合物(6)均为S构型;步骤a”’:化合物(4a)在碱作用下反应得到化合物(5-2);优选地,所述碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、碳酸氢钾或碳酸钾;优选地,所述化合物(4a)与碱的投料摩尔比为1∶(1~3),更优选为1∶(1.2~2.5),最优选为1∶1.5;优选地,所述反应温度为10℃~100℃,更优选地,所述反应温度为30℃~80℃,更进一步优选地,所述反应温度为40℃~60℃,最优选地,所述反应温度为50℃;步骤b”’:化合物(5-2)继续与氨基保护试剂进行氨基保护反应得到化合物(6);优选地,所述化合物(5-2)与氨基保护试剂的投料摩尔比为1∶(0.7~2);优选地,所述反应为低温反应,所述低温为为-5℃~15℃,更优选所述低温为0℃~10℃。
- 权利要求1-11任意一项所述的工艺或权利要求12-15任意一项所述的化合物在制备沙库必曲中的应用。
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