JP2018506541A - Nep阻害剤を調製するための方法および中間体 - Google Patents
Nep阻害剤を調製するための方法および中間体 Download PDFInfo
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- JP2018506541A JP2018506541A JP2017542062A JP2017542062A JP2018506541A JP 2018506541 A JP2018506541 A JP 2018506541A JP 2017542062 A JP2017542062 A JP 2017542062A JP 2017542062 A JP2017542062 A JP 2017542062A JP 2018506541 A JP2018506541 A JP 2018506541A
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- hydrogen
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- 238000000034 method Methods 0.000 title claims description 109
- 239000003112 inhibitor Substances 0.000 title abstract description 23
- 239000000543 intermediate Substances 0.000 title abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 195
- 239000003054 catalyst Substances 0.000 claims abstract description 62
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- -1 aldehyde compound Chemical class 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 46
- 238000006243 chemical reaction Methods 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 24
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- 239000007858 starting material Substances 0.000 claims description 23
- 230000008569 process Effects 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000004122 cyclic group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000002950 monocyclic group Chemical group 0.000 claims description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- 125000002619 bicyclic group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 8
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 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 8
- 150000002367 halogens Chemical class 0.000 claims description 7
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 7
- 238000006957 Michael reaction Methods 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- STNJBCKSHOAVAJ-UHFFFAOYSA-N Methacrolein Chemical compound CC(=C)C=O STNJBCKSHOAVAJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 4
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 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 claims description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 239000001384 succinic acid Substances 0.000 claims description 3
- 229940014800 succinic anhydride Drugs 0.000 claims description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 2
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 27
- 102000003729 Neprilysin Human genes 0.000 abstract description 26
- 108090000028 Neprilysin Proteins 0.000 abstract description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
- 238000005481 NMR spectroscopy Methods 0.000 description 56
- 239000000243 solution Substances 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 43
- 239000000203 mixture Substances 0.000 description 39
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 34
- 238000004128 high performance liquid chromatography Methods 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- 239000000047 product Substances 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- 230000002829 reductive effect Effects 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000000651 prodrug Substances 0.000 description 21
- 229940002612 prodrug Drugs 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 238000003818 flash chromatography Methods 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- 238000005984 hydrogenation reaction Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 9
- 150000002540 isothiocyanates Chemical class 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 229960001866 silicon dioxide Drugs 0.000 description 9
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 8
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- 150000001241 acetals Chemical class 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 150000007524 organic acids Chemical class 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 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 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- NDRCWDMNIVKTBC-KDOFPFPSSA-N (2R,4S)-2-methyl-4-nitro-5-(4-phenylphenyl)pentanal Chemical compound C1(=CC=C(C=C1)C[C@H](C[C@H](C=O)C)[N+](=O)[O-])C1=CC=CC=C1 NDRCWDMNIVKTBC-KDOFPFPSSA-N 0.000 description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 4
- VVBXKASDRZXWON-UHFFFAOYSA-N N=[PH3] Chemical compound N=[PH3] VVBXKASDRZXWON-UHFFFAOYSA-N 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 4
- 238000004296 chiral HPLC Methods 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229960003953 sacubitril Drugs 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- YSLCYHQURRXRPD-YNDBEVAQSA-N (2R,4S)-4-amino-2-methyl-5-(4-phenylphenyl)pentanoic acid hypochlorous acid Chemical compound OCl.C[C@H](C[C@H](N)Cc1ccc(cc1)-c1ccccc1)C(O)=O YSLCYHQURRXRPD-YNDBEVAQSA-N 0.000 description 3
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 3
- WMDHONPPLUVJCT-UHFFFAOYSA-N 1-(2-nitroethyl)-4-phenylbenzene Chemical group [N+](=O)([O-])CCC1=CC=C(C=C1)C1=CC=CC=C1 WMDHONPPLUVJCT-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000006845 Michael addition reaction Methods 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- 238000010521 absorption reaction Methods 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- GYBBYQZQWIDPGX-DYVFJYSZSA-N (2R,4S)-2-methyl-4-nitro-5-(4-phenylphenyl)pentanoic acid Chemical compound C1(=CC=C(C=C1)C[C@H](C[C@H](C(=O)O)C)[N+](=O)[O-])C1=CC=CC=C1 GYBBYQZQWIDPGX-DYVFJYSZSA-N 0.000 description 2
- WQQLDAFJPWYZCC-DYVFJYSZSA-N (2r,4s)-4-amino-2-methyl-5-(4-phenylphenyl)pentanoic acid Chemical compound C1=CC(C[C@@H](N)C[C@@H](C)C(O)=O)=CC=C1C1=CC=CC=C1 WQQLDAFJPWYZCC-DYVFJYSZSA-N 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 2
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
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- JMRYOSQOYJBDOI-UHFFFAOYSA-N dilithium;di(propan-2-yl)azanide Chemical compound [Li+].CC(C)[N-]C(C)C.CC(C)N([Li])C(C)C JMRYOSQOYJBDOI-UHFFFAOYSA-N 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
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- 125000003438 dodecyl group Chemical class [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000005446 heptyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical class [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
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- 239000012038 nucleophile Substances 0.000 description 1
- 125000002347 octyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000007833 oxidative deamination reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000000913 palmityl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical class C(CCCC)* 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HLIBNTOXKQCYMV-UHFFFAOYSA-N propylsulfamic acid Chemical compound CCCNS(O)(=O)=O HLIBNTOXKQCYMV-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical group CC(C)(C)OC(O)=O XKXIQBVKMABYQJ-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 125000005106 triarylsilyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 125000002948 undecyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003671 uranium compounds Chemical class 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/10—Preparation of nitro compounds by substitution of functional groups by nitro groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
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Abstract
Description
Raは、C6〜C10−アリール、複素環基、または、場合により、C6〜C10−アリールもしくは複素環基で置換されているC1〜C6−アルキルであり;
RbおよびRcは、2個の連結する炭素原子および結合した窒素基と一緒にキラルスキャフォールド(キラル骨格)(chiral scaffold)を形成し、ここでは、
(i)RbおよびRcは、2個の連結する炭素原子と一緒に5〜10員の環系を形成し、その環系は単環式もしくは二環式であり、飽和、部分的に不飽和、もしくは不飽和であってもよく、
または、
(ii)RbおよびRcはそれぞれ独立に、水素、C1〜C7−アルキル、C6〜C10−アリール、および複素環基から選択され、
RdおよびReは独立に、水素、C6〜C10−アリール、複素環基、および、場合により、ハロゲン、ヒドロキシル、アミノ、C6〜C10−アリール、もしくは複素環基から選択される1個、2個、もしくは3個の置換基で置換されているC1〜C6−アルキルから選択され;または
RdおよびReは、連結する窒素原子と一緒に、以下:
あるいは、Rbは、水素、C1〜C7−アルキル、C6〜C10−アリール、および複素環基から選択され;Rcは、連結する炭素原子および−N(Rd)(Re)基と一緒に縮合二環式7〜9員環系を形成し、その環系は、場合により、C1〜C7−アルキルもしくはC2〜C7−アルケニルによって置換されており;
ここでは、各複素環基は、5〜14個の環原子およびN、O、S、S(O)、またはS(O)2から独立に選択される1〜4個のヘテロ原子を有する、単環式、二環式、または三環式環系であり、
C6〜C10−アリールまたは複素環基はそれぞれ、場合により、C1〜C7−アルキル、ヒドロキシル、オキソ、C1〜C7−アルコキシ、C2〜C8−アルカノイル−オキシ、ハロゲン、ニトロ、シアノ、およびCF3からなる群から選択される、1個、2個または3個の残基によって置換されている)のうちの1種である。
ここでは、すべての式について、Raは、
の化合物の製造における、好ましくは、N−(3−カルボキシル−1−オキソプロピル)−(4S)−(p−フェニルフェニルメチル)−4−アミノ−(2R)−メチルブタン酸もしくはその塩、またはN−(3−カルボキシル−1−オキソプロピル)−(4S)−(p−フェニルフェニルメチル)−4−アミノ−(2R)−メチルブタン酸エチルエステルもしくはその塩の製造における使用を提供する。
上記および下記に使用する一般的定義は、異なる定義がされない限り、以下の意味を有しており、ここで、1つまたは複数またはすべての表現または記号は、発明の各実施形態で独立に、より具体的な定義に置き換えて、より好ましい実施形態にすることができる。
官能基 可逆性誘導体
カルボン酸 エステル、例えば、アルキルエステルが含まれる。
アルコール エステル、例えば、硫酸エステルおよびリン酸エステル、ならびにカルボン酸エステルが含まれる。
アミン アミド、カルバメート、イミン、エナミン、
カルボニル(アルデヒド、ケトン)イミン、オキシム、アセタール/ケタール、エノールエステル、オキサゾリジン、およびチアゾキソリジン(thiazoxolidine)
酸化的活性化
・ N−およびO−脱アルキル化
・ 酸化的脱アミノ化
・ N−酸化
・ エポキシ化
還元的活性化
・ アゾ還元
・ スルホキシド還元
・ ジスルフィド還元
・ 生体内還元性アルキル化
・ ニトロ還元
以下の節は、上のスキーム1〜5に提示した通りの個々の方法ステップについて説明する。
一実施形態では、式(1)の化合物は、次の立体化学を有する式(1−a)
一実施形態では、スキーム3のいずれか1つに従うマイケル付加反応は、次式:
上記は、以下に開示される。
左:
(1)Li, De Run; Organic Letters 2010, V12(8), P1756-1759 CAPLUS
(2)Zhang, Xue-jing; Tetrahedron: Asymmetry 2009, V20(12), P1451-1458 CAPLUS
(3)Yu, Feng; Organic & Biomolecular Chemistry 2010, V8(20), P4767-4774 CAPLUS
(4)Fu, Ji-Ya; Tetrahedron Letters 2010, V51(37), P4870-4873 CAPLUS
右:
(5)Galzerano, Patrizia; Chemistry - A European Journal 2009, V15(32), P7846-7849, S7846/1-S7846/45 CAPLUS
左:
(1)Sakamoto, Shota; Inokuma, Tsubasa; Takemoto, Yoshiji From Organic Letters (2011), 13(24), 6374-6377
(2)Bai, Jian-Fei; Wang, Liang-Liang; Peng, Lin; Guo, Yun-Long; Jia, Li-Na; Tian, Fang; He, Guang-Yun; Xu, Xiao-Ying; Wang, Li-Xin, From Journal of Organic Chemistry (2012), 77(6), 2947-2953
(3)Tripathi, Chandra Bhushan; Mukherjee, Santanu, from Organic Letters (2014), 16(12), 3368-3371
中央:
(4)Hu, Zhi-Peng; Lou, Chun-Liang; Wang, Jin-Jia; Chen, Chun-Xia; Yan, Ming, from Journal of Organic Chemistry (2011), 76(10), 3797-3804
(5)Sakamoto, Shota; Inokuma, Tsubasa; Takemoto, Yoshiji, from Organic Letters (2011), 13(24), 6374-6377.
(1)Nunez, Marta G.; Farley, Alistair J. M.; Dixon, Darren J., from Journal of the American Chemical Society (2013), 135(44), 16348
(1)Sigma−Aldrich Corporation(セントルイス、MO、米国)
(1)Gao, Yaojun; Ren, Qiao; Wu, Hao; Li, Maoguo; Wang, Jian, from Chemical Communications (Cambridge, United Kingdom) (2010), 46(48), 9232-9234
(2)Ren, Qiao; Gao, Yaojun; Wang, Jian, from Chemistry - A European Journal (2010), 16(46), 13594-13598,
(1)Berkessel, Albrecht; Seelig, Bianca; Schwengberg, Silke; Hescheler, Juergen; Sachinidis, Agapios, from ChemBioChem (2010), 11(2), 208
(2)Okino, Tomotaka; Hoashi, Yasutaka; Takemoto, Yoshiji, from Journal of the American Chemical Society (2003), 125(42), 12672
ならびに次式:
を有するものからなる群から選択される。
Cobb, Alexander J. A.; Organic & Biomolecular Chemistry 2005, V3(1), P84-96;およびLongbottom, Deborah A.; Franckevicius, Vilius; Ley, Steven V. Chimia (2007), 61(5), 247-256を参照されたい。
本開示において室温が言及される場合は必ず(実施例において20〜25℃を指す場合を除く)、これは好ましくは23±25℃、例えば23℃の温度を指す。
本発明は、例えば以下のものなどの、幾つかの反応ステップの組み合わせも網羅する。
・式(8)、好ましくは式(8−a)の化合物を式(1)、好ましくは式(1−a)の化合物からスキーム1に従って製造するための方法、ここでは、式(1)、好ましくは式(1−a)の出発化合物は、式(2)、好ましくは式(2−a)の化合物からスキーム2に従う方法によって得られる;
・式(1)、好ましくは式(1−a)の化合物を式(2)、好ましくは式(2−a)の化合物からスキーム2に従って製造するための方法、ここでは、式(2)、好ましくは式(2−a)の出発化合物は、スキーム3−1または3−2に従う方法によって得られる;
・式(8)、好ましくは式(8−a)の化合物を式(1)、好ましくは式(1−a)の化合物からスキーム1に従って製造するための方法、ここでは、式(1)、好ましくは式(1−a)の化合物は、式(2)、好ましくは式(2−a)の化合物からスキーム2に従う方法によって得られ、式(2)、好ましくは式(2−a)の出発化合物は、スキーム3−1または3−2に従う方法によって得られる;
・式(2)、好ましくは式(2−a)の化合物を式(7)の化合物からスキーム3−2に従って製造するための方法、ここでは、式(7)の出発化合物は、スキーム4に従う方法によって得られる;
・式(1)、好ましくは式(1−a)の化合物を式(2)の化合物からスキーム2に従って製造するための方法、ここでは、式(2)、好ましくは式(2−a)の出発化合物は、式(7)の化合物からスキーム3−2に従う方法に従って得られ、式(7)の出発化合物は、スキーム4に従う方法によって得られる;
・式(8)、好ましくは式(8−a)の化合物を式(1)、好ましくは式(1−a)の化合物からスキーム1に従って製造するための方法、ここでは、式(1)、好ましくは式(1−a)の化合物は、式(2)、好ましくは式(2−a)の化合物からスキーム2に従う方法によって得られ、式(2)、好ましくは式(2−a)の出発化合物は、スキーム3−2に従う方法によって得られ、式(7)の出発化合物は、スキーム4に従う方法によって得られる;
・式(7)の化合物を式(3)の化合物からスキーム4に従って製造するための方法、ここでは、式(7)の出発化合物は、スキーム5に従う方法によって得られる;
・式(2)、好ましくは式(2−a)の化合物を式(3)の化合物からスキーム3−1に従って製造するための方法、ここでは、式(3)の出発化合物は、スキーム5に従う方法によって得られる;
・式(2)、好ましくは式(2−a)の化合物を式(7)の化合物からスキーム3−2に従って製造するための方法、ここでは、式(7)の出発化合物は、式(3)の化合物からスキーム4に従う方法によって得られ、式(3)の出発化合物は、スキーム5に従う方法によって得られる。
本発明の別の実施形態では、本発明の方法の中間体および生成物は、NEP阻害剤またはその塩もしくはプロドラッグの合成に使用することができ、特に、それらは、γ−アミノ−δ−ビフェニル−α−メチルアルカン酸または酸エステルの骨格を含むNEP阻害剤の合成に使用することができる。γ−アミノ−δ−ビフェニル−α−メチルアルカン酸または酸エステルの骨格を含むNEP阻害剤またはそのプロドラッグとして、例えば、NEP阻害剤プロドラッグであるN−(3−カルボキシ−1−オキソプロピル)−(4S)−(p−フェニルフェニルメチル)−4−アミノ−(2R)−メチルブタン酸エチルエステルおよび対応するNEP阻害剤であるN−(3−カルボキシ−1−オキソプロピル)−(4S)−(p−フェニルフェニルメチル)−4−アミノ−(2R)−メチルブタン酸が挙げられる。
のNEP阻害剤プロドラッグを得る。
スキームZ:
σ 化学シフト
μl マイクロリットル
Ac アセチル
ACNL アセトニトリル
AcOH 酢酸
Ac2O 無水酢酸
Bn ベンジル
Boc tert−ブトキシカルボニル
BOC2O 炭酸ジ−tert−ブチル
ブライン 飽和(室温で)塩化ナトリウム水溶液
BuOH n−ブタノール
Cbz カルバミン酸ベンジル
Cbz−Cl クロロギ酸ベンジル
DBU 1,8−ジアザビシクロウンデカ−7−エン
DCM ジクロロメタン/塩化メチレン
de ジアステレオマー過剰率
DIPEA ジイソプロピルエチルアミン
DMAP 4−(ジメチルアミノ)ピリジン
DMF N,N−ジメチルホルムアミド
DMPU 1,3−ジメチル−3,4,5,6−テトラヒドロ−2(1H)−ピリミジノン
DMSO ジメチルスルホキシド
ee 鏡像異性体過剰率
ES エレクトロスプレー
ESI エレクトロスプレーイオン化
Et エチル
Et2O ジエチルエーテル
Et3N トリエタノールアミン
EtOH エタノール
EtOAc 酢酸エチル
GC ガスクロマトグラフィー
h 時間
Hep ヘプタン
Hex ヘキサン
HNMR プロトン核磁気共鳴
HOBt 1−ヒドロキシベンゾトリアゾール
HPLC 高速液体クロマトグラフィー
i−Pr イソプロピル
IPAまたはiPrOAc 酢酸イソプロピル
iPr2O イソプロピルアルコール
IR 赤外線
KHMDS カリウムビス(トリメチルシリル)アミド
L リットル
LC−MS 液体クロマトグラフィー−質量分析
LDA リチウムジイソプロピルアミド
LHMDS リチウムビス(トリメチルシリル)アミド
M モル濃度
m/e 質量電荷比
Me メチル
MeOH メタノール
mg ミリグラム
min 分
mL ミリリットル
mmol(複数) ミリモル
mol(複数) モル
MS 質量分析
NaHMDS ナトリウムビス(トリメチルシリル)アミド
nm ナノメートル
NMR 核磁気共鳴
Pd/C パラジウム炭素
Ph フェニル
PHCH3 トルエン
Piv ピバロイル
Piv−Cl 塩化ピバロイル
ppm 百万分率
psi ポンド/平方インチ
RP 逆相
RT 室温
rt 保持時間
SEM 2−(トリメチルシリル)エトキシメチル
SEM−Cl (2−クロロメトキシエチル)−トリメチルシラン
SM 出発物質
TEMPO (2,2,6,6−テトラメチル−ピペリジン−1−イル)オキシダニル
TES トリエチルシリル
Tf トリフリル、トリフルオロメタンスルホニル
TFA トリフルオロ酢酸
TFAA トリフルオロ酢酸無水物
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
TMEDA N,N,N’,N’−テトラメチルエチレンジアミン
TMS トリメチルシリル
tR 保持時間
Ts トシル
TsO トシレート
uPLC 超高速液体クロマトグラフィー
概要−スキームM1:
1H-NMR (300 MHz, CDCl3) δ 1.58 (s, 1 H), 3.37 (t, 2 H, J = 8 Hz), 4.65 (t, 2 H, J = 7.5 Hz), 7.263-7.384 (m, 2H), 7.423 (m, 1H), 7.448-7.472 (m, 2 H), 7.55-7.59 (m, 2 H).
13C-NMR (100 MHz, CDCl3) δ 33.0, 76.14, 127.0, 127.4, 127.6, 128.8, 129.0, 134.7, 140.3, 140.5
1H-NMR (300 MHz, CDCl3) δ 3.94 (s, 2 H), 5.53 (psd, 1 H), 6.56 (psd, 1 H), 7.30-7.38 (m, 3H), 7.44-7.47 (t, 2 H), 7.57-7.60 (m, 4 H).
13C-NMR (100 MHz, CDCl3) δ 36.1, 119.0, 127.1, 127.4, 127.6, 128.8, 129.4, 134.5, 140.3, 140.6, 157.5.
1H-NMR (400 MHz, CDCl3) δ 1.19 (d, 3H, J = 7.5 Hz), 1.98-2.06 (m, 1H), 2.21 (ddd, 1H, J1 = 3.3, J2 = 9.8, J3= 14.8 Hz), 2.43-2.53 (m, 1H), 3.12 (dd, 1H, J1 = 5.5, J2= 14.3 Hz), 3.31 (dd, 1H, J1 = 8.8, J2 = 14.3 Hz), 4.89-4.96 (m, 1H), 7.25 (psd, 2H), 7.33-7.37 (m, 1H), 7.44 (pst, 2H), 7.53-7.59 (m, 4H), 9.56 (s, 1 H).
13C-NMR (100 MHz, CDCl3) δ 14.2, 33.9, 40.0, 42.9, 87.8, 126.9, 127.3, 127.5, 128.7, 129.2, 133.9, 140.4, 140.4, 202.3.
LC−MS:[MH3O]+=315.2m/z
キラルHPLC、9.00(2R,4S)、10.17(2S、4S)、12.65(2R、4R)、14.89分(2S、4R);カラム Chiralpak ID 4.6mmφ×250mm、5μm(株式会社ダイセル、大阪、日本)、25℃;Hept:EtOAc:CH3CN、90:8:2
1H-NMR (400 MHz, CDCl3) δ 1.27 (d, 3H, J = 7.5 Hz), 2.12-2.22 (m, 2H), 2.51-2.57 (m, 1H), 3.12 (dd, 1H, J1 = 5.5, J2= 14.3 Hz), 3.30 (dd, 1H, J1 = 8.8, J2 = 14.3 Hz), 4.92-4.97 (m, 1H), 7.25 (psd, 2H), 7.34-7.37 (m, 1H), 7.44 (pst, 2H), 7.53-7.59 (m, 4H).
13C-NMR (100 MHz, CDCl3) δ 18.1, 36.0, 36.7, 40.1, 88.0, 127.0, 127.3, 127.5, 128.8, 129.3, 130.8, 140.0, 179.3.
概要−スキームM2:
この化合物は、実施例1に記載する通りに合成する。
1H-NMR (400 MHz, CDCl3) δ 1.19 (d, 3H, J = 7.5 Hz), 1.98-2.06 (m, 1H), 2.21 (ddd, 1H, J1 = 3.3, J2 = 9.8, J3= 14.8 Hz), 2.43-2.53 (m, 1H), 3.12 (dd, 1H, J1 = 5.5, J2= 14.3 Hz), 3.31 (dd, 1H, J1 = 8.8, J2 = 14.3 Hz), 4.89-4.96 (m, 1H), 7.25 (psd, 2H), 7.33-7.37 (m, 1H), 7.44 (pst, 2H), 7.53-7.59 (m, 4H), 9.56 (s, 1 H).
13C-NMR (100 MHz, CDCl3) δ 14.2, 33.9, 40.0, 42.9, 87.8, 126.9, 127.3, 127.5, 128.7, 129.2, 133.9, 140.4, 140.4, 202.3.
LC−MS:[MH3O]+=315.2m/z
キラルHPLC:9.00(2R、4S)、10.17(2S、4S)、12.65(2R、4R)、14.89分(2S、4R);カラム Chiralpak ID(株式会社ダイセル、大阪、日本)4.6mmφ×250mm、5μm;25℃;Hept:EtOAc:CH3CN、90:8:2
次いで、(2R,4S)−5−([1,1’−ビフェニル]−4−イル)−2−メチル−4−ニトロペンタン酸である7および(2R,4S)−4−アミノ−5−([1,1’−ビフェニル]−4−イル)−2−メチル−ペンタン酸クロロハイドレートである8を、実施例1、ステップi)およびステップh)に記載する通りに合成した。
エステル類似体についてのX線データが利用可能である:
概要−スキームM3:
化合物8およびメタクリル酸エチル(1.3当量)のトルエン中溶液に、DBU(1当量)を滴下添加し、混合物を室温で48時間撹拌した。NH4Cl(ss)を添加して、混合物を5分間撹拌した。相を分離し、水相をEtOAcで抽出した。合わせた有機相をMgSO4上で脱水し、溶媒を真空下で除去し、フラッシュクロマトグラフィーに供した。
温度 100(2)K
波長 1.54178Å
結晶系 斜方晶系
空間群 P212121
格子定数 a=5.448(2)Å =90°
b=8.286(2)Å =90°
c=40.777(12)Å =90°
体積 1840.8(10)Å3
Z 4
密度(計算値) 1.232g/cm3
吸収係数 0.696mm−1
F(000) 728
結晶サイズ 0.21×0.11×0.04mm3
データ収集のためのシータ範囲 2.17〜66.57°
指数範囲 −6<=h<=5、−9<=k<=9、−48<=l<=48
収集した反射 53449
独立反射 3246[R(int)=0.0429]
シータ=66.57°に対する完全性 99.5%
吸収補正 同等物から半経験的
最大および最小透過率 0.9727および0.8676
精密化方法 F2についての完全行列最小二乗
データ/抑制/パラメータ 3246/0/229
F2についての適合度 1.112
最終R指数[I>2シグマ(I)] R1=0.0324、wR2=0.0826
R指数(全データ) R1=0.0332、wR2=0.0831
絶対構造パラメータ 0.0(2)
吸光係数 0.0042(3)
最大示差ピークおよびホール 0.166および−0.158e.Å−3
この化合物は、上に示した式(8−a)の化合物から、Ksander(Med. Chem. 1995, 38, 1689-1700;この刊行物における化合物18が式(8−a)に相当し、それをAHU377およびその塩に変換する)に記載される通りに調製される。
あるいは、AHU377は、国際公開第2008/083967号パンフレットに記載される通りに製造することができる。
次の触媒を下記の通りに合成した:
系列1:
この系列は、キラルスキャフォールド110をc〜jに対応する第三級アミンと組み合わせて設計した。スキャフォールド110および塩基性窒素上の様々な残基によって、中間複合体を形成する間の、変動幅の小さいpKa値(pKa〜10)、立体容積の影響、および基質との潜在的な追加的相互作用(例えば水素の結合)を調査することが可能となった。
最後の系列は、キラルスキャフォールド110および111を、2つの異なる部分、すなわちグアニジンおよびイミノホスホランと組み合わせることによって生成した。これらの化合物の調製に関して、系列1に属する対応する第一級アミンを出発物質として使用した。グアニジン誘導体110kおよび111kは、それぞれ110aおよび111aを、N−[クロロ(ジメチルアミノ)メチレン]−N−メチルメタンアミニウムクロリド(131)と、トリエチルアミンの存在下で反応させることから合成した。そして化合物131は、テトラメチル尿素と塩化オキサリルとをビルスマイヤー(Vilsmeyer)条件下で反応させることによって生成した(スキームI)。
使用した市販の化学物質はすべて、Sigma−Aldrich、Merck、またはFlukaによって供給され、これらの試薬はすべて、さらに精製することなく使用した。すべての反応は、薄層クロマトグラフィー(TLC)分析によってモニタリングし、それは、Merckシリカゲル60 F254プレコートアルミニウムまたはガラスシート(0.2mm)上で行い、UV照射(254nm)で可視化した。NMRは、400MHz計測器で記録した。化学シフトは、TMSに対するδ(ppm)、多重度(sは一重線、dは二重線、tは三重線、qは四重線、mは多重線、およびbrは広幅である)、相対積分値、および結合定数J(Hz)によって与えられる。Rotavapor(Buchi)、フラッシュクロマトグラフィーシステム(Biotage)のような一般的な実験室装置および材料。高速液体クロマトグラフィー(HPLC)分析および逆相高速液体クロマトグラフィー(RP−HPLC)分析は、Agylentの計測器で、キラルカラムまたはRP−18カラムを使用して実施した(HPLC法に関する添付文書Aを参照されたい)。LC−MSは、Acquity UPLC/ESI MS内で行った。
1.110a、111a、および112aについての一般的手順
イソチオシアナト−3,5−ビス(トリフルオロメチル)ベンゼン(2.95mmol、1当量)を、乾燥THF(15mL)中の(1R,2R)−シクロヘキサン−1,2−ジアミン(2.95mmol、1当量)の撹拌溶液に、シリンジポンプ(0.5mL/分)を介して0℃で30分間にわたって添加し、反応物を室温でさらに15時間撹拌した。溶媒を除去し、残留物をbiotage機器でのフラッシュクロマトグラフィーによって精製した。
1H NMR (400 MHz, CDCl3): d (ppm) δ 1.25-1.34 (m, 4 H), 1.76-1.81 (m, 2 H), 1.95 (m, 1 H), 1.97-2.03 (m, 1 H), 2.07 (m, 1 H), 2.66-2.73 (m, 1 H), 3.39 (m, 1 H), 6.63 (s, 1 H), 7.58 (s, 1 H), 8.02 (s, 2H).
13C NMR (100 MHz, CDCl3): (ppm) δ 24.3, 31.7, 59.4, 118.6, 121.3, 124, 132.2-133.2, 138.6, 180.4.
LCMS(ESI):[M+H]+(C15H18F6N3S)について計算した精密質量の必要値はm/z 386.11、実測値はm/z 386.2である。
1H NMR (400 MHz, DMSO): d (ppm) δ 4.38 (d, 1 H, J= 8 Hz), 5.50 (d, 1 H, J= 8 Hz), 7.20-7.45 (m, 10 H), 7.71 (s, 1 H), 8.32 (s, 2 H), 10.58 (s, 1 H).
13C NMR (100 MHz, DMSO): (ppm) δ 59.9, 63.7, 116.3, 121.5, 122.3, 125.0, 127.3, 127.4, 127.5, 128.4, 128.6, 130.5, 141.4, 142.5, 143.4, 180.6.
LCMS(ESI):[M+H]+(C23H19F6N3S)について計算した精密質量の必要値はm/z 483.47、実測値はm/z 484.2である。
1H NMR (400 MHz, CDCl3): d (ppm) δ 6.87 (dd, 1 H, J1= 1.1 Hz, J2= 8.3 Hz), 7.04 (d, 1 H,J= 8.8 Hz), 7.16 (ddd, 1 H, J1= 1.5 Hz, J2= 6.8 Hz, J3= 8.3 Hz), 7.23 (ddd,1 H, J1= 1.3 Hz, J2= 6.8 Hz, J1= 8.1 Hz), 7.39-7.35 (m, 2 H), 7.59 - 7.53 (m, 3H), 7.62 (s, 1H), 7.72 (d, 2H, J = 3.0 Hz), 7.81 - 7.74 (m, 2H), 8.00 (dt, 1H, J1= 1.0 Hz, J2= 8.3 Hz), 8.13 - 8.05 (m, 2H).
13C NMR (100 MHz, CDCl3): (ppm) δ 76.7, 77.0, 77.2, 77.3, 11.9, 118.2, 119.7, 121.4, 122.9, 123.0, 124.1, 124.7, 124.9, 126.1, 126.9, 127.4, 127.5, 128.2, 128.4, 128.5, 129.7, 130.4, 132.2 (q), 132.7, 132.9, 133.2, 133.8, 138.7, 141.9, 180.1.
LCMS(ESI):[M+H]+(C29H19F6N3S)について計算した精密質量の必要値はm/z 555.2、実測値はm/z 556.2である。
1H NMR (400 MHz, CDCl3): d (ppm) δ 1.49 - 1.07 (m, 10H), 1.78 (d, 1H, J = 8.1 Hz), 1.85 (d, 1H, J= 8.1 Hz), 1.95 (d, 1H, J= 8.1 Hz), 2.36 (td, 3H, J1 = 3.9 Hz, J2= 11.1 Hz), 2.62 (t, 2H, J = 8.2 Hz), 2.73 (s, 1H), 3.75 (td, 1H, J1 = 4.0 Hz, J2= 10.5 Hz), 7.73 (s, 1H), 7.84 (s, 2H).
13C NMR (100 MHz, CDCl3): (ppm) δ 32.6, 49.6, 56.3, 68.9, 118.8, 119.0, 119.1, 119.2, 121.5, 124.3, 124.6, 127.0, 132.6 (q), 139.7, 182.
LCMS(ESI):[M+H]+(C20H25F6N3S)について計算した精密質量の必要値はm/z 453.5、実測値はm/z 454.3である。
1H NMR (400 MHz, CDCl3): d (ppm) δ 2.98 (dd, 1H, J1=10.1 Hz, J2= 15.3), 3.43 (dd, 1H, J1=15.1 Hz, J2= 8.3 Hz), 4.32 - 4.17 (m, 1H), 4.41 (d, 1H, J = 7.9 Hz), 6.96 (s, 1H), 7.45 - 7.22 (m, 4H), 7.65 (s, 1H), 8.19 (s, 2H), 12.72 (s, 1H),
13C NMR (100 MHz, CDCl3): (ppm) δ 36.5, 64.5, 65.3, 121.8, 123.0, 123.5, 124.8, 128.1, 128.7, 131.7 (q), 137.9, 141.7, 143.1, 182.6.
LCMS(ESI):[M+H]+(C20H25F6N3S)について計算した精密質量の必要値はm/z 419.4、実測値はm/z 420.2である。
1H NMR (400 MHz, CDCl3): d (ppm) δ 2.69 (dd, 1H, J1= 9.3 Hz, J2= 15.6), 3.40 (dd, 1H, J1= 8.2 Hz, J2= 15.8Hz), 3.67 (q, 1H, J = 8.5 Hz), 5.06 - 4.85 (m, 1H), 6.67 (s, 1H), 7.16 - 7.08 (m, 1H), 7.41 - 7.22 (m, 2H), 7.55 (s, 1H), 8.09 (s, 2H), 12.37 (s, 1H).
13C NMR (100 MHz, CDCl3): (ppm) δ 41.9, 62.9, 67.3, 117.9, 123.0, 123.3, 124.9, 128.03, 129.3, 131.8, 138.3, 139.8, 141.8, 182.6.
LCMS(ESI):[M+H]+(C18H15F6N3S)について計算した精密質量の必要値はm/z 419.3、実測値はm/z 420.1である。
SM(3.93mmol、1当量)をCH3CN(20ml)に懸濁させ、15分間撹拌し、HCOH水溶液(19.6mmol、5当量)を添加し、15分間撹拌した。懸濁液は溶液となり、NaCNBH3(7.86mmol、2当量)を添加し、5時間撹拌した。AcOH(2ml)を添加し、2時間磁気撹拌した後、溶液を2%MeOH−DCM(50ml)で希釈し、NaOH 1N(3×40ml)で洗浄し、MgSO4によって脱水し、減圧下で濃縮した。褐色がかった油状物を得、それをステップ2に直接使用した。それを、マイクロ波バイアル(20ml)中でEtOH(15ml)に溶解させ、HCl 6N(5ml)を添加した。溶液を120℃で3時間加熱した。NaOH 2N(40ml)を添加し、溶液をEtOAc(3×30ml)で抽出し、MgSO4によって脱水し、減圧下で濃縮して、褐色がかった油状物を得、それをステップ3に直接用いた。粗生成物のTHF(20ml)中溶液に、窒素大気下で、懸濁液として10分間撹拌しながら、イソチオシアネート(3.93mmol、1当量)を添加した。1時間撹拌した後、黄色の溶液を得た。反応混合物を減圧下で濃縮して、黄色油状物を得た。
1H NMR (400 MHz, CDCl3): d (ppm) δ 2.13(s, 1 H), 3.76 (d, 1H, J = 10.9 Hz), 5.20 (s, 2H), 5.34 (s, 1H), 6.99 (dd, 2H, J1= 2.4 Hz, J2= 6.7 Hz), 7.05 (s, 5H), 7.17 - 7.14 (m, 2H), 7.59 (s, 1H), 7.66 (s, 2H), 8.35 (s, 2H).
13C NMR (100 MHz, CDCl3): (ppm) δ 40.5, 53.4, 59.4, 74.0, 119.0, 121.6, 123.6, 124.3, 127.8, 128.6, 129.9, 131.3, 132.4, 139.1, 180.5.
LCMS(ESI):[M+H]+(C25H23F6N3S)について計算した精密質量の必要値はm/z 511.5、実測値はm/z 513.2である。
1H NMR (400 MHz, CDCl3): d (ppm) δ 2.47 (s, 6H), 5.21 (s, 2H), 6.82 (d, 1H, J = 8.5 Hz), 7.02 (ddd, 1H, J1= 1.4 Hz, J2= 6.6 Hz, J3= 8.3 Hz), 7.23 - 7.13 (m, 2H), 7.34 - 7.25 (m, 2H), 7.51 - 7.38 (m, 5H), 7.64 (d, 1H, J = 8.7 Hz), 7.75 (d, 1H, J = 8.1 Hz), 7.90 (t, 2H, J = 8.0 Hz), 7.99 (d, 1H, J = 8.6 Hz), δ 8.27 (s, 1H).
13C NMR (100 MHz, CDCl3): (ppm) δ 43.1, 52.4, 117.8, 117.9, 120.5, 121.9, 122.9, 123.0, 123.2, 123.9, 125.8, 126.2, 126.5, 127.4, 127.5, 128.9, 129.0, 129.5, 130.2, 130.6, 130.9, 131.0, 131.2, 131.9, 132.2, 132.3, 133.0, 138.6, 149.0, 178.8.
LCMS(ESI):[M+H]+(C31H23F6N3S)について計算した精密質量の必要値はm/z 583.59、実測値はm/z 585.2である。
1H NMR (400 MHz, CDCl3): d (ppm) δ 2.67 (s, 6H), 2.90 (dd, 1H, J1=9.3 Hz, J2= 15.7 Hz), 3.47 (dd, 1H, J1=8.8 Hz, J2= 15.7 Hz), 4.50 - 4.36 (m, 1H), 4.52 (d, 1H, J = 7.4 Hz), 6.83 - 6.68 (m, 1H), 7.45 - 7.28 (m, 4H), 7.65 (s, 1H), 8.12 (s, 2H), 13.05 (s, 1H).
13C NMR (100 MHz, CDCl3): (ppm) δ 36.7, 41.4, 60.0, 117.9, 121.8, 123.1, 124.5, 125.5, 127.2, 128.8, 131.7, 136.9, 139.3, 141.9, 182.6
LCMS(ESI):[M+H]+(C20H19F6N3S)について計算した精密質量の必要値はm/z 447.4、実測値は448.2である。
反応生成物を、HPLC(≧97%)、NMR、およびLC−MSによって分析した。
1H NMR (400 MHz, CDCl3): d (ppm) δ 2.45 (s, 6H), 3.11 - 2.89 (m, 2H), 3.69 (q, 1H, J = 8.5 Hz), 5.14 (dd, 1H, J1= 4.5 Hz, J2= 7.6 Hz), 6.59 (d, 1H, J = 4.0 Hz), 7.20 - 7.23 (m, 2H), 7.26 - 7.29 (m, 2H), 7.40 - 7.32 (m, 1H), 7.55 (t, 1H, J = 1.5 Hz), 8.03 (d, 2H, J = 1.7 Hz), 12.71 (s, 1H).
13C NMR (100 MHz, CDCl3): (ppm) δ.25.5, 40.9, 53.4, 62.6, 75.6, 117.8, 122.8, 123.5, 125.7, 128.0, 129.5, 131.7, 137.6, 139.9, 142.0, 182.5.
128(4.58mmol、1当量)、R−X(11.9mmol、2.5当量)、K2CO3(11.9mmol、2.5当量)、および水(18ml)を、マイクロ波バイアルに添加した。反応管をマイクロ波合成システム内に入れ、120℃で35分間動作させた。反応が完了した後(HPLCおよびLC−MSによってモニタリングした)、有機部分をEtOAc(3×20ml)中に抽出し、溶媒を減圧下で除去して黄色がかった固体を得、それをステップ2に直接用いた。粗生成物およびHCl 6N(10ml)をマイクロ波バイアル(10〜20ml)に添加した。反応管をマイクロ波合成システム内に入れ、150℃で1時間動作させた。反応が完了した後(HPLCおよびLC−MSによってモニタリングした)、有機部分をDCM(3×10ml)中に抽出した(HPLCによって安息香酸の存在が示された)。有機相をHCl 2N(3×10ml)で洗浄し、水相(3×15ml)を減圧下で濃縮し、MeOHで洗浄して、黄色がかった油状物を得、それをステップ3に直接用いた。ステップ2からの粗生成物に、THF(30ml)およびEt3N(1.5ml)を添加して、白色懸濁液を得、それを30分間撹拌した。THF(15ml)中の3,5−ビス−トリフルオロメチル−イソチオシアネート(isothiocianate)(4.58mmol、1当量)を滴下添加し、2時間撹拌した。反応は、HPLCおよびLC−MSによってモニタリングした。反応混合物をろ過してトリエチルアンモニウム塩を除去し、有機相をNaOH 1N(30ml)で洗浄し、減圧下で濃縮して、褐色がかった油状物を得た。粗生成物を、Biotage機器でのフラッシュクロマトグラフィーによって精製した。
1H NMR (400 MHz, DMSO-d6): d (ppm) δ 1.37 - 1.14 (m, 4H), 1.53 - 1.38 (m, 1H), 1.70 - 1.57 (m, 1H), 1.85 - 1.70 (m, 5H), 1.97 - 1.87 (m, 1H), 2.14 - 2.02 (m, 1H), 2.89 (s, 4H), 4.39 (s, 1H), 7.72 (s, 1H), 8.27 (s, 2H), 8.50 (s, 1H), 10.51 (s, 1H).
13C NMR (100 MHz, DMSO-d6): (ppm) δ 34.5, 47.2, 53.3, 118.4, 119.1, 119.2, 119.4, 121.7, 125.2, 127.1, 127.5, 132.4, 138.6, 182.
LCMS(ESI):[M+H]+(C19H23F6N3S)について計算した精密質量の必要値はm/z 439.5、実測値はm/z 441.2である。
1H NMR (400 MHz, DMSO-d6): d (ppm) δ 1.30 - 1.04 (m, 4H), 1.67 - 1.55 (m, 1H), 1.80 - 1.68 (m, 1H), 1.92 - 1.82 (m, 1H), 2.30 (s, 1H), 2.74 - 2.56 (m, 3H), 3.47 - 3.33 (m, 4H), 4.26 (s, 2H), 7.73 (s, 1H), 7.83 (s, 1H), 8.27 (s, 2H), 10.00 (s, 1H).
13C NMR (100 MHz, DMSO-d6): (ppm) δ 24.5, 25.5, 32.5, 53.4, 55.6, 61.0, 116.4, 122.4, 125.1, 130.7, 142.5, 179.8.
LCMS(ESI):[M+H]+(C19H25F6N3O2S)について計算した精密質量の必要値はm/z 473.2、実測値はm/z 474.3である。
1H NMR (400 MHz, DMSO-d6): d (ppm) δ 0.89 (s, 3 H), 0.91 (s, 3 H), 1,04 - 1,23 (m, 4 H), 1.26 - 1.42 (m, 3 H), 1.71 - 1.82 (m, 4 H), 2. 02 (m, 1 H), 2.75 (dt, J1=7.5 Hz, J2= 28.2 Hz, 1 H), 2.82 - 2.91 (m, 1 H), 3.19 (m, 2 H), 3.96 (dt, J1=7.5 Hz, J2=26.9 Hz, 1 H), 7.74 (s, 3 H)
13C NMR (100 MHz, DMSO-d6): (ppm) δ 19.9, 24.7, 26.0, 27.3, 31.1, 32.8, 57.0, 58.9, 120.3, 122.1, 124, 9, 125.0, 133.9, 139.5, 181.5.
一般的手順3に従って調製した。シリカゲルでのフラッシュカラムクロマトグラフィー(DCM:MeOH、100:0から95:5)によって精製して、521mgの最終生成物を得た。
全収率24%(HPLCによって純度≧96%と推定される)。反応は、NMRおよびLC−MSによってモニタリングした。
13C NMR (100 MHz, CDCl3): (ppm) δ 23.8, 27.1, 25.7 32.7, 53.6, 55.3, 61.4, 119.9, 121.1, 127.5, 128.6, 132.1, 133.2, 139.9, 180.7.
LCMS(ESI):[M+H]+(C23H23F6N3S)について計算した精密質量の必要値はm/z 487.5、実測値はm/z 489.2である。
1H NMR (400 MHz, CDCl3): d (ppm) δ 0.88 (qd, 1H, J1=3.9 Hz, J2= 13.3 Hz), 1.08 (qt, 1H, J1= 3.6 Hz, J2= 13.1 Hz), 1.34 - 1.23 (m, 2H), 1.63 (d, 1H, J = 13.4, 3.2 Hz), 1.79 (d, 1H, J = 12.0 Hz), 2.04 (d, 1H, J = 12.2 Hz), 2.33 (td, 1 H, J1=3.3 Hz, J2= 11.3 Hz), 2.55 (d, 1H, J = 11.8 Hz), 3.25 (d, 2H, J = 13.1 Hz), 3.68 (d, 2H, J = 13.2 Hz), 4.13 - 3.99 (m, 1H), 6.16 - 6.00 (m, 1H), 7.04 - 6.94 (m, 4H), 7.15 - 7.04 (m, 6H), 7.61 (s, 2H), 7.65 (s, 1H),
13C NMR (100 MHz, CDCl3): (ppm) δ 23.2, 24.5, 25.3 32.3, 53.3, 55.8, 61.0, 119.3, 121.4, 124.0, 127.2, 128.4, 129.8, 132.5, 132.8, 133.5, 139.5, 180.7.
LCMS(ESI):[M+H]+(C29H29F6N3S)について計算した精密質量の必要値はm/z 565.8、実測値はm/z 568.3である。
110a(5mmol、1当量)をACNL(10ml)に溶解させ、15分間撹拌した。試薬130(1.2当量)をACNL(12ml)に溶解させ、−10℃で滴下添加し、3時間撹拌した。水(20ml)中のNaOH(2当量)、およびEtOAc(30ml)を添加し、10分間撹拌した。有機相をMgSO4上で脱水し、減圧下で濃縮した。
1H NMR (400 MHz, CDCl3): d (ppm) δ 1.25-1.34 (m, 4 H), 1.76-1.81 (m, 2 H), 1.95 (m, 1 H), 1.97-2.03 (m, 1 H), 2.07 (m, 1 H), 2.72 (m, 12 H), 3.39 (m, 1 H), 6.63 (s, 1 H), 7.58 (s, 1 H), 8.02 (s, 2H).
13C NMR (100 MHz, CDCl3): (ppm) δ 24.3, 31.7, 39.2, 59.4, 118.6, 121.3, 124, 132.2-133.2, 138.6, 180.4.
1H NMR (400 MHz, DMSO): d (ppm) δ 2.65 (s, 12 H), 4.38 (d, 1 H, J= 8 Hz), 5.50 (d, 1 H, J= 8 Hz), 7.20-7.45 (m, 10 H), 7.71 (s, 1 H), 8.32 (s, 2 H), 10.58 (s, 1 H).
13C NMR (100 MHz, DMSO): (ppm) δ 34.4, 59.9, 63.7, 116.3, 121.5, 122.3, 125.0, 127.3, 127.4, 127.5, 128.4, 128.6, 130.5, 141.4, 142.5, 143.4, 180.6.
DCM(20ml)に溶解させた110a(0.4mmol、1当量)の溶液に、2−アジド−4,5−ジヒドロ−1,3−ジメチル−1H−イミダゾリウムヘキサフルオロホスフェート(0.46mmol、1.15当量)およびトリエチルアミン(2mmol、5当量)を添加し、この溶液を30分間撹拌した。反応をNaHCO3(20ml)で反応停止させ、次いでDCM(3×20ml)で抽出し、水、飽和(satured)ブラインで洗浄し、MgSO4上で脱水した。有機相を、乾燥に至らないように濃縮した。Et2O(5ml)を添加すると、溶液が形成した。トリフェニルホスフィン(0.4mmol、1当量)をEt2O(5ml)に溶解させ、反応物に滴下添加した。形成した固体をMeOHに溶解させ、SFCによって精製した。
1H NMR (400 MHz, CDCl3): d (ppm) δ 1.08 - 0.90 (m, 1H), 1.40 - 1.15 (m, 4H), 1.59 - 1.41 (m, 3H), 1.75 - 1.63 (m, 1H), 2.11 - 1.98 (m, 1H), 2.94 - 2.79 (m, 1H), 3.84 - 3.67 (m, 1H), 7.38 - 7.31 (m, 1H), 7.76 - 7.43 (m, 18H),
13C NMR (100 MHz, CDCl3): (ppm) δ 24.2, 25.0, 32.8, 37.5, 62.1, 66.0, 115.6, 121.9, 124.6, 128.4, 130.9, 131.9, 132.9, 144.0, 183.2
LCMS(ESI):[M+H]+(C33H30F6N3PS)について計算した精密質量の必要値はm/z 645.6、実測値はm/z 646.5である。
1H NMR (400 MHz, CDCl3): d (ppm) δ 4.43 (dd, 1H, J1= 8.8 Hz, J2= 15.7 Hz), 5.06 (d, 1H, J = 8.6 Hz), 7.01 - 6.84 (m, 7H), 7.22 - 7.05 (m, 5H), 7.63 - 7.37 (m, 25H), 8.23 (s, 1H)
13C NMR (100 MHz, CDCl3): (ppm) δ 60.7, 69.2, 116.5, 123.2, 123.7, 124.6, 125.6, 126.4, 128.4, 128.6, 128.7, 129.2, 131.9, 133.0, 140.4, 144.1, 157.2, 178.2.
LCMS(ESI):[M+H]+(C41H32F6N3PS)について計算した精密質量の必要値はm/z 747.7、実測値はm/z 748.9である。
SM(1g、2.595mmol)およびDIPEA(0.671g、5.19mmol)をDCM(25ml)に溶解させ、10分間撹拌した。1,3−ビス(tert−ブトキシカルボニル)−2−メチル−2−チオプソイド尿素(1.5g、5.19mmol)をDCM(25ml)に溶解させ、混合物に滴下添加し、16時間還流撹拌した。粗生成物を水で洗浄し、MgSO4で脱水し、減圧下で濃縮した。この中間体1をEtOH(15ml)に溶解させ、HCl 6N(10ml)を添加し、3時間還流撹拌した。NaOH 2N(60ml)を添加し、10分間撹拌した。混合物をEtOAc(3×40ml)で抽出し、ブラインで洗浄し、MgSO4で脱水し、減圧下で濃縮した。混合物をフラッシュクロマトグラフィーによって精製して、935mgの生成物を全収率84%で得た(純度はHPLCによって>97%と推定される)。
13C NMR (100 MHz, CDCl3): (ppm) δ 29.3, 29.8, 55.5, 56.9, 118.9, 119.9, 121.6, 122.6, 124.3, 126.9, 131.9, 139.6, 156.7, 179.3.
LCMS(ESI):[M+H]+(C16H19F6N5S)について計算した精密質量の必要値はm/z 427.4、実測値はm/z 429.1である。
Claims (24)
- 式(1)
の化合物またはその塩。 - 式(1−a)
によって表される、請求項1に記載の式(1)の化合物。 - 式(2)
- 式(2−a)
- 式(7)
- 式(1)
の化合物を製造するための方法であって、
式(2)
- 得られた式(1)の化合物またはその塩(式中、R1は水素である)を、C1〜C6−脂肪族アルコール、特にエタノールと同時にまたは別々にエステル化して、式(1)の化合物(式中、R1はC1〜C6−アルキルであり、特にエチルである)を得るステップを含む、請求項6に記載の方法。
- 式(2)
- 式(2)
- 前記有機触媒が、キラルプロリノールまたはキラルチオ尿素の有機触媒であり、
好ましくは、式(I)、(II)、(III)、または(IV)
Raは、C6〜C10−アリール、複素環基、または、場合により、C6〜C10−アリールもしくは複素環基で置換されているC1〜C6−アルキルであり;
RbおよびRcは、2個の連結する炭素原子および結合した窒素基と一緒にキラルスキャフォールドを形成し、ここでは、
(i)RbおよびRcは、2個の連結する炭素原子と一緒に5〜10員の環系を形成し、その環系は、単環式もしくは二環式であり、飽和、部分的に不飽和、もしくは不飽和であってもよく、
または、
(ii)RbおよびRcはそれぞれ独立に、水素、C1〜C7−アルキル、C6〜C10−アリール、および複素環基から選択され、
RdおよびReは独立に、水素、C6〜C10−アリール、複素環基、および、場合により、ハロゲン、ヒドロキシル、アミノ、C6〜C10−アリール、もしくは複素環基から選択される1個、2個、もしくは3個の置換基で置換されているC1〜C6−アルキルから選択され;または
RdおよびReは、連結する窒素原子と一緒に、以下:
あるいは、Rbは、水素、C1〜C7−アルキル、C6〜C10−アリール、および複素環基から選択され;Rcは、連結する炭素原子および−N(Rd)(Re)基と一緒に縮合二環式7〜9員環系を形成し、その環系は、場合により、C1〜C7−アルキルまたはC2〜C7−アルケニルによって置換されており;
ここでは、各複素環基は、5〜14個の環原子およびN、O、S、S(O)、またはS(O)2から独立に選択される1〜4個のヘテロ原子を有する、単環式、二環式、または三環式環系であり、
C6〜C10−アリールまたは複素環基はそれぞれ、場合により、C1〜C7−アルキル、ヒドロキシル、オキソ、C1〜C7−アルコキシ、C2〜C8−アルカノイル−オキシ、ハロゲン、ニトロ、シアノ、およびCF3からなる群から選択される、1個、2個または3個の残基によって置換されている)
の触媒であり、好ましくは、前記触媒は、次式:
を有する、請求項8または9に記載の方法。 - 前記有機触媒が、次式:
- 前記有機触媒が、次式:
- 前記有機触媒が、次式:
ならびに次式:
を有するものからなる群から選択される、請求項8または9に記載の方法。 - 式(7)
式(3)
- 前記式(7)の化合物が、請求項14に記載の方法に従って製造される、請求項9から13までのいずれか一項に記載の方法。
- 式(3)
- 式(4)
- 前記式(5)、式(4)、または両方の化合物が、式(6)
- 請求項6または7に記載の式(1)、好ましくは式(1−a)の化合物を製造するための方法であって、式(2)、好ましくは式(2−a)の出発化合物が、請求項8から13まで、15、および16から18までのいずれか一項に記載の方法によって得られる、方法。
- 式(8)
の化合物を製造するための方法であって、式(1)
の化合物を水素化することを含み、場合によって窒素保護基の導入を含むまたは続いて行う、方法。 - 前記式(1)、好ましくは式(1−a)の化合物が、請求項6から7まで、および19のいずれか一項に記載の方法によって得られる、請求項20に記載の方法。
- 得られた式(8)、好ましくは式(8−a)の化合物を、コハク酸またはその誘導体、好ましくはコハク酸無水物との反応によってさらに反応させて、式(10)
の化合物にする、請求項20または21に記載の方法。 - 次式:
- 式(10)
の化合物の製造における、好ましくは、N−(3−カルボキシル−1−オキソプロピル)−(4S)−(p−フェニルフェニルメチル)−4−アミノ−(2R)−メチルブタン酸もしくはその塩、またはN−(3−カルボキシル−1−オキソプロピル)−(4S)−(p−フェニルフェニルメチル)−4−アミノ−(2R)−メチルブタン酸エチルエステルもしくはその塩の製造における、請求項1から5までのいずれか一項の化合物の使用。
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US5217996A (en) | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
EP1903027A1 (en) | 2006-09-13 | 2008-03-26 | Novartis AG | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
NZ577910A (en) | 2007-01-12 | 2012-04-27 | Novartis Ag | Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid |
AR070176A1 (es) | 2008-01-17 | 2010-03-17 | Novartis Ag | Procesos de sintesis de inhibidores de nep, compuestos intermediarios y uso de los mismos en la sintesis |
CN101774941A (zh) | 2009-01-13 | 2010-07-14 | 浙江九洲药业股份有限公司 | 2-酰基氨基-3-联苯基丙酸的制备及拆分方法 |
BRPI1011657A2 (pt) * | 2009-05-28 | 2019-04-16 | Novartis Ag | derivados aminopropiônicos substituídos como inibidores de neprilisina |
CN102639486B (zh) | 2009-09-23 | 2014-12-31 | 浙江九洲药业股份有限公司 | 生产n-酰基联苯基丙氨酸的方法 |
BR112012017869A2 (pt) | 2010-01-22 | 2019-09-24 | Novartis Ag | "intermediários dos inibidores da endopeptidase neutraq e método de preparação dos mesmos" |
PL2609071T3 (pl) | 2010-08-23 | 2017-03-31 | Novartis Ag | Nowy sposób otrzymywania związków pośrednich użytecznych do wytwarzania inhibitorów NEP |
JP5705984B2 (ja) | 2010-08-23 | 2015-04-22 | ノバルティス アーゲー | Nep阻害剤を製造するための中間体の調製方法 |
AR092278A1 (es) | 2012-08-31 | 2015-04-08 | Novartis Ag | Proceso de obtencion de derivados n-acilicos de bifenil-alanina e intermediarios relacionados |
GB201219300D0 (en) | 2012-10-26 | 2012-12-12 | Isis Innovation | Bifunctional organic catalysts |
WO2015189862A1 (en) * | 2014-06-10 | 2015-12-17 | Council Of Scientific & Industrial Research | Chiral amines, a process for preparation and use thereof |
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EP3256444A1 (en) | 2017-12-20 |
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US10385004B2 (en) | 2019-08-20 |
CN107250100B (zh) | 2019-12-06 |
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