WO2021090856A1 - 立体障害の大きなアミノ酸を含むペプチド化合物の製造方法 - Google Patents
立体障害の大きなアミノ酸を含むペプチド化合物の製造方法 Download PDFInfo
- Publication number
- WO2021090856A1 WO2021090856A1 PCT/JP2020/041279 JP2020041279W WO2021090856A1 WO 2021090856 A1 WO2021090856 A1 WO 2021090856A1 JP 2020041279 W JP2020041279 W JP 2020041279W WO 2021090856 A1 WO2021090856 A1 WO 2021090856A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- amino acid
- resin
- group
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 467
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 245
- 150000001413 amino acids Chemical class 0.000 title claims abstract description 96
- 238000004519 manufacturing process Methods 0.000 title claims description 38
- -1 N-substituted amino Chemical group 0.000 claims abstract description 257
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 82
- 125000006239 protecting group Chemical group 0.000 claims abstract description 76
- 125000003277 amino group Chemical group 0.000 claims abstract description 52
- 125000001424 substituent group Chemical group 0.000 claims abstract description 39
- 108010016626 Dipeptides Proteins 0.000 claims abstract description 24
- 229920005989 resin Polymers 0.000 claims description 368
- 239000011347 resin Substances 0.000 claims description 368
- 238000000034 method Methods 0.000 claims description 128
- 229910052757 nitrogen Inorganic materials 0.000 claims description 111
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 106
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 102
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 81
- 239000000203 mixture Substances 0.000 claims description 71
- 239000002585 base Substances 0.000 claims description 69
- 125000000217 alkyl group Chemical group 0.000 claims description 68
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 63
- 150000003839 salts Chemical class 0.000 claims description 63
- 239000012453 solvate Substances 0.000 claims description 46
- 239000003153 chemical reaction reagent Substances 0.000 claims description 44
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 43
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 238000010532 solid phase synthesis reaction Methods 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 22
- 125000002723 alicyclic group Chemical group 0.000 claims description 22
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 21
- 125000004437 phosphorous atom Chemical group 0.000 claims description 21
- 229910052698 phosphorus Inorganic materials 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 102000001189 Cyclic Peptides Human genes 0.000 claims description 16
- 108010069514 Cyclic Peptides Proteins 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 16
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 15
- GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- OEBXWWBYZJNKRK-UHFFFAOYSA-N 1-methyl-2,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidine Chemical compound C1CCN=C2N(C)CCCN21 OEBXWWBYZJNKRK-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 10
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 10
- KPFBUSLHFFWMAI-HYRPPVSQSA-N [(8r,9s,10r,13s,14s,17r)-17-acetyl-6-formyl-3-methoxy-10,13-dimethyl-1,2,7,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1C[C@@H]2[C@](CCC(OC)=C3)(C)C3=C(C=O)C[C@H]2[C@@H]2CC[C@](OC(C)=O)(C(C)=O)[C@]21C KPFBUSLHFFWMAI-HYRPPVSQSA-N 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 210000004899 c-terminal region Anatomy 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 7
- YQHJFPFNGVDEDT-UHFFFAOYSA-N 2-tert-butyl-1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(N(C)C)=NC(C)(C)C YQHJFPFNGVDEDT-UHFFFAOYSA-N 0.000 claims description 7
- VSCBATMPTLKTOV-UHFFFAOYSA-N 2-tert-butylimino-n,n-diethyl-1,3-dimethyl-1,3,2$l^{5}-diazaphosphinan-2-amine Chemical compound CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C VSCBATMPTLKTOV-UHFFFAOYSA-N 0.000 claims description 7
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 claims description 5
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 5
- 239000007983 Tris buffer Substances 0.000 claims description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 5
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003875 Wang resin Substances 0.000 claims description 4
- NERFNHBZJXXFGY-UHFFFAOYSA-N [4-[(4-methylphenyl)methoxy]phenyl]methanol Chemical compound C1=CC(C)=CC=C1COC1=CC=C(CO)C=C1 NERFNHBZJXXFGY-UHFFFAOYSA-N 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- PVNUIRUAPVSSOK-UHFFFAOYSA-N tert-butylimino(tripyrrolidin-1-yl)-$l^{5}-phosphane Chemical compound C1CCCN1P(N1CCCC1)(=NC(C)(C)C)N1CCCC1 PVNUIRUAPVSSOK-UHFFFAOYSA-N 0.000 claims description 4
- 239000012096 transfection reagent Substances 0.000 claims description 4
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- YRNOSHBJMBLOSL-UHFFFAOYSA-N n-[tert-butylimino-bis(dimethylamino)-$l^{5}-phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)(N(C)C)=NC(C)(C)C YRNOSHBJMBLOSL-UHFFFAOYSA-N 0.000 claims description 3
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 3
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 3
- YZBBUYKPTHDZHF-KNVGNIICSA-N (3R)-7,2'-dihydroxy-4'-methoxyisoflavanol Chemical compound OC1=CC(OC)=CC=C1[C@H]1C(O)C2=CC=C(O)C=C2OC1 YZBBUYKPTHDZHF-KNVGNIICSA-N 0.000 claims description 2
- DSCJCKAURXOQPX-UHFFFAOYSA-N n-[bis(dimethylamino)-(2,4,4-trimethylpentan-2-ylimino)-$l^{5}-phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)(N(C)C)=NC(C)(C)CC(C)(C)C DSCJCKAURXOQPX-UHFFFAOYSA-N 0.000 claims description 2
- PSHHYQWGIGYWHP-UHFFFAOYSA-N 2-[8-[bis(dimethylamino)methylideneamino]naphthalen-1-yl]-1,1,3,3-tetramethylguanidine Chemical compound C1=CC(N=C(N(C)C)N(C)C)=C2C(N=C(N(C)C)N(C)C)=CC=CC2=C1 PSHHYQWGIGYWHP-UHFFFAOYSA-N 0.000 claims 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 230000009471 action Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 405
- 239000000243 solution Substances 0.000 description 250
- 229940024606 amino acid Drugs 0.000 description 169
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 150
- 238000006243 chemical reaction Methods 0.000 description 114
- 125000001309 chloro group Chemical group Cl* 0.000 description 112
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 104
- 238000004458 analytical method Methods 0.000 description 96
- 230000014759 maintenance of location Effects 0.000 description 91
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 53
- 230000015572 biosynthetic process Effects 0.000 description 50
- 238000003786 synthesis reaction Methods 0.000 description 37
- 230000002829 reductive effect Effects 0.000 description 33
- 150000001408 amides Chemical class 0.000 description 28
- 239000000047 product Substances 0.000 description 28
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 26
- 238000007069 methylation reaction Methods 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- 125000000753 cycloalkyl group Chemical group 0.000 description 24
- 150000001721 carbon Chemical group 0.000 description 23
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 23
- 125000001072 heteroaryl group Chemical group 0.000 description 23
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 23
- 239000007791 liquid phase Substances 0.000 description 23
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 22
- 125000003342 alkenyl group Chemical group 0.000 description 22
- 125000000304 alkynyl group Chemical group 0.000 description 22
- 230000000052 comparative effect Effects 0.000 description 21
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- 238000005755 formation reaction Methods 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000012535 impurity Substances 0.000 description 13
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 12
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 12
- 238000010647 peptide synthesis reaction Methods 0.000 description 12
- 238000007363 ring formation reaction Methods 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000006482 condensation reaction Methods 0.000 description 10
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 10
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 239000007790 solid phase Substances 0.000 description 9
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 230000002441 reversible effect Effects 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 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 8
- KSDTXRUIZMTBNV-INIZCTEOSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)butanedioic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)O)C(O)=O)C3=CC=CC=C3C2=C1 KSDTXRUIZMTBNV-INIZCTEOSA-N 0.000 description 7
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 7
- XBJFCYDKBDVADW-UHFFFAOYSA-N acetonitrile;formic acid Chemical compound CC#N.OC=O XBJFCYDKBDVADW-UHFFFAOYSA-N 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 125000000000 cycloalkoxy group Chemical group 0.000 description 7
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 125000004430 oxygen atom Chemical group O* 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- 241001102832 Meseres Species 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 238000005520 cutting process Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000007876 drug discovery Methods 0.000 description 6
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 6
- 0 *C(C(*)=O)N(*)C(C(*)(*)N*)=O Chemical compound *C(C(*)=O)N(*)C(C(*)(*)N*)=O 0.000 description 5
- HOZZVEPRYYCBTO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)-2-methylpropanoic acid Chemical compound C1=CC=C2C(COC(=O)NC(C)(C)C(O)=O)C3=CC=CC=C3C2=C1 HOZZVEPRYYCBTO-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- 238000006751 Mitsunobu reaction Methods 0.000 description 5
- CJUMAFVKTCBCJK-UHFFFAOYSA-N N-benzyloxycarbonylglycine Chemical compound OC(=O)CNC(=O)OCC1=CC=CC=C1 CJUMAFVKTCBCJK-UHFFFAOYSA-N 0.000 description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 208000012839 conversion disease Diseases 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 230000011987 methylation Effects 0.000 description 5
- 125000003386 piperidinyl group Chemical group 0.000 description 5
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 5
- 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 5
- CVZUKWBYQQYBTF-ZDUSSCGKSA-N (4s)-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-5-phenylmethoxypentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CCC(O)=O)C(=O)OCC1=CC=CC=C1 CVZUKWBYQQYBTF-ZDUSSCGKSA-N 0.000 description 4
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 description 4
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 4
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 4
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- AKCRVYNORCOYQT-YFKPBYRVSA-N N-methyl-L-valine Chemical compound CN[C@@H](C(C)C)C(O)=O AKCRVYNORCOYQT-YFKPBYRVSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 229910052796 boron Inorganic materials 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000006200 ethylation reaction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000007306 functionalization reaction Methods 0.000 description 4
- 125000005252 haloacyl group Chemical group 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 3
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 3
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 3
- WDBHYTAEQAWRCQ-UHFFFAOYSA-N 1-nonen-4-one Chemical compound CCCCCC(=O)CC=C WDBHYTAEQAWRCQ-UHFFFAOYSA-N 0.000 description 3
- UJORPFQWUKFXIE-UHFFFAOYSA-N 2-[1-[(4-ethoxy-2,6-difluorophenyl)methyl]-5,6-dihydro-4h-cyclopenta[c]pyrazol-3-yl]-5-methoxy-n-pyridin-4-ylpyrimidin-4-amine Chemical compound FC1=CC(OCC)=CC(F)=C1CN1C(CCC2)=C2C(C=2N=C(NC=3C=CN=CC=3)C(OC)=CN=2)=N1 UJORPFQWUKFXIE-UHFFFAOYSA-N 0.000 description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 3
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 3
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 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 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 238000007126 N-alkylation reaction Methods 0.000 description 3
- SCIFESDRCALIIM-VIFPVBQESA-N N-methyl-L-phenylalanine Chemical compound C[NH2+][C@H](C([O-])=O)CC1=CC=CC=C1 SCIFESDRCALIIM-VIFPVBQESA-N 0.000 description 3
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 3
- 125000003725 azepanyl group Chemical group 0.000 description 3
- 125000000707 boryl group Chemical group B* 0.000 description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 3
- 125000002843 carboxylic acid group Chemical group 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 3
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 125000004475 heteroaralkyl group Chemical group 0.000 description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 3
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000012022 methylating agents Substances 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 3
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 description 2
- UGNIYGNGCNXHTR-SFHVURJKSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UGNIYGNGCNXHTR-SFHVURJKSA-N 0.000 description 2
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 2
- YCXXXPZNQXXRIG-IBGZPJMESA-N (2s)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N(C)[C@@H](C(C)C)C(O)=O)C3=CC=CC=C3C2=C1 YCXXXPZNQXXRIG-IBGZPJMESA-N 0.000 description 2
- RAUJVFYNXLFAKY-JTQLQIEISA-N (2s)-2-azaniumyl-3-cyclohexyl-2-methylpropanoate Chemical compound OC(=O)[C@](N)(C)CC1CCCCC1 RAUJVFYNXLFAKY-JTQLQIEISA-N 0.000 description 2
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 description 2
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 2
- TXYQMVROVVJZHJ-UHFFFAOYSA-N 1,1,2,3-tetramethyl-3-[8-[methyl-(n,n,n'-trimethylcarbamimidoyl)amino]naphthalen-1-yl]guanidine Chemical compound C1=CC(N(C)C(=NC)N(C)C)=C2C(N(C)C(N(C)C)=NC)=CC=CC2=C1 TXYQMVROVVJZHJ-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 2
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- VBXZSFNZVNDOPB-UHFFFAOYSA-N 1,4,5,6-tetrahydropyrimidine Chemical group C1CNC=NC1 VBXZSFNZVNDOPB-UHFFFAOYSA-N 0.000 description 2
- VUTZFAOGDXUYEJ-UHFFFAOYSA-N 1-[chloro(diphenyl)methyl]-4-methylbenzene Chemical compound C1=CC(C)=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 VUTZFAOGDXUYEJ-UHFFFAOYSA-N 0.000 description 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 2
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 2
- XETRHNFRKCNWAJ-UHFFFAOYSA-N 2,2,3,3,3-pentafluoropropanoyl 2,2,3,3,3-pentafluoropropanoate Chemical compound FC(F)(F)C(F)(F)C(=O)OC(=O)C(F)(F)C(F)(F)F XETRHNFRKCNWAJ-UHFFFAOYSA-N 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 2
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- ARSWQPLPYROOBG-ZETCQYMHSA-N 2-methylleucine Chemical compound CC(C)C[C@](C)(N)C(O)=O ARSWQPLPYROOBG-ZETCQYMHSA-N 0.000 description 2
- FJANWAMBKVZTRG-UHFFFAOYSA-N 4-bromo-2-chloro-1-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(Br)C=C1Cl FJANWAMBKVZTRG-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 2
- WWLBWFDOHOYGIL-UHFFFAOYSA-N CN(C)[PH4] Chemical compound CN(C)[PH4] WWLBWFDOHOYGIL-UHFFFAOYSA-N 0.000 description 2
- TYKMVQJMRWCQPY-FQEVSTJZSA-N CN([C@@H](C1CCC1)C(O)=O)C(OCC1C2=CC=CC=C2C2=CC=CC=C12)=O Chemical compound CN([C@@H](C1CCC1)C(O)=O)C(OCC1C2=CC=CC=C2C2=CC=CC=C12)=O TYKMVQJMRWCQPY-FQEVSTJZSA-N 0.000 description 2
- XKWRUNAXYMBDHT-QFIPXVFZSA-N CN([C@@H](CC1CCCC1)C(O)=O)C(OCC1C2=CC=CC=C2C2=C1C=CC=C2)=O Chemical compound CN([C@@H](CC1CCCC1)C(O)=O)C(OCC1C2=CC=CC=C2C2=C1C=CC=C2)=O XKWRUNAXYMBDHT-QFIPXVFZSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 2
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 2
- QZUPHAGRBBOLTB-UHFFFAOYSA-N NSC 244302 Chemical compound C=1C=CC=CC=1P(C(C)(C)C)C1=CC=CC=C1 QZUPHAGRBBOLTB-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 description 2
- 238000005937 allylation reaction Methods 0.000 description 2
- 125000003275 alpha amino acid group Chemical group 0.000 description 2
- 150000001409 amidines Chemical group 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 2
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000004858 cycloalkoxyalkyl group Chemical group 0.000 description 2
- 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 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 125000000532 dioxanyl group Chemical group 0.000 description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 2
- SJMLNDPIJZBEKY-UHFFFAOYSA-N ethyl 2,2,2-trichloroacetate Chemical compound CCOC(=O)C(Cl)(Cl)Cl SJMLNDPIJZBEKY-UHFFFAOYSA-N 0.000 description 2
- DBOFMRQAMAZKQY-UHFFFAOYSA-N ethyl 2,2,3,3,3-pentafluoropropanoate Chemical compound CCOC(=O)C(F)(F)C(F)(F)F DBOFMRQAMAZKQY-UHFFFAOYSA-N 0.000 description 2
- 230000006203 ethylation Effects 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 description 2
- 230000001035 methylating effect Effects 0.000 description 2
- CFUKEHPEQCSIOM-UHFFFAOYSA-N n-[dimethylamino-ethylimino-[[tris(dimethylamino)-$l^{5}-phosphanylidene]amino]-$l^{5}-phosphanyl]-n-methylmethanamine Chemical compound CCN=P(N(C)C)(N(C)C)N=P(N(C)C)(N(C)C)N(C)C CFUKEHPEQCSIOM-UHFFFAOYSA-N 0.000 description 2
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical group CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 2
- CRSOQBOWXPBRES-UHFFFAOYSA-N neopentane Chemical compound CC(C)(C)C CRSOQBOWXPBRES-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 description 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000001302 tertiary amino group Chemical group 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 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 2
- 125000001984 thiazolidinyl group Chemical group 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 2
- IVIIAEVMQHEPAY-UHFFFAOYSA-N tridodecyl phosphite Chemical compound CCCCCCCCCCCCOP(OCCCCCCCCCCCC)OCCCCCCCCCCCC IVIIAEVMQHEPAY-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 description 1
- TXLUWFPQLXODBP-IBGZPJMESA-N (2S)-2-cyclobutyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1([C@H](NC(=O)OCC2C3=CC=CC=C3C3=CC=CC=C32)C(=O)O)CCC1 TXLUWFPQLXODBP-IBGZPJMESA-N 0.000 description 1
- BXRZCDISGRVJCA-KRWDZBQOSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)azetidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 BXRZCDISGRVJCA-KRWDZBQOSA-N 0.000 description 1
- ZPGDWQNBZYOZTI-SFHVURJKSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-SFHVURJKSA-N 0.000 description 1
- FODJWPHPWBKDON-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 FODJWPHPWBKDON-IBGZPJMESA-N 0.000 description 1
- GBROUWPNYVBLFO-QHCPKHFHSA-N (2s)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-phenylpropanoic acid Chemical compound C([C@H](N(C)C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(O)=O)C1=CC=CC=C1 GBROUWPNYVBLFO-QHCPKHFHSA-N 0.000 description 1
- BUJQSIPFDWLNDC-FQEVSTJZSA-N (2s)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N(C)[C@@H](CC(C)C)C(O)=O)C3=CC=CC=C3C2=C1 BUJQSIPFDWLNDC-FQEVSTJZSA-N 0.000 description 1
- JOFHWKQIQLPZTC-LBPRGKRZSA-N (2s)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N(C)[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 JOFHWKQIQLPZTC-LBPRGKRZSA-N 0.000 description 1
- POCBCUUEAYQHQO-YFKPBYRVSA-N (2s)-2-amino-3-methoxy-2-methylpropanoic acid Chemical compound COC[C@](C)(N)C(O)=O POCBCUUEAYQHQO-YFKPBYRVSA-N 0.000 description 1
- JGWHUIQSEKGLAQ-FQEVSTJZSA-N (2s)-2-cyclopentyl-2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1([C@H](NC(=O)OCC2C3=CC=CC=C3C3=CC=CC=C32)C(=O)O)CCCC1 JGWHUIQSEKGLAQ-FQEVSTJZSA-N 0.000 description 1
- WOAPUHMPKSQFJV-NRFANRHFSA-N (2s)-2-cyclopentyl-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetic acid Chemical compound C1([C@H](N(C)C(=O)OCC2C3=CC=CC=C3C3=CC=CC=C32)C(O)=O)CCCC1 WOAPUHMPKSQFJV-NRFANRHFSA-N 0.000 description 1
- FOJRBUNCWCPLNH-FQEVSTJZSA-N (2s)-3-cyclobutyl-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1CCC1 FOJRBUNCWCPLNH-FQEVSTJZSA-N 0.000 description 1
- SZQWVTJZNYDCRV-QHCPKHFHSA-N (2s)-3-cyclohexyl-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid Chemical compound C([C@H](N(C)C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(O)=O)C1CCCCC1 SZQWVTJZNYDCRV-QHCPKHFHSA-N 0.000 description 1
- NVZVRXJTMCMDNR-NRFANRHFSA-N (2s)-3-cyclopentyl-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1CCCC1 NVZVRXJTMCMDNR-NRFANRHFSA-N 0.000 description 1
- XJODGRWDFZVTKW-LURJTMIESA-N (2s)-4-methyl-2-(methylamino)pentanoic acid Chemical compound CN[C@H](C(O)=O)CC(C)C XJODGRWDFZVTKW-LURJTMIESA-N 0.000 description 1
- QXVFEIPAZSXRGM-DJJJIMSYSA-N (2s,3s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@@H](C)CC)C(O)=O)C3=CC=CC=C3C2=C1 QXVFEIPAZSXRGM-DJJJIMSYSA-N 0.000 description 1
- GXAUJSQFKHUHKZ-CYBMUJFWSA-N (3r)-3-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanoic acid Chemical compound C1=CC=C2C(COC(=O)N(C)[C@@H](CC(O)=O)C)C3=CC=CC=C3C2=C1 GXAUJSQFKHUHKZ-CYBMUJFWSA-N 0.000 description 1
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical group C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- USVVENVKYJZFMW-ONEGZZNKSA-N (e)-carboxyiminocarbamic acid Chemical compound OC(=O)\N=N\C(O)=O USVVENVKYJZFMW-ONEGZZNKSA-N 0.000 description 1
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 1
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- ZBOWKDHBOFMERX-UHFFFAOYSA-N 1,3-diazepane Chemical group C1CCNCNC1 ZBOWKDHBOFMERX-UHFFFAOYSA-N 0.000 description 1
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical group C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical compound C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- OBOHMJWDFPBPKD-UHFFFAOYSA-N 1-[chloro(diphenyl)methyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 OBOHMJWDFPBPKD-UHFFFAOYSA-N 0.000 description 1
- NILQLFBWTXNUOE-UHFFFAOYSA-N 1-aminocyclopentanecarboxylic acid Chemical compound OC(=O)C1(N)CCCC1 NILQLFBWTXNUOE-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- PDELQDSYLBLPQO-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-indole Chemical group C1CCCC2NCCC21 PDELQDSYLBLPQO-UHFFFAOYSA-N 0.000 description 1
- BYPZMCUQTKOUOT-UHFFFAOYSA-N 2,3,5,6-tetrahydro-1h-pyrrolo[1,2-c]imidazole Chemical compound C1NCC2=CCCN21 BYPZMCUQTKOUOT-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- ZHKQIADIIYMFOZ-UHFFFAOYSA-N 2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetic acid Chemical compound C1=CC=C2C(COC(=O)N(CC(O)=O)C)C3=CC=CC=C3C2=C1 ZHKQIADIIYMFOZ-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- KVTHPKXDLVYNCH-UHFFFAOYSA-N 2-iodoethylbenzene Chemical compound ICCC1=CC=CC=C1 KVTHPKXDLVYNCH-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- BZKGQXQXVPOXKL-UHFFFAOYSA-N 3-cyclohexyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methylpropanoic acid Chemical compound CC(CC1CCCCC1)(C(=O)O)NC(=O)OCC2C3=CC=CC=C3C4=CC=CC=C24 BZKGQXQXVPOXKL-UHFFFAOYSA-N 0.000 description 1
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LTIHQJISYQLFQR-UHFFFAOYSA-N 3-oxa-1-azaspiro[4.4]non-1-en-4-one Chemical compound O=C1OC=NC11CCCC1 LTIHQJISYQLFQR-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- HASRFXGIJALRRB-UHFFFAOYSA-N 4-(3-phenylpropyl)piperidine Chemical compound C=1C=CC=CC=1CCCC1CCNCC1 HASRFXGIJALRRB-UHFFFAOYSA-N 0.000 description 1
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical group O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 1
- ZYASLTYCYTYKFC-UHFFFAOYSA-N 9-methylidenefluorene Chemical compound C1=CC=C2C(=C)C3=CC=CC=C3C2=C1 ZYASLTYCYTYKFC-UHFFFAOYSA-N 0.000 description 1
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical group [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 description 1
- OBFWGNQUXBJEAY-QHCPKHFHSA-N C1=2C3=CC=CC=C3C(COC(=O)N[C@@H](CCC3=CC=C(C(F)(F)F)C(Cl)=C3)C(=O)O)C1=CC=CC=2 Chemical compound C1=2C3=CC=CC=C3C(COC(=O)N[C@@H](CCC3=CC=C(C(F)(F)F)C(Cl)=C3)C(=O)O)C1=CC=CC=2 OBFWGNQUXBJEAY-QHCPKHFHSA-N 0.000 description 1
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 1
- QOOVAUCGJDRKRX-IBGZPJMESA-N CC(C)(C)OC(N[C@@H](CCC(ON(C(c1ccccc11)=O)C1=O)=O)C(OCc1ccccc1)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC(ON(C(c1ccccc11)=O)C1=O)=O)C(OCc1ccccc1)=O)=O QOOVAUCGJDRKRX-IBGZPJMESA-N 0.000 description 1
- BHQPXPLCVNDUIZ-IBGZPJMESA-N CC(C)(C)OC(N[C@@H](CCc1ccc(C(F)(F)F)c(Cl)c1)C(OCc1ccccc1)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCc1ccc(C(F)(F)F)c(Cl)c1)C(OCc1ccccc1)=O)=O BHQPXPLCVNDUIZ-IBGZPJMESA-N 0.000 description 1
- QZAJOFVRBSOVIP-PCPUGGRXSA-N CC(C)[C@@H](C(N(C)[C@H](C)CC(OC(c1ccccc1)(c1ccc(C2C(C3)C3CCCCCCC2)cc1)c(cccc1)c1Cl)=O)=O)NC(C(C)(C)N(C)C(C(F)(F)F)=O)=O Chemical compound CC(C)[C@@H](C(N(C)[C@H](C)CC(OC(c1ccccc1)(c1ccc(C2C(C3)C3CCCCCCC2)cc1)c(cccc1)c1Cl)=O)=O)NC(C(C)(C)N(C)C(C(F)(F)F)=O)=O QZAJOFVRBSOVIP-PCPUGGRXSA-N 0.000 description 1
- PXBIPBGMWKYYIM-RJMPGTMSSA-N CC(C)[C@@H](C(N(C)[C@H](C)CC(OC(c1ccccc1)(c1ccc(C2CCC(C3)[C@H]3CCCCCC2)cc1)c1ccccc1Cl)=O)=O)NC(C(C)(C)NC(C(F)(F)F)=O)=O Chemical compound CC(C)[C@@H](C(N(C)[C@H](C)CC(OC(c1ccccc1)(c1ccc(C2CCC(C3)[C@H]3CCCCCC2)cc1)c1ccccc1Cl)=O)=O)NC(C(C)(C)NC(C(F)(F)F)=O)=O PXBIPBGMWKYYIM-RJMPGTMSSA-N 0.000 description 1
- YVLGOBOZEMSFDM-FPOVZHCZSA-N CC(C)[C@@H](C(N[C@@H](CC(O)=O)C(N1CCCC1)=O)=O)N(C)C(C(C)(C)N(Cc1ccccc1)C(C(F)(F)F)=O)=O Chemical compound CC(C)[C@@H](C(N[C@@H](CC(O)=O)C(N1CCCC1)=O)=O)N(C)C(C(C)(C)N(Cc1ccccc1)C(C(F)(F)F)=O)=O YVLGOBOZEMSFDM-FPOVZHCZSA-N 0.000 description 1
- YEXLXUWVLRSMQN-KHOMTPLRSA-N CC(C)[C@@H](C(N[C@@H](CC(O)=O)C(N1CCCC1)=O)=O)N(C)C([C@](C)(Cc1ccccc1)NC(C(F)(F)F)=O)=O Chemical compound CC(C)[C@@H](C(N[C@@H](CC(O)=O)C(N1CCCC1)=O)=O)N(C)C([C@](C)(Cc1ccccc1)NC(C(F)(F)F)=O)=O YEXLXUWVLRSMQN-KHOMTPLRSA-N 0.000 description 1
- FMRMWSPJCFUNGI-ZXRKZBAXSA-N CC(C)[C@@H](C(N[C@@H](CC(O)=O)C(N1CCCC1)=O)=O)NC([C@H](C(C)C)NC(OCC1c2ccccc2-c2ccccc12)=O)=O Chemical compound CC(C)[C@@H](C(N[C@@H](CC(O)=O)C(N1CCCC1)=O)=O)NC([C@H](C(C)C)NC(OCC1c2ccccc2-c2ccccc12)=O)=O FMRMWSPJCFUNGI-ZXRKZBAXSA-N 0.000 description 1
- JHFFMVWHRCKBLW-UHFFFAOYSA-N CC(CC(OC(c1ccccc1)(c1ccc(C2CCCCCCCC2)cc1)c(cccc1)c1Cl)=O)N(C)C(OCC1c2ccccc2-c2ccccc12)=O Chemical compound CC(CC(OC(c1ccccc1)(c1ccc(C2CCCCCCCC2)cc1)c(cccc1)c1Cl)=O)N(C)C(OCC1c2ccccc2-c2ccccc12)=O JHFFMVWHRCKBLW-UHFFFAOYSA-N 0.000 description 1
- XJBIITNPBOPEKX-XZWHSSHBSA-N CCCCCCCCCCCCSC(CCC=C1)=C1S(N(CCC)[C@H](CN[C@@H](CC(O)=O)C(N1CCCC1)=O)C(C)C)(=O)=O Chemical compound CCCCCCCCCCCCSC(CCC=C1)=C1S(N(CCC)[C@H](CN[C@@H](CC(O)=O)C(N1CCCC1)=O)C(C)C)(=O)=O XJBIITNPBOPEKX-XZWHSSHBSA-N 0.000 description 1
- XVUQTUCDKLFSCQ-RDJZCZTQSA-N CCCN(C(C)(C)C(N(C)[C@@H](C(C)C)C(N[C@@H](CC(O)=O)C(N1CCCC1)=O)=O)=O)C(C(F)(F)F)=O Chemical compound CCCN(C(C)(C)C(N(C)[C@@H](C(C)C)C(N[C@@H](CC(O)=O)C(N1CCCC1)=O)=O)=O)C(C(F)(F)F)=O XVUQTUCDKLFSCQ-RDJZCZTQSA-N 0.000 description 1
- VRPXUVWVESGNRD-NRFANRHFSA-N CN([C@@H](CC1CCC1)C(=O)O)C(=O)OCC2C3=CC=CC=C3C4=CC=CC=C24 Chemical compound CN([C@@H](CC1CCC1)C(=O)O)C(=O)OCC2C3=CC=CC=C3C4=CC=CC=C24 VRPXUVWVESGNRD-NRFANRHFSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 1
- UFXVVKXNZRAKFE-UHFFFAOYSA-N FC(C1=NC2(CCCC2)C(=O)O1)(F)F Chemical compound FC(C1=NC2(CCCC2)C(=O)O1)(F)F UFXVVKXNZRAKFE-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- KSPIYJQBLVDRRI-WDSKDSINSA-N N-methyl-L-isoleucine Chemical compound CC[C@H](C)[C@H](NC)C(O)=O KSPIYJQBLVDRRI-WDSKDSINSA-N 0.000 description 1
- RPYZOGUATSHGSD-UHFFFAOYSA-A P(=O)([O-])([O-])[O-].P(=O)([O-])([O-])[O-].P(=O)([O-])([O-])[O-].P(=O)([O-])([O-])[O-].P(=O)([O-])([O-])[O-].P(=O)([O-])([O-])[O-].N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C Chemical compound P(=O)([O-])([O-])[O-].P(=O)([O-])([O-])[O-].P(=O)([O-])([O-])[O-].P(=O)([O-])([O-])[O-].P(=O)([O-])([O-])[O-].P(=O)([O-])([O-])[O-].N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C.N1(N=NC2=C1C=CC=C2)OC(=[N+](C)C)N(C)C.N2(N=NC1=C2C=CC=C1)OC(=[N+](C)C)N(C)C RPYZOGUATSHGSD-UHFFFAOYSA-A 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 244000191761 Sida cordifolia Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- RDWDVLFMPFUBDV-PXMDEAMVSA-N [(e)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-tripyrrolidin-1-ylphosphanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(O/N=C(C(=O)OCC)\C#N)N1CCCC1 RDWDVLFMPFUBDV-PXMDEAMVSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 description 1
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-M alaninate Chemical compound CC(N)C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-M 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000006323 alkenyl amino group Chemical group 0.000 description 1
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 description 1
- 125000005090 alkenylcarbonyl group Chemical group 0.000 description 1
- 125000005091 alkenylcarbonylamino group Chemical group 0.000 description 1
- 125000005193 alkenylcarbonyloxy group Chemical group 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 1
- 125000005136 alkenylsulfinyl group Chemical group 0.000 description 1
- 125000005137 alkenylsulfonyl group Chemical group 0.000 description 1
- 125000005108 alkenylthio group Chemical group 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005130 alkyl carbonyl thio group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000006319 alkynyl amino group Chemical group 0.000 description 1
- 125000005095 alkynylaminocarbonyl group Chemical group 0.000 description 1
- 125000005087 alkynylcarbonyl group Chemical group 0.000 description 1
- 125000005088 alkynylcarbonylamino group Chemical group 0.000 description 1
- 125000005198 alkynylcarbonyloxy group Chemical group 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- 125000005225 alkynyloxycarbonyl group Chemical group 0.000 description 1
- 125000005134 alkynylsulfinyl group Chemical group 0.000 description 1
- 125000005139 alkynylsulfonyl group Chemical group 0.000 description 1
- 125000005109 alkynylthio group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- HYOWVAAEQCNGLE-JTQLQIEISA-N alpha-methyl-L-phenylalanine Chemical compound OC(=O)[C@](N)(C)CC1=CC=CC=C1 HYOWVAAEQCNGLE-JTQLQIEISA-N 0.000 description 1
- 229910000147 aluminium phosphate Chemical group 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000005126 aryl alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 1
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005141 aryl amino sulfonyl group Chemical group 0.000 description 1
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 1
- 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 1
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910021386 carbon form Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 description 1
- 125000005145 cycloalkylaminosulfonyl group Chemical group 0.000 description 1
- 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 description 1
- 125000005201 cycloalkylcarbonyloxy group Chemical group 0.000 description 1
- 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 description 1
- 125000005149 cycloalkylsulfinyl group Chemical group 0.000 description 1
- 125000005144 cycloalkylsulfonyl group Chemical group 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 125000006622 cycloheptylmethyl group Chemical group 0.000 description 1
- GCHPUFAZSONQIV-RXMQYKEDSA-N d-isovaline Chemical compound CC[C@@](C)(N)C(O)=O GCHPUFAZSONQIV-RXMQYKEDSA-N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 125000005131 dialkylammonium group Chemical group 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 1
- DWYMPOCYEZONEA-UHFFFAOYSA-L fluoridophosphate Chemical compound [O-]P([O-])(F)=O DWYMPOCYEZONEA-UHFFFAOYSA-L 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-L glutarate(2-) Chemical compound [O-]C(=O)CCCC([O-])=O JFCQEDHGNNZCLN-UHFFFAOYSA-L 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 description 1
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 1
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 description 1
- 125000005204 heteroarylcarbonyloxy group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 description 1
- 125000005150 heteroarylsulfinyl group Chemical group 0.000 description 1
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 1
- 125000005419 heteroarylsulfonylamino group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical group C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- GCHPUFAZSONQIV-UHFFFAOYSA-N isovaline Chemical compound CCC(C)(N)C(O)=O GCHPUFAZSONQIV-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- JPQDXOCZVZPRTL-UHFFFAOYSA-N methyl 2-acetamido-2-methylpropanoate Chemical compound COC(=O)C(C)(C)NC(C)=O JPQDXOCZVZPRTL-UHFFFAOYSA-N 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical group COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical group C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- QGKLPGKXAVVPOJ-UHFFFAOYSA-N pyrrolidin-3-one Chemical group O=C1CCNC1 QGKLPGKXAVVPOJ-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 238000011935 selective methylation Methods 0.000 description 1
- LMUMMJCCZMWLEN-UHFFFAOYSA-N spiro[3.3]heptyl Chemical group [CH]1CCC11CCC1 LMUMMJCCZMWLEN-UHFFFAOYSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 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
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- RLTPJVKHGBFGQA-UHFFFAOYSA-N thiadiazolidine Chemical compound C1CSNN1 RLTPJVKHGBFGQA-UHFFFAOYSA-N 0.000 description 1
- 125000005304 thiadiazolidinyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
- C07K1/026—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution by fragment condensation in solution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
- C07K1/063—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha-amino functions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
Definitions
- the present invention relates to a method for producing a peptide compound containing an amino acid having a large steric hindrance.
- Examples of so-called tough-targets that could not be used as drug discovery targets in conventional drugs include drug discovery that targets intracellular molecules, etc., or drug discovery by inhibiting protein-protein interaction. These have not been used as targets for drug discovery because the molecules of the drug cannot reach the target molecule of the disease, or the shape of the site of action of the target molecule is a shape that is difficult for conventional drugs to act on. (Non-Patent Document 1).
- Non-Patent Document 2 Cyclic peptides are indicated not only for improving their ability to bind to targets, but also for being drug-like (drug-like: preferably showing both membrane permeability and metabolic stability). , Efficient cyclic peptide screening methods have been considered (Non-Patent Documents 3 and 4). In addition, the conditions required for an unnatural cyclic peptide containing a drug-like unnatural amino acid have been clarified, and its importance and its recognition in drug discovery are increasing (Patent Document 1).
- Unnatural amino acids are an important element of this unnatural peptide, where unnatural amino acids, such as peptides containing N-methyl (or N-alkyl) amino acids, and in some cases N-methyl (or N-alkyl) amino acids, are important elements. It is widely recognized that the synthesis of a peptide containing a unit in which an alkyl) amino acid is contiguous is more difficult than that of a natural peptide due to its bulkiness (Non-Patent Documents 5 and 6).
- Non-Patent Document 7 ⁇ , ⁇ -di-substituted amino acids in which the ⁇ -position of the amino acid is substituted with two substituents are due to increased lipophilicity and steric damage. It has been reported that it contributes to limiting the degree of conformational freedom of peptides containing ⁇ and ⁇ -di-substituted amino acids and stabilizing them in vivo. Non-Patent Document 7). Can be expected to have an effect.
- Non-Patent Document 8 In the method for producing peptides containing these unnatural amino acids, the Fmoc method, which is most commonly used for peptide synthesis, is known to be unsuitable due to the structural bulkiness of these unnatural amino acids ().
- Non-Patent Document 8 In the method for producing peptides containing these unnatural amino acids, the Fmoc method, which is most commonly used for peptide synthesis, is known to be unsuitable due to the structural bulkiness of these unnatural amino acids ().
- Non-Patent Documents 9 and 10 A method for selectively N-alkylating a target NH group is known (Non-Patent Documents 9 and 10). However, these methods are methods for binding ⁇ -mono-substituted amino acids and N-alkyl amino acids, and are practical for peptides having a sequence in which N-alkyl- ⁇ , ⁇ -di-substituted amino acids and N-alkyl amino acids are linked. No synthetic method is known.
- Non-Patent Document 5 exemplifies a method for producing a peptide containing an N-alkyl amino acid as a method for producing a peptide containing a bulky amino acid.
- this document only describes the mechanism of side reactions in the condensation reaction of amino acids and the condensation reagent, and does not describe the condensation reaction of bulky ⁇ , ⁇ -di-substituted amino acids.
- Non-Patent Document 6 exemplifies a method for producing an N-alkyl amino acid and a method for producing a peptide containing an N-alkyl amino acid. Although this document exemplifies a production method focusing on an amino acid condensing agent, the condensation reaction of a bulkier ⁇ , ⁇ -di-substituted amino acid is not described.
- Non-Patent Document 7 describes a method for producing ⁇ , ⁇ -di-substituted amino acids, usefulness of peptides containing ⁇ , ⁇ -di-substituted amino acids, examples of ⁇ , ⁇ -di-substituted amino acids, and methods for producing them. However, there is no description about the production of peptides containing sterically bulky amino acids.
- Non-Patent Document 8 exemplifies a method for producing a peptide that is difficult to synthesize. This document describes the production of peptides with low solubility or easy aggregation, but does not describe how to solve the problem by using a condensation reaction.
- Non-Patent Document 9 exemplifies a method for forming a peptide bond with an N-alkyl amino acid using a trifluoroacetyl group that can be removed under mild conditions, and a method for producing a peptide containing an N-alkyl amino acid.
- the condensation reaction with the bulkier ⁇ , ⁇ -di-substituted amino acids.
- an isomer by-product in which the alkyl group is also introduced may be generated in the oxygen atom of the trifluoroacetyl group.
- Non-Patent Document 10 describes a method for producing a peptide containing an N-alkyl amino acid by introducing an alkyl group into the nitrogen atom of an amino acid protected by a nosyl group.
- Non-Patent Document 9 it is known that there is a problem in the production of the target product because a side reaction occurs in the step of deprotecting the nosyl group.
- N-substituted- ⁇ , ⁇ -di-substituted amino acids such as N-alkyl- ⁇ and ⁇ -di-substituted amino acids and N-substituted amino acids such as N-alkyl amino acids
- the present invention has been made in view of such circumstances, and provides a method for producing a peptide compound containing N-substituted- ⁇ , ⁇ -di-substituted amino acid residues, and / or N-substituted amino acid residues. Is the subject.
- N-substituted- ⁇ and ⁇ -di-substituted amino acids into N-substituted amino acids.
- the present inventors have found a method for linking an N-substituted amino acid with an N-substituted- ⁇ , ⁇ -di substituted amino acid. Specifically, it is sterically less bulky than N-substituted amino acids, and N-unsubstituted-in which the reactivity of the carboxyl group is improved by protecting the amino group with an electron-attracting protecting group. It was found that the target amino acid can be efficiently introduced by using ⁇ and ⁇ -di-substituted amino acids.
- an N-functionalization reaction such as an N-alkylation reaction is selectively carried out on the NH group whose acidity has increased due to the electron-attracting protecting group. Found to progress. Furthermore, focusing on the fact that the acidity of the NH group is increased due to the electron-attracting protective group, a specific base used for the N-functionalization reaction was found, and the present invention was completed. I arrived.
- the present invention includes the following in a specific non-limiting aspect.
- a method for producing a peptide compound, a salt thereof, or a mixture thereof which comprises the following steps: Step A: Protection of electron attraction with N-substituted amino acids, salts thereof, or mixtures thereof, or peptide compounds having an N-substituted amino acid residue at the N-terminal, salts thereof, or mixtures thereof.
- N-unsubstituted- ⁇ , ⁇ -disubstituted amino acids with amino groups protected by groups, salts thereof, dehydrated products thereof, or solvates thereof are reacted in the presence or absence of a condensing reagent.
- N-unsubstituted- ⁇ , ⁇ -di-substituted amino acid residue whose amino group is protected by an electron-attracting protective group which has an N-unsubstituted- ⁇ , ⁇ -di-substituted amino acid residue at the N-terminal.
- Step B A step of obtaining a peptide compound, a salt thereof, or a solvate thereof containing a dipeptide residue in which an N-substituted amino acid residue is linked, and step B: an amino group with an electron-attracting protective group at the N-terminal.
- a substituent is introduced into the amino group of the protected N-unsubstituted- ⁇ , ⁇ -di-substituted amino acid residue, and the amino group is an electron-attracting protective group.
- Protected N-substituted- ⁇ , ⁇ -disubstituted amino acid residue at the N-terminal, and the dipeptide residue in which the N-substituted- ⁇ , ⁇ -disubstituted amino acid residue and the N-substituted amino acid residue are linked A step of obtaining a peptide compound containing a group, a salt thereof, or a mixture thereof.
- the electron-attracting protecting group is a protecting group having a pKa (in water) of 6 to 11 for the NH group to which the protecting group is bonded.
- [3] The method according to [1] or [2], wherein the pKa (in acetonitrile) of the conjugate acid of the base is 18 to 31.
- [4] The method according to any one of [1] to [3], wherein the N-substituted amino acid or the peptide compound having an N-substituted amino acid residue at the N-terminal is supported on the resin for solid phase synthesis.
- a peptide compound having an N-substituted amino acid or an N-substituted amino acid residue at the N-terminal is represented by the formula (2): [During the ceremony, P 2 is C 1- C 6 alkyl, C 2- C 6 alkenyl, or C 7- C 14 aralkyl.
- R 2 is C 1- C 6 alkyl, C 1- C 6 haloalkyl, C 1- C 6 hydroxyalkyl, C 1- C 6 alkyl sulfonyl C 1- C 6 alkyl, C 2- C 6 alkynyl, 1 or C 1- C 6 Alkoxy C 1- C 6 Alkyne, C 3- C 8 Cycloalkyl, C 3- C 8 Cycloalkyl C 1- C 6 Alkyne, C 3- C 8 May Be Substituted by Multiple Halogen Cycloalkoxy C 1- C 6 alkyl, or C 7- C 14 alkyl, R 3 is hydroxy, O-PG 2 , any amino acid residue, or any peptide residue. PG 2 is a carboxyl-protecting group.
- R 1 and Q 1 may be a 3- to 8-membered alicyclic ring or a 3- to 8-membered alicyclic ring together with the carbon atom to which they are attached. It forms a 4- to 7-membered saturated heterocycle.
- the peptide compound obtained in step A is the formula (4): [During the ceremony, PG 1, R 1, and Q 1 is the same meaning as PG 1, R 1, and Q 1 of formula (3), P 2, R 2, and R 3 are each synonymous with P 2, R 2, and R 3 of formula (2)] The method according to any one of [1] to [6] represented by.
- the substituent-introducing agent in step B is P 1 X (in the formula, P 1 is synonymous with P 1 in formula (1) and X is a leaving group), which is obtained in step B.
- the peptide compound is of formula (1): [During the ceremony, P 1 is C 1- C 6 alkyl, C 2- C 6 alkenyl, or C 7- C 14 aralkyl. PG 1, R 1, and Q 1 is the same meaning as PG 1, R 1, and Q 1 of formula (3), P 2, R 2, and R 3 are each synonymous with P 2, R 2, and R 3 of formula (2)] The method according to any one of [1] to [7] represented by.
- Formula (1) including the following steps: [During the ceremony, PG 1 is an amino protecting group and P 1 is C 1- C 6 alkyl, C 2- C 6 alkenyl, or C 7- C 14 aralkyl.
- R 1 and Q 1 are C 1- C 6 alkyl, C 2- C 6 alkenyl, C 1- C 6 alkoxy C 1- C 6 alkyl, C 3- C 8 cycloalkyl C 1- C 6 alkyl, or substitutions. It may be selected independently of the C 7- C 14 alkoxy, or R 1 and Q 1 may be a 3- to 8-membered alicyclic ring or a 3- to 8-membered alicyclic ring together with the carbon atom to which they are attached.
- P 2 is C 1- C 6 alkyl, C 2- C 6 alkenyl, or C 7- C 14 aralkyl.
- R 2 is C 1- C 6 alkyl, C 1- C 6 haloalkyl, C 1- C 6 hydroxyalkyl, C 1- C 6 alkyl sulfonyl C 1- C 6 alkyl, C 2- C 6 alkynyl, 1 or C 1- C 6 Alkoxy C 1- C 6 Alkyne, C 3- C 8 Cycloalkyl, C 3- C 8 Cycloalkyl C 1- C 6 Alkyne, C 3- C 8 May Be Substituted by Multiple Halogen Cycloalkoxy C 1- C 6 alkyl, or C 7- C 14 alkyl, R 3 is hydroxy, O-PG 2 , any amino acid residue, or any peptide residue.
- PG 2 is a carboxyl-protecting group.
- the compound represented by (2), a salt thereof, a dehydrated product thereof, or a solvate thereof is reacted with a condensing reagent, or a compound represented by the formula (2), a salt thereof, or a solvate thereof is used.
- a dehydrated product of the compound represented by the formula (3), a salt thereof, or a solvate thereof is reacted to form the formula (4):
- PG 1, P 2, Q 1, and R 1 ⁇ R 3 are each a PG 1, P 2, Q 1, and R 1 ⁇ R 3 of formula (1) synonymous]
- a compound represented by, a salt thereof or obtaining a solvate thereof and Step B: a compound represented by the formula (4), a salt thereof or a solvate thereof, is reacted with P 1 transfection reagent A step of obtaining a peptide compound represented by the formula (1), a salt thereof, or a solvate thereof.
- R 1 and Q 1 form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, or a tetrahydropyran ring together with the carbon atom to which they are bonded, or R 1 and Q 1 and Q 1 is independently selected from methyl, ethyl, 2-methylpropyl, allyl, methoxymethyl, cyclohexylmethyl, optionally substituted benzyl, or optionally substituted phenethyl.
- the method according to any one of [6] to [9].
- the dehydrated body has the following formula: Wherein, Q 1 and R 1 are each as Q 1 and R 1 of formula (1) the same meaning, R 4 is a C 1 -C 5 haloalkyl. ] The method according to any one of [1] to [13] represented by. [15] The method according to [14], wherein R 1 and Q 1 form a 3- to 8-membered alicyclic ring together with the carbon atom to which they are bonded.
- R 4 is trifluoromethyl, trichloromethyl, pentafluoroethyl, 1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl or 2,2,2, -1-
- [17] The method according to any one of [8] to [16], wherein P 1 is methyl, ethyl, n-propyl, i-propyl, allyl, benzyl, or phenethyl.
- the base is [During the ceremony, RB 1 and RB 4 are either each independently C 1 -C 4 alkyl or RB 1 and RB 4, is together with the carbon atom to which the nitrogen atom and RB 4 RB 1 is bonded is bonded to form a 5- to 8-membered ring, RB 2 and RB 3 is either each independently C 1 -C 4 alkyl, or RB 2 and RB 3 is a nitrogen atom and the nitrogen atom and RB 3 RB 2 is bonded is bonded The nitrogen atom forms a 5- to 8-membered ring together with the carbon atom to which it is bonded], [During the ceremony, RB 6 is C 1 -C 4 alkyl, RB 5 and RB 7 are each either independently a C 1 -C 4 alkyl, which together with the nitrogen atom and the carbon atom to which respective nitrogen atom is bonded are bonded 5-8 Form a member ring, RB 8 is C 1- C 4 alkyl and RB 9 is C 1- C 1- C
- the two B2s may be fused with two benzene rings of the phenyl group to form naphthalene],.
- RB 10 is C 1 -C 4 alkyl either or RB 10 and RB 11, together with the nitrogen atom to which they are attached form a 5-8 membered ring, RB 11, except where RB 10 and RB 11 to form a 5- to 8-membered ring, or a C 1 -C 4 alkyl or RB 11 and RB 12, is, and the nitrogen atom they are attached Together with the phosphorus atom to which each nitrogen atom is bonded, a 5- to 8-membered ring is formed.
- RB 12 except where RB 11 and RB 12 to form a 5- to 8-membered ring, C 1 -C 4 alkyl either or RB 12 and RB 13, is together with the nitrogen atom to which they are attached
- RB 13 except where RB 12 and RB 13 to form a 5- to 8-membered ring, or a C 1 -C 4 alkyl or RB 13 and RB 14, is, and the nitrogen atom they are attached Together with the phosphorus atom to which each nitrogen atom is bonded, a 5- to 8-membered ring is formed.
- RB 14 except where RB 13 and RB 14 to form a 5- to 8-membered ring, or a C 1 -C 4 alkyl or RB 14 and RB 15, is together with the nitrogen atom to which they are attached
- RB 15 except where RB 14 and RB 15 to form a 5- to 8-membered ring, C 1 -C 4 alkyl, RB 16 is hydrogen, C 1 -C 8 alkyl or C 6 -C 10 aryl.
- RB 17 is either C 1 -C 4 alkyl independently or RB 17 and RB 18, together with the nitrogen atom to which they are attached form a 5-8 membered ring, RB 18, except where RB 17 and RB 18 to form a 5- to 8-membered ring, or a C 1 -C 4 alkyl or RB 18 and RB 19, is, and the nitrogen atom they are attached Together with the phosphorus atom to which each nitrogen atom is bonded, a 5- to 8-membered ring is formed.
- RB 19 is together with the nitrogen atom to which they are attached
- RB 20 except where RB 19 and RB 20 to form a 5- to 8-membered ring, C 1 -C 4 alkyl
- RB 21 is either C 1 -C 4 alkyl or RB 21 and RB 22, together with the nitrogen atom to which they are attached form a 5-8 membered ring
- RB 22 except where RB 21 and RB 22 to form a 5- to 8-membered ring, or a C 1 -C 4 alkyl or RB 22 and RB 23, is, and the nitrogen atom they are attached Together with the phosphorus atom to which each nitrogen atom is bonded, a 5- to 8-membered ring is formed.
- RB 25 except where RB 24 and RB 25 to form a 5- to 8-membered ring, C 1 -C 4 alkyl either or RB 25 and RB 26, is together with the nitrogen atom to which they are attached
- RB 26 except where RB 25 and RB 26 to form a 5- to 8-membered ring, C 1 -C 4 alkyl, RB 27 is a C 1 -C 4 alkyl or C 6 -C 10 aryl.
- the bases are 1,8-diazabicyclo [5.4.0] undeca-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-bis ( Tetramethylguanidino) naphthalene (TMGN), 7-methyl-1,5,7-triazabicyclo [4.4.0] deca-5-ene (MTBD), 2-tert-butyl-1,1,3,3- Tetramethylguanidine (BTMG), 1,5,7-triazabicyclo [4.4.0] deca-5-ene (TBD), tert-butylimino-tris (dimethylamino) phosphorane (P1-tBu), tert-butylimino- Tri (pyrrolidino) phosphorane (P1-t-Bu-tris (tetramethylene), BTPP), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza
- step B is carried out in a solvent selected from the group consisting of DMF, NMP, DMI, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile.
- a peptide compound containing a dipeptide residue in which an N-substituted- ⁇ , ⁇ -disubstituted amino acid residue and an N-substituted amino acid residue are linked which comprises the method according to any one of [1] to [26].
- the cyclic peptide compound contains 8 to 15 amino acid residues, contains at least 3 N-substituted amino acid residues, and contains at least one non-N-substituted amino acid residue, with at least 8 amino acid residues in the cyclic portion.
- the method comprising a group.
- a dipeptide residue in which an N-substituted- ⁇ , ⁇ -disubstituted amino acid residue and an N-substituted amino acid residue are linked which is useful for searching for a peptide drug, a peptide drug, and / or supplying a drug substance of a drug.
- a peptide compound containing a group can be efficiently produced. Further, since a peptide compound in which various unnatural amino acid residues are bound can also be produced, a peptide compound having various structures can be provided.
- FIG. 1 is a diagram showing the results of LCMS analysis (analysis condition: SQDFA05) of the reaction mixture of Example 2-4 detected at the maximum absorption wavelength using a photodiode array detector.
- FIG. 2 is a diagram showing the results of LCMS analysis (analysis condition: SQDFA05) of the reaction mixture of Comparative Example 1 detected at the maximum absorption wavelength using a photodiode array detector.
- FIG. 3 is a diagram showing the results of LCMS analysis (analysis condition: SQDFA05) of the reaction mixture of Comparative Example 2-4 detected at the maximum absorption wavelength using a photodiode array detector.
- FIG. 4 is a diagram showing the results of LCMS analysis (analysis condition: SQDFA05) of the reaction mixture of Comparative Example 2-5 detected at the maximum absorption wavelength using a photodiode array detector.
- AA Ammonium acetate CSA: (+) -10-Camfersulfonic acid
- DBU 1,8-diazabicyclo [5.4.0] -7-Undecene
- DCC N, N'-dicyclohexylcarbodiimide
- DCM dichloromethaneDCE: 1,2 -Dichloroethane
- DEAD azodicarboxylic acid diethyl
- DMA dimethylacetamide
- DMF N, N-dimethylformamide
- DIAD azodicarboxylic acid diisopropyl
- DIC N, N'-diisopropylcarbodiimide
- DIPEA N, N-diisopropylethylamine
- DMAP N, N-dimethyl -4-Aminopyridine
- dtbbpy 4,4'-di-tert-butyl-2,2'-bipyridyl
- EDTA ethylenedidi
- halogen atom examples include F, Cl, Br or I.
- alkyl is a monovalent group derived from an aliphatic hydrocarbon by removing one arbitrary hydrogen atom, and refers to a hetero atom (an atom other than carbon and a hydrogen atom) in the skeleton. ) Or has a subset of hydrocarbyl or hydrocarbon group structures that do not contain unsaturated carbon-carbon bonds and contain hydrogen and carbon atoms.
- Alkyl includes not only linear ones but also branched chain ones. Specifically, the alkyl is an alkyl having 1 to 20 carbon atoms (C 1- C 20 , hereinafter, "C p- C q " means that the number of carbon atoms is p to q).
- alkyl preferably C 1 -C 10 alkyl, or more preferably C 1 -C 6 alkyl.
- alkyl specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-pentyl).
- Methylbutyl t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2 -Methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl , 1,3-Dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl and the like.
- alkenyl is a monovalent group having at least one double bond (two adjacent sp 2 carbon atoms). Depending on the arrangement of the double bond and the substitution (if any), the geometry of the double bond can be in the entogen (E) or tuzanmen (Z), cis or trans arrangement. Alkenyl includes not only linear ones but also branched chain ones.
- C 2 -C 10 alkenyl alkenyl more preferably include C 2 -C 6 alkenyl, specifically, for example, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (Including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl and the like can be mentioned.
- C 2 -C 6 alkenyl specifically, for example, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (Including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl and the like can be mentioned.
- alkynyl is a monovalent group having at least one triple bond (two adjacent SP carbon atoms).
- Alkynyls include not only linear ones but also branched chain ones.
- C 2 -C 10 alkynyl as alkynyl more preferably include C 2 -C 6 alkynyl, specifically, for example, ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl -2-Propynyl, 3- (2'-fluorophenyl) -2-propynyl, 2-hydroxy-2-propynyl, 3- (3-fluorophenyl) -2-propynyl, 3-methyl- (5-phenyl)- 4-Pentynyl and the like can be mentioned.
- cycloalkyl means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, and includes a monocyclic ring, a bicyclo ring, and a spiro ring.
- a monocyclic ring Preferably include C 3 -C 8 cycloalkyl the cycloalkyl, specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, spiro [ 3.3] Heptyl and the like can be mentioned.
- aryl means a monovalent aromatic hydrocarbon ring, preferably C 6- C 10 aryl. Specific examples of the aryl include phenyl and naphthyl (for example, 1-naphthyl and 2-naphthyl).
- heterocyclyl means a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms.
- the heterocyclyl may have double and / or triple bonds in the ring, and the carbon atom in the ring may be oxidized to form a carbonyl, which may be a monocyclic or fused ring.
- the number of atoms constituting the ring is preferably 4 to 10 (4 to 10-membered heterocyclyl), more preferably 4 to 7 (4 to 7-membered heterocyclyl).
- heterocyclyl examples include azetidinyl, oxetanyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazoridinyl, imidazolinyl, Imidazolidinyl, oxazolidinyl, isooxazolidinyl, thiazolidinyl, isothiazolydinyl, 1,2-thiadinane, thiadiazolidinyl, azetidinel, oxazolidone, benzodioxanyl, benzoxazolyl, dioxolanyl, dioxanyl, tetrahydropyrrolo [1 , 2-c] Imid
- heteroaryl means an aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to a carbon atom.
- the ring may be a single ring, a fused ring with another ring, or may be partially saturated.
- the number of atoms constituting the ring is preferably 5 to 10 (5 to 10-membered heteroaryl), and more preferably 5 to 7 (5 to 7-membered heteroaryl).
- heteroaryl for example, frill, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridadinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl.
- Alkoxy as used herein, means an oxy group "alkyl” is bonded defined above, with preference given to C 1 -C 6 alkoxy. Specific examples of the alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, 3-methylbutoxy and the like.
- Acyl (alkanoyl) herein means that the hydrogen or the "alkyl” is a group in which a carbonyl group is bonded, preferably, C 1 -C 6 acyl, more preferably C 2 -C 4 Acyl is mentioned. Specific examples of the acyl include formyl, acetyl, propionyl, butanoyl and the like.
- cycloalkoxy as used herein, means an oxy group "cycloalkyl" is bonded defined above, with preference given to C 3 -C 8 cycloalkoxy. Specific examples of cycloalkoxy include cyclopropoxy, cyclobutoxy, cyclopentyloxy and the like.
- Alkylsulfonyl as used herein, means a sulfonyl group “alkyl” is bonded defined above, with preference given to C 1 -C 6 alkylsulfonyl. Specific examples of the alkyl sulfonyl include methyl sulfonyl and the like.
- Hydroalkyl herein means a group wherein one of the “alkyl” definition, or more hydrogens are replaced by hydroxyl, C 1 -C 6 hydroxyalkyl are preferred. Specific examples of the hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 5-hydroxypentyl and the like.
- Haloalkyl refers to a group in which one or more hydrogens "alkyl” defined above is substituted with halogen, C 1 -C 6 haloalkyl are preferred, C 1 -C 6 fluoroalkyl Is more preferable. Specifically, as haloalkyl, for example, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5 -Difluoropentyl and the like.
- Haloalkoxy refers to a group in which one or more hydrogens "alkoxy" defined above is substituted with halogen, C 1 -C 6 haloalkoxy is preferred. Specific examples of haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and the like.
- Haloacyl herein means that the carbonyl group in the "haloalkyl” is a group attached, preferably, C 2 -C 6 haloacyl, more preferably C 2 -C 4 haloacyl Can be mentioned.
- Specific examples of haloacyl include trifluoroacetyl, trichloroacetyl, pentafluoropropionyl, 2,3,3,3-tetrafluoro-2- (trifluoromethyl) propionyl, 3,3,3-trifluoro-2-. Examples include (trifluoromethyl) propionyl.
- alkoxyalkyl as used herein, the one or more hydrogens "alkyl” definition means been substituted with the "alkoxy" defined above, C 1 -C 6 alkoxy C 1 -C 6 alkyl are preferred, C 1 -C 6 alkoxy C 1 -C 2 alkyl is more preferable.
- alkoxyalkyl for example, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, Examples thereof include 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl and 2-ethoxyethyl.
- cycloalkylalkyl means a group in which one or more hydrogens of the "alkyl” defined above are substituted with the "cycloalkyl” defined above, and C 3- C 8 cycloalkyl C.
- 1- C 6 alkyl is preferred, and C 3- C 6 cycloalkyl C 1- C 2 alkyl is more preferred.
- Specific examples of the cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
- cycloalkoxyalkyl means a group in which one or more hydrogens of the "alkyl” in the above definition are substituted with the "cycloalkoxy” in the above definition, and C 3- C 8 cycloalkoxy C.
- 1- C 6 alkyl is preferred, and C 3- C 6 cycloalkoxy C 1- C 2 alkyl is more preferred.
- Specific examples of the cycloalkoxyalkyl include cyclopropoxymethyl and cyclobutoxymethyl.
- Alkylsulfonyl alkyl as used herein, means one or more of “alkylsulfonyl” substituted radicals of hydrogen the definition of "alkyl” defined above, C 1 -C 6 alkylsulfonyl C 1- C 6 alkyl is preferred, and C 1- C 6 alkyl sulfonyl C 1- C 2 alkyl is more preferred.
- Specific examples of the alkylsulfonylalkyl include methylsulfonylmethyl and 2- (methylsulfonyl) ethyl.
- Alkyl (arylalkyl) as used herein, means at least one hydrogen atom is replaced by "aryl" defined group of "alkyl” defined above, preferably C 7 -C 14 aralkyl , C 7- C 10 aryl kills are more preferred.
- Specific examples of the aralkyl include benzyl, phenethyl, 3-phenylpropyl and the like.
- heteroarylkyl means a group in which at least one hydrogen atom of the "alkyl” defined above is substituted with the "heteroaryl” defined above, and is a 5- to 10-membered hetero.
- Aryl C 1- C 6 alkyl is preferred, and 5-10 membered heteroaryl C 1- C 2 alkyl is more preferred.
- Specific examples of the heteroarylalkyl include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-pyridyl) ethyl, and 2- (3-pyridyl).
- the "carboxyl group protecting group” includes an alkyl ester type protecting group, a benzyl ester type protecting group, a substituted alkyl ester type protecting group and the like.
- Specific examples of the carboxyl-protecting group include a methyl group, an ethyl group, a t-Bu group, a benzyl group, a trityl group, a cumyl group, a methoxytrityl group, a 2- (trimethylsilyl) ethyl group, and 2,2,2-trichloro. Ethyl group, allyl group and the like are exemplified.
- the "amino group protecting group” includes a carbamate type protecting group, an amide type protecting group, an imide type protecting group, a sulfonamide type protecting group and the like.
- Specific examples of the amino-protecting group include Fmoc, Boc, Cbz, Alloc, trifluoroacetyl, pentafluoropropionyl, phthaloyl, tosyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, and 2,4-dinitrobenzenesulfonyl. Illustrated.
- the "alicyclic ring” in the present specification means a non-aromatic hydrocarbon ring.
- the alicyclic ring may have an unsaturated bond in the ring or may be a polycyclic ring having two or more rings. Further, the carbon atoms constituting the ring may be oxidized to form a carbonyl.
- the alicyclic ring is preferably a 3- to 8-membered alicyclic ring, and specific examples thereof include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicyclo [ 2.2.1] Heptane ring and the like can be mentioned.
- heterocycle in the present specification means a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to a carbon atom.
- the heterocycle may have double and / or triple bonds in the ring, and the carbon atom in the ring may be oxidized to form a carbonyl, or may be a monocycle, a condensed ring, or a spiro ring.
- the number of atoms constituting the ring is not limited, but is preferably 3 to 12 (3 to 12-membered heterocycle), and more preferably 4 to 7 (4 to 7-membered heterocycle).
- heterocycle examples include piperazine, pyrrolidine, piperidine, morpholine, homomorpholine, hexahydropyrazine, 3-oxopiperazine, 2-oxopyrrolidine, azetidine, 2-oxoimidazolidine, oxazolidine, dihydrofuran, and tetrahydrofuran.
- saturated heterocycle means a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to a carbon atom and containing no double or / or triple bonds in the ring. To do.
- the saturated heterocycle may be a monocyclic ring, or may form a fused ring with another ring, for example, an aromatic ring such as a benzene ring.
- the saturated heterocycle When the saturated heterocycle forms a fused ring, the saturated heterocycle preferably includes a 4- to 7-membered saturated heterocycle, and specifically, for example, an azetidine ring, an oxazolidine ring, a tetrahydrofuran ring, a tetrahydropyrrol ring, and a morpholin ring.
- Thiomorpholin ring pyrrolidine ring, 4-oxopyrrolidine ring, piperidine ring, 4-oxopiperidine ring, piperazin ring, pyrazolidine ring, imidazolidine ring, oxazolidine ring, isooxazolidine ring, thiazolidine ring, isothiazolidine ring, thiazilidine ring
- Examples thereof include a ring, a sazolidone ring, a dioxolan ring, a dioxane ring, a thietan ring, an octahydroindole ring, and an indolin ring.
- peptide chain refers to a peptide chain in which one or more natural and / or unnatural amino acids are linked by an amide bond and / or an ester bond.
- the peptide chain is preferably a peptide chain containing 1 to 15 amino acid residues, and more preferably a peptide chain containing 5 to 12 amino acid residues.
- the "peptide compound” in the present invention is not particularly limited as long as it is a peptide compound in which natural amino acids and / or unnatural amino acids are linked by an amide bond or an ester bond, but the number of amino acid residues is preferably 5 to 30 residues. It is more preferably a peptide compound having 8 to 15 residues, and even more preferably 9 to 13 residues. Peptide compounds also include those supported on solid-phase synthetic resins.
- the peptide compound synthesized in the present invention preferably contains at least 3 N-substituted amino acids in one peptide, and more preferably contains at least 5 or more N-substituted amino acids. These N-substituted amino acids may be present continuously or discontinuously in the peptide compound.
- amino acid constituting the peptide compound
- amino acid residue constituting all or part of the peptide compound
- peptide residue constituting all or part of the peptide compound
- the peptide compound in the present invention may be linear or cyclic, and a cyclic peptide compound is preferable.
- the "cyclic peptide compound” in the present invention is a cyclic peptide compound that can be obtained by cyclizing the N-terminal side group and the C-terminal side group of the linear peptide compound.
- the cyclization is a carbon-nitrogen bond cyclization such as an amide bond, a carbon-oxygen bond cyclization such as an ester bond or an ether bond, a carbon-sulfur bond cyclization such as a thioether bond, or a carbon-carbon bond. It may be in any form, such as cyclization by cyclization by, or cyclization by construction of a heterocycle.
- cyclization via a covalent bond such as an amide bond or a carbon-carbon bond is preferable, and cyclization via an amide bond between a carboxylic acid group in the side chain and an amino group in the N-terminal main chain is more preferable. ..
- the positions of the carboxylic acid group, amino group, etc. used for cyclization may be those on the main chain or side chains, and are not particularly limited as long as they are in cyclizable positions.
- one or more means one or two or more numbers.
- the term means the number from one to the maximum number of substituents the group allows. Specific examples of "one or more” include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or larger numbers.
- the "resin for solid phase synthesis” is not particularly limited as long as it can be used for the synthesis of peptide compounds by the solid phase method.
- Specific examples of such solid-phase synthesis resins include CTC resin, Wang resin, SASRIN resin, trityl chloride resin (Trt resin), 4-methyltrityl chloride resin (Mtt resin), and 4-methoxytrityl chloride. Examples thereof include those that can be removed under acidic conditions such as resin (Mmt).
- the resin can be appropriately selected according to the functional group on the amino acid side used.
- a carboxylic acid main chain carboxylic acid or side chain carboxylic acid represented by Asp or Glu
- a hydroxy group on the aromatic ring phenol group represented by Tyr
- Trt resin trityl chloride resin
- CTC resin 2-chlorotrityl chloride resin
- the resin is trityl chloride resin (Trt resin) or 2-chlorotrityl chloride resin (CTC resin).
- a resin may be described as a resin.
- the resin for solid-phase synthesis can be linked to an amino acid at an arbitrary position, which is not limited to the C-terminal amino acid in the peptide.
- the carboxyl group of the C-terminal amino acid is preferably linked to the resin for solid-phase synthesis, and the carboxyl group may be a carboxyl group in the main chain or a carboxyl group in the side chain.
- the type of polymer constituting the resin is also not particularly limited. In the case of a resin composed of polystyrene, either 100-200 mesh or 200-400 mesh may be used.
- the cross-linking rate is also not particularly limited, but a 1% DVB (divinylbenzene) cross-linked product is preferable.
- examples of the type of polymer constituting the resin include Tentagel and Chemmatrix.
- the substituents include, for example, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, alkylsulfonyl, alkyl.
- substituents include, for example, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, alkylsulfonyl, alkyl.
- substituents include, for example, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, alkylsulfonyl, alkyl.
- examples thereof include sulfonylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, halogen, nitro, amino, monoalkylamino, dialkylamino, cyano, carboxyl, alkoxycarbonyl, for
- substituents may be added to each of these, and these substituents are also not limited, and any substitution including, for example, a halogen atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom.
- a halogen atom an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom.
- One or two or more may be freely selected independently from the group. That is, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, cycloalkyl and the like which may be substituted are exemplified.
- the compound described in the present invention can be a salt thereof or a solvate thereof.
- the salts of the compounds described in the present invention include, for example, hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; methanesulfonate, p-toluenesulfonate.
- Sulfates such as acetates, citrates, malates, tartrates, succinates, salicylates and the like; or alkali metal salts such as sodium and potassium salts; magnesium salts, calcium salts and the like.
- Alkaline earth metal salts such as; ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts and the like are included. These salts are produced, for example, by contacting the compound with an acid or base.
- the solvate of the compound described in the present invention refers to a phenomenon in which a solute molecule strongly attracts a solvent molecule in a solution to form one molecular group, and if the solvent is water, it is called a hydrate.
- the compounds described in the present invention are solvated with an organic solvent such as alcohol (eg, methanol, ethanol, 1-propanol, 2-propanol, etc.), dimethylformamide, or diglyme, or a single solvent selected from water and the like. It may be a product or a solvent product with a plurality of solvents.
- an organic solvent such as alcohol (eg, methanol, ethanol, 1-propanol, 2-propanol, etc.), dimethylformamide, or diglyme, or a single solvent selected from water and the like. It may be a product or a solvent product with a plurality of solvents.
- amino acid in the present specification includes natural amino acids and unnatural amino acids (sometimes referred to as amino acid derivatives).
- natural amino acid refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Ph, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, Pro. Point to.
- the unnatural amino acid (amino acid derivative) is not particularly limited, and examples thereof include ⁇ -amino acid, D-type amino acid, N-substituted amino acid, ⁇ , ⁇ -di-substituted amino acid, amino acid having a side chain different from that of natural amino acid, and hydroxycarboxylic acid. ..
- any configuration is allowed, but it is preferably an L-type amino acid.
- the selection of the side chain of the amino acid is not particularly limited, but in addition to the hydrogen atom, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroaralkyl group, a cycloalkyl group, or a spiro bond. It is freely selected from the cycloalkyl groups.
- Substituents may be added to each, and these substituents are also not limited, and any substituent including, for example, a halogen atom, an O atom, an S atom, an N atom, a B atom, a Si atom, or a P atom.
- substituents include, for example, a halogen atom, an O atom, an S atom, an N atom, a B atom, a Si atom, or a P atom.
- One or two or more may be freely selected independently from the above. That is, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a cycloalkyl group and the like which may be substituted, or an oxo, aminocarbonyl, a halogen atom and the like are exemplified.
- the amino acid herein may be a compound having a
- Examples of the substituent containing a halogen atom in the present specification include an alkyl group having a halogen as a substituent, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group and the like, and more specifically. Is exemplified by fluoroalkyl, difluoroalkyl, trifluoroalkyl and the like.
- Examples of oxy (-OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy and the like.
- the alkoxy, C 1 -C 4 alkoxy, is C 1 -C 2 alkoxy preferred, methoxy or ethoxy are preferred.
- Examples of carbonyloxy include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, aralkylcarbonyloxy and the like. ..
- carbonylthio examples include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, aralkylcarbonylthio and the like. ..
- alkylaminocarbonyl e.g., C 1 -C 6 or C 1 -C 4 alkylaminocarbonyl, among others ethylaminocarbonyl, methyl aminocarbonyl are exemplified
- Cycloalkylaminocarbonyl alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,
- Examples of carbonylamino include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylcarbonylamino and the like. ..
- Examples of oxycarbonylamino include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aralkyloxy. Examples include carbonylamino.
- sulfonylamino examples include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino and the like.
- H atom bonded to the N atom in the -NH-SO 2 -R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, include other substituents aralkyl.
- aminosulfonyl examples include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl and the like.
- H atom bonded to the N atom in the -SO 2 -NHR alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl include other substituents aralkyl.
- sulfamoylamino examples include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenyl sulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, hetero.
- Aryl sulfamoyl amino, alkyne sulfamoyl amino and the like can be mentioned.
- the two H atoms bonded to the N atom in -NH-SO 2- NHR are substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl. It may be substituted, and these two substituents may form a ring.
- Fluorosulfanilic (-SF 5 ) can be mentioned.
- thio As an example of thio (-SR), it is selected from alkyl thio, cycloalkyl thio, alkenyl thio, alkynyl thio, aryl thio, hetero aryl thio, aralkyl thio and the like.
- sulfinyl examples include alkylsulfinyl, cycloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl and the like.
- sulfonyl examples include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl and the like.
- Substituents containing N atoms include azide (-N 3 , also referred to as "azido group”), cyano (-CN), primary amino (-NH 2 ), secondary amino (-NH-R; mono-substituted amino).
- Examples of the secondary amino (-NH-R) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, aralkylamino and the like.
- tertiary aminos examples include, for example, alkyl (aralkyl) amino, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., respectively.
- Amino groups having any two substituents selected above may be mentioned, and these any two substituents may form a ring.
- dialkylamino among others C 1 -C 6 dialkylamino, C 1 -C 4 dialkylamino, dimethylamino, diethylamino and the like.
- C p- C q dialkylamino group refers to a group in which two C p- C q alkyl groups are substituted on an amino group, and both C p- C q alkyl groups are the same. May also be different.
- the three substituents R, R', and R'' on the N atom are alkyl, cycloalkyl, alkenyl, alkynyl, aryl. , Heteroaryl, groups independently selected from aralkyl, for example, alkyl (aralkyl) (aryl) amidino and the like.
- substituted guanidinos include R, R', R', and R''' as alkyl, cycloalkyl, alkenyl, alkynyl. , Aryl, heteroaryl, groups independently selected from alkynes, or groups in which these form a ring, and the like can be mentioned.
- aminocarbonylamino examples include R, R', and R'' of hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl. Examples thereof include groups independently selected from the group, or groups forming a ring.
- substituent containing a B atom examples include boron (-BR (R')) and dioxyboryl (-B (OR) (OR')). These two substituents R and R'are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., or they may form a ring. .. Specifically, a cyclic boryl group is mentioned, and more specifically, a pinacholate boryl group, a neopentane diolato boryl group, a catecholate boryl group and the like can be mentioned.
- alkyl C 1 -C 6 alkyl, C 1 -C 4 alkyl, methyl, C 7 -C 14 aralkyl, benzyl, phenethyl and the like Illustrated.
- the main chain amino group of an amino acid may be unsubstituted (-NH 2 ) or substituted (ie, -NHR, where R may have a substituent alkyl, alkenyl, alkynyl, aryl. , Heteroaryl, aralkyl, cycloalkyl, and a carbon chain bonded to an N atom and a carbon atom at the ⁇ -position, such as proline, may form a ring).
- Such an amino acid in which the hydrogen atom of the main chain amino group is substituted may be referred to as an "N-substituted amino acid" in the present specification.
- N- substituted amino acid as used herein, preferably N- alkyl amino acids, N-C 1 -C 6 alkyl amino acids, N-C 1 -C 4 alkyl amino acids, N- methyl amino acids, N-C 2 - Examples thereof include, but are not limited to, C 6 alkenyl amino acid, N-allyl amino acid, NC 7- C 14 aralkyl amino acid, N-benzyl amino acid, and N-phenethyl amino acid.
- amino acid includes all isotopes corresponding to each.
- An isotope of an “amino acid” is one in which at least one atom is replaced with an atom having the same atomic number (number of protons) but different mass number (sum of numbers of protons and neutrons).
- isotopes contained in the "amino acid” as used herein is a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, include a chlorine atom, respectively, 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 35 S, 18 F, 36 Cl and the like are included.
- the present invention has an N-substituted- ⁇ , ⁇ -disubstituted amino acid residue at the N-terminus, comprising the steps A and B described below, said N-substituted- ⁇ , ⁇ -disubstituted amino acid residue.
- the present invention relates to a method for producing a peptide compound, a salt thereof, or a mixture thereof, which comprises a dipeptide residue in which and an N-substituted amino acid residue are linked.
- Step A is an electron-attracting agent of an N-substituted amino acid, a salt thereof, or a mixture thereof, or a peptide compound having an N-substituted amino acid residue at the N-terminal, a salt thereof, or a solvent thereof.
- N-unsubstituted- ⁇ , ⁇ -disubstituted amino acids with amino groups protected by protective groups, salts thereof, dehydrated products thereof, or their solvates are reacted in the presence or absence of a condensing reagent.
- a dipeptide residue having an N-unsubstituted- ⁇ , ⁇ -disubstituted amino acid residue at the N-terminal and the N-unsubstituted- ⁇ , ⁇ -disubstituted amino acid residue linked to the N-substituted amino acid residue is a step of obtaining a peptide compound, a salt thereof, or a mixture thereof, which comprises.
- the inclusion of a dipeptide in a peptide compound means that the dipeptide is contained in the amino acid sequence constituting the peptide compound.
- the "N-substituted amino acid" used in step A is any natural or unnatural amino acid in which the amino group of the backbone is -NHR, where R is any group other than hydrogen. ..
- R for example, an alkyl which may be substituted, an alkenyl which may be substituted, an alkynyl which may be substituted, an aryl which may be substituted, a heteroaryl which may be substituted, and the like.
- Alkyne which may be substituted, cycloalkyl which may be substituted, and the like can be mentioned, and in R, even if the carbon chain bonded to the N atom and the carbon atom at the ⁇ -position form a ring like proline. Often, the ring may be further substituted with any substituent.
- the N-substituted amino acid may be in the form of a salt or a solvate.
- the "peptide compound having an N-substituted amino acid residue at the N-terminal" used in step A is included in the peptide compound if it has the N-substituted amino acid residue at the N-terminal.
- the type and number of amino acids in the above are not limited. Further, the peptide compound may be in the form of a salt or a solvate.
- the N-substituted amino acid or the peptide compound having an N-substituted amino acid residue at the N-terminal used in step A is purchased from a commercial supplier or prepared by modifying the one purchased from a commercial supplier. May be good.
- R 2 is C 1- C 6 alkyl, C 1- C 6 haloalkyl, C 1- C 6 hydroxyalkyl, C 1- C 6 alkyl sulfonyl C 1- C 6 alkyl, C 2- C 6 alkynyl, 1 or C 1- C 6 Alkoxy C 1- C 6 Alkyne, C 3- C 8 Cycloalkyl, C 3- C 8 Cycloalkyl C 1- C 6 Alkyne, C 3- C 8 May Be Substituted by Multiple Halogen Cycloalkoxy C 1- C 6 alkyl, or C 7- C 14 alkyl, R 3 is hydroxy, O-PG 2 , any amino acid residue, or any peptide residue. PG 2 is a carboxyl-protecting group. ] Examples thereof include the compound represented by, or a salt thereof, or a solvate thereof.
- the "N-unsubstituted- ⁇ , ⁇ -disubstituted amino acid in which the amino group is protected by an electron-attracting protective group" used in step A is any two optional amino acids other than hydrogen on the ⁇ carbon.
- Amino acid having a substituent of, the amino group of the main chain of the amino acid is unsubstituted, and the amino group is protected by an electron-attracting protective group (that is, "protective group-NH-").
- the amino acid may be in the form of a salt or a solvate.
- the two substituents attached to the ⁇ -carbon may be the same or different.
- substituents include, for example, an alkyl which may be substituted, an alkoxyalkyl which may be substituted, an alkenyl which may be substituted, an alkynyl which may be substituted, and an alkyl which may be substituted.
- examples include good aryls, optionally substituted heteroaryls, optionally substituted aralkyls, optionally substituted heteroaralkyls, optionally substituted cycloalkyls, optionally substituted cycloalkylalkyls and the like. Be done.
- the two substituents attached to the ⁇ -carbon form an alicyclic ring that may be substituted together with the carbon atom to which they are attached, or a heterocycle that may be substituted. May be.
- N-unsubstituted- ⁇ , ⁇ -disubstituted amino acids in which the amino group is protected by the electron-attracting protecting group used in step A are purchased from a commercial supplier or purchased from a commercial supplier. It may be prepared by modifying one.
- step A can carry out the reaction in the presence of a condensation reagent.
- the condensation reaction proceeds, for example, when a dehydrated product of N-unsubstituted- ⁇ , ⁇ -disubstituted amino acids is used, the reaction may be carried out in the absence of a condensation reagent.
- R 1 and Q 1 are C 1- C 6 alkyl, C 2- C 6 alkenyl, C 1- C 6 alkoxy C 1- C 6 alkyl, C 3- C 8 cycloalkyl C 1- C 6 alkyl, or substitutions. It may be selected independently of the C 7- C 14 alkoxy, or R 1 and Q 1 may be a 3- to 8-membered alicyclic ring or a 3- to 8-membered alicyclic ring together with the carbon atom to which they are attached. It forms a 4- to 7-membered saturated heterocycle.
- Examples thereof include the compound represented by, or a salt thereof, or a solvate thereof.
- the electron-attracting protecting group attached to the N-unsubstituted- ⁇ , ⁇ -disubstituted amino acid is a protecting group in which the NH group to which the protecting group is attached has a pKa (in water) of 6 to 11.
- a protecting group having an NH group pKa (in water) of 8 to 11 is preferable.
- protecting groups include C 2 -C 6 haloacyl, more specifically, trifluoroacetyl, trichloroacetyl, pentafluoropropionyl, 2,3,3,3-fluoro-2 -(Trifluoromethyl) propionyl, 3,3,3-trifluoro-2- (trifluoromethyl) propionyl and the like can be mentioned.
- the N-unsubstituted- ⁇ , ⁇ -disubstituted amino acid residue obtained by step A has an N-terminal at the N-terminus, and the N-unsubstituted- ⁇ , ⁇ -disubstituted amino acid residue and the N-substituted amino acid residue.
- the following formula (4) [During the ceremony, PG 1, R 1, and Q 1 is the same meaning as PG 1, R 1, and Q 1 of formula (3), P 2, R 2, and R 3 are each synonymous with P 2, R 2, and R 3 of formula (2)] Examples thereof include the compound represented by, or a salt thereof, or a solvate thereof.
- step B the amino group of the N-unsubstituted- ⁇ , ⁇ -disubstituted amino acid residue whose amino group is protected by an electron-attracting protective group at the N-terminal of the peptide compound obtained in step A is added to the amino group.
- a substituent is introduced to have an N-substituted- ⁇ , ⁇ -disubstituted amino acid residue at the N-terminal in which the amino group is protected by an electron-attracting protective group.
- substituents introduced in this step include an alkyl which may be substituted, an alkenyl which may be substituted, an alkynyl which may be substituted, an aralkyl which may be substituted, and an substituted aralkyl. Cycloalkyl and the like may be mentioned.
- the base used in step B preferably has a pKa (in acetonitrile) of its conjugate acid of 23 to 30.
- a base having an amidine skeleton a base having a guanidine skeleton, and a base having a phosphazene skeleton, which will be described later.
- the substituent-introducing agent used in step B is an amino group (an amino group of an N-unsubstituted- ⁇ , ⁇ -disubstituted amino acid residue in which the amino group is protected by an electron-attracting protective group at the N-terminal. That is, it is used to introduce a substituent into "protective group-NH-").
- An electrophile can be used as the substituent introduction agent.
- a compound in which the substituent to be introduced and the elimination group for example, a sulfonic acid group such as a halogen, a trifluoromethanesulfonyl group, a methanesulfonyl group, or a tosyl group, or a phosphoric acid group
- a substituent to be introduced and the elimination group for example, a sulfonic acid group such as a halogen, a trifluoromethanesulfonyl group, a methanesulfonyl group, or a tosyl group, or a phosphoric acid group
- PG 1, R 1, and Q 1 is the same meaning as PG 1, R 1, and Q 1 of formula (3), P 2, R 2, and R 3 are each synonymous with P 2, R 2, and R 3 of formula (2)] Examples thereof include the compound represented by, or a salt thereof, or a solvate thereof.
- the N-substituted- ⁇ , ⁇ -disubstituted amino acid residue produced by the method of the present invention has an N-substituted amino acid residue at the N-terminal, and the N-substituted- ⁇ , ⁇ -disubstituted amino acid residue and the N-substituted amino acid residue are present.
- the "peptide compound containing the linked dipeptide residue" may be one in which the amino group at the N-terminal thereof is protected by a protective group, or one in which the protective group is removed and the amino group is free (NHR-).
- the protecting group is the "N-unsubstituted- ⁇ , ⁇ -di, in which the amino group is protected by an electron-attracting protecting group" used in step A. It may be an electron-attracting protecting group due to a "substituted amino acid” or another protecting group (eg, Fmoc group) introduced after the electron-attracting protecting group has been deprotected.
- the present invention can include a step of removing an electron-attracting protecting group and a step of introducing an arbitrary protecting group other than the protecting group.
- the method described in “Greene's,” Protective Groups in Organic Synthesis "(5th edition, John Wiley & Sons 2014)" can be used for the attachment / detachment of the protecting group.
- the present invention comprises a peptide compound, a salt thereof, comprising a structure in which two amino acid residues represented by formula (1) are linked, comprising Step A and Step B as shown in the following scheme.
- the present invention relates to a method for producing a solvate thereof.
- PG 1 is a protecting group for an amino group
- a protecting group such that the pKa of the NH group to which PG 1 is bound is 11 or less is preferably used.
- the pKa of the NH group to which PG 1 is bound is 11 or less, preferably 6 to 11, more preferably 8 to 11
- P 1 is selectively attached to the NH group of the formula (4) to which PG 1 is bound. It is possible to introduce a group.
- pKa a calculated value using Advanced Chemistry Development (ACD / Labs) Software V11.02 ((C) 1994-2019 ACD / Labs) can be used.
- the NH group pka of tert-butyl (2,2,2-trifluoroacetyl) alaninate, to which trifluoroacetyl is attached to a nitrogen atom is 9.71 and 2-methyl-2- (2,2).
- the NH group pka of tert-butyl 2-trifluoroacetamide) propanoate is 9.21.
- the pka of the NH group of methyl 2-methyl-2- (2,2,3,3,3-pentafluoropropanamide) propanoate in which pentafluoropropionyl was bonded to a nitrogen atom was 9.27, and trichloro.
- the pka of the NH group of methyl 2-methyl-2- (2,2,2-trichloroacetamide) propanoate, in which acetyl is attached to the nitrogen atom, is 9.72.
- the pka of the NH group of methyl 2-acetamido-2-methylpropanoate in which an acetyl group having a weaker electron-attracting force than these haloacyl groups is bonded to a nitrogen atom is 14.36, and the acidity of the NH group is 14.36. Weaker than haloacyl groups.
- PG 1 is a protecting group of the electron-withdrawing, such as acidity increases protons of NH groups are preferred, C 2 -C 6 haloacyl can be mentioned as such protecting groups.
- the C 2 -C 6 haloacyl, trifluoroacetyl, trichloroacetyl, pentafluoropropionyl, 2,3,3,3-tetrafluoro-2- (trifluoromethyl) propionyl or 3,3,3, - 2- (Trifluoromethyl) propionyl and the like are preferable.
- P 1 is C 1- C 6 alkyl, C 2- C 6 alkenyl, or C 7- C 14 aralkyl.
- the C 1- C 6 alkyl is preferably methyl, ethyl, n-propyl, or i-propyl
- P 1 is C 1- C 6 alkenyl. in some cases, preferably a C 1 -C 6 alkenyl, allyl
- P 1 is, if a C 7 -C 14 aralkyl, preferably a C 7 -C 14 aralkyl, benzyl or phenethyl.
- R 1 and Q 1 is, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl C 1 - Selected independently of C 6 alkyl, or optionally substituted C 7- C 14 alkoxy, or R 1 and Q 1 are 3-8 together with the carbon atom to which they are attached. It forms a member alicyclic ring or a 4- to 7-membered saturated heterocycle.
- R 1 and / or Q 1 is a C 1 -C 6 alkyl, preferably a C 1 -C 6 alkyl, methyl, ethyl, i- propyl, 2-methylpropyl. If R 1 and / or Q 1 is a C 2 -C 6 alkenyl, preferably a C 2 -C 6 alkenyl is allyl.
- R 1 and / or Q 1 is C 1- C 6 alkoxy C 1- C 6 alkyl
- the C 1- C 6 alkoxy C 1- C 6 alkyl is preferably methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, or 2-ethoxyethyl Is.
- C 3- C 8 cycloalkyl C 1- C 6 alkyl is preferably cyclopropyl methyl, cyclobutyl methyl, cyclopentyl. Methyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl.
- R 1 and / or Q 1 may be substituted C 7- C 14 aralkyl
- the C 7- C 14 aralkyl is preferably benzyl or phenethyl and is an aryl substituent of C 7- C 14 aralkyl. preferably halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and one or more groups selected from the group consisting of cyano as Is.
- R 1 and Q 1 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle together with the carbon atoms to which they are bonded, as a 3- to 8-membered alicyclic ring.
- a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring are preferable, and a tetrahydropyran ring is preferable as a 4- to 7-membered saturated heterocycle.
- P 2 is a C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 7 -C 14 aralkyl.
- the C 1- C 6 alkyl is preferably methyl, ethyl, n-propyl, or i-propyl
- P 2 is C 1- C 6 alkenyl. in some cases, preferably a C 1 -C 6 alkenyl, allyl
- P 2 is, if a C 7 -C 14 aralkyl, preferably a C 7 -C 14 aralkyl, benzyl or phenethyl.
- R 2 is C 1- C 6 alkyl, C 1- C 6 haloalkyl, C 1- C 6 hydroxyalkyl, C 1- C 6 alkyl sulfonyl C 1- C 6 alkyl, C 2- C 6 alkynyl, one or more of which may C 1 -C be the 6 alkoxy C 1 -C 6 alkyl substituted by halogen, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, C 3- C 8 cycloalkoxy C 1- C 6 alkyl, or C 7- C 14 alkyl.
- R 2 C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 4 hydroxyalkyl, methylsulfonyl C 1 -C 2 alkyl, C 2 -C 3 alkynyl, one or more C 1- C 4 alkoxy which may be substituted with fluorine C 1- C 2 alkyl, C 3- C 6 cycloalkyl, C 3- C 6 cycloalkyl C 1- C 2 alkyl, C 3- C 6 cycloalkoxy C 1 -C 2 alkyl, benzyl, phenethyl.
- R 2 for example, methyl, ethyl, n- propyl, i- propyl, 1-methylpropyl, 2-methylpropyl, n- butyl, 2-methylbutyl, 3-methylbutyl, n- pentyl, propargyl, 3,3-Difluorobutyl, 5,5-difluoropentyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, n-propoxymethyl, 1-hydroxyethyl, cyclopropoxymethyl, cyclobutoxymethyl, (2,2) Examples thereof include 2-trifluoroethoxy) methyl, 2-methylsulfonylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl and phenethyl.
- R 3 is hydroxy, O-PG 2 , any amino acid residue, or any peptide residue, where PG 2 is a protecting group for the carboxyl group.
- PG 2 is a protecting group for the carboxyl group.
- specific examples of PG 2 include alkyl such as t-butyl, trityl, cumyl, allyl, and benzyl.
- R 3 is an arbitrary amino acid residue or an arbitrary peptide residue
- the amino acid residue or peptide residue may be supported on a solid-phase synthesis resin.
- the peptide residue is supported on the solid-phase synthesis resin, the resin is supported on the amino acid residue at the C-terminal of the peptide residue, but is supported on the amino acid residue at any other position.
- the solid-phase synthesis resin examples include CTC resin, Wang resin, and SASRIN resin, and more preferably CTC resin.
- R 3 is an arbitrary peptide residue
- the peptide residue is composed of any kind and number of amino acid residues.
- the number of amino acid residues constituting the peptide residue is preferably 2 to 13, and more preferably 2 to 9.
- equation (1) the following equation: Specifically, as the amino acid residue represented by, for example, MeAib, MecLeu, Me (Me) Phe, Me (Me) Abu, Me (Me) Leu, Me (Me) Ser (Me), Me (Me) Examples include Phe, Me (Me) Cha, Me (Me) Val, EtAib, nPrAib, AllylAib, and BnAib.
- equation (1) the following equation: Specifically, as the amino acid residue represented by, for example, MeAla, MeLeu, MeCha, MeVal, MeAla (cPent), MeAla (cBu), MeAla (cPr), MeChg, MeGly (cPent), MeGly (cBu), MeGly (cPr), MeAbu, MeNva, MeNle, MeNva (5-F2), MeHle, MeIle, MeSer (nPr), MeSer (cPr), MeHnl, MeHnl (7-F2), MePRA, MeSer (Me), MeThr, Examples include MeSer (cBu), MeSer (Tfe), MeThr (Me), MeHse (Me), MeMet (O2), EtVal, and nPrVal.
- MeAla MeLeu, MeCha, MeVal, MeAla (cPent), MeAla (cBu), MeAla (cPr), MeChg, MeGly (cPent
- R 3 is an arbitrary amino acid residue, specifically, as the amino acid residue, for example, MeSer (tBuOH), bAla, bMeAla, MeGly, MePhe, MePhe (3-F), MePhe (4-F), D-MePhe, 2-ACHxC, 2-ACPnC, 3-CF3-bAla, Asp-mor, Asp-mor (26-bicyc), Asp-mor (SO2), Asp-NMe2, Asp -oxz, Asp-pip, Asp-pip (345-F6), Asp-pip (4-Me), Asp-pip-tBu, Asp-piz (oxe), Asp-pyrro, Asp-pyrro (34-F4) , Asp-pyrro (3-Me2), D- (Propargyl) Gly- (C # CH2), D-3-Abu, D-3-MeAbu, D-Gly (Allyl
- step A a compound represented by the formula (2), a salt thereof, or a solvate thereof and a compound represented by the formula (3), a salt thereof, a dehydrated product thereof, or a solvate thereof are prepared.
- a dehydrated form of the compound represented by the formula (3) that is, the compound represented by the formula (3')
- a salt thereof, or a solvate thereof was reacted in the absence of a condensing reagent.
- the compound represented by the following formula (2) can be purchased from a commercial supplier, or, if necessary, a modified compound purchased from a commercial supplier can be used. Specifically, for example, a compound represented by the formula (2), by introducing the P 2 to those purchased from commercial suppliers, it can be produced.
- P 2, R 2, and R 3 of formula (2) are respectively synonymous with P 2, R 2, and R 3 of formula (1).
- the compound represented by the following formula (3) can be purchased from a commercial supplier, or, if necessary, a modified compound purchased from a commercial supplier can be used.
- the compound represented by the formula (3) can be produced by introducing PG 1 into a compound purchased from a commercial supplier using a base and a PG 1 introduction reagent in a solvent. Can be done.
- Specific examples of the PG 1 introduction reagent include ethyl trifluoroacetate, ethyl pentafluoropropionate, or ethyl trichloroacetate, trifluoroacetic anhydride, pentafluoropropionic anhydride, trichloroacetic anhydride and the like.
- the base include N, N-diisopropylethylamine, triethylamine, sodium methoxydo, and sodium ethoxydo.
- the solvent used when introducing PG 1 include methanol, ethanol, and the like when ethyl trifluoroacetate, ethyl pentafluoropropionate, or ethyl trichloroacetate is used as the introduction reagent. ..
- examples thereof include dichloromethane, tetrahydrofuran, and pyridine.
- PG 1, Q 1, and R 1 is PG 1, Q 1 of formula (1), and R 1 to be the same meanings.
- Step A can be carried out by applying the reaction conditions known in the literature.
- the methods described in the solid-phase synthesis handbook published by Merck Group on May 1, 2002 are exemplified, and these may be appropriately used according to the reaction conditions.
- the condensation reagent used in step A DCC (N, N'-dicyclohexylcarbodiimide), DIC (N, N'-diisopropylcarbodiimide), EDCI ⁇ HCl (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride)
- a combination of a carbodiimide-based condensing agent typified by salt), a carbodiimide-based condensing agent and an additive typified by HOAt, HOBt, and oxyma, HATU (O- (7-aza-1H-benzotriazole-1-yl) -N , N, N', N'-tetramethyluronium hex
- PG 1 is a C 2 -C 6 haloacyl
- the oxazolone of formula (3 ') is a dehydration of the compound in Step A You can also do it.
- Carbon atoms between the oxygen atoms and oxygen atoms and nitrogen atoms constituting the oxazolone ring is derived from the carbonyl group of C 2 -C 6 haloacyl of PG 1, C 2 -C 6 haloacyl haloalkyl group of R 4 is PG 1 from a C 1 -C 5 haloalkyl.
- reactant for preparing the oxazolone include N, N'-diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, thionyl chloride and the like.
- R 1 and Q 1 are the same meaning as that of R 1 and Q 1 of formula (3).
- R 1 and Q 1 may form a 3- to 8-membered alicyclic ring together with the carbon atoms to which they are bonded, and are specifically referred to as such a 3- to 8-membered alicyclic ring. Examples thereof include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring.
- R 4 is C 1- C 5 haloalkyl, and specifically as C 1- C 5 haloalkyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, 1,2. , 2,2-Tetrafluoro-1- (trifluoromethyl) ethyl, 2,2,2-trifluoro-1- (trifluoromethyl) ethyl and the like. Of these, trifluoromethyl is preferred.
- Step B the compound represented by formula (4), a salt thereof or a solvate thereof is reacted with P 1 transfer reagent, peptide compounds represented by the formula (1), a salt thereof or their, This is a step of obtaining a solvate.
- P 1 X as P 1 transfection reagent (wherein, P 1 has the same meaning as P 1 of the formula (1), X is a leaving group) can be used in combination with a base.
- step B the compound represented by the formula (4), by the action of P 1 X in the presence of a suitable pKa of a base, selectively introducing a P 1 to the nitrogen atom to which PG 1 is bonded Can be done.
- alkyl iodide, alkyl bromide, alkyl trifluoromethanesulfonate, alkyl p-toluenesulfonic acid alkenyl iodide, alkenyl bromide, alkenyl trifluoromethanesulfonate, p-toluenesulfonic acid.
- alkenyl, aralkyl iodide, aralkyl bromide, aralkyl trifluoromethanesulfonate, and aralkyl p-toluenesulfonic acid examples thereof include alkenyl, aralkyl iodide, aralkyl bromide, aralkyl trifluoromethanesulfonate, and aralkyl p-toluenesulfonic acid.
- P 1-introducing reagent is a methylating reagent, specifically as a methylating reagent, for example, include methyl iodide, dimethyl sulfate, methyl trifluoromethanesulfonate, p- toluenesulfonate methyl, such as methane sulfonic acid methyl is, if P 1-introducing reagent is ethyl reagent, specifically as ethyl reagent, e.g., ethyl iodide, ethyl bromide, diethyl sulfate, trifluoromethanesulfonic acid ethyl, p- toluenesulfonate, ethyl methanesulfonate Examples thereof include ethyl sulfonate.
- P 1-introducing reagent is allyl reagent, specifically as allyl reagent, e.g., allyl chloride, allyl bromide and the like.
- P 1-introducing reagent is benzyl reagent, specifically as benzyl reagent, e.g., benzyl chloride, benzyl bromide and the like.
- P 1-introducing reagent is phenethyl reagent, specifically as phenethyl reagents, for example, (2-iodoethyl) benzene, and the like (2-bromoethyl) benzene.
- a base having a basicity suitable for introducing P 1 into a target nitrogen atom can be used.
- the basicity of a base is represented by the pKa of the conjugate acid of the base.
- the pKa of the conjugate acid of the base is sometimes called the pKa of the base.
- a base having pKa which is sufficient to dehydrogenate the hydrogen of the NH group to which P 1 is bonded, can be used.
- the pKa of the conjugate acid of the base is a calculated value using Advanced Chemistry Development (ACD / Labs) Software V11.02 ((c) 1994-2019 ACD / Labs), Chem. Eur. J. 2002, 8, 1682-1693. , J. Org. Chem. 2005, 70, 3, 1019-1028, Eur. J. Org. Chem., 2019, 40, 6735-6748, or the values listed in the catalog of Sigma-Aldrich, etc. as appropriate. Can be done.
- PKa depends on the solvent.
- the pKa of the conjugate acids of DBU, DBN, TMGN, MTBD, and BTMG in water are 13.28, 13.42, 12.26, 14.37, and 13.81, respectively.
- the pKa of the conjugate acids of DBU, TMGN, MTBD, P1-tBu, BTPP and BEMP in acetonitrile was 24.32, 25.1, 25.43, 26.9, 28.4, 27.6. Yes (Chem. Eur. J. 2002, 8, 1682-1693, Sigma-Aldrich catalog value).
- the pKa of the conjugate acid of DBN in acetonitrile is 23.89 (Eur. J. Org. Chem., 2019, 40, 6735-6748).
- the pKa value of the conjugate acid of the base in water (Advanced Chemistry Development (ACD / Labs) Software V11.02 ((C) 1994-2019 calculated by ACD / Labs)) and the pKa value in acetonitrile are in acetonitrile.
- the pKa value of is about 10 to 14 larger.
- a protecting group having a pKa (in water) of 11 or less for the NH group to which PG 1 is bound is preferably used.
- the pKa (in water) of the NH group to which PG 1 is bound is preferably 6 to 11, and more preferably 8 to 11.
- the pKa of the conjugate acid of the base required for deprotonating the proton of the NH group should be at least 2 or more, preferably 2 to 3, and more preferably 2 to 6 away from the pKa of the NH group. is necessary.
- the pKa of the conjugate acid of the base used is (1) larger than the pKa of the NH group, and (2) the pKa is at least 2 or more, preferably at least 2.
- Bases that are separated by 6 or more and have a value of (3) a larger value of pKa by the equivalent value of pKa in acetonitrile (10 to 14) in acetonitrile are preferable. If the pKa value (in acetonitrile) of the specific base conjugate acid is 18 to 31, 22 to 29, 22 to 30, 22 to 31, 23 to 29, 23 to 30, 23 to 31, the base of this reaction. Can be used as.
- the range of pKa (in acetonitrile) of the conjugate acid of the base to be used is preferably 22 to 31.
- the pKa (in acetonitrile) of the NH group to which PG 1 is bound is 8 to 11
- the pKa (in acetonitrile) of the conjugate acid of the base used is 20 to 31, 20 to 30, 20 to 29, 21 to 31.
- 21-30, 21-29, 22-31, 22-30, 22-29, 23-31, 23-30, 23-29 can be used as the base for this reaction.
- the range of pKa (in acetonitrile) of the conjugate acid of the base to be used is preferably 23 to 30.
- the base is represented by the following formula B1 having an amidine skeleton.
- RB 1 and RB 4 are either each independently C 1 -C 4 alkyl or RB 1 and RB 4, is together with the carbon atom to which the nitrogen atom and RB 4 RB 1 is bonded is bonded
- RB 2 and RB 3 is either each independently C 1 -C 4 alkyl, or RB 2 and RB 3 is a nitrogen atom and the nitrogen atom and RB 3 RB 2 is bonded is bonded
- B1 having an amidine skeleton.
- RB 1 ⁇ RB 4 is, when a C 1 -C 4 alkyl, and preferably methyl, ethyl as the C 1 -C 4 alkyl.
- the 5- to 8-membered ring is preferably a pyrrolidine ring, a piperidine ring, an azepane ring, or the like.
- the 5- to 8-membered ring is preferably a 1,4,5,6-tetrahydropyrimidine ring or the like.
- DBU 1,8-diazabicyclo [5.4.0] undeca-7-ene
- DBN 1,5-diazabicyclo [4.3.0] non-5-ene
- the base is represented by the following formula B2, which has a guanidine skeleton.
- RB 6 is hydrogen or C 1 -C 4 alkyl
- RB 5 and RB 7 are each either independently a C 1 -C 4 alkyl, which together with the nitrogen atom and the carbon atom to which respective nitrogen atom is bonded are bonded 5-8
- RB 8 is C 1- C 4 alkyl
- RB 9 is C 1- C 4 alkyl or phenyl
- RB 8 and RB 9 are each nitrogen atom to which they are attached and each nitrogen atom.
- the two B2s may be formed by condensing the two benzene rings of the phenyl group to form naphthalene.
- the C 1- C 4 alkyl is preferably methyl
- RB 9 is C 1- C 4 alkyl
- the 4- alkyl is preferably t-butyl.
- the 5- to 8-membered ring is preferably an imidazolidine ring, a hexahydropyrimidine ring, a 1,3-diazepan ring or the like.
- the 5- to 8-membered ring is preferably a 1,4,5,6-tetrahydropyrimidine ring or the like.
- TMGN 1,8-bis (tetramethylguanidineno) naphthalene
- MTBD 7-methyl-1,5,7-triazabicyclo [4.4.0] deca- 5-ene
- BTMG 2-tert-butyl-1,1,3,3-tetramethylguanidine
- TBD 1,5,7-triazabicyclo [4.4.0] deca-5-ene
- the base is represented by the following formula B3, which has a phosphazene skeleton.
- RB 10 is C 1 -C 4 alkyl either or RB 10 and RB 11, together with the nitrogen atom to which they are attached form a 5-8 membered ring, RB 11, except where RB 10 and RB 11 to form a 5- to 8-membered ring, or a C 1 -C 4 alkyl or RB 11 and RB 12, is, and the nitrogen atom they are attached Together with the phosphorus atom to which each nitrogen atom is bonded, a 5- to 8-membered ring is formed.
- RB 12 except where RB 11 and RB 12 to form a 5- to 8-membered ring, C 1 -C 4 alkyl either or RB 12 and RB 13, is together with the nitrogen atom to which they are attached
- RB 13 except where RB 12 and RB 13 to form a 5- to 8-membered ring, or a C 1 -C 4 alkyl or RB 13 and RB 14, is, and the nitrogen atom they are attached Together with the phosphorus atom to which each nitrogen atom is bonded, a 5- to 8-membered ring is formed.
- RB 14 except where RB 13 and RB 14 to form a 5- to 8-membered ring, or a C 1 -C 4 alkyl or RB 14 and RB 15, is together with the nitrogen atom to which they are attached
- RB 15 except where RB 14 and RB 15 to form a 5- to 8-membered ring, C 1 -C 4 alkyl, RB 16 is hydrogen, C 1 -C 8 alkyl or C 6 -C 10 aryl.
- the C 1- C 4 alkyl is preferably methyl or ethyl
- RB 16 is C 1- C 8 alkyl
- the C 1 as preferably -C 8 alkyl t- butyl, t- octyl.
- the 5- to 8-membered ring is preferably a pyrrolidine ring, a piperidine ring, an azepane ring, or the like. Can be mentioned.
- the 5-8 membered ring is bound to RB 11 , RB 12 , RB 13 and RB 14. It is preferably a 5- to 8-membered saturated ring containing no heteroatom other than each nitrogen atom and the phosphorus atom to which each nitrogen atom is bonded.
- tert-butylimino-tris (dimethylamino) phosphorane (P1-tBu), tert-octylimimino-tris (dimethylamino) phosphorane (P1-t-Oct), tert-Butyl imino-tri (pyrrolidino) phosphorane (P1-t-Bu-tris (tetramethylene), BTPP), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin (BEMP), imino-tris (dimethylamino) phosphorane (HP1 (dma)) and the like.
- the base is represented by B4 below, which has a phosphazene skeleton containing two phosphorus atoms via a nitrogen atom.
- RB 17 is either C 1 -C 4 alkyl independently or RB 17 and RB 18, together with the nitrogen atom to which they are attached form a 5-8 membered ring, RB 18, except where RB 17 and RB 18 to form a 5- to 8-membered ring, or a C 1 -C 4 alkyl or RB 18 and RB 19, is, and the nitrogen atom they are attached Together with the phosphorus atom to which each nitrogen atom is bonded, a 5- to 8-membered ring is formed.
- RB 19 is together with the nitrogen atom to which they are attached
- RB 20 except where RB 19 and RB 20 to form a 5- to 8-membered ring, C 1 -C 4 alkyl
- RB 21 is either C 1 -C 4 alkyl or RB 21 and RB 22, together with the nitrogen atom to which they are attached form a 5-8 membered ring
- RB 22 except where RB 21 and RB 22 to form a 5- to 8-membered ring, or a C 1 -C 4 alkyl or RB 22 and RB 23, is, and the nitrogen atom they are attached Together with the phosphorus atom to which each nitrogen atom is bonded, a 5- to 8-membered ring is formed.
- RB 25 is a C 1 -C 4 alkyl or C 6 -C 10 aryl.
- the C 1- C 4 alkyl is preferably methyl or ethyl
- the C 1 -C 4 the preferred alkyl is t- butyl.
- the 5- to 8-membered ring is preferable. Examples thereof include a pyrrolidine ring, a piperidine ring, and an azepane ring.
- RB 17 and RB 18 is C 1 -C 4 alkyl both preferably RB 19 and RB 20 also are both C 1 -C 4 alkyl, RB 17 and RB 18 to form a 5- to 8-membered ring , RB 19 and RB 20 also preferably form a 5- to 8-membered ring.
- RB 21 and RB 22 are both C 1- C 4 alkyl
- RB 23 and RB 24 and RB 25 and RB 26 are both C 1- C 4 alkyl
- RB 21 and RB 22 are 5 to 5 to It is preferable that RB 23 and RB 24 and RB 25 and RB 26, which form an 8-membered ring, also form a 5- to 8-membered ring.
- the 5-8 membered ring is bound to RB 11 , RB 12 , RB 13 and RB 14. It is preferably a 5- to 8-membered saturated ring containing no heteroatom other than each nitrogen atom and the phosphorus atom to which each nitrogen atom is bonded.
- the solvent used in the reaction is an amide solvent typified by DMF or NMP, a urea solvent typified by DMI, tetrahydrofuran or 2 -Examples include an ether solvent typified by methyltetrahydrofuran and acetonitrile, and among these, an amide solvent is preferable.
- pKa of the amino group protected by PG 1 water and is 6 ⁇ 11
- pKa of a base conjugate acid (in acetonitrile) is 23-30
- a combination of PG 1 and a base is preferred.
- pKa of a base conjugate acid (in acetonitrile) is more preferably a combination of PG 1 and a base to be 23-27.
- PG 1 is trifluoroacetyl
- P 1 X is methyl iodide, dimethyl sulfate, ethyl iodide, allyl bromide, n-propyl iodide, bromide. It is preferably benzyl and the base is P1-tBu, TMGN, or MTBD.
- Specific examples of the combination of PG 1 and a base include trifluoroacetyl and TMGN, trifluoroacetyl and P1-tBu, and trifluoroacetyl and MTBD.
- the present invention has an N-substituted- ⁇ , ⁇ -disubstituted amino acid residue at the N-terminal, and the N-substituted- ⁇ , ⁇ -disubstituted amino acid residue and the N-substituted amino acid residue are linked.
- N-substituted- ⁇ , ⁇ -disubstituted amino acid residues and N-substituted amino acid residues were ligated, including the method for producing a peptide compound, a salt thereof, or a mixture thereof containing the dipeptide residue. It relates to a method for producing a peptide compound, a salt thereof, or a mixture thereof, which comprises a dipeptide residue.
- the method has an N-substituted- ⁇ , ⁇ -disubstituted amino acid residue produced by the method described herein at the N-terminal, and the N-substituted- ⁇ , ⁇ -disubstituted amino acid residue and N.
- a step of further condensing one or more amino acid residues and / or peptide residues at the N-terminal and / or C-terminal of a peptide compound containing a dipeptide residue linked to a substituted amino acid residue can be included.
- the peptide compound produced by this method is any peptide compound containing a dipeptide residue in which an N-substituted- ⁇ , ⁇ -disubstituted amino acid residue and an N-substituted amino acid residue are linked.
- a peptide compound in which any number and type of amino acids are linked to the N-terminal side and the C-terminal side of the dipeptide residue is included.
- the invention desorbs an N-terminal protecting group (eg, PG 1 ) from the peptide compound of formula (1), a salt thereof, or a solvate thereof produced by the method of the invention. It also relates to a method for producing a cyclic peptide compound, further comprising a step of protecting, optionally extending a peptide chain, and a step of cyclizing a C-terminal group and an N-terminal group to form a cyclic portion.
- the cyclic peptide compound contains 8 to 15 amino acid residues, preferably 10 to 13 amino acid residues, and has at least 3, preferably at least 3 to (the number of amino acid residues constituting the cyclic peptide compound-1). Contains at least one, preferably at least three non-N-substituted amino acid residues, with at least eight circular amino acid residues, preferably at least 10 amino acid residues. Includes groups.
- a known method such as the method described in WO2013 / 100132 or WO2018 / 225864 can be used.
- a step of cutting out from the resin may be included before the extension step and the step of forming the cyclic portion.
- Example 1 Preparation of amino acids used in this example, peptides supported on the resin, etc.
- Example 1-1 Fmoc-amino acids used for peptide synthesis by a peptide synthesizer In the peptide synthesis described in the present specification, the Fmoc-amino acids shown in Tables 3 to 5 were used for the synthesis by the peptide synthesizer. The Fmoc-amino acids listed in Tables 3 and 5 were purchased from commercial suppliers. The Fmoc-amino acids shown in Table 4 were synthesized according to the scheme shown below.
- Examples 1-11 Compound AA2-001, (2S) -4- [3-chloro-4- (trifluoromethyl) phenyl] -2- (9H-fluorene-9-ylmethoxycarbonylamino) butanoic acid , (Fmoc-Hph (4-CF3-3-Cl) -OH) synthesis
- a toluene solution (900 mL) of compound AA2-001-b (75 g, 158.93 mmol) was cooled to 0 ° C. and trifluoromethanesulfonic acid (TfOH) (42 mL, 3.00 eq) was added dropwise. After stirring at room temperature for 1 hour, water (75 mL) was added. The mixed solution was extracted with water, and the combined aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- TfOH trifluoromethanesulfonic acid
- Example 1-1-2 Compound AA2-002, (2S) -3-cyclobutyl-2- [9H-fluorene-9-ylmethoxycarbonyl (methyl) amino] propanoic acid (Fmoc-MeAla (cBu) -OH) Synthesis of
- Boron trifluoride diethyl ether complex (BF 3. OEt 2 ) (3.50 mL, 27.6 mmol) was added, and the mixture was stirred for 2 hours.
- An aqueous solution obtained by diluting a saturated aqueous sodium chloride solution with water to a half concentration was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes.
- the organic layer separated from the obtained mixture was solvent-distilled under reduced pressure.
- Example 1-1-3 Compound AA2-003, (2S) -2-cyclopentyl-2- [9H-fluorene-9-ylmethoxycarbonyl (methyl) amino] acetic acid (Fmoc-MeGly (cPent) -OH) Synthetic
- Trifluoroacetic acid (76 mL, 984 mmol) was added to a mixture of the obtained compound AA2-003-b (31 g, 82 mmol) and triethylsilane (TES) (65.5 mL, 410 mmol) in dichloroethane (DCE) (90 mL). was added, and the mixture was stirred at 60 ° C. for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained solid was washed with n-hexane / ethyl acetate (95/5) and dried under reduced pressure to prepare compound AA2-003 ((2S) -2-cyclopentyl-2).
- TES triethylsilane
- DCE dichloroethane
- Example 1-1-4 Compound AA2-004, (2S) -2-cyclobutyl-2- [9H-fluorene-9-ylmethoxycarbonyl (methyl) amino] acetic acid (Fmoc-MeGly (cBu) -OH) Synthetic
- Example 1-1-5 Compound AA2-005, (2S) -3-cyclopentyl-2- [9H-fluorene-9-ylmethoxycarbonyl (methyl) amino] propanoic acid (Fmoc-MeAla (cPent) -OH) Synthesis of
- Example 1-2 Preparation of amino acids, peptides, etc. supported on the resin used in this example.
- the polymer or resin site when a compound is bonded to a polymer or resin, the polymer or resin site may be indicated by a circle. In addition, for the purpose of clarifying the reaction point of the resin site, it may be connected to ⁇ to indicate the chemical structure of the reaction site.
- the 2-chlorotrityl group of the resin is an ester with the side chain carboxylic acid of Asp. They are connected through a bond.
- pyrro means pyrrolidine, and in the above structure, the C-terminal carboxylic acid group forms an amide bond with pyrrolidine.
- the support reaction of Fmoc amino acid on the resin was carried out according to the method described in WO2013 / 100132 or WO2018 / 225864.
- 2-Chlorotrityl chloride resin (1.60 mmol / g, 100-200 mesh, 1% DVB, 48.7 g) and dehydrated dichloromethane (500 mL) were placed in a reaction vessel with a filter and shaken at room temperature for 20 minutes. After removing dichloromethane by applying nitrogen pressure, dehydrated methanol (12.63 mL) and diisopropylethylamine (DIPEA) (32.6 mL) were added to compound 1-2-1-b (15.91 g) and dehydrated dichloromethane (350 mL).
- DIPEA diisopropylethylamine
- the added mixture was added to the reaction vessel and shaken for 60 minutes. After removing the reaction solution by applying nitrogen pressure, a mixed solution of dehydrated methanol (97.3 mL) and diisopropylethylamine (DIPEA) (32.6 mL) added to dehydrated dichloromethane (350 mL) was added to the reaction vessel for 1 hour. Shake for 30 minutes. After removing the reaction solution by applying nitrogen pressure, dichloromethane (350 mL) was added and shaken for 5 minutes, and then nitrogen pressure was applied to remove the reaction solution.
- DIPEA diisopropylethylamine
- the obtained compound 1-2-1 (12.6 mg) was placed in a reaction vessel, DMF (2 mL) was added, and the mixture was shaken at room temperature for 1 hour. Then, DBU (40 ⁇ L) was added and shaken at 30 ° C. for 30 minutes. Then, DMF (8 mL) was added to the reaction mixture, and 1 mL of the solution was diluted with DMF (11.5 mL). The absorbance (294 nm) of the obtained diluted solution was measured (measured using Shimadzu, UV-1600PC (cell length 1.0 cm)).
- the Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2) used in this example was prepared by a peptide synthesizer (Multipep RS; manufactured by Intavis). Was used by the Fmoc method. For the detailed operation procedure, follow the manual attached to the synthesizer.
- Fmoc-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-1, 0.464 mmol / g) (100 mg per column) prepared in Example 1-2-1.
- the solution (10% v / v) was set in the synthesizer.
- dichloromethane DCM
- Fmoc-Asp O-Trt (2-Cl) -resin
- pyrro Compound 1-2-1, 0.464 mmol / g
- De-Fmoc step 1,8-diazabicyclo [5.4.0] -7-Undecene (DBU) in DMF solution (2% v / v) was added 0.7 mL per column and allowed to stand for 5 to 10 minutes. De-Fmoc was performed. Subsequently, the resin was washed with DMF (0.7 mL per column, repeated 4 times).
- DBU diazabicyclo [5.4.0] -7-Undecene
- Extension step Add a mixture of the set Fmoc-amino acid solution (0.30 mL per column) and DIC / DMF solution (0.36 mL per column) to the resin that has undergone the de-Fmoc step, and at 40 ° C. It was left still. After completion of the reaction, the resin was washed with DMF (0.7 mL per column, repeated 4 times).
- Example 1-2-3 Preparation of Fmoc-MePhe-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-3)
- Example 1-2-4 (3R) -3- [9H-fluorene-9-ylmethoxycarbonyl (methyl) amino] butanoic acid-2-chlorotrityl resin (Fmoc-D-3-MeAbu-O-Trt) Synthesis of 2-Cl) resin, compound 1-2-4)
- Example 1-3 Amino acid protected by a protecting group other than Fmoc used for peptide synthesis, and its dehydrated amino acid protected by a protecting group other than Fmoc used in the peptide synthesis described herein, and an amino acid thereof.
- the dehydrated product was synthesized as follows.
- Example 1-3-1 2-Methyl-2-[(2,2,2-trifluoroacetyl) amino] Preparation of propanoic acid (Tfa-Aib-OH) (Compound 1-3-1)
- Example 2 An N-unsubstituted- ⁇ , ⁇ -di-substituted amino acid having a Tfa-protected N-terminal is extended to an amino acid residue whose N-terminal is N-substituted in a peptide during solid phase synthesis.
- An experiment attempting to introduce N-substituted- ⁇ and ⁇ -di substituted amino acid residues through N-functionalization on the solid phase
- Example 2-1 Elongation of Tfa-Aib-OH after de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2)
- Example 2-1-1 After de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2), Tfa-Aib-OH using DIC Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2) (0.473 mmol) prepared in Example 1-2-2 in a reaction vessel equipped with an extension filter.
- the obtained resin (Compound 2-1-1) was cut out as a peptide with a TFE / DCM solution (1/1 (v / v)), and the cut out solution was subjected to LCMS.
- the analysis confirmed the production of the target peptide Tfa-Aib-MeVal-Asp-pyrro (Compound 2-1 *). No other peptide components were detected.
- This resin (Compound 2-1-1) was used in Example 2-3.
- Example 2-1-2 After de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2), oxyma was added as an additive using DIC.
- Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2) prepared in Example 1-2-2 was placed in a reaction vessel equipped with an extension filter of Tfa-Aib-OH. -2) (0.473 mmol / g, 100 mg) was added, and Tfa-Aib was extended by the same method as in Example 2-1-1 except for the extension reagent.
- Example 2-1-3 After de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2), Tfa-Aib-using EDCI-HCl. Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2) (0) prepared in Example 1-2-2 in a reaction vessel equipped with an extension filter for OH. .473 mmol / g, 100 mg) was added, and Tfa-Aib was extended by the same method as in Example 2-1-1 except for the extension reagent.
- the extension reagent a solution obtained by mixing a 0.6 M Tfa-Aib-OH / NMP solution (0.3 mL) and an EDCI / HCl (48 mg, 0.250 mmol) / DMF solution (0.36 mL) was used.
- a solution obtained by mixing a 0.6 M Tfa-Aib-OH / NMP solution (0.3 mL) and an EDCI / HCl (48 mg, 0.250 mmol) / DMF solution (0.36 mL) was used.
- As a result of cutting out a peptide from the resin in the same manner as in Example 2-1-1 and analyzing it by LCMS it was added to the target peptide Tfa-Aib-MeVal-Asp-pyrro (Compound 2-1 *) 93.1% (UVarea).
- Example 2-2 Nucleophilic substitution reaction of Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-1) to the Tfa amide site (methyl iodide as a methylating agent) , Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2) prepared in Example 2-1 in a reaction vessel equipped with an N-methylation filter using DBU) as a base.
- DBU N-methylation filter using DBU
- Example 2-3 Nucleophilic substitution reaction of Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-1) to the Tfa amide site (methyl iodide as a methylating agent) , Various bases) in a reaction vessel with an N-methylation filter, Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2) prepared in Example 2-1.
- Dichloromethane (1 mL) was added to 1-1 or 2-1-3) (25 mg) and shaken at room temperature for 15 minutes to swell the resin. After removing the dichloromethane with a filter, the resin was washed 4 times with DMF (0.7 mL).
- Example 2-4 Tfa-protected deprotected nitrogen atmosphere of Tfa-MeAib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-2) after N-alkylation, hydrogen Triglym (triethylene glycol dimethyl ether) (6.6 mL) was added to sodium borohydride (0.5 g), and the mixture was stirred at room temperature for 10 minutes to obtain a 2.0 M sodium borohydride / trigrim solution.
- hydrogen Triglym triethylene glycol dimethyl ether
- the Tfa-protected raw material peptide Tfa-MeAib-MeVal-Asp-pyrro (Compound 2-2 *) was completely consumed, and the target peptide H-MeAib-MeVal-Asp-pyrro (Compound 2-4 *) was observed. ..
- the LC chart is as shown in FIG. 1, and it was confirmed that synthesis with high purity is possible.
- the present invention can introduce N-methyl- ⁇ and ⁇ -dialkyl amino acids with high purity following the bulky N-alkyl amino acids. Further, it has been confirmed that the subsequent de-Tfa step also proceeds satisfactorily, and it is possible to continue to carry out conventional peptide extension or the like from the N-terminal.
- Example 2-5 Experiment in which various N-methyl- ⁇ and ⁇ -dialkyl amino acids were introduced on the solid phase following the bulky N-methyl amino acid (MeVal). Compound 2 was used using various Tfa-amino acids according to the following general formula. -5-1-1 to Compound 2-5-7-1 and Compound 2-5-1-2 to Compound 2-5-7-2 were synthesized.
- Example 2-5-1 Synthesis of Tfa-Me (Me) Abu-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-1-2)
- Example 2-5-1-1 After de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2), it was carried out in a reaction vessel with an extension filter of Tfa- (Me) Abu-OH.
- Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2) (0.552 mmol / g, 100 mg) prepared by the same method as in Example 1-2-2. ) was added, dichloromethane (1 mL) was added, and the mixture was shaken at room temperature for 45 minutes to swell the resin. After removing the dichloromethane with a filter, the resin was washed 3 times with DMF (0.7 mL). Subsequently, a 2% DBU / DMF solution (de-Fmoc solution: 0.7 mL) was added to the resin and shaken at room temperature for 5 minutes to de-Fmoc. After removing the de-Fmoc solution, the resin was washed 4 times with DMF (0.7 mL).
- Example 2-5-1-2 With N-methylation filter by nucleophilic substitution reaction for Tfa amide site of Tfa- (Me) Abu-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-1-1)
- Tfa- (Me) Abu-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro Compound 2-5-1).
- 1) 45 mg
- dichloromethane (1 mL
- the mixture was shaken at room temperature for 45 minutes to swell the resin. After removing the dichloromethane with a filter, the resin was washed 4 times with DMF (0.7 mL).
- the same operation was performed three more times for the purpose of improving the reaction conversion rate.
- the second methylation was performed at 40 degrees with shaking for 1.5 hours.
- the third and fourth methylations were performed at 40 degrees with shaking for 1 hour.
- the resin was washed 4 times with DMF and 4 times with DCM to give compound 2-5-1-2.
- a part of the obtained resin was taken out, the peptide was excised with a TFE / DCM / DIPEA solution (1: 1: 0.015), and the excised solution was analyzed by LCMS to obtain the target peptide Tfa-Me (Me). 6.
- Example 2-5-2 Synthesis of Tfa-Me (Me) Leu-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-2-2)
- Example 2-5-2-1 After de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2), extension of Tfa- (Me) Leu-OH
- Compound 1-2-2 Compound 1-2-2 (0.552 mmol / g, 100 mg), 0.6 M Tfa- (Me) Leu-OH (Compound 1-3-3-b) / DMF solution (0.
- Example 2-5-2-2 Examples of N-methylation by nucleophilic substitution reaction of Tfa- (Me) Leu-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-2-1) with respect to the Tfa amide site.
- Compound 2-5-2-2 (Tfa-Me (Me) Leu-MeVal-Asp (O-)) using compound 2-5-2-1 (45 mg) according to the method shown in 2-5-1-2. Trt (2-Cl) -resin) -pyrro) was synthesized in the same manner.
- Example 2-5-3 Synthesis of Tfa-Me (Me) Ser (Me) -MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-3-2)
- Examples 2-5-3-1 After de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2), extension of Tfa- (Me) Ser (Me) -OH
- Compound 1-2-2 0.552 mmol / g, 100 mg
- 0.6 M Tfa- (Me) Ser (Me) -OH Compound 1-3-4-b
- Example 2-5-3-2 N-methyl by nucleophilic substitution reaction of Tfa- (Me) Ser (Me) -MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-3-1) with respect to the Tfa amide site.
- compound 2-5-3-1 45mg
- compound 2-5-3-2 Tfa-Me (Me) Ser (Me) - MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro
- Examples 2-5-4 Synthesis of Tfa-Me (Me) Phe-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-4-2) Examples 2-5-4-1. After de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2), extension of Tfa- (Me) Phe-OH Example 2-5-1 Compound 1-2-2 (0.552 mmol / g, 100 mg), 0.6 M Tfa- (Me) Phe-OH (Compound 1-3-5) by setting the reaction time to 72 hours by the same method as in 1.
- Example 2-5-4-2 Examples of N-methylation by nucleophilic substitution reaction of Tfa- (Me) Phe-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-4-1) with respect to the Tfa amide site.
- Compound 2-5-4-2 (Tfa-Me (Me) Phe-MeVal-Asp (O-)) using compound 2-5-4-1 (45 mg) according to the method shown in 2-5-1-2.
- Trt (2-Cl) -resin) -pyrro) was synthesized in the same manner. At this time, the second N-methylation was also carried out in 1 hour.
- Examples 2-5-5 Synthesis of Tfa-Me (Me) Cha-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-5-2) Examples 2-5-5-1. After de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2), extension of Tfa- (Me) Cha-OH Example 2-5-1 Compound 1-2-2 (0.552 mmol / g, 100 mg), 0.6 M Tfa- (Me) Cha-OH (Compound 1-3-6) by setting the reaction time to 72 hours by the same method as in 1.
- Example 2-5-5-2 Examples of N-methylation by nucleophilic substitution reaction of Tfa- (Me) Phe-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-5-1) with respect to the Tfa amide site.
- Compound 2-5-5-2 (Tfa-Me (Me) Cha-MeVal-Asp (O-)) using compound 2-5-5-1 (45 mg) according to the method shown in 2-5-1-2. Trt (2-Cl) -resin) -pyrro) was synthesized in the same manner. At this time, the second N-methylation was also carried out in 1 hour.
- Example 2-5-6 Synthesis of Tfa-Me (Me) Val-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-6-2) Examples 2-5-6-1. After de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2), extension of Tfa- (Me) Val-OH Example 2-5-1 Compound 1-2-2 (0.552 mmol / g, 100 mg), 0.6 M Tfa- (Me) Val-OH (Compound 1-3-7) by setting the reaction time to 72 hours by the same method as in 1.
- Example 2-5-6-2 Examples of N-methylation by nucleophilic substitution reaction of Tfa- (Me) Val-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-6-1) with respect to the Tfa amide site. Based on the method shown in 2-5-1-2, the reaction temperature was set to 60 ° C., and compound 2-5-6-2 (40 mg) was used to compound compound 2-5-6-2 (Tfa-Me (Me)). Val-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro) was synthesized in the same manner. At this time, the second N-methylation was also carried out in 1 hour.
- Examples 2-5-7 Synthesis of Tfa-MecLeu-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-7-2) Examples 2-5-7-1. After de-Fmoc of Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2), extension of Tfa-cLeu-OH is shown in Example 2-5-1-1. Compound 1-2-2 (0.552 mmol / g, 100 mg), 0.6 M Tfa-cLeu-OH (Compound 1-3-8-b) / DMF solution (0.3 mL) was used according to the above procedure.
- Example 2-5-7-2 N-methylation by nucleophilic substitution reaction of Tfa-cLeu-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-5-7-1) to the Tfa amide site
- Compound 2-5-7-2 Compound 2-5-7-2 (Tfa-MecLeu-MeVal-Asp (O-Trt (2-Cl)-) using compound 2-5-7-1 (45 mg) according to the method shown in 1-2. Resin) -pyrro) was synthesized in the same manner.
- Example 2-5 As described above, based on the results of Example 2-5, it is practical to introduce various N-methyl- ⁇ and ⁇ -dialkyl amino acids other than MeAib, following the bulky N-methyl amino acid in solid-phase synthesis by the method of the present invention. It was shown that it is possible at various levels.
- Example 2-6 Experiment in which various N-substituted- ⁇ , ⁇ -dialkyl amino acids were introduced on the solid phase following the bulky N-methyl amino acid (MeVal) Compound 2 was used using various Tfa-amino acids according to the following general formula. -6-1 to compound 2-6-4 were synthesized.
- Example 2-6-1 Example 2-1-1 in a reaction vessel with an N-ethylation filter for the Tfa amide moiety of Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-1).
- Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-1) (0.552 mmol / g, 50 mg) prepared by the same method as above, and dichloromethane ( 1 mL) was added and shaken at room temperature for 45 minutes to swell the resin. After removing the dichloromethane with a filter, the resin was washed 4 times with DMF (0.7 mL).
- the same operation was carried out four more times for the purpose of improving the reaction conversion rate.
- the resin was washed 4 times with DMF and 4 times with DCM to give compound 2-6-1 (Tfa-EtAib-MeVal-Asp (O-Trt (2-Cl) -resin).
- -Pyrro was obtained.
- a part of the obtained resin was taken out, the peptide was cut out with a TFE / DCM / DIPEA solution (1: 1: 0.015), and the cut out solution was analyzed by LCMS to analyze the target peptide Tfa-EtAib-MeVal-.
- Example 2-6-2 Nn-propylation of Tfaamide site of Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-1) by the method shown in Example 2-6-1. , Compound 2-1 (0.552 mmol / g, 50 mg), compound 2-6-2 (Tfa-nPrAib-MeVal-Asp (O-Trt (2-Trt)) with n-propyl iodide (54 ⁇ L ⁇ 5). Cl) -resin) -pyrro) was synthesized in the same manner.
- Examples 2-6-3 N-allylation of the Tfa amide moiety of Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-1) N-allylation of the compound by the method shown in Example 2-6-1.
- Compound 2-6-3 (Tfa-AllylAib-MeVal-Asp (O-Trt (2-Cl) -resin) using 2-1 (0.552 mmol / g, 50 mg) and allyl bromide (48 ⁇ L ⁇ 5).
- -Pyrro was synthesized in the same manner.
- Examples 2-6-4 N-Benzylation of Tfaamide site of Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-1) Compound by the method shown in Example 2-6-1.
- Compound 2-6-4 (Tfa-BnAib-MeVal-Asp (O-Trt (2-Cl) -resin) using 2-1 (0.552 mmol / g, 50 mg), benzyl bromide (66 ⁇ L ⁇ 5).
- -Pyrro was synthesized in the same manner.
- Example 2-6 As described above, based on the results of Example 2-6, according to the method of the present invention, following the bulky N-methyl amino acid in solid-phase synthesis, not only N-methyl- ⁇ and ⁇ -dialkyl amino acids, but also N-substituted- ⁇ , It has been shown that the introduction of ⁇ -dialkyl amino acids is possible at a practical level.
- Example 2-7 Experiment in which N-methyl- ⁇ , ⁇ -dialkylamino acid (MecLeu) was introduced on the solid phase following the bulky N-alkyl amino acid (EtVal / nPrVal) Compound 2-7-1 to Compound 2-7-1 to the following general formula. Compound 2-7-2, compound 2-7-3-1 to compound 2-7-3-4 and compound 2-7-4-1 to compound 2-7-4-4 were synthesized.
- Example 2-7-1 Preparation of Fmoc-Val-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-1) Prepared in a reaction vessel with a filter by the same method as in Example 1-2-1. Add Fmoc-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-1) (0.552 mmol / g, 100 mg), add dichloromethane (1 mL), and at room temperature. The resin was shaken for 45 minutes to swell the resin. After removing the dichloromethane with a filter, the resin was washed 3 times with DMF (0.7 mL).
- the extension reaction was Fmoc-Val-OH (0.6 mol / L), 1-hydroxy-7-azabenzotriazole (HOAt, 0.375 mol / L) in NMP solution (0.3 mL) and 10% DIC / DMF. A solution mixed with the solution (0.36 mL) was added to the resin, and the mixture was shaken at 40 ° C. for 3 hours.
- Example 2-7-2 Example 2-7-1 in a reaction vessel with Fmoc-Val-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-1) de-Fmoc and an N-terminal Ns filter. Add Fmoc-Val-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-1) (0.552 mmol / g, 100 mg per column) prepared in the above, and dichloromethane ( 1 mL) was added and shaken at room temperature for 45 minutes to swell the resin. After removing the dichloromethane with a filter, the resin was washed twice with DMF (0.7 mL).
- a 2% DBU / DMF solution (de-Fmoc solution: 0.7 mL) was added to the resin and shaken at room temperature for 10 minutes to de-Fmoc.
- the resin is a DMF solution of DMF (0.7 mL), 1-hydroxy-7-azabenzotriazole (HOAt, 0.157 mol / L) and DIPEA (0.157 mol / L). It was washed sequentially with (0.7 mL) and DMF (0.7 mL), followed by 3 washes with THF (0.7 mL).
- Examples 2-7-3-1 Example 2-in a reaction vessel with an N-ethylation filter by Mitsunobu reaction on the Ns amide moiety of Ns-Val-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-2). Add Ns-Val-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-2) (0.552 mmol / g, 100 mg) prepared in 7-2, and dichloromethane ( 1 mL) was added and shaken at room temperature for 45 minutes to swell the resin. After removing the dichloromethane with a filter, the resin was washed twice with THF (1 mL).
- Example 2-7-3-2 In a reaction vessel with a de-Ns filter for Ns-EtVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-3-1), in Example 2-7-3-1. Add Ns-Val-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-3-1) (0.552 mmol / g, 100 mg) prepared in the above, and dichloromethane (1 mL). ) was added and shaken at room temperature for 45 minutes to swell the resin. After removing the dichloromethane with a filter, the resin was washed twice with NMP (0.7 mL).
- Examples 2-7-3-3 The extension reaction of Tfa-cLeu-OH to H-EtVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-3-2) was 2- (trifluoromethyl)-on the resin.
- Example 2-7-in a reaction vessel with an extension filter for Tfa-cLeu using 3-oxa-1-azaspiro [4.4] nona-1-en-4-one (Compound 1-3-9).
- Add H-EtVal-Asp (O-Trt (2-Cl) -resin) -pyrro (0.552 mmol / g, 100 mg) prepared in 3-2.
- Examples 2-7-3-4 Reaction vessel with N-methylation filter by nucleophilic substitution reaction on Tfa amide site of Tfa-cLeu-EtVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-3-3)
- Tfa-cLeu-EtVal-Asp (O-Trt (2-Cl) -resin) -pyrro (66 mg) prepared in Example 2-7-3-3.
- dichloromethane (1 mL) was added, and the mixture was shaken at room temperature for 1 hour to swell the resin. After removing the dichloromethane with a filter, the resin was washed 4 times with DMF (0.7 mL).
- Examples 2-7-4-1 Nn-propylation by Mitsunobu reaction of Ns-Val-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-2) to the Ns amide site
- Example 2-7-3-1 Compound 2-7-4-1 (Ns-nPrVal-) with compound 2-7-2 (0.552 mmol / g, 100 mg) and 1-propanol (41 ⁇ L, 0.552 mmol) according to the procedure shown in.
- Asp (O-Trt (2-Cl) -resin) -pyrro) was synthesized in the same manner.
- Examples 2-7-4-2 De-Nsization of Ns-nPrVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-4-1) Compound 2 by the method shown in Example 2-7-3-2. Compound 2-7-4-2 (HnPrVal-Asp (O-Trt (2-Cl) -resin) -pyrro) was similarly added using -7-4-1 (0.552 mmol / g, 100 mg). Synthesized.
- Examples 2-7-4-3 2- (Trifluoromethyl) -3-oxa-1-azaspiro for H-nPrVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-7-4-2) [4.4] Extension of Tfa-cLeu with Nona-1-en-4-one (Compound 1-3-9) Compound 2-7-4-2 (0) by the method shown in Example 2-7-3-3. Compound 2-7-4-3 (Tfa-cLeu-nPrVal-Asp (O-Trt (2-Cl) -resin) -pyrro) was similarly synthesized using .552 mmol / g, 100 mg).
- Examples 2-7-4-4 N-methylation of Tfa-cLeu-nPrVal-Asp (OTrt (2-Cl) -resin) -pyrro (Compound 2-7-4-3) by nucleophilic substitution reaction on the Tfa amide site
- Compound 2-7-4-3 Compound 2-7-4-3 (0.552 mmol / g, 60 mg) was used in Compound 2-7-4-4 (Tfa-Methyl-nPrVal-Asp (O-Trt (2)) according to the method shown in -4. -Cl) -resin) -pyrro) was synthesized in the same manner.
- Example 3 MeAib was introduced by the method of the present invention and peptide synthesis was carried out.
- Peptide elongation was carried out by the following basic route according to the peptide synthesis method by the Fmoc method described in WO2013 / 100132 or WO2018 / 225864. .. That is, 1) A peptide extension reaction by the Fmoc method from the N-terminal of an amino acid, although the Asp side chain carboxylic acid or the peptide main chain carboxylic acid was supported on 2-chlorotrityl resin.
- Example 3-1 (5S, 8S, 11S, 15R, 18S, 23aS, 29S, 35S, 37aS) -8,11-di ((S) -sec-butyl) -29- (3-chloro-4- (Trifluoromethyl) Penetyl) -35- (Cyclohexylmethyl) -18-Isopropyl-5,6,12,15,16,19,21,21,22,33,36-Undecamethyltetracosahydro-2H- Azete [2,1-u] Pyrrolo [2,1-i] [1,4,7,10,13,16,19,22,25,28,31] Undecaazacyclotetratoriacontin-4,7 , 10, 13, 17, 20, 23, 28, 31, 34, 37 (14H) -Synthesis of undecaone (Compound 3-1)
- the obtained compound 3-1-a was swollen with DCM (1 mL) and then washed 4 times with DMF (1 mL).
- a DMF solution (180 ⁇ L) of phosphazene base P1-tBu (38 ⁇ L, 0.150 mmol) and a DMF solution (180 ⁇ L) of methyl iodide (62 ⁇ L, 1 mmol) were added, and the mixture was shaken at 40 ° C. for 30 minutes in a closed seal.
- the resin was washed 4 times with DMF (1 mL) and further washed 4 times with DCM (1 mL) to obtain compound 3-1-b.
- a part of the obtained resin was cut out by TFE / DCM (1/1 (v / v)) and analyzed by LCMS to confirm the formation of compound 3-1-b *.
- Solution 1 and solution 2 were mixed with the mixing vial of the synthesizer and then added to the resin to carry out a condensation reaction between the amino group on the resin and the Fmoc amino acid.
- Synthesis was performed using a DMF solution (2% v / v) of diazabicycloundecene (DBU) as an Fmoc deprotecting solution. After washing the resin with DMF, the Fmoc deprotection was followed by a condensation reaction of Fmoc amino acids in one cycle, and this cycle was repeated to extend the peptide on the resin surface. After the peptide elongation was completed, the N-terminal Fmoc group of the resin was removed on a peptide synthesizer, and then the resin was washed with DMF.
- DBU diazabicycloundecene
- Example 3-2 Example in which peptide synthesis was carried out in the same manner as in Example 3-1 Compounds 3-2 to 3-9 were also synthesized in the same manner by the method shown in Example 3-1.
- the relationship between the formal names, structures, and abbreviations of the amino acid residues constituting the cyclic peptides described in Compounds 3-1 to 3-9 (structural formulas are shown in Table 13) is shown in Tables 3 to 5 and Tables 3 to 5 above. It can be grasped from Table 11 below.
- the LCMS analysis results are shown in Table 12.
- Comparative Example 1 N-methylation of Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-1) by Mitsunobu reaction with respect to the Tfa amide site
- a known method of performing the Mitsunobu reaction (Org. Lett. 2013, 15, 5012-5015) was attempted as a selective N-methylation method at the trifluoroacetamide site.
- Tfa-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 2-1-2) prepared in Example 2-1-2 in a reaction vessel with a filter.
- Dichloromethane (1 mL) was added to 473 mmol / g, 100 mg) and shaken at room temperature for 15 minutes to swell the resin. After removing the dichloromethane with a filter, the resin was washed 4 times with THF (0.7 mL).
- the obtained resin was cleaved with a TFE / DCM solution (1/1 (v / v)), and the cleaved solution was analyzed by LCMS.
- the target peptide Tfa-MeAib-MeVal-Asp-pyrro In addition to the formation of compound 2-2 *), an O-methylated product of the Tfa amide moiety (compound C1-1), from which hydrolysis proceeded, H-Aib-MeVal-Asp-pyrro (compound C1-2). ) was detected.
- the LC chart is shown in FIG.
- Comparative Example 2 After extension of Fmoc-Aib-OH following N-methylamino acid in the conventional solid phase synthesis method, switching from Fmoc protection to Ns protection, N-methylation on an N-terminal resin, and de-Ns As a comparative example with the present invention, which attempted to introduce MeAib , N- in the solid phase synthesis method was performed by the same method as described in the literature (Nature Protocols 2012, 7, 3, 432-444). After the extension of Fmoc-Aib-OH following the methyl amino acid, the introduction of MeAib was attempted by switching from Fmoc protection to Ns protection, N-methylation on the N-terminal resin, and de-Ns.
- Comparative Example 2-1 Fmoc-Aib-OH with a solid-phase extension reaction filter for Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2) Fmoc-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-2) (0.464 mmol / g, 100 mg) prepared in Example 1-2-2 was placed in a reaction vessel. ) was added with dichloromethane (1 mL) and shaken at room temperature for 30 minutes to swell the resin.
- the resin was washed 4 times with DMF (0.7 mL) and 4 times with dichloromethane (0.7 mL).
- the peptide was excised with a TFE / DCM solution (1/1 (v / v)), and the excised solution was analyzed by LCMS.
- the target peptide Fmoc-Aib-MeVal-Asp-pyrro (Compound C2-1 *) was used. ) was generated at 60.4%.
- the unreacted points of the obtained resin were capped with Z-Gly-OH (N- ⁇ -carbobenzoxglycine, CAS: 1138-80-3) purchased from a commercial supplier.
- Comparative Example 2-2 Fmoc-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound C2-1) in a reaction vessel with de-Fmoc and N-terminal Ns conversion filter.
- the resin was washed twice with DMF (1 mL). Subsequently, a 2% DBU / DMF solution (de-Fmoc solution: 0.7 mL) was added to the resin and shaken at room temperature for 10 minutes to de-Fmoc. After removing the de-Fmoc solution, the resin was washed 3 times with DMF (1 mL) followed by 4 times with THF (1 mL).
- the unreacted points of the obtained resin were capped with Z-Gly-OH.
- For capping add a mixture of 0.6M Z-Gly-OH / NMP solution (0.3 mL) and 10% DIC / DMF solution (0.36 mL) to the resin and shake at 40 ° C. for 2 hours. It was carried out by.
- Comparative Example 2-3 Reaction vessel with N-methylation filter by Mitsunobu reaction on Ns amide site of Ns-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound C2-2)
- Ns-Aib-MeVal-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound C2-2) (0.464 mmol / g, 100 mg) prepared in Comparative Example 2-2 was added to dichloromethane (100 mg). 1 mL) was added and shaken at room temperature for 20 minutes to swell the resin. After removing the dichloromethane with a filter, the resin was washed 4 times with THF (1 mL).
- Comparative Example 2-4 Ns-MeAib-MeVal-Asp (Ns-MeAib-MeVal-Asp) prepared in Comparative Example 2-3 was placed in a reaction vessel equipped with a de-Ns filter for Ns-MeAib-MeVal-Asp-pyrro resin (Compound C2-3). Add dichloromethane (0.5 mL) to O-Trt (2-Cl) -resin) -pyrro (Compound C2-3) (0.464 mmol / g, 50 mg) and shake at room temperature for 20 minutes to swell the resin. Was done. After removing the dichloromethane with a filter, the resin was washed 4 times with NMP (0.5 mL).
- NMP 0.5 mL
- Ns- prepared by the same operation as in Comparative Examples 2-1 to 2-3 with respect to Compound 1-2-3 (100 mg) prepared in Example 1-2-3.
- MeAib-MePhe-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound C2-5-1) (0.464 mmol / g, 50 mg) with dichloromethane (0.5 mL) added at room temperature 20
- the resin was shaken for a minute to swell the resin. After removing the dichloromethane with a filter, the resin was washed 4 times with NMP (0.5 mL).
- Fmoc-MePhe-Asp (O-Trt (2-Cl) -resin) -pyrro (Compound 1-2-3) (0.464 mmol /) prepared in Example 1-2-3 in a reaction vessel with a filter. g, 100 mg) was added, and the extension of Fmoc-MeAib was attempted by the same operation as in Reference Example 1. The elongation reaction was carried out at 40 ° C. for 15 hours.
- a peptide compound containing a dipeptide residue in which an N-substituted- ⁇ , ⁇ -disubstituted amino acid residue and an N-substituted amino acid residue are linked is efficiently produced. It was found that it can be manufactured in.
- the present invention is useful in the field of peptide synthesis.
Abstract
Description
〔1〕N-置換-α,αジ置換アミノ酸残基をN末端に有し、該N-置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含む、ペプチド化合物、その塩、またはそれらの溶媒和物を製造する方法であって、以下の工程を含む方法:
工程A:N-置換アミノ酸、その塩、もしくはそれらの溶媒和物、またはN-置換アミノ酸残基をN末端に有するペプチド化合物、その塩、もしくはそれらの溶媒和物と、電子求引性の保護基でアミノ基が保護されているN-非置換-α,αジ置換アミノ酸、その塩、その脱水体、またはそれらの溶媒和物とを、縮合試薬の存在下または非存在下で反応させて、電子求引性の保護基でアミノ基が保護されているN-非置換-α,αジ置換アミノ酸残基をN末端に有し、該N-非置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含む、ペプチド化合物、その塩、もしくはそれらの溶媒和物を得る工程、および
工程B:N末端の電子求引性の保護基でアミノ基が保護されているN-非置換-α,αジ置換アミノ酸残基のアミノ基に、塩基と置換基導入剤の存在下、置換基を導入して、電子求引性の保護基でアミノ基が保護されているN-置換-α,αジ置換アミノ酸残基をN末端に有し、該N-置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含む、ペプチド化合物、その塩、またはそれらの溶媒和物を得る工程。
〔2〕電子求引性の保護基が、該保護基が結合しているNH基のpKa(水中)が6~11となる保護基である、〔1〕に記載の方法。
〔3〕塩基の共役酸のpKa(アセトニトリル中)が18~31である、〔1〕または〔2〕に記載の方法。
〔4〕N-置換アミノ酸、またはN-置換アミノ酸残基をN末端に有するペプチド化合物が、固相合成用樹脂に担持されている、〔1〕~〔3〕のいずれかに記載の方法。
〔5〕N-置換アミノ酸、またはN-置換アミノ酸残基をN末端に有するペプチド化合物が、式(2):
[式中、
P2は、C1-C6アルキル、C2-C6アルケニル、またはC7-C14アラルキルであり、
R2は、C1-C6アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルキルスルホニルC1-C6アルキル、C2-C6アルキニル、1つまたは複数のハロゲンによって置換されていてもよいC1-C6アルコキシC1-C6アルキル、C3-C8シクロアルキル、C3-C8シクロアルキルC1-C6アルキル、C3-C8シクロアルコキシC1-C6アルキル、またはC7-C14アラルキルであり、
R3は、ヒドロキシ、O-PG2、任意のアミノ酸残基、または任意のペプチド残基であり、
PG2は、カルボキシル基の保護基である。]
で表される、〔1〕~〔4〕のいずれかに記載の方法。
〔6〕電子求引性の保護基でアミノ基が保護されているN-非置換-α,αジ置換アミノ酸が、式(3):
[式中、
PG1は、電子求引性の保護基であり、
R1およびQ1は、C1-C6アルキル、C2-C6アルケニル、C1-C6アルコキシC1-C6アルキル、C3-C8シクロアルキルC1-C6アルキル、または置換されていてもよいC7-C14アラルキルから独立して選択されるか、あるいは
R1およびQ1は、それらが結合している炭素原子と一緒になって3~8員脂環式環または4~7員飽和複素環を形成する。]
で表される、〔1〕~〔5〕のいずれかに記載の方法。
〔7〕工程Aで得られるペプチド化合物が、式(4):
[式中、
PG1、R1、およびQ1は式(3)のPG1、R1、およびQ1とそれぞれ同義であり、
P2、R2、およびR3は式(2)のP2、R2、およびR3とそれぞれ同義である]
で表される、〔1〕~〔6〕のいずれかに記載の方法。
〔8〕工程Bにおける置換基導入剤がP1X(式中、P1は、式(1)のP1と同義であり、Xは脱離基である)であり、工程Bで得られるペプチド化合物が、式(1):
[式中、
P1は、C1-C6アルキル、C2-C6アルケニル、またはC7-C14アラルキルであり、
PG1、R1、およびQ1は式(3)のPG1、R1、およびQ1とそれぞれ同義であり、
P2、R2、およびR3は式(2)のP2、R2、およびR3とそれぞれ同義である]
で表される、〔1〕~〔7〕のいずれかに記載の方法。
〔9〕以下の工程を含む、式(1):
[式中、
PG1は、アミノ基の保護基であり、
P1は、C1-C6アルキル、C2-C6アルケニル、またはC7-C14アラルキルであり、
R1およびQ1は、C1-C6アルキル、C2-C6アルケニル、C1-C6アルコキシC1-C6アルキル、C3-C8シクロアルキルC1-C6アルキル、または置換されていてもよいC7-C14アラルキルから独立して選択されるか、あるいは
R1およびQ1は、それらが結合している炭素原子と一緒になって3~8員脂環式環または4~7員飽和複素環を形成し、
P2は、C1-C6アルキル、C2-C6アルケニル、またはC7-C14アラルキルであり、
R2は、C1-C6アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルキルスルホニルC1-C6アルキル、C2-C6アルキニル、1つまたは複数のハロゲンによって置換されていてもよいC1-C6アルコキシC1-C6アルキル、C3-C8シクロアルキル、C3-C8シクロアルキルC1-C6アルキル、C3-C8シクロアルコキシC1-C6アルキル、またはC7-C14アラルキルであり、
R3は、ヒドロキシ、O-PG2、任意のアミノ酸残基、または任意のペプチド残基であり、
PG2は、カルボキシル基の保護基である。]
で表される2つのアミノ酸残基が連結された構造を含む、ペプチド化合物、その塩、またはそれらの溶媒和物を製造する方法:
工程A:式(2):
[式中、P2、R2、およびR3は、式(1)のP2、R2、およびR3とそれぞれ同義である]
で表される化合物、その塩、またはそれらの溶媒和物、および式(3):
[式中、PG1、Q1、およびR1は式(1)のPG1、Q1、およびR1とそれぞれ同義である]
で表される化合物、その塩、その脱水体、またはそれらの溶媒和物を縮合試薬と反応させるか、または該式(2)で表される化合物、その塩、またはそれらの溶媒和物と、該式(3)で表される化合物の脱水体、その塩、またはそれらの溶媒和物とを反応させて、式(4):
[式中、PG1、P2、Q1、およびR1~R3は、式(1)のPG1、P2、Q1、およびR1~R3とそれぞれ同義である]
で表される化合物、その塩、またはそれらの溶媒和物を得る工程、および
工程B:式(4)で表される化合物、その塩、またはそれらの溶媒和物をP1導入試薬と反応させて、式(1)で表されるペプチド化合物、その塩、またはそれらの溶媒和物を得る工程。
〔10〕R1およびQ1は、それらが結合している炭素原子と一緒になってシクロプロパン環、シクロブタン環、シクロペンタン環、シクロヘキサン環、もしくはテトラヒドロピラン環を形成するか、または
R1およびQ1は、メチル、エチル、2-メチルプロピル、アリル、メトキシメチル、シクロヘキシルメチル、置換されていてもよいベンジル、もしくは置換されていてもよいフェネチルから独立して選択される、
〔6〕~〔9〕のいずれかに記載の方法。
〔11〕式(3)および/または式(4)において、PG1が結合しているNH基のpKa(水中)が6~11である、〔6〕~〔10〕のいずれかに記載の方法。
〔12〕PG1が、C2-C6ハロアシルである、〔6〕~〔11〕のいずれかに記載の方法。
〔13〕C2-C6ハロアシルが、トリフルオロアセチル、トリクロロアセチル、ペンタフルオロプロピオニル、2,3,3,3-テトラフルオロ-2-(トリフルオロメチル)プロピオニル、または3,3,3-トリフルオロ-2-(トリフルオロメチル)プロピオニルである、〔12〕に記載の方法。
〔14〕脱水体が、下記式:
[式中、Q1およびR1は、式(1)のQ1およびR1とそれぞれ同義であり、R4は、C1-C5ハロアルキルである。]
で表される、〔1〕~〔13〕のいずれかに記載の方法。
〔15〕R1およびQ1が、それらが結合している炭素原子と一緒になって3~8員脂環式環を形成する、〔14〕に記載の方法。
〔16〕R4が、トリフルオロメチル、トリクロロメチル、ペンタフルオロエチル、1,2,2,2-テトラフルオロ-1-(トリフルオロメチル)エチル、または2,2,2-トリフルオロ-1-(トリフルオロメチル)エチルである、〔14〕または〔15〕に記載の方法。
〔17〕P1が、メチル、エチル、n-プロピル、i-プロピル、アリル、ベンジル、またはフェネチルである、〔8〕~〔16〕のいずれかに記載の方法。
〔18〕P2が、メチル、エチル、n-プロピル、i-プロピル、アリル、ベンジル、またはフェネチルである、〔5〕~〔17〕のいずれかに記載の方法。
〔19〕R3が、固相合成用樹脂に担持された任意のアミノ酸残基または任意のペプチド残基である、〔5〕~〔18〕のいずれかに記載の方法。
〔20〕固相合成用樹脂が、CTC樹脂、Wang樹脂、またはSASRIN樹脂である、〔4〕~〔8〕および〔19〕のいずれかに記載の方法。
〔21〕縮合試薬がDICもしくはEDCI・HClのいずれか、またはDICおよびOxymaの組み合わせである、〔1〕~〔20〕のいずれかに記載の方法。
〔22〕P1導入試薬が、P1X(式中、P1は、式(1)のP1と同義であり、Xは脱離基である)と塩基の組み合わせである、〔9〕~〔21〕のいずれかに記載の方法。
〔23〕塩基の共役酸のpKa(アセトニトリル中)が18~31である、〔22〕に記載の方法。
〔24〕塩基が、
[式中、
RB1とRB4は、それぞれ独立してC1-C4アルキルであるか、またはRB1とRB4は、RB1が結合している窒素原子およびRB4が結合している炭素原子と一緒になって5~8員環を形成し、
RB2とRB3は、それぞれ独立してC1-C4アルキルであるか、またはRB2とRB3は、RB2が結合している窒素原子およびRB3が結合している窒素原子ならびに該窒素原子が結合している炭素原子と一緒になって5~8員環を形成する]、
[式中、
RB6は、C1-C4アルキルであり、
RB5とRB7は、それぞれ独立してC1-C4アルキルであるか、それらが結合している各窒素原子および該各窒素原子が結合している炭素原子と一緒になって5~8員環を形成し、
RB8は、C1-C4アルキルであり、かつRB9はC1-C4アルキルまたはフェニルであるか、RB8とRB9は、それらが結合している各窒素原子および該各窒素原子が結合している炭素原子と一緒になって5~8員環を形成し、
ここでRB9がフェニルである場合、2つのB2は、該フェニル基の2つのベンゼン環が縮合してナフタレンを形成してもよい]、
[式中、
RB10は、C1-C4アルキルであるか、またはRB10およびRB11は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB11は、RB10およびRB11が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB11およびRB12は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB12は、RB11およびRB12が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB12およびRB13は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB13は、RB12およびRB13が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB13およびRB14は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB14は、RB13およびRB14が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB14およびRB15は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB15は、RB14およびRB15が5~8員環を形成する場合を除き、C1-C4アルキルであり、
RB16は水素、C1-C8アルキル、またはC6-C10アリールである。]、および
[式中、
RB17は、独立してC1-C4アルキルであるか、またはRB17およびRB18は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB18は、RB17およびRB18が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB18およびRB19は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB19は、RB18およびRB19が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB19およびRB20は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB20は、RB19およびRB20が5~8員環を形成する場合を除き、C1-C4アルキルであり、
RB21は、C1-C4アルキルであるか、またはRB21およびRB22は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB22は、RB21およびRB22が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB22およびRB23は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB23は、RB22およびRB23が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB23およびRB24は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB24は、RB23およびRB24が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB24およびRB25は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB25は、RB24およびRB25が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB25およびRB26は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB26は、RB25およびRB26が5~8員環を形成する場合を除き、C1-C4アルキルであり、
RB27は、C1-C4アルキル、またはC6-C10アリールである。]
からなる群から選ばれる、〔3〕~〔8〕および〔22〕~〔23〕のいずれかに記載の方法。
〔25〕塩基が、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(DBU)、1,5-ジアザビシクロ[4.3.0]ノン-5-エン(DBN)、1,8-ビス(テトラメチルグアニジノ)ナフタレン(TMGN)、7-メチル-1,5,7-トリアザビシクロ[4.4.0]デカ-5-エン(MTBD)、2-tert-ブチル-1,1,3,3-テトラメチルグアニジン(BTMG)、1,5,7-トリアザビシクロ[4.4.0]デカ-5-エン(TBD)、tert-ブチルイミノ-トリス(ジメチルアミノ)ホスホラン(P1-tBu)、tert-ブチルイミノ-トリ(ピロリジノ)ホスホラン(P1-t-Bu-トリス(テトラメチレン), BTPP)、2-tert-ブチルイミノ-2-ジエチルアミノ-1,3-ジメチルペルヒドロ-1,3,2-ジアザホスホリン(BEMP)、tert-オクチルイミノ-トリス(ジメチルアミノ)ホスホラン(P1-t-Oct)、イミノ-トリス(ジメチルアミノ)ホスホラン(HP1(dma))、1-tert-ブチル-2,2,4,4,4-ペンタキス(ジメチルアミノ)-2λ5,4λ5-カテナジ(ホスファゼン)(P2-t-Bu)、および1-エチル-2,2,4,4,4-ペンタキス(ジメチルアミノ)-2λ5,4λ5-カテナジ(ホスファゼン)(P2-Et)からなる群より選択される、〔3〕~〔8〕および〔22〕~〔24〕のいずれかに記載の方法。
〔26〕工程Bが、DMF、NMP、DMI、テトラヒドロフラン、2-メチルテトラヒドロフラン、およびアセトニトリルからなる群から選ばれる溶媒中で行われる、〔1〕~〔25〕のいずれかに記載の方法。
〔27〕〔1〕~〔26〕のいずれかに記載の方法を含む、N-置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含むペプチド化合物、その塩、またはそれらの溶媒和物を製造する方法。
〔28〕〔1〕~〔27〕のいずれかに記載の方法によって製造されたペプチド化合物、その塩、またはそれらの溶媒和物からN末端の保護基を脱保護する工程、
任意でペプチド鎖を伸長する工程、および
C末端側の基とN末端側の基を環化して環状部を形成する工程を含む、環状ペプチド化合物、その塩、またはそれらの溶媒和物の製造方法であって、
該環状ペプチド化合物が、8~15のアミノ酸残基を含み、少なくとも3つのN置換アミノ酸残基を含み、かつ少なくとも1つのN置換されていないアミノ酸残基を含み、環状部が少なくとも8つのアミノ酸残基を含む、前記方法。
AA:酢酸アンモニウム
CSA:(+)-10-カンファースルホン酸
DBU:1,8-ジアザビシクロ[5.4.0]-7-ウンデセン
DCC:N,N’-ジシクロヘキシルカルボジイミド
DCM:ジクロロメタン
DCE:1,2-ジクロロエタン
DEAD:アゾジカルボン酸ジエチル
DMA:ジメチルアセトアミド
DMF:N,N-ジメチルホルムアミド
DIAD:アゾジカルボン酸ジイソプロピル
DIC:N,N’-ジイソプロピルカルボジイミド
DIPEA:N,N-ジイソプロピルエチルアミン
DMAP:N,N-ジメチル-4-アミノピリジン
dtbbpy:4,4’-ジ-tert-ブチル-2,2’-ビピリジル
EDTA:エチレンジアミン四酢酸
FA:ギ酸
Fmoc:9-フルオレニルメチルオキシカルボニル基
NMP:N-メチル-2-ピロリドン
TBME:t-ブチルメチルエーテル
TES:トリエチルシラン
TFA:トリフルオロ酢酸
TFE:2,2,2-トリフルオロエタノール
THF:テトラヒドロフラン
THP:テトラヒドロピラニル基
TMSCl:クロロトリメチルシラン
HFIP:1,1,1,3,3,3-ヘキサフルオロイソプロピルアルコール
HOAt:1-ヒドロキシ-7-アザベンゾトリアゾール
HOBt:1-ヒドロキシベンゾトリアゾール
HOOBt:3,4-ジヒドロ-3-ヒドロキシ-4-オキソ-1,2,3-ベンゾトリアジン
IPAC:酢酸イソプロピル
oxyma:シアノ(ヒドロキシイミノ)酢酸エチル
PPTS:p-トルエンスルホン酸ピリジニウム
EDCI・HCl:1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩
TIPS:トリイソプロピルシラン
TfOH:トリフルオロメタンスルホン酸
HATU:O-(7-アザ-1H-ベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウムヘキサフルオロリン酸塩
DMSO:ジメチルスルホキシド
Fmoc-Cl:カルボノクロリド酸(9H-フルオレン-9-イル)メチル
Fmoc-OSu:炭酸N-スクシンイミジル9-フルオレニルメチル
Ns:o-ニトロベンゼンスルホニル基
Trt:トリフェニルメチル基、またはトリチル基
Tfa:トリフルオロアセチル基
MTBD:7-メチル-1,5,7-トリアザビシクロ[4.4.0]デカ-5-エン
TMGN:1,8-ビス(テトラメチルグアニジノ)ナフタレン
P1-tBu:tert-ブチルイミノ-トリス(ジメチルアミノ)ホスホラン
本明細書における「ハロゲン原子」としては、F、Cl、BrまたはIが例示される。
ある態様において、本発明は、後述の工程Aおよび工程Bを含む、N-置換-α,αジ置換アミノ酸残基をN末端に有し、該N-置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含む、ペプチド化合物、その塩、またはそれらの溶媒和物を製造する方法に関する。
工程Aは、N-置換アミノ酸、その塩、もしくはそれらの溶媒和物、またはN-置換アミノ酸残基をN末端に有するペプチド化合物、その塩、もしくはそれらの溶媒和物と、電子求引性の保護基でアミノ基が保護されているN-非置換-α,αジ置換アミノ酸、その塩、その脱水体、またはそれらの溶媒和物とを、縮合試薬の存在下または非存在下で反応させて、N-非置換-α,αジ置換アミノ酸残基をN末端に有し、該N-非置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含む、ペプチド化合物、その塩、もしくはそれらの溶媒和物を得る工程である。本明細書において、ペプチド化合物がジペプチドを含むとは、該ペプチド化合物を構成するアミノ酸配列中に該ジペプチドを含むことを意味する。
[式中、
P2は、C1-C6アルキル、C2-C6アルケニル、またはC7-C14アラルキルであり、
R2は、C1-C6アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルキルスルホニルC1-C6アルキル、C2-C6アルキニル、1つまたは複数のハロゲンによって置換されていてもよいC1-C6アルコキシC1-C6アルキル、C3-C8シクロアルキル、C3-C8シクロアルキルC1-C6アルキル、C3-C8シクロアルコキシC1-C6アルキル、またはC7-C14アラルキルであり、
R3は、ヒドロキシ、O-PG2、任意のアミノ酸残基、または任意のペプチド残基であり、
PG2は、カルボキシル基の保護基である。]
で表される化合物、またはその塩、もしくはそれらの溶媒和物が挙げられる。
[式中、
PG1は、電子求引性の保護基であり、
R1およびQ1は、C1-C6アルキル、C2-C6アルケニル、C1-C6アルコキシC1-C6アルキル、C3-C8シクロアルキルC1-C6アルキル、または置換されていてもよいC7-C14アラルキルから独立して選択されるか、あるいは
R1およびQ1は、それらが結合している炭素原子と一緒になって3~8員脂環式環または4~7員飽和複素環を形成する。]
で表される化合物、またはその塩、もしくはそれらの溶媒和物が挙げられる。
[式中、
PG1、R1、およびQ1は式(3)のPG1、R1、およびQ1とそれぞれ同義であり、
P2、R2、およびR3は式(2)のP2、R2、およびR3とそれぞれ同義である]
で表される化合物、またはその塩、もしくはそれらの溶媒和物が挙げられる。
工程Bは、工程Aによって得られたペプチド化合物のN末端にある電子求引性の保護基でアミノ基が保護されているN-非置換-α,αジ置換アミノ酸残基のアミノ基に、塩基と置換基導入剤の存在下、置換基を導入して、電子求引性の保護基でアミノ基が保護されているN-置換-α,αジ置換アミノ酸残基をN末端に有し、かつ該N-置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含む、ペプチド化合物、その塩、またはそれらの溶媒和物を得る工程である。
[式中、
P1は、C1-C6アルキル、C2-C6アルケニル、またはC7-C14アラルキルであり、
PG1、R1、およびQ1は式(3)のPG1、R1、およびQ1とそれぞれ同義であり、
P2、R2、およびR3は式(2)のP2、R2、およびR3とそれぞれ同義である]
で表される化合物、またはその塩、もしくはそれらの溶媒和物が挙げられる。
R1およびQ1は、それらが結合している炭素原子と一緒になって3~8員脂環式環または4~7員飽和複素環を形成する。
で表されるアミノ酸残基として具体的には、たとえば、MeAib、MecLeu、Me(Me)Phe、Me(Me)Abu、Me(Me)Leu、Me(Me)Ser(Me)、Me(Me)Phe、Me(Me)Cha、Me(Me)Val、EtAib、nPrAib、AllylAib、BnAibが挙げられる。
で表されるアミノ酸残基として具体的には、たとえば、MeAla、MeLeu、MeCha、MeVal、MeAla(cPent)、MeAla(cBu)、MeAla(cPr)、MeChg、MeGly(cPent)、MeGly(cBu)、MeGly(cPr)、MeAbu、MeNva、MeNle、MeNva(5-F2)、MeHle、MeIle、MeSer(nPr)、MeSer(cPr)、MeHnl、MeHnl(7-F2)、MePRA、MeSer(Me)、MeThr、MeSer(cBu)、MeSer(Tfe)、MeThr(Me)、MeHse(Me)、MeMet(O2)、EtVal、nPrValが挙げられる。
式(2)のP2、R2、およびR3は、式(1)のP2、R2、およびR3とそれぞれ同義である。
式中、PG1、Q1、およびR1は式(1)のPG1、Q1、およびR1とそれぞれ同義である。
具体的には、P1が結合しているNH基の水素を脱水素化するに足る、pKaを持つ塩基を用いることができる。
[式中、
RB1とRB4は、それぞれ独立してC1-C4アルキルであるか、またはRB1とRB4は、RB1が結合している窒素原子およびRB4が結合している炭素原子と一緒になって5~8員環を形成し、
RB2とRB3は、それぞれ独立してC1-C4アルキルであるか、またはRB2とRB3は、RB2が結合している窒素原子およびRB3が結合している窒素原子ならびに該窒素原子が結合している炭素原子と一緒になって5~8員環を形成する]
RB1とRB4が5~8員環を形成する場合、該5~8員環として好ましくは、ピロリジン環、ピペリジン環、アゼパン環などが挙げられる。
RB2とRB3が5~8員環を形成する場合、該5~8員環として好ましくは、1,4,5,6-テトラヒドロピリミジン環などが挙げられる。
[式中、
RB6は、水素またはC1-C4アルキルであり、
RB5とRB7は、それぞれ独立してC1-C4アルキルであるか、それらが結合している各窒素原子および該各窒素原子が結合している炭素原子と一緒になって5~8員環を形成し、
RB8は、C1-C4アルキルであり、かつRB9はC1-C4アルキルまたはフェニルであるか、RB8とRB9は、それらが結合している各窒素原子および該各窒素原子が結合している炭素原子と一緒になって5~8員環を形成し、
ここでRB9がフェニルである場合、2つのB2は、該フェニル基の2つのベンゼン環が縮合してナフタレンを形成してもよい。]
RB5とRB7が5~8員環を形成する場合、該5~8員環として好ましくは、イミダゾリジン環、ヘキサヒドロピリミジン環、1,3-ジアゼパン環などが挙げられる。
RB8とRB9が5~8員環を形成する場合、該5~8員環として好ましくは、1,4,5,6-テトラヒドロピリミジン環などが挙げられる。
[式中、
RB10は、C1-C4アルキルであるか、またはRB10およびRB11は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB11は、RB10およびRB11が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB11およびRB12は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB12は、RB11およびRB12が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB12およびRB13は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB13は、RB12およびRB13が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB13およびRB14は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB14は、RB13およびRB14が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB14およびRB15は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB15は、RB14およびRB15が5~8員環を形成する場合を除き、C1-C4アルキルであり、
RB16は水素、C1-C8アルキル、またはC6-C10アリールである。]
RB10とRB11、RB12とRB13、および/またはRB14とRB15が5~8員環を形成する場合、該5~8員環として好ましくは、ピロリジン環、ピペリジン環、アゼパン環などが挙げられる。
RB11とRB12、および/またはRB13とRB14が5~8員環を形成する場合、該5~8員環は、RB11、RB12、RB13、およびRB14が結合している各窒素原子および該各窒素原子が結合しているリン原子以外にヘテロ原子を含まない、5~8員の飽和環であることが好ましい。
[式中、
RB17は、独立してC1-C4アルキルであるか、またはRB17およびRB18は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB18は、RB17およびRB18が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB18およびRB19は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB19は、RB18およびRB19が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB19およびRB20は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB20は、RB19およびRB20が5~8員環を形成する場合を除き、C1-C4アルキルであり、
RB21は、C1-C4アルキルであるか、またはRB21およびRB22は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB22は、RB21およびRB22が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB22およびRB23は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB23は、RB22およびRB23が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB23およびRB24は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB24は、RB23およびRB24が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB24およびRB25は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB25は、RB24およびRB25が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB25およびRB26は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB26は、RB25およびRB26が5~8員環を形成する場合を除き、C1-C4アルキルであり、
RB27は、C1-C4アルキル、またはC6-C10アリールである。]
RB17とRB18、RB19とRB20、RB21とRB22、RB23とRB24、RB25とRB26が5~8員環を形成する場合、該5~8員環として好ましくは、ピロリジン環、ピペリジン環、アゼパン環などが挙げられる。
RB17とRB18が共にC1-C4アルキルである場合、RB19とRB20も共にC1-C4アルキルであることが好ましく、RB17とRB18が5~8員環を形成する、RB19とRB20も5~8員環を形成することが好ましい。
RB21とRB22が共にC1-C4アルキルである場合、RB23とRB24およびRB25とRB26も共にC1-C4アルキルであることが好ましく、RB21とRB22が5~8員環を形成する、RB23とRB24およびRB25とRB26も5~8員環を形成することが好ましい。
RB18とRB19、および/またはRB22とRB23が5~8員環を形成する場合、該5~8員環は、RB11、RB12、RB13、およびRB14が結合している各窒素原子および該各窒素原子が結合しているリン原子以外にヘテロ原子を含まない、5~8員の飽和環であることが好ましい。
環状ペプチド化合物は、8~15のアミノ酸残基、好ましくは10~13のアミノ酸残基を含み、少なくとも3個、好ましくは少なくとも3個~(環状ペプチド化合物を構成するアミノ酸残基数-1)個のN置換アミノ酸残基を含み、かつ少なくとも1個、好ましくは少なくとも3個のN置換されていないアミノ酸残基を含み、環状部が少なくとも8個のアミノ酸残基、好ましくは少なくとも10個のアミノ酸残基を含む。
実施例1-1:ペプチド合成機によるペプチド合成に用いるFmoc-アミノ酸
本明細書内に記載するペプチド合成において、ペプチド合成機による合成には表3~表5に記載するFmoc-アミノ酸を用いた。
表3、および表5記載のFmoc-アミノ酸は商業的供給業者から購入した。
表4記載のFmoc-アミノ酸は以下に示すスキームのとおり合成した。
LCMS(ESI)m/z=505.2(M+Na)+
保持時間:0.992分(分析条件SMDmethod_16)
LCMS(ESI)m/z=494(M+Na)+
保持時間:2.863分(分析条件SMDmethod_17)
LCMS(ESI)m/z=525.8(M+Na)+
保持時間:2.180分(分析条件SMDmethod_21)
1H―NMR(300MHz,DMSO-d6)δ12.70(s,1H),7.91(d,J=7.5Hz,2H),7.79-7.59(m,5H),7.45-7.28(m,5H),4.40-4.19(m,3H),3.96-3.88(m,1H),2.82-2.60(m,2H),2.11-1.77(m,2H)
LCMS(ESI)m/z=378(M+H)+
保持時間:1.01分(分析条件SQDFA05)
LCMS(ESI)m/z=380(M+H)+
保持時間:0.94分(分析条件SQDFA05)
LCMS(ESI)m/z=378(M+H)+
保持時間:1.01分(分析条件SQDFA05)
LCMS(ESI)m/z=380(M+H)+
保持時間:0.92分(分析条件SQDFA05)
LCMS(ESI)m/z=364(M+H)+
保持時間:0.97分(分析条件SQDFA05)
LCMS(ESI)m/z=366(M+H)+
保持時間:0.88分(分析条件SQDFA05)
LCMS(ESI)m/z=392(M+H)+
保持時間:1.05分(分析条件SQDFA05)
LCMS(ESI)m/z=394(M+H)+
保持時間:0.98分(分析条件SQDFA05)
実施例1-2-1:化合物1-2-1、(3S)-3-(9H-フルオレン-9-イルメトキシカルボニルアミノ)-4-オキソ-4-ピロリジン-1-イルブタン酸-2-クロロトリチルレジン(Fmoc-Asp(O-Trt(2-Cl)-resin)-pyrro)の合成
LCMS(ESI)m/z=465(M+H)+
保持時間:1.05分(分析条件SQD化合物AA05)
LCMS(ESI)m/z=409(M+H)+
保持時間:0.83分(分析条件SQD化合物AA05)
なお、同様に合成した担持量が異なる別ロットについてもペプチド合成や検討等に使用した。
1,8-ジアザビシクロ[5.4.0]-7-ウンデセン(DBU)のDMF溶液(2%v/v)を1カラムあたり0.7mLを加えて5~10分間静置し、脱Fmocを行った。続いて、レジンをDMF(1カラムあたり0.7mL、4回繰り返す)にて洗浄した。
脱Fmoc工程を経たレジンに対し、セットしたFmoc-アミノ酸溶液(1カラムあたり0.30mL)とDIC/DMF溶液(1カラムあたり0.36mL)とを混合した溶液を加え、40度にて静置した。反応完結後、レジンをDMF(1カラムあたり0.7mL、4回繰り返す)にて洗浄した。
なお、化合物1-2-2が得られたことを確認する目的で、得られたレジンの一部に対し、TFE/DCM溶液(1/1(v/v))にてペプチドの切り出しをおこなった。切り出した溶液をLCMSにて分析したところ、目的ペプチドFmoc-MeVal-Asp-pyrro(化合物1-2-2*)の生成が確認された。なお、本実施例において、化合物番号に*を付した場合には、反応の確認のためにレジンからペプチドを切り出して確認した化合物を示す。化合物1-2-2*は、化合物1-2-2に含まれるペプチドのカルボン酸と、レジンの2-クロロトリチル基との結合を切断したペプチド化合物を示す。
なお、同様に合成した担持量が異なる別ロットにおいても本実施例におけるペプチド合成に使用した。
本明細書内に記載するペプチド合成において用いる、Fmoc以外の保護基で保護されたアミノ酸、およびその脱水体は以下のとおり合成した。
LCMS (ESI) m/z = 197.93 (M-H)-
保持時間:0.40分(分析条件SQDFA05)
LCMS(ESI)m/z=214.0(M+H)+
保持時間:0.32分(分析条件SQDFA05)
LCMS(ESI)m/z=242.1(M+H)+
保持時間:0.66分(分析条件SQDFA05)
LCMS(ESI)m/z=228.2(M-H)-
保持時間:0.41分(分析条件SQDFA05)
LCMS(ESI)m/z=274.0(M-H)-
保持時間:0.68分(分析条件SQDFA05)
LCMS(ESI)m/z=186.1(M+H)+
保持時間:0.32分(分析条件SQDFA05)
LCMS(ESI)m/z=280.2(M-H)-
保持時間:0.75分(分析条件SQDFA05)
LCMS(ESI)m/z=226.1(M-H)-
保持時間:0.54分(分析条件SQDFA05)
LCMS(ESI)m/z=224.0(M-H)-
保持時間:0.49分(分析条件SQDFA05)
LCMS(ESI)m/z=208.1(M+H)+
保持時間:0.86分(分析条件SQDAA05)
実施例2-1-1:Fmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)の脱Fmoc後、DICを用いたTfa-Aib-OHの伸長
フィルター付きの反応容器に、実施例1-2-2にて調製したFmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)(0.473mmol/g,100mg)をいれ、ジクロロメタン(1mL)を加えて室温にて1時間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(0.7mL)で3回洗浄した。続いて、レジンに2%DBU/DMF溶液(脱Fmoc溶液:0.7mL)を加えて室温にて5分間振とうし、脱Fmocをおこなった。脱Fmoc溶液を除去した後、レジンをDMF(0.7mL)で4回洗浄した。
得られたレジンに対し、Tfa-Aib-OHの伸長反応を実施した。
フィルター付きの反応容器に、実施例1-2-2にて調製したFmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)(0.473mmol/g,100mg)をいれ、伸長試薬以外は実施例2-1-1と同様の方法にてTfa-Aibの伸長をおこなった。伸長試薬は、0.6M Tfa-Aib-OH/0.375M oxyma/NMP溶液(0.3mL)と10%DIC/DMF溶液(0.36mL)とを混合した溶液を使用した。実施例2-1-1と同様にレジンからペプチドを切り出し、LCMSにて分析した結果、目的ペプチドTfa-Aib-MeVal-Asp-pyrro(化合物2-1*)87.50%(UVarea)に加えて、未反応のH-MeVal-Asp-pyrroが2.2%(UVarea)、および2つの同定されないピーク(それぞれ8.85,1.43%(UVarea))が確認された。このレジン(化合物2-1のロット2、以下では化合物2-1-2と記載)は、比較例1にて使用した。
フィルター付きの反応容器に、実施例1-2-2にて調製したFmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)(0.473mmol/g,100mg)をいれ、伸長試薬以外は実施例2-1-1と同様の方法にてTfa-Aibの伸長をおこなった。伸長試薬は、0.6M Tfa-Aib-OH/NMP溶液(0.3mL)とEDCI・HCl(48mg、0.250mmol)/DMF溶液(0.36mL)とを混合した溶液を使用した。実施例2-1-1と同様にレジンからペプチドを切り出し、LCMSにて分析した結果、目的ペプチドTfa-Aib-MeVal-Asp-pyrro(化合物2-1*)93.1%(UVarea)に加えて、未反応のH-MeVal-Asp-pyrroが3.0%(UVarea)、同定されない3.9%(UVarea)のピークが確認された。このレジン(化合物2-1のロット3、以下では化合物2-1-3と記載)は、実施例2-2および実施例2-3にて使用した。
フィルター付きの反応容器に、実施例2-1にて調製したTfa-Aib-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物2-1-3)(25mg)にジクロロメタン(1mL)を加えて室温にて15分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをNMP(0.7mL)で4回洗浄した。
フィルター付きの反応容器に、実施例2-1にて調製したTfa-Aib-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物2-1-1または2-1-3)(25mg)にジクロロメタン(1mL)を加えて室温にて15分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(0.7mL)で4回洗浄した。
切り出して反応確認をした結果は、表7に示す通りだった。P1-tBuを塩基として使用した場合には、過剰にメチル化された生成物(化合物2-3*)の生成も僅かに認められた。
窒素雰囲気下、水素化ホウ素ナトリウム(0.5g)にトリグリム(トリエチレングリコールジメチルエーテル)(6.6mL)を加え、室温にて10分間撹拌し、2.0M水素化ホウ素ナトリウム/トリグリム溶液を得た。
以下の一般式に従い、種々のTfa-アミノ酸を用いて化合物2-5-1-1~化合物2-5-7-1および化合物2-5-1-2~化合物2-5-7-2を合成した。
実施例2-5-1-1.Fmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)の脱Fmoc後、Tfa-(Me)Abu-OHの伸長
フィルター付きの反応容器に、実施例1-2-2と同様の手法により調製したFmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)(0.552 mmol/g, 100 mg)をいれ、ジクロロメタン(1 mL)を加えて室温にて45分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(0.7 mL)で3回洗浄した。続いて、レジンに2% DBU/DMF溶液(脱Fmoc溶液:0.7 mL)を加えて室温にて5分間振とうし、脱Fmocをおこなった。脱Fmoc溶液を除去した後、レジンをDMF(0.7 mL)で4回洗浄した。
LCMS(ESI)m/z=495.4(M+H)+
保持時間:0.56分(分析条件SQDFA05)
フィルター付きの反応容器に、実施例2-5-1-1にて調製したTfa-(Me)Abu-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物2-5-1-1)(45 mg)をいれ、ジクロロメタン(1 mL)を加えて室温にて45分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(0.7 mL)で4回洗浄した。
実施例2-5-2-1.Fmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)の脱Fmoc後、Tfa-(Me)Leu-OHの伸長
実施例2-5-1-1に示した手法により、化合物1-2-2(0.552mmol/g,100mg),0.6M Tfa-(Me)Leu-OH(化合物1-3-3-b)/DMF溶液(0.3mL)を用いて化合物2-5-2-1(Tfa-(Me)Leu-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-(Me)Leu-MeVal-Asp-pyrro(化合物2-5-2-1*)(84.5% UVarea)に加えてMeVal-Asp-pyrroの過剰伸長体(化合物2-5-2-1a*)6.8%(UVarea)を主な不純物として確認した(脱Fmoc後の変換効率は>99%)。
実施例2-5-1-2に示した手法により、化合物2-5-2-1(45mg)を用いて化合物2-5-2-2(Tfa-Me(Me)Leu-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-Me(Me)Leu-MeVal-Asp-pyrro(化合物2-5-2-2*)(68.5% UVarea)に加えてTfaアミド部位のO-メチル化体(化合物2-5-2-2a*)17.0%(UVarea)、出発原料である化合物2-5-2-1*(14.5% UVarea)を確認した。
実施例2-5-3-1.Fmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)の脱Fmoc後、Tfa-(Me)Ser(Me)-OHの伸長
実施例2-5-1-1に示した手法により、化合物1-2-2(0.552mmol/g,100mg),0.6M Tfa-(Me)Ser(Me)-OH(化合物1-3-4-b)/DMF溶液(0.3mL)を用いて化合物2-5-3-1(Tfa-(Me)Ser(Me)-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-(Me)Ser(Me)-MeVal-Asp-pyrro(化合物2-5-3-1*)の生成を確認した。他のペプチド成分は検出されなかった。
実施例2-5-1-2に示した手法により、化合物2-5-3-1(45mg)を用いて化合物2-5-3-2(Tfa-Me(Me)Ser(Me)-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-Me(Me)Ser(Me)-MeVal-Asp-pyrro(化合物2-5-3-2*)の生成を確認した(94.0% UVarea)。
実施例2-5-4-1.Fmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)の脱Fmoc後、Tfa-(Me)Phe-OHの伸長
実施例2-5-1-1と同様の手法により、反応時間を72時間とすることで化合物1-2-2(0.552mmol/g,100mg),0.6M Tfa-(Me)Phe-OH(化合物1-3-5-b)/DMF溶液(0.3mL)を用いて化合物2-5-4-1(Tfa-(Me)Phe-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-(Me)Phe-MeVal-Asp-pyrro(化合物2-5-4-1*)の生成を確認した(81.4% UVarea)。脱Fmoc後の変換効率は>99%であり、主な不純物としてMeVal-Asp-pyrroの過剰伸長体(化合物2-5-4-1a*)4.1%(UVarea)の他、構造不明のピークが検出された。
実施例2-5-1-2に示した手法により、化合物2-5-4-1(45mg)を用いて化合物2-5-4-2(Tfa-Me(Me)Phe-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。この時2回目のN-メチル化も1時間で実施した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-Me(Me)Phe-MeVal-Asp-pyrro(化合物2-5-4-2*)(79.7% UVarea)の生成を確認した他、MeVal-Asp-pyrroの過剰伸長体(化合物2-5-4-2a*)とTfaアミド部位のO-メチル化体(化合物2-5-4-2b*)(あわせて11.8% UVarea)を不純物として検出した(出発原料の変換効率は100%)。
実施例2-5-5-1.Fmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)の脱Fmoc後、Tfa-(Me)Cha-OHの伸長
実施例2-5-1-1と同様の手法により、反応時間を72時間とすることで化合物1-2-2(0.552mmol/g,100mg),0.6M Tfa-(Me)Cha-OH(化合物1-3-6-c)/DMF溶液(0.3mL)を用いて化合物2-5-5-1(Tfa-(Me)Cha-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-(Me)Cha-MeVal-Asp-pyrro(化合物2-5-5-1*)の生成を確認した(81.1% UVarea)。主な不純物としてMeVal-Asp-pyrroの過剰伸長体(化合物2-5-5-1a*)を含む複数の構造不明のピークが検出された(脱Fmoc後の変換効率は100%)。
実施例2-5-1-2に示した手法により、化合物2-5-5-1(45mg)を用いて化合物2-5-5-2(Tfa-Me(Me)Cha-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。この時2回目のN-メチル化も1時間で実施した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-Me(Me)Cha-MeVal-Asp-pyrro(化合物2-5-5-2*)(74.4% UVarea)に加えてTfaアミド部位のO-メチル化体(化合物2-5-5-2a*)12.1%(UVarea)、出発原料である化合物2-5-5-1*(13.5% UVarea)を確認した。
実施例2-5-6-1.Fmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)の脱Fmoc後、Tfa-(Me)Val-OHの伸長
実施例2-5-1-1と同様の手法により、反応時間を72時間とすることで化合物1-2-2(0.552mmol/g,100mg),0.6M Tfa-(Me)Val-OH(化合物1-3-7-b)/DMF溶液(0.3mL)を用いて化合物2-5-6-1(Tfa-(Me)Val-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-(Me)Val-MeVal-Asp-pyrro(化合物2-5-6-1*)の生成を確認した(66.6% UVarea)。不純物としてMeVal-Asp-pyrroの過剰伸長体(化合物2-5-6-1a*)を含む複数の構造不明のピークが検出された(脱Fmoc後の変換効率は98%)。
実施例2-5-1-2に示した手法に基づき、反応温度を60度とし、化合物2-5-6-1(40mg)を用いて化合物2-5-6-2(Tfa-Me(Me)Val-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。この時2回目のN-メチル化も1時間で実施した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-Me(Me)Val-MeVal-Asp-pyrro(化合物2-5-6-2*)(21.2% UVarea)に加えてTfaアミド部位のO-メチル化体(化合物2-5-6-2a*)17.1%(UVarea)、出発原料である化合物2-5-6-1*(39.6% UVarea)を確認した。また、複数の構造不明ピークを検出した。
実施例2-5-7-1.Fmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)の脱Fmoc後、Tfa-cLeu-OHの伸長
実施例2-5-1-1に示した手法により、化合物1-2-2(0.552mmol/g,100mg),0.6M Tfa-cLeu-OH(化合物1-3-8-b)/DMF溶液(0.3mL)を用いて化合物2-5-7-1(Tfa-cLeu-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-cLeu-MeVal-Asp-pyrro(化合物2-5-7-1*)の生成を確認した。他のペプチド成分は検出されなかった。
実施例2-5-1-2に示した手法により、化合物2-5-7-1(45mg)を用いて化合物2-5-7-2(Tfa-MecLeu-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-MecLeu-MeVal-Asp-pyrro(化合物2-5-7-2*)(92.1% UVarea)の生成を確認した他、Tfaアミド部位のO-メチル化体(化合物2-5-7-2a*)7.9%(UVarea)を不純物として検出した(出発原料の変換効率は100%)。
以下の一般式に従い、種々のTfa-アミノ酸を用いて化合物2-6-1~化合物2-6-4を合成した。
フィルター付きの反応容器に、実施例2-1-1と同様の手法により調製したTfa-Aib-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物2-1)(0.552 mmol/g, 50 mg)をいれ、ジクロロメタン(1 mL)を加えて室温にて45分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(0.7 mL)で4回洗浄した。
実施例2-6-1に示した手法により、化合物2-1(0.552mmol/g,50mg),n-プロピルヨージド(54 μL×5)を用いて化合物2-6-2(Tfa-nPrAib-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-nPrAib-MeVal-Asp-pyrro(化合物2-6-2*)(10.0% UVarea)に加えてTfaアミド部位のO-n-プロピル化体(化合物2-6-2a*)6.3% (UVarea)、出発原料化合物2-1*(82.7% UVarea)等を確認した。
実施例2-6-1に示した手法により、化合物2-1(0.552mmol/g,50mg),アリルブロミド(48 μL×5)を用いて化合物2-6-3(Tfa-AllylAib-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-AllylAib-MeVal-Asp-pyrro(化合物2-6-3*)(20.3% UVarea)に加えてTfaアミド部位のO-アリル化体(化合物2-6-3a*)6.9%(UVarea)、出発原料化合物2-1*(72.8% UVarea)を確認した。
実施例2-6-1に示した手法により、化合物2-1(0.552mmol/g,50mg),ベンジルブロミド(66 μL×5)を用いて化合物2-6-4(Tfa-BnAib-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-BnAib-MeVal-Asp-pyrro(化合物2-6-4*)(6.2% UVarea)に加えてTfaアミド部位のO-ベンジル化体(化合物2-6-4a*)7.7%(UVarea)、出発原料化合物2-1*(79.5% UVarea)を確認した。
以下の一般式に従い、化合物2-7-1~化合物2-7-2、化合物2-7-3-1~化合物2-7-3-4および化合物2-7-4-1~化合物2-7-4-4を合成した。
フィルター付きの反応容器に、実施例1-2-1と同様の手法により調製したFmoc-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-1)(0.552 mmol/g, 100 mg)をいれ、ジクロロメタン(1 mL)を加えて室温にて45分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(0.7 mL)で3回洗浄した。続いて、レジンに2% DBU/DMF溶液(脱Fmoc溶液:0.7 mL)を加えて室温にて5分間振とうし、脱Fmocをおこなった。脱Fmoc溶液を除去した後、レジンをDMF(0.7 mL)で4回洗浄した。
伸長反応はFmoc-Val-OH(0.6 mol/L)、1-ヒドロキシ-7-アザベンゾトリアゾール(HOAt, 0.375 mol/L)のNMP溶液(0.3mL)と10% DIC/DMF溶液(0.36 mL)とを混合した溶液をレジンに加え、40度にて3時間振とうすることで実施した。
フィルター付きの反応容器に、実施例2-7-1にて調製したFmoc-Val-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物2-7-1)(0.552 mmol/g, 1カラムにつき100 mg)をいれ、ジクロロメタン(1 mL)を加えて室温にて45分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(0.7 mL)で2回洗浄した。続いて、レジンに2% DBU/DMF溶液(脱Fmoc溶液:0.7 mL)を加えて室温にて10分間振とうし、脱Fmocをおこなった。脱Fmoc溶液を除去した後、レジンをDMF(0.7 mL)、1-ヒドロキシ-7-アザベンゾトリアゾール(HOAt, 0.157 mol/L)とDIPEA(0.157 mol/L)のDMF溶液(0.7mL)、DMF(0.7mL)で順に洗浄し、続いてTHF(0.7 mL)で3回洗浄した。
フィルター付きの反応容器に、実施例2-7-2にて調製したNs-Val-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物2-7-2)(0.552 mmol/g, 100 mg)をいれ、ジクロロメタン(1 mL)を加えて室温にて45分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをTHF(1 mL)で2回洗浄した。
フィルター付きの反応容器に、実施例2-7-3-1にて調製したNs-Val-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物2-7-3-1)(0.552 mmol/g, 100 mg)をいれ、ジクロロメタン(1 mL)を加えて室温にて45分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをNMP(0.7 mL)で2回洗浄した。
フィルター付きの反応容器に、実施例2-7-3-2にて調製したH-EtVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物2-7-3-2)(0.552 mmol/g, 100 mg)をいれ、ジクロロメタン(1 mL)を加えて室温にて45分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(0.7 mL)で3回洗浄した。Tfa-cLeu-OHの伸長反応は、レジンに2-(トリフルオロメチル)-3-オキサ-1-アザスピロ[4.4]ノナ-1-エン-4-オン(化合物1-3-9)(0.582g,2.81mmol)をニートで加え、60度で48時間振盪することで実施した。反応の進行を確認するため、24時間後に少量の得られたレジンをサンプリングし、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドの生成を確認した。伸長反応後の液相をフィルターで除去した後、レジンをDMF(1 mL)で4回、ジクロロメタン(1 mL)で4回洗浄し、化合物2-7-3-3(Tfa-cLeu-EtVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を得た。
フィルター付きの反応容器に、実施例2-7-3-3にて調製したTfa-cLeu-EtVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物2-7-3-3)(66 mg)をいれ、ジクロロメタン(1 mL)を加えて室温にて1時間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(0.7 mL)で4回洗浄した。
実施例2-7-3-1に示した手法により、化合物2-7-2(0.552mmol/g,100mg)および1-プロパノール(41 μL、0.552 mmol)を用いて化合物2-7-4-1(Ns-nPrVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドNs-nPrVal-Asp-pyrro(化合物2-7-4-1*)94.7%(UVarea)の生成を確認した(化合物2-7-2からの変換率は100%)。
実施例2-7-3-2に示した手法により、化合物2-7-4-1(0.552mmol/g,100mg)を用いて化合物2-7-4-2(H-nPrVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドH-nPrVal-Asp-pyrro(化合物2-7-4-2*)81.1%(UVarea)に加えてに加え、Ns保護のニトロ基に対して1-ドデカンチオールがイプソ置換したと推定される不純物(化合物2-7-4-2a*)(15.1% UVarea)を検出した。
実施例2-7-3-3に示した手法により、化合物2-7-4-2(0.552mmol/g,100mg)を用いて化合物2-7-4-3(Tfa-cLeu-nPrVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-cLeu-nPrVal-Asp-pyrro(化合物2-7-4-3*)(53.1% UVarea)の生成を確認した他、nPrVal-Asp-pyrroの過剰伸長体(化合物2-7-4-3a*)(31.0% UVarea)、Ns保護のニトロ基に対して1-ドデカンチオールがイプソ置換したと推定される不純物(化合物2-7-4-2a*)(13.3% UVarea)等を検出した。また、Tfa-cLeu-OHがレジンに担持されたようなピークも検出した。
実施例2-7-3-4に示した手法により、化合物2-7-4-3(0.552mmol/g,60mg)を用いて化合物2-7-4-4(Tfa-MecLeu-nPrVal-Asp(O-Trt(2-Cl)-resin)-pyrro)を同様に合成した。得られたレジンを一部取り出し、TFE/DCM/DIPEA溶液(1:1:0.015)にてペプチドの切り出しを行い、切り出した溶液をLCMSにて分析し、目的ペプチドTfa-MecLeu-nPrVal-Asp-pyrro(化合物2-7-4-4*)(46.1% UVarea)に加えてnPrVal-Asp-pyrroが過剰伸長した後にMe化された化合物(化合物2-7-4-4a*)(38.3% UVarea)、Ns保護のニトロ基に対して1-ドデカンチオールがイプソ置換したと推定される不純物(化合物2-7-4-2a*)(12.6% UVarea)等を確認した。また、Tfa-cLeu-OHがレジンに担持され、Me化されたようなピークも検出した。
WO2013/100132もしくはWO2018/225864に記載のFmoc法によるペプチド合成法に従い、下記の基本ルートでペプチドの伸長を行った。すなわち、
1)Asp側鎖のカルボン酸もしくはペプチド主鎖カルボン酸を2-クロロトリチルレジンに担持させたものの、アミノ酸のN末からのFmoc法によるペプチド伸長反応、
2)2-クロロトリチルレジンからのペプチドの切り出し過程、
3)切り出し過程によって2-クロロトリチルレジンから外れて生じたAsp側鎖のカルボン酸もしくはペプチド主鎖カルボン酸と、ペプチド鎖N末端(三角ユニット)のアミノ基との縮合によるアミド環化、
4)必要に応じたペプチド鎖に含む側鎖官能基の保護基の脱保護、
5)preparativeHPLCによる化合物の精製、の5段階の工程である。本実施例において、特に記述がない限り、この基本ルートをもとにペプチド化合物の合成をおこなった。
LCMSの分析結果は表12に記載した。
実施例3-1にて示した手法により、化合物3-2~化合物3-9についても同様に合成した。なお、化合物3-1~化合物3-9(構造式は表13に記載)に記載の環状ペプチドを構成する各アミノ酸残基の正式名称、構造、および略称の関係は上述の表3~5および以下の表11から把握される。
LCMSの分析結果は表12に記載した。
本発明との比較例として、トリフルオロアセタミド部位での選択的なN-メチル化法として、光延反応を行う既知の手法(Org. Lett. 2013, 15, 5012-5015)を試みた。
LCMS (ESI) m/z = 385.26 (M+H)+
保持時間:0.35分(分析条件SQDFA05)
本発明との比較例として、文献記載と同様の方法(Nature Protocols 2012, 7, 3, 432-444)にて、固相合成法でのN-メチルアミノ酸に続くFmoc-Aib-OH伸長後に、Fmoc保護からNs保護への掛け替え、N末端のレジン上でのN-メチル化、および脱Nsを行うことで、MeAibの導入を試みた。
フィルター付きの反応容器に、実施例1-2-2にて調製したFmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)(0.464mmol/g,100mg)にジクロロメタン(1mL)を加えて室温にて30分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(1mL)で2回洗浄した。続いて、レジンに2%DBU/DMF溶液(脱Fmoc溶液:0.7mL)を加えて室温にて10分間振とうし、脱Fmocをおこなった。脱Fmoc溶液を除去した後、レジンをDMF(0.7mL)で4回洗浄した。
伸長反応は0.6M Fmoc-Aib-OH/0.375M oxyma/NMP溶液(0.3mL)と10%DIC/DMF溶液(0.36mL)とを混合した溶液をレジンに加え、50度にて15時間振とうすることで実施した。
本伸長反応をさらに2回繰り返した。(2回目伸長条件:50度24時間、3回目伸長条件:50度20時間)
キャッピングは、0.6M Fmoc-Gly-OH/0.375M HOAt/NMP溶液(0.3mL)と10%DIC/DMF溶液(0.36mL)とを混合した溶液をレジンに加え、40度にて45分間振とうすることで実施した。
伸長反応の液相をフィルターで除去した後、レジンをDMF(0.7mL)で4回、ジクロロメタン(0.7mL)で4回洗浄した。
フィルター付きの反応容器に、比較例2-1にて調製したFmoc-Aib-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物C2-1)(0.464mmol/g,100mg)を入れ、ジクロロメタン(1mL)を加えて室温にて30分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをDMF(1mL)で2回洗浄した。続いて、レジンに2%DBU/DMF溶液(脱Fmoc溶液:0.7mL)を加えて室温にて10分間振とうし、脱Fmocをおこなった。脱Fmoc溶液を除去した後、レジンをDMF(1mL)で3回、続いてTHF(1mL)で4回洗浄した。
キャッピングは、0.6M Z-Gly-OH/NMP溶液(0.3mL)と10%DIC/DMF溶液(0.36mL)とを混合した溶液をレジンに加え、40度にて2時間振とうすることで実施した。
フィルター付きの反応容器に、比較例2-2にて調製したNs-Aib-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物C2-2)(0.464mmol/g,100mg)にジクロロメタン(1mL)を加えて室温にて20分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをTHF(1mL)で4回洗浄した。
LCMS (ESI) m/z = 582.47 (M-H)-
保持時間:0.63分(分析条件SQDFA05)
フィルター付きの反応容器に、比較例2-3にて調製したNs-MeAib-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物C2-3)(0.464mmol/g,50mg)にジクロロメタン(0.5mL)を加えて室温にて20分間振とうし、レジンの膨潤をおこなった。ジクロロメタンをフィルターで除去した後、レジンをNMP(0.5mL)で4回洗浄した。
参照例1:Fmoc-MeVal-Asp(O-Trt(2-Cl)-resin)-pyrro(化合物1-2-2)に対する、Fmoc-MeAib-OHの固相での伸長反応
LCMS (ESI) m/z = 669.43 (M+H)+
保持時間:0.88分(分析条件SQDFA05)
Claims (28)
- N-置換-α,αジ置換アミノ酸残基をN末端に有し、該N-置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含む、ペプチド化合物、その塩、またはそれらの溶媒和物を製造する方法であって、以下の工程を含む方法:
工程A:N-置換アミノ酸、その塩、もしくはそれらの溶媒和物、またはN-置換アミノ酸残基をN末端に有するペプチド化合物、その塩、もしくはそれらの溶媒和物と、電子求引性の保護基でアミノ基が保護されているN-非置換-α,αジ置換アミノ酸、その塩、その脱水体、またはそれらの溶媒和物とを、縮合試薬の存在下または非存在下で反応させて、電子求引性の保護基でアミノ基が保護されているN-非置換-α,αジ置換アミノ酸残基をN末端に有し、該N-非置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含む、ペプチド化合物、その塩、もしくはそれらの溶媒和物を得る工程、および
工程B:N末端の電子求引性の保護基でアミノ基が保護されているN-非置換-α,αジ置換アミノ酸残基のアミノ基に、塩基と置換基導入剤の存在下、置換基を導入して、電子求引性の保護基でアミノ基が保護されているN-置換-α,αジ置換アミノ酸残基をN末端に有し、該N-置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含む、ペプチド化合物、その塩、またはそれらの溶媒和物を得る工程。 - 電子求引性の保護基が、該保護基が結合しているNH基のpKa(水中)が6~11となる保護基である、請求項1に記載の方法。
- 塩基の共役酸のpKa(アセトニトリル中)が18~31である、請求項1または2に記載の方法。
- N-置換アミノ酸、またはN-置換アミノ酸残基をN末端に有するペプチド化合物が、固相合成用樹脂に担持されている、請求項1~3のいずれか一項に記載の方法。
- N-置換アミノ酸、またはN-置換アミノ酸残基をN末端に有するペプチド化合物が、式(2):
[式中、
P2は、C1-C6アルキル、C2-C6アルケニル、またはC7-C14アラルキルであり、
R2は、C1-C6アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルキルスルホニルC1-C6アルキル、C2-C6アルキニル、1つまたは複数のハロゲンによって置換されていてもよいC1-C6アルコキシC1-C6アルキル、C3-C8シクロアルキル、C3-C8シクロアルキルC1-C6アルキル、C3-C8シクロアルコキシC1-C6アルキル、またはC7-C14アラルキルであり、
R3は、ヒドロキシ、O-PG2、任意のアミノ酸残基、または任意のペプチド残基であり、
PG2は、カルボキシル基の保護基である。]
で表される、請求項1~4のいずれか一項に記載の方法。 - 以下の工程を含む、式(1):
[式中、
PG1は、アミノ基の保護基であり、
P1は、C1-C6アルキル、C2-C6アルケニル、またはC7-C14アラルキルであり、
R1およびQ1は、C1-C6アルキル、C2-C6アルケニル、C1-C6アルコキシC1-C6アルキル、C3-C8シクロアルキルC1-C6アルキル、または置換されていてもよいC7-C14アラルキルから独立して選択されるか、あるいは
R1およびQ1は、それらが結合している炭素原子と一緒になって3~8員脂環式環または4~7員飽和複素環を形成し、
P2は、C1-C6アルキル、C2-C6アルケニル、またはC7-C14アラルキルであり、
R2は、C1-C6アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルキルスルホニルC1-C6アルキル、C2-C6アルキニル、1つまたは複数のハロゲンによって置換されていてもよいC1-C6アルコキシC1-C6アルキル、C3-C8シクロアルキル、C3-C8シクロアルキルC1-C6アルキル、C3-C8シクロアルコキシC1-C6アルキル、またはC7-C14アラルキルであり、
R3は、ヒドロキシ、O-PG2、任意のアミノ酸残基、または任意のペプチド残基であり、
PG2は、カルボキシル基の保護基である。]
で表される2つのアミノ酸残基が連結された構造を含む、ペプチド化合物、その塩、またはそれらの溶媒和物を製造する方法:
工程A:式(2):
[式中、P2、R2、およびR3は、式(1)のP2、R2、およびR3とそれぞれ同義である]
で表される化合物、その塩、またはそれらの溶媒和物、および式(3):
[式中、PG1、Q1、およびR1は式(1)のPG1、Q1、およびR1とそれぞれ同義である]
で表される化合物、その塩、その脱水体、またはそれらの溶媒和物を縮合試薬と反応させるか、または該式(2)で表される化合物、その塩、またはそれらの溶媒和物と、該式(3)で表される化合物の脱水体、その塩、またはそれらの溶媒和物とを反応させて、式(4):
[式中、PG1、P2、Q1、およびR1~R3は、式(1)のPG1、P2、Q1、およびR1~R3とそれぞれ同義である]
で表される化合物、その塩、またはそれらの溶媒和物を得る工程、および
工程B:式(4)で表される化合物、その塩、またはそれらの溶媒和物をP1導入試薬と反応させて、式(1)で表されるペプチド化合物、その塩、またはそれらの溶媒和物を得る工程。 - R1およびQ1は、それらが結合している炭素原子と一緒になってシクロプロパン環、シクロブタン環、シクロペンタン環、シクロヘキサン環、もしくはテトラヒドロピラン環を形成するか、または
R1およびQ1は、メチル、エチル、2-メチルプロピル、アリル、メトキシメチル、シクロヘキシルメチル、置換されていてもよいベンジル、もしくは置換されていてもよいフェネチルから独立して選択される、
請求項6~9のいずれか一項に記載の方法。 - 式(3)および/または式(4)において、PG1が結合しているNH基のpKa(水中)が6~11である、請求項6~10のいずれかに記載の方法。
- PG1が、C2-C6ハロアシルである、請求項6~11のいずれか一項に記載の方法。
- C2-C6ハロアシルが、トリフルオロアセチル、トリクロロアセチル、ペンタフルオロプロピオニル、2,3,3,3-テトラフルオロ-2-(トリフルオロメチル)プロピオニル、または3,3,3-トリフルオロ-2-(トリフルオロメチル)プロピオニルである、請求項12に記載の方法。
- R1およびQ1が、それらが結合している炭素原子と一緒になって3~8員脂環式環を形成する、請求項14に記載の方法。
- R4が、トリフルオロメチル、トリクロロメチル、ペンタフルオロエチル、1,2,2,2-テトラフルオロ-1-(トリフルオロメチル)エチル、または2,2,2-トリフルオロ-1-(トリフルオロメチル)エチルである、請求項14または15に記載の方法。
- P1が、メチル、エチル、n-プロピル、i-プロピル、アリル、ベンジル、またはフェネチルである、請求項8~16のいずれかに記載の方法。
- P2が、メチル、エチル、n-プロピル、i-プロピル、アリル、ベンジル、またはフェネチルである、請求項5~17のいずれかに記載の方法。
- R3が、固相合成用樹脂に担持された任意のアミノ酸残基または任意のペプチド残基である、請求項5~18のいずれか一項に記載の方法。
- 固相合成用樹脂が、CTC樹脂、Wang樹脂、またはSASRIN樹脂である、請求項4~8および19のいずれか一項に記載の方法。
- 縮合試薬がDICもしくはEDCI・HClのいずれか、またはDICおよびOxymaの組み合わせである、請求項1~20のいずれか一項に記載の方法。
- P1導入試薬が、P1X(式中、P1は、式(1)のP1と同義であり、Xは脱離基である)と塩基の組み合わせである、請求項9~21のいずれか一項に記載の方法。
- 塩基の共役酸のpKa(アセトニトリル中)が18~31である、請求項22に記載の方法。
- 塩基が、
[式中、
RB1とRB4は、それぞれ独立してC1-C4アルキルであるか、またはRB1とRB4は、RB1が結合している窒素原子およびRB4が結合している炭素原子と一緒になって5~8員環を形成し、
RB2とRB3は、それぞれ独立してC1-C4アルキルであるか、またはRB2とRB3は、RB2が結合している窒素原子およびRB3が結合している窒素原子ならびに該窒素原子が結合している炭素原子と一緒になって5~8員環を形成する]、
[式中、
RB6は、水素またはC1-C4アルキルであり、
RB5とRB7は、それぞれ独立してC1-C4アルキルであるか、それらが結合している各窒素原子および該各窒素原子が結合している炭素原子と一緒になって5~8員環を形成し、
RB8は、C1-C4アルキルであり、かつRB9はC1-C4アルキルまたはフェニルであるか、RB8とRB9は、それらが結合している各窒素原子および該各窒素原子が結合している炭素原子と一緒になって5~8員環を形成し、
ここでRB9がフェニルである場合、2つのB2は、該フェニル基の2つのベンゼン環が縮合してナフタレンを形成してもよい]、
[式中、
RB10は、C1-C4アルキルであるか、またはRB10およびRB11は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB11は、RB10およびRB11が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB11およびRB12は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB12は、RB11およびRB12が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB12およびRB13は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB13は、RB12およびRB13が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB13およびRB14は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB14は、RB13およびRB14が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB14およびRB15は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB15は、RB14およびRB15が5~8員環を形成する場合を除き、C1-C4アルキルであり、
RB16は水素、C1-C8アルキル、またはC6-C10アリールである。]、および
[式中、
RB17は、独立してC1-C4アルキルであるか、またはRB17およびRB18は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB18は、RB17およびRB18が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB18およびRB19は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB19は、RB18およびRB19が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB19およびRB20は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB20は、RB19およびRB20が5~8員環を形成する場合を除き、C1-C4アルキルであり、
RB21は、C1-C4アルキルであるか、またはRB21およびRB22は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB22は、RB21およびRB22が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB22およびRB23は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB23は、RB22およびRB23が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB23およびRB24は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB24は、RB23およびRB24が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB24およびRB25は、それらが結合している各窒素原子および該各窒素原子が結合しているリン原子と一緒になって5~8員環を形成し、
RB25は、RB24およびRB25が5~8員環を形成する場合を除き、C1-C4アルキルであるか、またはRB25およびRB26は、それらが結合している窒素原子と一緒になって5~8員環を形成し、
RB26は、RB25およびRB26が5~8員環を形成する場合を除き、C1-C4アルキルであり、
RB27は、C1-C4アルキル、またはC6-C10アリールである。]
からなる群から選ばれる、請求項3~8および22~23のいずれか一項に記載の方法。 - 塩基が、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(DBU)、1,5-ジアザビシクロ[4.3.0]ノン-5-エン(DBN)、1,8-ビス(テトラメチルグアニジノ)ナフタレン(TMGN)、7-メチル-1,5,7-トリアザビシクロ[4.4.0]デカ-5-エン(MTBD)、2-tert-ブチル-1,1,3,3-テトラメチルグアニジン(BTMG)、1,5,7-トリアザビシクロ[4.4.0]デカ-5-エン(TBD)、tert-ブチルイミノ-トリス(ジメチルアミノ)ホスホラン(P1-tBu)、tert-ブチルイミノ-トリ(ピロリジノ)ホスホラン(P1-t-Bu-トリス(テトラメチレン), BTPP)、2-tert-ブチルイミノ-2-ジエチルアミノ-1,3-ジメチルペルヒドロ-1,3,2-ジアザホスホリン(BEMP)、tert-オクチルイミノ-トリス(ジメチルアミノ)ホスホラン(P1-t-Oct)、イミノ-トリス(ジメチルアミノ)ホスホラン(HP1(dma))、1-tert-ブチル-2,2,4,4,4-ペンタキス(ジメチルアミノ)-2λ5,4λ5-カテナジ(ホスファゼン)(P2-t-Bu)、および1-エチル-2,2,4,4,4-ペンタキス(ジメチルアミノ)-2λ5,4λ5-カテナジ(ホスファゼン)(P2-Et)からなる群より選択される、請求項3~8および22~24のいずれか一項に記載の方法。
- 工程Bが、DMF、NMP、DMI、テトラヒドロフラン、2-メチルテトラヒドロフラン、およびアセトニトリルからなる群から選ばれる溶媒中で行われる、請求項1~25のいずれか一項に記載の方法。
- 請求項1~26のいずれか一項に記載の方法を含む、N-置換-α,αジ置換アミノ酸残基とN-置換アミノ酸残基とが連結したジペプチド残基を含むペプチド化合物、その塩、またはそれらの溶媒和物を製造する方法。
- 請求項1~27のいずれか一項に記載の方法によって製造されたペプチド化合物、その塩、またはそれらの溶媒和物からN末端の保護基を脱保護する工程、
任意でペプチド鎖を伸長する工程、および
C末端側の基とN末端側の基を環化して環状部を形成する工程を含む、環状ペプチド化合物、その塩、またはそれらの溶媒和物の製造方法であって、
該環状ペプチド化合物が、8~15のアミノ酸残基を含み、少なくとも3つのN置換アミノ酸残基を含み、かつ少なくとも1つのN置換されていないアミノ酸残基を含み、環状部が少なくとも8つのアミノ酸残基を含む、前記方法。
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020227017551A KR20220092912A (ko) | 2019-11-07 | 2020-11-05 | 입체 장애가 큰 아미노산을 포함하는 펩티드 화합물의 제조 방법 |
JP2021554957A JPWO2021090856A1 (ja) | 2019-11-07 | 2020-11-05 | |
EP20884129.6A EP4056580A4 (en) | 2019-11-07 | 2020-11-05 | METHOD FOR MANUFACTURING A PEPTIDE COMPOUND CONTAINING A HIGHLY STERICALLY HINDERED AMINO ACID |
CN202080075047.8A CN114630835A (zh) | 2019-11-07 | 2020-11-05 | 包含空间位阻大的氨基酸的肽化合物的制备方法 |
US17/773,734 US20230026641A1 (en) | 2019-11-07 | 2020-11-05 | Method for producing peptide compound comprising highly sterically hindered amino acid |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2019202408 | 2019-11-07 | ||
JP2019-202408 | 2019-11-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021090856A1 true WO2021090856A1 (ja) | 2021-05-14 |
Family
ID=75848549
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2020/041279 WO2021090856A1 (ja) | 2019-11-07 | 2020-11-05 | 立体障害の大きなアミノ酸を含むペプチド化合物の製造方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20230026641A1 (ja) |
EP (1) | EP4056580A4 (ja) |
JP (1) | JPWO2021090856A1 (ja) |
KR (1) | KR20220092912A (ja) |
CN (1) | CN114630835A (ja) |
WO (1) | WO2021090856A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022097540A1 (ja) | 2020-11-05 | 2022-05-12 | 中外製薬株式会社 | ジケトピペラジン形成による欠損を抑制するペプチド合成方法 |
WO2024080333A1 (ja) * | 2022-10-13 | 2024-04-18 | 中外製薬株式会社 | N-置換アミノ酸残基を含む環状ペプチド化合物の製造方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013100132A1 (ja) | 2011-12-28 | 2013-07-04 | 中外製薬株式会社 | ペプチド化合物の環化方法 |
JP2015509940A (ja) * | 2012-02-15 | 2015-04-02 | エイルロン セラピューティクス,インコーポレイテッド | ペプチドミメティック大環状化合物 |
WO2018225864A1 (ja) | 2017-06-09 | 2018-12-13 | 中外製薬株式会社 | 膜透過性の高い環状ペプチド化合物、及びこれを含むライブラリ |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7229158B2 (ja) * | 2017-06-09 | 2023-02-27 | 中外製薬株式会社 | N-置換アミノ酸を含むペプチドの合成方法 |
-
2020
- 2020-11-05 EP EP20884129.6A patent/EP4056580A4/en active Pending
- 2020-11-05 US US17/773,734 patent/US20230026641A1/en active Pending
- 2020-11-05 KR KR1020227017551A patent/KR20220092912A/ko unknown
- 2020-11-05 CN CN202080075047.8A patent/CN114630835A/zh active Pending
- 2020-11-05 WO PCT/JP2020/041279 patent/WO2021090856A1/ja unknown
- 2020-11-05 JP JP2021554957A patent/JPWO2021090856A1/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013100132A1 (ja) | 2011-12-28 | 2013-07-04 | 中外製薬株式会社 | ペプチド化合物の環化方法 |
JP2015509940A (ja) * | 2012-02-15 | 2015-04-02 | エイルロン セラピューティクス,インコーポレイテッド | ペプチドミメティック大環状化合物 |
WO2018225864A1 (ja) | 2017-06-09 | 2018-12-13 | 中外製薬株式会社 | 膜透過性の高い環状ペプチド化合物、及びこれを含むライブラリ |
Non-Patent Citations (20)
Title |
---|
ACS CHEM. BIOL., vol. 8, 2013, pages 488 - 499 |
ANNU. REV. PHARMACOL. TOXICOL., vol. 56, 2016, pages 23 - 40 |
BRANDT WOLFGANG, HERBERG THOMAS, WESSJOHANN LUDGER: "Systematic conformational investigations of peptoids and peptoid-peptide chimeras", BIOPOLYMERS (PEPTIDE SCIENCE, vol. 96, no. 5, 2011, pages 651 - 668, XP055821617, DOI: 10.1002/bip.21620 * |
BROWN ZACHARY Z., SCHAFMEISTER CHRISTIAN E.: "Exploiting an inherent neighboring group effect of alpha- amino acids to synthes Z.ize extremely hindered dipeptides", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 130, no. 44, 2008, pages 14382 - 14383, XP055821615, DOI: 10.1021/ ja806063k * |
CARPINO, L. A. ET AL.: "Protected amino acid chlorides vs. protected amino acid fluorides: reactivity comparisons", TETRAHEDRON LETTERS, vol. 39, no. 3 / 4, 1998, pages 241 - 244, XP004100931, DOI: 10.1016/S0040-4039(97)10504-4 * |
CAS , no. 30924-93-7 |
CHEM. EUR. J., vol. 8, 2002, pages 1682 - 1693 |
CHEM. SOC. REV., vol. 45, 2016, pages 631 - 654 |
DRUG DISCOVERY TODAY, vol. 19, 2014, pages 388 - 399 |
EUR. J. ORG. CHEM., vol. 40, 2019, pages 6735 - 6748 |
FUTURE MED. CHEM., vol. 1, 2009, pages 1289 - 1310 |
GREENE: "Protective Groups in Organic Synthesis", 2014, JOHN WILEY & SONS |
J. AM. CHEM. SOC., vol. 119, 1997, pages 2301 - 2302 |
J. ORG. CHEM., vol. 70, no. 3, 2005, pages 1019 - 1028 |
J. PEPTIDE RES., vol. 65, 2005, pages 153 - 166 |
JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY, JAPAN, vol. 60, no. 2, 2002, pages 125 - 136 |
MERCK: "Solid-Phase Synthesis Handbook", 1 May 2002 |
NATURE PROTOCOLS, vol. 7, no. 3, 2012, pages 432 - 444 |
ORG. LETT., vol. 15, 2013, pages 5012 - 5015 |
See also references of EP4056580A4 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022097540A1 (ja) | 2020-11-05 | 2022-05-12 | 中外製薬株式会社 | ジケトピペラジン形成による欠損を抑制するペプチド合成方法 |
WO2024080333A1 (ja) * | 2022-10-13 | 2024-04-18 | 中外製薬株式会社 | N-置換アミノ酸残基を含む環状ペプチド化合物の製造方法 |
Also Published As
Publication number | Publication date |
---|---|
JPWO2021090856A1 (ja) | 2021-05-14 |
EP4056580A1 (en) | 2022-09-14 |
KR20220092912A (ko) | 2022-07-04 |
EP4056580A4 (en) | 2023-12-06 |
CN114630835A (zh) | 2022-06-14 |
US20230026641A1 (en) | 2023-01-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2018225851A1 (ja) | N-置換アミノ酸を含むペプチドの合成方法 | |
WO2021090856A1 (ja) | 立体障害の大きなアミノ酸を含むペプチド化合物の製造方法 | |
US11492369B2 (en) | Method for producing peptide, and method for processing bases | |
US11732002B2 (en) | Deprotection method and resin removal method in solid-phase reaction for peptide compound or amide compound, and method for producing peptide compound | |
JP2022543391A (ja) | トロフィネチドの組成物 | |
JPH10500123A (ja) | アミノスルホン酸の誘導体、プソイドペプチドの合成における同誘導体の利用、およびその製造法 | |
WO2022097540A1 (ja) | ジケトピペラジン形成による欠損を抑制するペプチド合成方法 | |
EP4086272A1 (en) | Methods for producing cyclic compounds comprising n-substituted amino acid residues | |
EP4269422A1 (en) | Method for producing peptide compound containing n-substituted-amino acid residue | |
JP2022186851A (ja) | N-置換アミノ酸残基を含む環状化合物の製造方法 | |
PT98813B (pt) | Processo para a preparacao de peptidos por sintese em fase solida | |
JP2009528282A (ja) | 修飾アミノ酸 | |
WO2023214577A1 (ja) | ジケトピペラジン形成による欠損を抑制するペプチド合成方法 | |
TW202210498A (zh) | 高難度序列之有效率的胜肽縮合法 | |
EP4249496A1 (en) | Method for supporting amino acid on resin for solid-phase synthesis | |
CN116615411A (zh) | 包含n-取代氨基酸残基的肽化合物的制造方法 | |
Kudaj et al. | An efficient synthesis of optically pure α-alkyl-β-azido-and α-alkyl-β-aminoalanines via ring opening of 3-amino-3-alkyl-2-oxetanones | |
CN117279928A (zh) | 包含n-取代氨基酸残基的环状化合物的制备方法 | |
JP5670332B2 (ja) | ピペコリン酸リンカーおよび固体支持体についての化学へのその使用 | |
Roshna | Synthetic oligomers with heterogeneous backbones featuring alpha/beta-conjugated building blocks | |
WO2002099045A2 (en) | Peptide beta-strand mimics based on 1,2-dihydro-3(6h)-pyridinone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20884129 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2021554957 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20227017551 Country of ref document: KR Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2020884129 Country of ref document: EP Effective date: 20220607 |