CA2738280A1 - Peptide compound and method for producing the same - Google Patents
Peptide compound and method for producing the same Download PDFInfo
- Publication number
- CA2738280A1 CA2738280A1 CA2738280A CA2738280A CA2738280A1 CA 2738280 A1 CA2738280 A1 CA 2738280A1 CA 2738280 A CA2738280 A CA 2738280A CA 2738280 A CA2738280 A CA 2738280A CA 2738280 A1 CA2738280 A1 CA 2738280A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- salt
- ibu
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 133
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 67
- 108090000765 processed proteins & peptides Proteins 0.000 title abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims description 106
- -1 aralkoxy Chemical group 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 125000006239 protecting group Chemical group 0.000 claims description 26
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 238000010511 deprotection reaction Methods 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 10
- 239000004473 Threonine Substances 0.000 claims description 10
- 238000009833 condensation Methods 0.000 claims description 9
- 230000005494 condensation Effects 0.000 claims description 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 2
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 abstract description 29
- 238000006731 degradation reaction Methods 0.000 abstract description 11
- 230000002829 reductive effect Effects 0.000 abstract description 10
- 230000015556 catabolic process Effects 0.000 abstract description 9
- 238000000746 purification Methods 0.000 abstract description 7
- 108010069514 Cyclic Peptides Proteins 0.000 abstract description 5
- 102000001189 Cyclic Peptides Human genes 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- 238000004587 chromatography analysis Methods 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 238000000926 separation method Methods 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000013078 crystal Substances 0.000 description 11
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 11
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 11
- 235000019796 monopotassium phosphate Nutrition 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000007836 KH2PO4 Substances 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 10
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 239000008399 tap water Substances 0.000 description 10
- 235000020679 tap water Nutrition 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 235000017550 sodium carbonate Nutrition 0.000 description 9
- 229960002898 threonine Drugs 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 229910000397 disodium phosphate Inorganic materials 0.000 description 7
- 235000019800 disodium phosphate Nutrition 0.000 description 7
- 125000004430 oxygen atom Chemical group O* 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- 125000004434 sulfur atom Chemical group 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 210000004899 c-terminal region Anatomy 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 241000711549 Hepacivirus C Species 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- UGWULZWUXSCWPX-UHFFFAOYSA-N 2-sulfanylideneimidazolidin-4-one Chemical compound O=C1CNC(=S)N1 UGWULZWUXSCWPX-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000003028 elevating effect Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 229940117953 phenylisothiocyanate Drugs 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 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 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-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
- 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 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- HJYNXYDCBBAUKT-UHFFFAOYSA-N 3-(1-hydroxyethyl)-1-methylpiperazine-2,5-dione Chemical compound OC(C)C1C(N(CC(N1)=O)C)=O HJYNXYDCBBAUKT-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZZRIQDWDJVLELF-UHFFFAOYSA-N 3-phenyl-2-sulfanylideneimidazolidin-4-one Chemical compound O=C1CNC(=S)N1C1=CC=CC=C1 ZZRIQDWDJVLELF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- WXNXCEHXYPACJF-ZETCQYMHSA-N N-acetyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(C)=O WXNXCEHXYPACJF-ZETCQYMHSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241001279361 Stachybotrys Species 0.000 description 1
- 241001279364 Stachybotrys chartarum Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229960000669 acetylleucine Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005055 alkyl alkoxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 238000005516 engineering process 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
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000002013 hydrophilic interaction chromatography Methods 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- OZSJLLVVZFTDEY-HJXLNUONSA-N methyl (2s,3r)-2-amino-3-hydroxybutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)[C@@H](C)O OZSJLLVVZFTDEY-HJXLNUONSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000004682 monohydrates Chemical class 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Provided is an efficient production method which is designed for an industrial production process and is superior in operability, purity, etc. As a result of conducting the study on an efficient production method which is designed for an industrial production process, and is superior in operability, and with which a high purity intermediate can be obtained, it found that a method with which the number of steps (of eliminating diamino acid) can be reduced, purification by chromatography is not needed, and an intermediate can be obtained at a high purity, and found a method for producing a cyclic peptide compound known to have an anti-HCV activity, a peptide intermediate useful for the production, and a method for producing the intermediate, which are relevant to the present invention. In the method, it is not necessary to repeat Edman degradation, it becomes possible to supply a large amount of the peptide intermediate and the cyclic peptide compound without performing the step of chromatography associated with the reaction.
Description
DESCRIPTION
Title of Invention: PEPTIDE COMPOUND AND METHOD FOR PRODUCING THE
SAME
Technical Field [0001]
The present invention relates to a method for producing a cyclic peptide compound useful as an active ingredient for a pharmaceutical composition, particularly a pharmaceutical composition for treatment of hepatitis C virus (HCV), which is known as an inhibitor against the RNA replication of hepatitis C virus replicons, an intermediate useful for production of the cyclic peptide compound, and a method for producing the same.
Background Art [0002]
It is reported that a cyclic peptide compound of the following formula (A) or a salt thereof is useful as an active ingredient of a pharmaceutical composition for treatment of HCV, based on its inhibitory activity against the RNA replication of hepatitis C virus replicons (Patent Citation 1).
[Chem. 1 ]
Me HO Me Me iBu Me O
HN(NN N OH
iBuO 0 Pr Me 0 O x 0 We iBu O (A) OH H
N Y O
Me N( N N
H Me O Me iBu O
[For the symbols in the formula, refer to Patent Citation 1.]
Title of Invention: PEPTIDE COMPOUND AND METHOD FOR PRODUCING THE
SAME
Technical Field [0001]
The present invention relates to a method for producing a cyclic peptide compound useful as an active ingredient for a pharmaceutical composition, particularly a pharmaceutical composition for treatment of hepatitis C virus (HCV), which is known as an inhibitor against the RNA replication of hepatitis C virus replicons, an intermediate useful for production of the cyclic peptide compound, and a method for producing the same.
Background Art [0002]
It is reported that a cyclic peptide compound of the following formula (A) or a salt thereof is useful as an active ingredient of a pharmaceutical composition for treatment of HCV, based on its inhibitory activity against the RNA replication of hepatitis C virus replicons (Patent Citation 1).
[Chem. 1 ]
Me HO Me Me iBu Me O
HN(NN N OH
iBuO 0 Pr Me 0 O x 0 We iBu O (A) OH H
N Y O
Me N( N N
H Me O Me iBu O
[For the symbols in the formula, refer to Patent Citation 1.]
[0003]
Patent Citation 1 discloses that the compound of the formula (A) or a salt thereof can be produced using an FR901459 substance (Patent Citation 2) which is a fermentation product as a starting material via the compound of the formula (I) or a salt thereof. Specifically, it is carried out via the steps <1> to <6> below.
<1> Production of the compound of the formula (I) or a salt thereof by N-O
rearrangement and then ring-opening of the FR901459 substance or a salt thereof.
<2> Production of the compound of the formula (A2-2) or a salt thereof by condensing threonine to a C-terminal of the compound of the formula (I) or a salt thereof.
<3> Production of the compound of the formula (A3) or a salt thereof by carrying out Edman degradation three times on the compound of the formula (A2-2) or a salt thereof.
<4> Production of the compound of the formula (A4-4) or a salt thereof by condensing a diamino acid to the N-terminal of the compound of the formula (A3) or a salt thereof.
<5> Production of the compound of the formula (A) or a salt thereof by cyclizing the compound of the formula (A4-4) or a salt thereof.
<6> Production of the compound of the formula (Ab) or a salt thereof by reducing the compound of the formula (Aa) or a salt thereof.
Each of the steps will be described in detail below.
Patent Citation 1 discloses that the compound of the formula (A) or a salt thereof can be produced using an FR901459 substance (Patent Citation 2) which is a fermentation product as a starting material via the compound of the formula (I) or a salt thereof. Specifically, it is carried out via the steps <1> to <6> below.
<1> Production of the compound of the formula (I) or a salt thereof by N-O
rearrangement and then ring-opening of the FR901459 substance or a salt thereof.
<2> Production of the compound of the formula (A2-2) or a salt thereof by condensing threonine to a C-terminal of the compound of the formula (I) or a salt thereof.
<3> Production of the compound of the formula (A3) or a salt thereof by carrying out Edman degradation three times on the compound of the formula (A2-2) or a salt thereof.
<4> Production of the compound of the formula (A4-4) or a salt thereof by condensing a diamino acid to the N-terminal of the compound of the formula (A3) or a salt thereof.
<5> Production of the compound of the formula (A) or a salt thereof by cyclizing the compound of the formula (A4-4) or a salt thereof.
<6> Production of the compound of the formula (Ab) or a salt thereof by reducing the compound of the formula (Aa) or a salt thereof.
Each of the steps will be described in detail below.
[0004]
<1> This step is a step of producing the compound of the formula (I) or a salt thereof from an FR901459 substance represented by the formula (A1-1) or a salt thereof.
Specifically, the compound of the formula (I) or a salt thereof is produced by subjecting the FR901459 substance to an N-O rearrangement reaction under weakly acidic conditions, and then hydrolysis of the compound of the formula (A1-2) or a salt thereof obtained by protection of an amino group to effect ring-opening.
[Chem. 2]
Me HO Me Me iBu Me O H
HN(N N N OH
iBu p 0 Pr Me 0 0 NMe (A1-1) O NMpe H iBu O H iBu N
Me N N" N O
H Me O Me iBu 0 Me Me iBu Me O HO Mc Me Prot HN~N~N 10- NH
1) Rearrangement Bup 0 Pr Me O O NMe (A1 -2) 2) Protection O NMe O H iBu O H iBu Me NNNN O
H Me O Me iBu 0 Me Me HO
iBu Me 0 Me HNNN O HO Me 3) Hydrolysis iBu p 0 iPr Me OH O N Prot O N N
0 H iBu 0 H iBu Me Me NA-~_N~N N
~N O (I) H Me O Me iBu 0 Me [wherein Prot means a protective group. For the other symbols in the formula, 5 refer to Patent Citation 1.]
[0005]
<2> This step is a step of producing the compound of the formula (A2-2) or a salt thereof from the compound of the formula (I) or a salt thereof. The compound of the formula (A2-2) or a salt thereof is produced by condensing the compound of the formula (A2-1) to the compound of the formula (I) or a salt thereof.
[Chem. 3]
Me O HO Me O
H N iBu Me O H HO Me 1) R' HN N N N R' o Me OH iBuYO O ipr Me O O N-Prot (A2-1) O We Me OH N, Me H
O H Bu 0 H iBu 2) Deprotection Me NIyN NN N O
H Me O Me iBu O Me (A2-2) [wherein Prot means a protective group. For the other symbols, refer to Patent Citation 1.]
<1> This step is a step of producing the compound of the formula (I) or a salt thereof from an FR901459 substance represented by the formula (A1-1) or a salt thereof.
Specifically, the compound of the formula (I) or a salt thereof is produced by subjecting the FR901459 substance to an N-O rearrangement reaction under weakly acidic conditions, and then hydrolysis of the compound of the formula (A1-2) or a salt thereof obtained by protection of an amino group to effect ring-opening.
[Chem. 2]
Me HO Me Me iBu Me O H
HN(N N N OH
iBu p 0 Pr Me 0 0 NMe (A1-1) O NMpe H iBu O H iBu N
Me N N" N O
H Me O Me iBu 0 Me Me iBu Me O HO Mc Me Prot HN~N~N 10- NH
1) Rearrangement Bup 0 Pr Me O O NMe (A1 -2) 2) Protection O NMe O H iBu O H iBu Me NNNN O
H Me O Me iBu 0 Me Me HO
iBu Me 0 Me HNNN O HO Me 3) Hydrolysis iBu p 0 iPr Me OH O N Prot O N N
0 H iBu 0 H iBu Me Me NA-~_N~N N
~N O (I) H Me O Me iBu 0 Me [wherein Prot means a protective group. For the other symbols in the formula, 5 refer to Patent Citation 1.]
[0005]
<2> This step is a step of producing the compound of the formula (A2-2) or a salt thereof from the compound of the formula (I) or a salt thereof. The compound of the formula (A2-2) or a salt thereof is produced by condensing the compound of the formula (A2-1) to the compound of the formula (I) or a salt thereof.
[Chem. 3]
Me O HO Me O
H N iBu Me O H HO Me 1) R' HN N N N R' o Me OH iBuYO O ipr Me O O N-Prot (A2-1) O We Me OH N, Me H
O H Bu 0 H iBu 2) Deprotection Me NIyN NN N O
H Me O Me iBu O Me (A2-2) [wherein Prot means a protective group. For the other symbols, refer to Patent Citation 1.]
[0006]
<3> This step is a step of producing the compound of the formula (A3) or a salt thereof from the compound of the formula (A2-2) or a salt thereof. The compound of the formula (A3) or a salt thereof is produced by subjecting the compound of the formula (A2-2) or a salt thereof to Edman degradation three times, that is, to elimination of amino acids sequentially from the N-terminal of the compound of the formula (A2-2) or a salt thereof.
[Chem. 4]
Me HO hMe n iBu Me O
HNN-N N R' Edman degradation iBu 0 iPr Me O
Me O
O H
(A2-2) 30 O We (3 times) iBu 0 I -T- O N NH
Me NN 2 H Me O Me iBu (A3) [For the symbols in the formula, refer to Patent Citation 1.]
<3> This step is a step of producing the compound of the formula (A3) or a salt thereof from the compound of the formula (A2-2) or a salt thereof. The compound of the formula (A3) or a salt thereof is produced by subjecting the compound of the formula (A2-2) or a salt thereof to Edman degradation three times, that is, to elimination of amino acids sequentially from the N-terminal of the compound of the formula (A2-2) or a salt thereof.
[Chem. 4]
Me HO hMe n iBu Me O
HNN-N N R' Edman degradation iBu 0 iPr Me O
Me O
O H
(A2-2) 30 O We (3 times) iBu 0 I -T- O N NH
Me NN 2 H Me O Me iBu (A3) [For the symbols in the formula, refer to Patent Citation 1.]
[0007]
<4> This step is a step of producing the compound of the formula (A4-4) or a salt thereof from the compound of the formula (A3) or a salt thereof. The compound of the formula (A4-4) or a salt thereof is produced by condensing the protected amino acid of the formula (A4-3) to the compound of the formula (A4-2) or a salt thereof, which has been obtained by subjecting the compound of the formula (A3) or a salt thereof to introduction of an amino acid to the N-terminal and deprotection.
[Chem. 5]
Me 1) L 1" Prot3 HO He iBu Me 0 O
HNN N N OMe (A3) (A4-1) 2) Deprotection Bu O 0 iPr Me 0 Me OH
O We iB
O H u O H (A4-2) Me NJk/N NNYY.H
H Me O Me iBu O
Me HO
iBu Me O H Me 0 LYX,Prota HN-N N N OMe 0 iBu\ ~O O iPr Me O Me OH
(A4-3) (A4-4) 0 NMe iBu O OH H
N N Y X, a Me N N Y Y Prot H Me O Me iBu O 0 [wherein each of Prot3 and Prot4 means a protective group. For the other symbols, refer to Patent Citation 1.]
<4> This step is a step of producing the compound of the formula (A4-4) or a salt thereof from the compound of the formula (A3) or a salt thereof. The compound of the formula (A4-4) or a salt thereof is produced by condensing the protected amino acid of the formula (A4-3) to the compound of the formula (A4-2) or a salt thereof, which has been obtained by subjecting the compound of the formula (A3) or a salt thereof to introduction of an amino acid to the N-terminal and deprotection.
[Chem. 5]
Me 1) L 1" Prot3 HO He iBu Me 0 O
HNN N N OMe (A3) (A4-1) 2) Deprotection Bu O 0 iPr Me 0 Me OH
O We iB
O H u O H (A4-2) Me NJk/N NNYY.H
H Me O Me iBu O
Me HO
iBu Me O H Me 0 LYX,Prota HN-N N N OMe 0 iBu\ ~O O iPr Me O Me OH
(A4-3) (A4-4) 0 NMe iBu O OH H
N N Y X, a Me N N Y Y Prot H Me O Me iBu O 0 [wherein each of Prot3 and Prot4 means a protective group. For the other symbols, refer to Patent Citation 1.]
[0008]
<5> This step is a step of producing the compound of the formula (Aa) or a salt thereof from the compound of the formula (A4-4) or a salt thereof. The compound of the formula (Aa) or a salt thereof is produced by subjecting the compound of the formula (A4-4) or a salt thereof to deprotection and then to macrolactamization.
[Chem. 6]
Me iBu Me O O Me Me H
HNN N N OH
(A44) Deprote30 iBu\ 1 AO O Pr Me O O X
(Aa) Cyclization O N iBu O 0 H H
N Y O
Me N~N~N~
H Me 0 Me iBu O
[For the symbols in the formula, refer to Patent Citation 1.]
<5> This step is a step of producing the compound of the formula (Aa) or a salt thereof from the compound of the formula (A4-4) or a salt thereof. The compound of the formula (Aa) or a salt thereof is produced by subjecting the compound of the formula (A4-4) or a salt thereof to deprotection and then to macrolactamization.
[Chem. 6]
Me iBu Me O O Me Me H
HNN N N OH
(A44) Deprote30 iBu\ 1 AO O Pr Me O O X
(Aa) Cyclization O N iBu O 0 H H
N Y O
Me N~N~N~
H Me 0 Me iBu O
[For the symbols in the formula, refer to Patent Citation 1.]
[0009]
<6> This step is a step of producing the compound of the formula (Ab) or a salt thereof from the compound of the formula (Aa) or a salt thereof. The compound of the formula (Ab) or a salt thereof is produced by the usual catalytic reduction.
[Chem. 7]
Me iBu Me HO O 1Me Me H
Catalytic H N N OH (Aa) reduction iBu O 0 Pr Me 0 O X (Ab) O NMe iBu O OH H
O
Me N _11-y N Y'_ N _-1y N Y
H Me 0 Me iBu O
[For the symbols in the formula, refer to Patent Citation 1.]
<6> This step is a step of producing the compound of the formula (Ab) or a salt thereof from the compound of the formula (Aa) or a salt thereof. The compound of the formula (Ab) or a salt thereof is produced by the usual catalytic reduction.
[Chem. 7]
Me iBu Me HO O 1Me Me H
Catalytic H N N OH (Aa) reduction iBu O 0 Pr Me 0 O X (Ab) O NMe iBu O OH H
O
Me N _11-y N Y'_ N _-1y N Y
H Me 0 Me iBu O
[For the symbols in the formula, refer to Patent Citation 1.]
[0010]
This is a process of repeatedly carrying out Edman degradation which may cause a problem when production of the compound of the formula (A) of a salt thereof in the above-described production method is scaled up to an industrial level. Since by-products obtained by Edman degradation potentially make the next reaction complex, purification is required. It is particularly preferable not to carry out column chromatography requiring complicated operations when scaled up to the industrial level.
In Patent Citation 1 (for example, Prep 3), a step of purifying by means of column chromatography is included between the steps.
Prior Art Citation Patent Citation [0011]
[Patent Citation 1] WO 2007/049803 [Patent Citation 2] JP-A-5-271267 Summary of Invention Problem to Be Solved by the Invention [0012]
An efficient method for producing the compound of the formula (A), which is designed for an industrial production process and is superior in operability, purity, and the like, an intermediate useful for the production, and a method for producing the intermediate, are provided.
Means for Solving the Problem [0013]
The present inventors have made extensive studies on an efficient production method which is designed for an industrial production process and is superior in operability, purity, and the like. As a result, they have found a reaction with which the number of steps can be reduced, and have thus found a method for producing a compound of the formula (A) with a view to industrial production, in which the compound can be 2S obtained at a high purity even without purification by which requires operations, an intermediate useful for the production, and a method for producing the intermediate, thereby completing the present invention.
This is a process of repeatedly carrying out Edman degradation which may cause a problem when production of the compound of the formula (A) of a salt thereof in the above-described production method is scaled up to an industrial level. Since by-products obtained by Edman degradation potentially make the next reaction complex, purification is required. It is particularly preferable not to carry out column chromatography requiring complicated operations when scaled up to the industrial level.
In Patent Citation 1 (for example, Prep 3), a step of purifying by means of column chromatography is included between the steps.
Prior Art Citation Patent Citation [0011]
[Patent Citation 1] WO 2007/049803 [Patent Citation 2] JP-A-5-271267 Summary of Invention Problem to Be Solved by the Invention [0012]
An efficient method for producing the compound of the formula (A), which is designed for an industrial production process and is superior in operability, purity, and the like, an intermediate useful for the production, and a method for producing the intermediate, are provided.
Means for Solving the Problem [0013]
The present inventors have made extensive studies on an efficient production method which is designed for an industrial production process and is superior in operability, purity, and the like. As a result, they have found a reaction with which the number of steps can be reduced, and have thus found a method for producing a compound of the formula (A) with a view to industrial production, in which the compound can be 2S obtained at a high purity even without purification by which requires operations, an intermediate useful for the production, and a method for producing the intermediate, thereby completing the present invention.
[0014]
According to the present invention, Edman degradation may be carried out once, and even without purification by means of column chromatography which follows as a post-treatment, the compound of the formula (A) and an intermediate useful for the production thereof can be provided at a high purity.
According to the present invention, Edman degradation may be carried out once, and even without purification by means of column chromatography which follows as a post-treatment, the compound of the formula (A) and an intermediate useful for the production thereof can be provided at a high purity.
[0015]
[1]
A method for producing a compound of the formula (III) or a salt thereof:
[Chem. 9]
Me HO
iBu Me O Me iBuO O Pr Me ORX
(III) O NMOe H iBu 0 H iBu Me N ~N ~N -~-yN ~NH
H Me O Me Bu 0 Me (wherein RX means -H or a protective group, iBu means isobutyl, iPr means isopropyl, and Me means methyl), which comprises eliminating a diamino acid from a compound of the formula (II) or a salt thereof:
[Chem. 8]
Me HO
iBu Me O Me HN(N N 0 HO Me iBu O O Pr Me ORX O NH2 (II) O NMOe H iBu 0 H Bu NMe Me N N
AY N N N
H Me O Me iBu 0 Me in a single step.
[2]
A method for producing a compound of the formula (VI) or a salt thereof-[Chem. 11 ]
Me HO Me iBu Me O
HNN N ORX
iBuO 0 iPr Me 0 (VI) O
3: NMe Bu O OH H
N N.
Me NN Prot H Me 0 Me iBu (wherein Rx means -H or a protective group, iBu means isobutyl, iPr means isopropyl, Me means methyl, and Prot and Protl mean protective groups), which comprises subjecting a compound of the formula (I) or a salt thereof:
[Chem. 10]
Me HO
iBu Me O Me HN --~ N N 0 HO Me Bu L . O iPr Me ORX O N.Prot (I) O NMe iBu 0 iBu NH
O H H 'Me N N
Me N N N O
H Me 0 Me Bu 0 Me to a deprotection reaction to obtain a compound of the formula (II) or a salt thereof, and introducing a protective group to the compound of the formula (III) or a salt thereof obtained by the step described in [1].
[1]
A method for producing a compound of the formula (III) or a salt thereof:
[Chem. 9]
Me HO
iBu Me O Me iBuO O Pr Me ORX
(III) O NMOe H iBu 0 H iBu Me N ~N ~N -~-yN ~NH
H Me O Me Bu 0 Me (wherein RX means -H or a protective group, iBu means isobutyl, iPr means isopropyl, and Me means methyl), which comprises eliminating a diamino acid from a compound of the formula (II) or a salt thereof:
[Chem. 8]
Me HO
iBu Me O Me HN(N N 0 HO Me iBu O O Pr Me ORX O NH2 (II) O NMOe H iBu 0 H Bu NMe Me N N
AY N N N
H Me O Me iBu 0 Me in a single step.
[2]
A method for producing a compound of the formula (VI) or a salt thereof-[Chem. 11 ]
Me HO Me iBu Me O
HNN N ORX
iBuO 0 iPr Me 0 (VI) O
3: NMe Bu O OH H
N N.
Me NN Prot H Me 0 Me iBu (wherein Rx means -H or a protective group, iBu means isobutyl, iPr means isopropyl, Me means methyl, and Prot and Protl mean protective groups), which comprises subjecting a compound of the formula (I) or a salt thereof:
[Chem. 10]
Me HO
iBu Me O Me HN --~ N N 0 HO Me Bu L . O iPr Me ORX O N.Prot (I) O NMe iBu 0 iBu NH
O H H 'Me N N
Me N N N O
H Me 0 Me Bu 0 Me to a deprotection reaction to obtain a compound of the formula (II) or a salt thereof, and introducing a protective group to the compound of the formula (III) or a salt thereof obtained by the step described in [1].
[0016]
[3]
A method for producing a compound of the formula (A) or a salt thereof-[Chem. 12]
Me iBu Me O O H Me H
HNN _~IN N OH
iBu O 0 Pr Me 0 O X (A) I: --"~ NMe Bu O OH H
N N Y O
Me N N
H Me O Me iBu O
(wherein Xis [Chem. 13]
N/
or [Chem. 14]
N
R1 is -H, or lower alkyl;
R2 is -H, aryl, or lower alkyl, wherein the lower alkyl may be substituted with one suitable substituent selected from the group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, aralkoxy, carbamoyloxy which may be substituted, and amino which may be substituted;
[Chem. 15]
N
is a nitrogen-containing heterocycle; and Y is [Chem. 16]
N
or [Chem. 17]
O
10 R3 is cycloalkyl, aryl, a heterocycle which may be substituted, or lower alkyl, wherein the lower alkyl may be substituted with one suitable substituent selected from the group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, aralkoxy, lower alkoxy-lower alkylene-O-, amino which may be substituted, and -OC(O)NR6R7, (wherein R6 and R7 each independently represent -H or lower alkyl, or R6 and 15 R7, together with a nitrogen atom to which they bind, represent a nitrogen-containing heterocycle, which may be substituted with lower alkyl);
R4 and R5 each independently represent -H or lower alkyl;
represents a single bond or a double bond.
(provided that if R2 is -H, R3 is cycloalkyl, aryl, a heterocycle which may be substituted, lower alkoxymethyl, aralkyl, t-butyl, sec-butyl, cycloalkyl, or ethyl, wherein the ethyl may be substituted with one suitable substituent selected from the group consisting of lower alkyl, or hydroxy, lower alkyl-O-, aryl-lower alkylene-O-, lower alkyl-O-lower alkylene-O-, amino which may be substituted, and -OC(O) NR6R7)), from the compound of the formula (VI) or a salt thereof obtained from the compound of the formula (I) or a salt thereof by the production method of [2].
[4]
A method for producing a compound of the formula (VIII) or a salt thereof-[Chem. 18]
Me HO Me o iBu Me O H
HNNN N 0 .Prot2 iBu O 0 Pr Me OMe OH
O NMe iBu 0 (VIII) NH
Me N N 2 H Me O Me iBu (wherein Prot2 means a protective group), which comprises subjecting the compound of the formula (VI) or a salt thereof obtained from the compound of the formula (I) or a salt thereof according to the production method of [2] to condensation with a protected threonine at the carboxylic acid terminal, and deprotecting the amino terminal.
[5]
A method for producing a compound of the formula (A) or a salt thereof, which comprises subjecting the compound of the formula (VIII) or a salt thereof obtained from the compound of the formula (I) or a salt thereof according to the method described in [3] to condensation with a diamino acid at the amino terminal, carrying out deprotection, and then carrying out cyclization.
[3]
A method for producing a compound of the formula (A) or a salt thereof-[Chem. 12]
Me iBu Me O O H Me H
HNN _~IN N OH
iBu O 0 Pr Me 0 O X (A) I: --"~ NMe Bu O OH H
N N Y O
Me N N
H Me O Me iBu O
(wherein Xis [Chem. 13]
N/
or [Chem. 14]
N
R1 is -H, or lower alkyl;
R2 is -H, aryl, or lower alkyl, wherein the lower alkyl may be substituted with one suitable substituent selected from the group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, aralkoxy, carbamoyloxy which may be substituted, and amino which may be substituted;
[Chem. 15]
N
is a nitrogen-containing heterocycle; and Y is [Chem. 16]
N
or [Chem. 17]
O
10 R3 is cycloalkyl, aryl, a heterocycle which may be substituted, or lower alkyl, wherein the lower alkyl may be substituted with one suitable substituent selected from the group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, aralkoxy, lower alkoxy-lower alkylene-O-, amino which may be substituted, and -OC(O)NR6R7, (wherein R6 and R7 each independently represent -H or lower alkyl, or R6 and 15 R7, together with a nitrogen atom to which they bind, represent a nitrogen-containing heterocycle, which may be substituted with lower alkyl);
R4 and R5 each independently represent -H or lower alkyl;
represents a single bond or a double bond.
(provided that if R2 is -H, R3 is cycloalkyl, aryl, a heterocycle which may be substituted, lower alkoxymethyl, aralkyl, t-butyl, sec-butyl, cycloalkyl, or ethyl, wherein the ethyl may be substituted with one suitable substituent selected from the group consisting of lower alkyl, or hydroxy, lower alkyl-O-, aryl-lower alkylene-O-, lower alkyl-O-lower alkylene-O-, amino which may be substituted, and -OC(O) NR6R7)), from the compound of the formula (VI) or a salt thereof obtained from the compound of the formula (I) or a salt thereof by the production method of [2].
[4]
A method for producing a compound of the formula (VIII) or a salt thereof-[Chem. 18]
Me HO Me o iBu Me O H
HNNN N 0 .Prot2 iBu O 0 Pr Me OMe OH
O NMe iBu 0 (VIII) NH
Me N N 2 H Me O Me iBu (wherein Prot2 means a protective group), which comprises subjecting the compound of the formula (VI) or a salt thereof obtained from the compound of the formula (I) or a salt thereof according to the production method of [2] to condensation with a protected threonine at the carboxylic acid terminal, and deprotecting the amino terminal.
[5]
A method for producing a compound of the formula (A) or a salt thereof, which comprises subjecting the compound of the formula (VIII) or a salt thereof obtained from the compound of the formula (I) or a salt thereof according to the method described in [3] to condensation with a diamino acid at the amino terminal, carrying out deprotection, and then carrying out cyclization.
[0017]
[6]
A compound or a salt thereof selected from the group consisting of-[Table 1]
Me HO Me iBu Me O
HN N N R~
iBu O O Pr Me 0 O NMe iBu O OH H
N N. 2 Me N N R
H Me 0 Me iBu iBu O Me NH2 -OH -N~N Me 0 MeO OH
iBu -OH NH
0 Me iBu S
-OH NNHPh --~ I
0 Me -OH -H
-OH -Boc H O
O,Me -Boc Me OH
[6]
A compound or a salt thereof selected from the group consisting of-[Table 1]
Me HO Me iBu Me O
HN N N R~
iBu O O Pr Me 0 O NMe iBu O OH H
N N. 2 Me N N R
H Me 0 Me iBu iBu O Me NH2 -OH -N~N Me 0 MeO OH
iBu -OH NH
0 Me iBu S
-OH NNHPh --~ I
0 Me -OH -H
-OH -Boc H O
O,Me -Boc Me OH
[0018]
The intermediate obtained by the production method of the present invention is useful from the viewpoints shown below.
The intermediate obtained by the production method of the present invention is useful from the viewpoints shown below.
[0019]
(1) The compound of the formula (VIII) or a salt thereof obtained by the above-described production method [4] is useful as an intermediate for production since by subjecting it to condensation of a diamino acid to the N-terminal, deprotection, and then cyclization, the compound of the formula (A) or a salt thereof can be produced, which is reported to be useful as an active ingredient of an anti-HCV pharmaceutical composition for treatment.
(1) The compound of the formula (VIII) or a salt thereof obtained by the above-described production method [4] is useful as an intermediate for production since by subjecting it to condensation of a diamino acid to the N-terminal, deprotection, and then cyclization, the compound of the formula (A) or a salt thereof can be produced, which is reported to be useful as an active ingredient of an anti-HCV pharmaceutical composition for treatment.
[0020]
(2) The compound of the formula (VI) or a salt thereof obtained by the above-described production method [2] is useful as an intermediate for production since by subjecting it to condensation of a protected threonine to the C-terminal and deprotection of the N-terminal, the compound of the formula (VIII) or a salt thereof can be produced, and the compound of the formula (VIII) or a salt thereof thus obtained allows production of the compound of the formula (A) or a salt thereof, which is reported to be useful as an active ingredient of an anti-HCV pharmaceutical composition for treatment, by the method as described in (1) above.
(3) The compound of the formula (III) or a salt thereof obtained by the above-described production method [1] is useful as an intermediate for production since by subjecting it to Edman degradation once and then protection of the N-terminal, the compound of the formula (VI) or a salt thereof can be produced, and the compound of the formula (VI) or a salt thereof thus obtained allows production of the compound of the formula (A) or a salt thereof, which is reported to be useful as an active ingredient of an anti-HCV pharmaceutical composition for treatment, by the methods as described in (1) and (2) above.
(2) The compound of the formula (VI) or a salt thereof obtained by the above-described production method [2] is useful as an intermediate for production since by subjecting it to condensation of a protected threonine to the C-terminal and deprotection of the N-terminal, the compound of the formula (VIII) or a salt thereof can be produced, and the compound of the formula (VIII) or a salt thereof thus obtained allows production of the compound of the formula (A) or a salt thereof, which is reported to be useful as an active ingredient of an anti-HCV pharmaceutical composition for treatment, by the method as described in (1) above.
(3) The compound of the formula (III) or a salt thereof obtained by the above-described production method [1] is useful as an intermediate for production since by subjecting it to Edman degradation once and then protection of the N-terminal, the compound of the formula (VI) or a salt thereof can be produced, and the compound of the formula (VI) or a salt thereof thus obtained allows production of the compound of the formula (A) or a salt thereof, which is reported to be useful as an active ingredient of an anti-HCV pharmaceutical composition for treatment, by the methods as described in (1) and (2) above.
[0021]
Furthermore, unless specifically described otherwise, in the case where the symbols in any of the formulae in the present specification are also used in other formulae, the same symbols denote the same meanings.
Effects of the Invention [0022]
The present production method is superior in operability from the viewpoints that a diamino acid can be eliminated in a single step. According to the present production method, for example, since the compound of the formula (III) or a salt thereof of the present invention does not cause by-production of thiohydantoins or the like in a step in which an Edman degradation reaction can be omitted, even without purification by means of chromatography, the compound of the formula (A), an intermediate for producing the same, or a salt of each thereof can be obtained at a high purity by crystallization. Accordingly, it can be scaled up to the industrial level.
Best Mode for Carrying Out the Invention [0023]
Hereinbelow, the present invention will be described in detail.
In the present specification, the "protective group" is a group which does not have any effect on a functional group even during the deprotection while not interfering with the reaction. Examples thereof include protective groups described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)", edited by P. G.
M. Wuts and T. W. Greene, and the like, and the protective group may be appropriately selected according the reaction conditions and used.
Furthermore, unless specifically described otherwise, in the case where the symbols in any of the formulae in the present specification are also used in other formulae, the same symbols denote the same meanings.
Effects of the Invention [0022]
The present production method is superior in operability from the viewpoints that a diamino acid can be eliminated in a single step. According to the present production method, for example, since the compound of the formula (III) or a salt thereof of the present invention does not cause by-production of thiohydantoins or the like in a step in which an Edman degradation reaction can be omitted, even without purification by means of chromatography, the compound of the formula (A), an intermediate for producing the same, or a salt of each thereof can be obtained at a high purity by crystallization. Accordingly, it can be scaled up to the industrial level.
Best Mode for Carrying Out the Invention [0023]
Hereinbelow, the present invention will be described in detail.
In the present specification, the "protective group" is a group which does not have any effect on a functional group even during the deprotection while not interfering with the reaction. Examples thereof include protective groups described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)", edited by P. G.
M. Wuts and T. W. Greene, and the like, and the protective group may be appropriately selected according the reaction conditions and used.
[0024]
As for the "N-terminal" or the "C-terminal", in the linear peptide, an amino group or a carboxyl group exists on both terminals, but the "N-terminal" means a side on which an amino group exists and the "C-terminal" means a side on which a carboxyl group exists.
As for the "N-terminal" or the "C-terminal", in the linear peptide, an amino group or a carboxyl group exists on both terminals, but the "N-terminal" means a side on which an amino group exists and the "C-terminal" means a side on which a carboxyl group exists.
[0025]
The expression "which may be substituted" means which is not substituted or which has 1 to 5 substituents. Further, if it has a plurality of substituents, such substituents may be the same as or different from each other.
The expression "which may be substituted" means which is not substituted or which has 1 to 5 substituents. Further, if it has a plurality of substituents, such substituents may be the same as or different from each other.
[0026]
Unless otherwise specifically denoted, the "lower" means a group having 1 to 6 carbon atoms (hereinafter simply referred to as C1_6), and preferably 1 to 4 carbon atoms.
Unless otherwise specifically denoted, the "lower" means a group having 1 to 6 carbon atoms (hereinafter simply referred to as C1_6), and preferably 1 to 4 carbon atoms.
[0027]
The "lower alkyl" is linear or branched C1_6 alkyl, and it is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or the like, in another embodiment, C1_4 alkyl, and in a further embodiment, methyl, ethyl, or propyl.
The "lower alkyl" is linear or branched C1_6 alkyl, and it is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or the like, in another embodiment, C1_4 alkyl, and in a further embodiment, methyl, ethyl, or propyl.
[0028]
The "lower alkylene" is a linear or branched C1_6 alkylene, and it is, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, or the like, and in another embodiment, C14 alkylene.
The "lower alkylene" is a linear or branched C1_6 alkylene, and it is, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, or the like, and in another embodiment, C14 alkylene.
[0029]
The "lower alkoxy" is a linear or branched C1_6 alkylalkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, and the like. In another embodiment, it is methoxy, ethoxy, or propoxy.
The "lower alkoxy" is a linear or branched C1_6 alkylalkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, and the like. In another embodiment, it is methoxy, ethoxy, or propoxy.
[0030]
The "cycloalkyl" is C3_6 alkylcyclic alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The "cycloalkyl" is C3_6 alkylcyclic alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[0031]
The "aryl" is phenyl, naphthyl, anthryl, or the like.
The "aryl" is phenyl, naphthyl, anthryl, or the like.
[0032]
The "aralkyl" is lower alkyl substituted with 1 to 5 aryl groups, such as phenylpropyl, phenethyl, benzyl, and the like.
The "aralkyl" is lower alkyl substituted with 1 to 5 aryl groups, such as phenylpropyl, phenethyl, benzyl, and the like.
[0033]
The "aralkoxy" is lower alkoxy substituted with 1 to 5 aryl groups, such as phenylpropoxy, phenethyloxy, benzyloxy, and the like.
The "aralkoxy" is lower alkoxy substituted with 1 to 5 aryl groups, such as phenylpropoxy, phenethyloxy, benzyloxy, and the like.
[0034]
Suitable examples of the "amino which may be substituted" include amino which may be substituted with 1 or 2 suitable substituent(s), such as lower alkyl, an amino protective group (for example, benzyloxycarbonyl, Boc, and the like), etc.
Suitable examples of the "amino which may be substituted" include amino which may be substituted with 1 or 2 suitable substituent(s), such as lower alkyl, an amino protective group (for example, benzyloxycarbonyl, Boc, and the like), etc.
[0035]
Suitable examples of the "carbamoyloxy which may be substituted" include carbamoyloxy which may be substituted with 1 or 2 suitable substituent(s), such as lower alkyl, a protective group for an amino group (for example, benzyloxycarbonyl, Boc, and the like), etc.
Suitable examples of the "carbamoyloxy which may be substituted" include carbamoyloxy which may be substituted with 1 or 2 suitable substituent(s), such as lower alkyl, a protective group for an amino group (for example, benzyloxycarbonyl, Boc, and the like), etc.
[0036]
The "heterocycle" is as follows:
(1) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 to 4 nitrogen atom(s), such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (for example: 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, and the like), tetrazolyl (for example 1H-tetrazolyl, 2H-tetrazolyl, and the like), azepinyl, and the like;
(2) a saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 to 4 nitrogen atom(s), such as aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, 2,5-methanopiperazinyl, hexahydroazepinyl, and the like;
(3) an unsaturated condensed heterocycle containing 1 to 4 nitrogen atom(s), such as indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroindolyl, dihydroindazolyl, and the like;
(4) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), such as oxazolyl, isoxazolyl, oxadiazolyl (for example: 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, and the like), and the like;
(5) saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), such as morpholinyl, sydnonyl, and the like;
(6) an unsaturated condensed heterocycle containing 1 or 2 oxygen atom(s) and to 3 nitrogen atom(s), such as benzoxazolyl, benzoxadiazolyl, and the like;
(7) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), such as thiazolyl, isothiazolyl, thiadiazolyl (for example: 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, and the like), dihydrothiazinyl, and the like;
(8) a saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), such as thiazolidinyl, and the like;
(9) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 sulfur atom(s), such as thienyl, dihydrodithiinyl, dihydrodithionyl, and the like;
(10) an unsaturated condensed heterocycle containing 1 or 2 sulfur atom(s) and to 3 nitrogen atom(s), such as benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, and the like;
(11) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing an oxygen atom, such as furyl and the like;
(12) a saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 oxygen atom(s), such as oxiranyl, 1,3-dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like;
(13) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing an oxygen atom and 1 or 2 sulfur atom(s), such as dihydroxathiinyl, and the like;
(14) an unsaturated condensed heterocycle containing 1 or 2 sulfur atom(s), such as benzothienyl, benzodithiinyl, and the like;
(15) an unsaturated condensed heterocycle containing an oxygen atom and 1 or 2 sulfur atom(s), such as benzoxathiinyl and the like;
(16) a saturated condensed heteromonocycle containing 1 to 3 nitrogen atom(s), such as tetrahydropyridopyrrolidinyl and the like; etc.
The "heterocycle" is as follows:
(1) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 to 4 nitrogen atom(s), such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (for example: 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, and the like), tetrazolyl (for example 1H-tetrazolyl, 2H-tetrazolyl, and the like), azepinyl, and the like;
(2) a saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 to 4 nitrogen atom(s), such as aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, 2,5-methanopiperazinyl, hexahydroazepinyl, and the like;
(3) an unsaturated condensed heterocycle containing 1 to 4 nitrogen atom(s), such as indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroindolyl, dihydroindazolyl, and the like;
(4) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), such as oxazolyl, isoxazolyl, oxadiazolyl (for example: 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, and the like), and the like;
(5) saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), such as morpholinyl, sydnonyl, and the like;
(6) an unsaturated condensed heterocycle containing 1 or 2 oxygen atom(s) and to 3 nitrogen atom(s), such as benzoxazolyl, benzoxadiazolyl, and the like;
(7) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), such as thiazolyl, isothiazolyl, thiadiazolyl (for example: 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, and the like), dihydrothiazinyl, and the like;
(8) a saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), such as thiazolidinyl, and the like;
(9) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 sulfur atom(s), such as thienyl, dihydrodithiinyl, dihydrodithionyl, and the like;
(10) an unsaturated condensed heterocycle containing 1 or 2 sulfur atom(s) and to 3 nitrogen atom(s), such as benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, and the like;
(11) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing an oxygen atom, such as furyl and the like;
(12) a saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 oxygen atom(s), such as oxiranyl, 1,3-dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like;
(13) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing an oxygen atom and 1 or 2 sulfur atom(s), such as dihydroxathiinyl, and the like;
(14) an unsaturated condensed heterocycle containing 1 or 2 sulfur atom(s), such as benzothienyl, benzodithiinyl, and the like;
(15) an unsaturated condensed heterocycle containing an oxygen atom and 1 or 2 sulfur atom(s), such as benzoxathiinyl and the like;
(16) a saturated condensed heteromonocycle containing 1 to 3 nitrogen atom(s), such as tetrahydropyridopyrrolidinyl and the like; etc.
[0037]
Suitable examples of the "nitrogen-containing heterocycle" are those in (1) to (7) as described above, and in another embodiment, are heterocycles containing at least one nitrogen atom, such as pyrrolidinyl, piperidyl, morpholinyl, thiazolyl, oxazolyl, and the like.
Suitable examples of the "nitrogen-containing heterocycle" are those in (1) to (7) as described above, and in another embodiment, are heterocycles containing at least one nitrogen atom, such as pyrrolidinyl, piperidyl, morpholinyl, thiazolyl, oxazolyl, and the like.
[0038]
Suitable examples of the "heterocycle" which may be substituted are the above-described heterocycles, which may be substituted with at least one appropriate substituent, such as lower alkyl, lower alkoxy, aryl, amino, lower alkoxycarbonyl, and the like.
Suitable examples of the "heterocycle" which may be substituted are the above-described heterocycles, which may be substituted with at least one appropriate substituent, such as lower alkyl, lower alkoxy, aryl, amino, lower alkoxycarbonyl, and the like.
[0039]
The "halogen" means fluorine, chlorine, bromine, or iodine.
The "halogen" means fluorine, chlorine, bromine, or iodine.
[0040]
In the present specification, the following abbreviations may be used in some cases.
CPME=cyclopentylmethylether, DIBOC=di-tert-butyl dicarbonate, DME=1,2-dimethoxyethane, DMF=N,N-dimethylformamide, DMI=1,3-dimethyl-2-3 0 imidazolidinone, DMSO=dimethylsulfoxdie, DIPEA=diisopropylethylamine, DPPA=diphenylphosphorylazide, EtOAc=ethyl acetate, Ex= Example No., HOBt=1-hydroxybenzotriazole, IPA=isopropyl alcohol, KH2PO4=potassium dihydrogen phosphate, NMP=N-methylpyrrolidone, Na2CO3=sodium carbonate, Na2HPO4=disodium hydrogen phosphate, TEA=triethylamine, TFA=trifluoroacetic acid, WSC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, tBuOH=tertiary butanol, LR-ESIMS=1ow-resolution-ESIMS, HR-ESIMS=high-resolution-ESIMS, Me=methyl, iBu=isobutyl, iPr=isopropyl, Boc=tertiary butoxycarbonyl, Ph=phenyl, No.=number.
In the present specification, the following abbreviations may be used in some cases.
CPME=cyclopentylmethylether, DIBOC=di-tert-butyl dicarbonate, DME=1,2-dimethoxyethane, DMF=N,N-dimethylformamide, DMI=1,3-dimethyl-2-3 0 imidazolidinone, DMSO=dimethylsulfoxdie, DIPEA=diisopropylethylamine, DPPA=diphenylphosphorylazide, EtOAc=ethyl acetate, Ex= Example No., HOBt=1-hydroxybenzotriazole, IPA=isopropyl alcohol, KH2PO4=potassium dihydrogen phosphate, NMP=N-methylpyrrolidone, Na2CO3=sodium carbonate, Na2HPO4=disodium hydrogen phosphate, TEA=triethylamine, TFA=trifluoroacetic acid, WSC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, tBuOH=tertiary butanol, LR-ESIMS=1ow-resolution-ESIMS, HR-ESIMS=high-resolution-ESIMS, Me=methyl, iBu=isobutyl, iPr=isopropyl, Boc=tertiary butoxycarbonyl, Ph=phenyl, No.=number.
[0041]
The compound of the present invention may exist in the form of geometric isomers. In the present specification, the compound of the present invention shall be described in only one form of isomer, but the present invention includes such an isomer, isolated forms of the isomers, or a mixture thereof.
In addition, the compound of the present invention has asymmetric carbon atoms, and correspondingly, it exists in the form of optical isomers. The present invention includes both an isolated form of these optical isomers of the compound of the present invention, or a mixture thereof.
The compound of the present invention may exist in the form of geometric isomers. In the present specification, the compound of the present invention shall be described in only one form of isomer, but the present invention includes such an isomer, isolated forms of the isomers, or a mixture thereof.
In addition, the compound of the present invention has asymmetric carbon atoms, and correspondingly, it exists in the form of optical isomers. The present invention includes both an isolated form of these optical isomers of the compound of the present invention, or a mixture thereof.
[0042]
Furthermore, the compound of the present invention may form a salt with an acid or a base, depending on the kind of substituents, in some cases. Specifically, examples of the salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditolyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like or organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, salts with various amino acids or amino acid derivatives such as acetylleucine and the like, ammonium salts, etc.
Furthermore, the compound of the present invention may form a salt with an acid or a base, depending on the kind of substituents, in some cases. Specifically, examples of the salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditolyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like or organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, salts with various amino acids or amino acid derivatives such as acetylleucine and the like, ammonium salts, etc.
[0043]
In addition, the present invention also includes various hydrates or solvates, and polymorphic crystal substances of the compound of the present invention and a salt thereof. Also, the present invention includes compounds labeled with various radioactive or non-radioactive isotopes.
In addition, the present invention also includes various hydrates or solvates, and polymorphic crystal substances of the compound of the present invention and a salt thereof. Also, the present invention includes compounds labeled with various radioactive or non-radioactive isotopes.
[0044]
(Production Methods) Hereinbelow, representative production methods for the compounds of the formula (I) to (VIII) will be described.
(First Step) [Chem. 19]
Me iBu Me O O Me HN N N O HO Me iBu\ -I-O 0 Pr Me ORx O N.Prot (I) O NMe H
O H u 0 H iBu N, Me iB
~
Me N NyN N -N O
H Me 0 Me iBu 0 Me Me HO
iBu Me 0 Me HN(N N O HO Me Deprotection iBu O 0 Pr Me OR x O NH2 (II) 0 NMOe H iBu O H iBu N, Me N N ~O
Me N NIN
H Me O Me iBu 0 Me Me HO
iBu Me 0 Me HN(N)A N O H Me OH
Elimination of BuO 0 Pr Me ORx + 0 N
Diamino Acid N 0 0 NMe O H iBu O H iBu Me Me IN NNN NH
H (III-1) Me 0 Me iBu 0 Me (III) [wherein Prot means a protective group].
(Production Methods) Hereinbelow, representative production methods for the compounds of the formula (I) to (VIII) will be described.
(First Step) [Chem. 19]
Me iBu Me O O Me HN N N O HO Me iBu\ -I-O 0 Pr Me ORx O N.Prot (I) O NMe H
O H u 0 H iBu N, Me iB
~
Me N NyN N -N O
H Me 0 Me iBu 0 Me Me HO
iBu Me 0 Me HN(N N O HO Me Deprotection iBu O 0 Pr Me OR x O NH2 (II) 0 NMOe H iBu O H iBu N, Me N N ~O
Me N NIN
H Me O Me iBu 0 Me Me HO
iBu Me 0 Me HN(N)A N O H Me OH
Elimination of BuO 0 Pr Me ORx + 0 N
Diamino Acid N 0 0 NMe O H iBu O H iBu Me Me IN NNN NH
H (III-1) Me 0 Me iBu 0 Me (III) [wherein Prot means a protective group].
[0045]
The present step is a step in which the N-terminal is deprotected, and then a diamino acid is eliminated in a single step under the heating condition.
When R" is a protective group, examples thereof include lower alkyl which may be substituted with phenyl, lower alkyl which may be substituted with aryl, and the like.
In another embodiment, examples thereof include lower alkyl, benzyl, and tert-butyl.
Examples of Prot include carbamate, toluenesulfonyl, nitrobenzenesulfonyl, and the like. In another embodiment, examples thereof include Boc, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and allyloxycarbonyl.
For deprotection, reference may be made to, for example, a deprotection reaction for each protective group as described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)", edited by P. G. M. Wuts and T. W. Greene, and the deprotection may be appropriately selected and used according to these reaction conditions.
By warming the starting material intermediate in a solvent, the diamino acid is eliminated. As a reaction temperature, conditions from heating to reflux are preferable.
The solvent is not limited as long as it does not disturb the reaction. As the solvent, for example, CPME, dioxane, THF, DMSO, DMF, IPA, tBuOH, NMP, DMI, DME, water, or the like is used, ether-based solvents or water is preferable, and CPME-aqueous solvents are particularly preferable. The reaction may be either homogeneous or biphase, but biphase is particularly preferred. It may be advantageous to carry out the reaction in the presence of an acid or a base, or salts. Usually, to the reaction liquid is added a buffer solution, and thus, the reaction is carried out in the water-containing system. Examples of the buffer solution include phosphate buffers, Tris buffers, and the like, but phosphate buffers are preferred. The temperature varies depending on the solvent, and the reaction is carried out at a temperature of from 30 C to a refluxing temperature of the solvent, for example, from 30 C to 180 C. A temperature from 50 C to 120 C is preferred, and a temperature from 60 C to 85 C is particularly preferred. As in the description in Examples as described later, the product can be obtained as a crystal even without a seed crystal, but when the seed crystal is added to precipitate the crystal, the crystal may be easily precipitated in some cases.
The present step is a step in which the N-terminal is deprotected, and then a diamino acid is eliminated in a single step under the heating condition.
When R" is a protective group, examples thereof include lower alkyl which may be substituted with phenyl, lower alkyl which may be substituted with aryl, and the like.
In another embodiment, examples thereof include lower alkyl, benzyl, and tert-butyl.
Examples of Prot include carbamate, toluenesulfonyl, nitrobenzenesulfonyl, and the like. In another embodiment, examples thereof include Boc, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and allyloxycarbonyl.
For deprotection, reference may be made to, for example, a deprotection reaction for each protective group as described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)", edited by P. G. M. Wuts and T. W. Greene, and the deprotection may be appropriately selected and used according to these reaction conditions.
By warming the starting material intermediate in a solvent, the diamino acid is eliminated. As a reaction temperature, conditions from heating to reflux are preferable.
The solvent is not limited as long as it does not disturb the reaction. As the solvent, for example, CPME, dioxane, THF, DMSO, DMF, IPA, tBuOH, NMP, DMI, DME, water, or the like is used, ether-based solvents or water is preferable, and CPME-aqueous solvents are particularly preferable. The reaction may be either homogeneous or biphase, but biphase is particularly preferred. It may be advantageous to carry out the reaction in the presence of an acid or a base, or salts. Usually, to the reaction liquid is added a buffer solution, and thus, the reaction is carried out in the water-containing system. Examples of the buffer solution include phosphate buffers, Tris buffers, and the like, but phosphate buffers are preferred. The temperature varies depending on the solvent, and the reaction is carried out at a temperature of from 30 C to a refluxing temperature of the solvent, for example, from 30 C to 180 C. A temperature from 50 C to 120 C is preferred, and a temperature from 60 C to 85 C is particularly preferred. As in the description in Examples as described later, the product can be obtained as a crystal even without a seed crystal, but when the seed crystal is added to precipitate the crystal, the crystal may be easily precipitated in some cases.
[0046]
(Second Step) [Chem. 20]
Me Me iBu Me O HO
PhN=C=S HNNN O
(B1) iBu\ ~O 0 Pr Me ORX (IV) (III) ~ ~' O NMOe H iBu 0 H iBu S
Me N N N N N NHPh H Me 0 Me iBu 0 Me Me iBu Me O HO Me HNYNN O
iBu,O 0 Pr Me ORX
f Ac d (V) O NMe iBu 0 O N
Me N--'Y yj_N-I-yNH z H Me 0 Me iBu [0047]
The present step is Edman degradation, which is a step of eliminating an amino acid of the peptide from the N-terminal.
It includes two steps of subjecting phenyl isothiocyanate at the N-terminal under weakly basic conditions, and eliminating the amino acid under acidic conditions as 3-phenyl-2-thiohydantoin. As for the solvent, the reaction is usually carried out in a common solvent such as an organic solvent not giving an adverse effect on the reaction, such as acetonitrile, acetone, alcohols such as MeOH, EtOH, and the like, THF, dioxane, toluene, methylene chloride, chloroform, EtOAc, DMF, and the like, or a mixed solvent thereof, and the like. The reaction temperature is not limited, and the reaction is usually carried out under conditions from cooling to heating. The present reaction can be carried out by, for example, the method disclosed in M. K. Eberle et al., J.
Org. Chem. 59, 7249-725 8 (1994) or the like, or an equivalent method.
(Second Step) [Chem. 20]
Me Me iBu Me O HO
PhN=C=S HNNN O
(B1) iBu\ ~O 0 Pr Me ORX (IV) (III) ~ ~' O NMOe H iBu 0 H iBu S
Me N N N N N NHPh H Me 0 Me iBu 0 Me Me iBu Me O HO Me HNYNN O
iBu,O 0 Pr Me ORX
f Ac d (V) O NMe iBu 0 O N
Me N--'Y yj_N-I-yNH z H Me 0 Me iBu [0047]
The present step is Edman degradation, which is a step of eliminating an amino acid of the peptide from the N-terminal.
It includes two steps of subjecting phenyl isothiocyanate at the N-terminal under weakly basic conditions, and eliminating the amino acid under acidic conditions as 3-phenyl-2-thiohydantoin. As for the solvent, the reaction is usually carried out in a common solvent such as an organic solvent not giving an adverse effect on the reaction, such as acetonitrile, acetone, alcohols such as MeOH, EtOH, and the like, THF, dioxane, toluene, methylene chloride, chloroform, EtOAc, DMF, and the like, or a mixed solvent thereof, and the like. The reaction temperature is not limited, and the reaction is usually carried out under conditions from cooling to heating. The present reaction can be carried out by, for example, the method disclosed in M. K. Eberle et al., J.
Org. Chem. 59, 7249-725 8 (1994) or the like, or an equivalent method.
[0048]
(Third Step) [Chem. 21]
Me HO
iBu Me 0 Me HNNN ORX
i Bu (V) Protection O O iPr Me 0 (VI) O We iBu O O H H
Me N N N N'Prot' H Me 0 Me iBu Me HO
iBu Me 0 H Me 0 (1) Deprotection (when HN N N N 0P rot Rx is a protective group) iBu\ O O iPr Me 0 Me OH
(VII) 0 2 0 NMOe H iBu O H
H rot N N.
(2) O Me N
N Prot AY I
Me OH H Me O Me iBu (B2) Condensation Me HO Me O
iBu Me O
HNNN N 0-Prot2 Deprotection iBuO 0 iPr Me 0 Me OH
O NMe (VIII) iBu 0 Me N 0 H N N H 5 H Me 0 Me iBu [wherein each of Prot' and Prot2 means a protective group].
(Third Step) [Chem. 21]
Me HO
iBu Me 0 Me HNNN ORX
i Bu (V) Protection O O iPr Me 0 (VI) O We iBu O O H H
Me N N N N'Prot' H Me 0 Me iBu Me HO
iBu Me 0 H Me 0 (1) Deprotection (when HN N N N 0P rot Rx is a protective group) iBu\ O O iPr Me 0 Me OH
(VII) 0 2 0 NMOe H iBu O H
H rot N N.
(2) O Me N
N Prot AY I
Me OH H Me O Me iBu (B2) Condensation Me HO Me O
iBu Me O
HNNN N 0-Prot2 Deprotection iBuO 0 iPr Me 0 Me OH
O NMe (VIII) iBu 0 Me N 0 H N N H 5 H Me 0 Me iBu [wherein each of Prot' and Prot2 means a protective group].
[0049]
The present step is a step in which the N-terminal of a chained peptide as an intermediate is protected, a protected threonine is condensed to a C-terminal, and then the N-terminal is deprotected.
Examples of Prot2 include lower alkyl which may be substituted with phenyl, lower alkyl which may be substituted with aryl, and the like. In another embodiment, examples thereof include lower alkyl, benzyl, and tert-butyl.
Examples of Prot' include carbamate, toluenesulfonyl, nitrobenzenesulfonyl, and the like. In another embodiment, examples thereof include Boc, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl.
In order to condense a protected threonine to the C-terminal of the chained peptide of the substrate, the condensation can be carried out in the same manner as a so-called amidation reaction. Specifically, the compound of the formula (VII) or a salt thereof can be obtained by reacting the compound of the formula (VI) or a salt thereof with the protected threonine of the formula (B2). In this reaction, the compound of the formula (VI) or a salt thereof and the protected threonine of the formula (B2) are used in equal amounts or with an excess amount of either, and the mixture is stirred under any temperature condition from cooling to heating in a solvent which is inert to the reaction, preferably at -20 C to 60 C, usually for 0.1 hours to 5 days. Examples of the solvent used herein are not particularly limited, but the examples include aromatic hydrocarbons such as toluene, xylene, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, ethers such as diethyl ether, THF, dioxane, dimethoxyethane, and the like, DMF, DMSO, EtOAc, MeCN, water, and a mixture thereof. Examples of the condensing agent include, but are not limited to, WSC, DPPA, and phosphorous oxychloride. It may be preferable for the reaction to use an additive (for example, HOBt) in some cases. It may be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of organic bases such as TEA, DIPEA, N-methylmorpholine, and the like, or inorganic bases such as K2CO3, Na2CO3, KOH, and the like.
Furthermore, a method in which the compound of the formula (VII) or a salt thereof is converted to its reactive derivative, followed by performing a reaction with the protected threonine of the formula (B2) may be used. Examples of the reactive derivative of the carboxylic acid include acid halides that can be obtained by the reaction of a halogenating agent such as phosphorus oxychloride, thionyl chloride, and the like, mixed acid anhydrides obtained by the reaction of isobutyl chloroformate or the like, active esters obtained by the condensation with HOBt or the like, etc. The reaction of the reactive derivative and the protected threonine of the formula (B2) can be carried out at a temperature from under cooling to heating, preferably at -20 C to 60 C, in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like.
[Citation] "Organic Functional Group Preparations", S. R. Sandler and W. Karo, 2a edition, Vol. 1, Academic Press Inc., 1991 "Courses in Experimental Chemistry (5th edition)", edited by The Chemical Society of Japan, vol. 16 (2005) (Maruzen Company, Limited) [0050]
(Fourth Step) The compound of the formula (III) or a salt thereof, the compound of the formula (V) or a salt thereof, or the compound of the formula (VIII) or a salt thereof can be protected or deprotected using a suitable protective group in a suitable process, and condensed with an amino acid or peptide, thereby producing the compound of the formula (A) or a salt thereof. The cyclization reaction is amidation, and thus, it can be carried out according to the method as in the above-described third step, and accordingly, reference may be made to the third step for the reagent and reaction conditions used (for example, a solvent, a reaction temperature, and the like).
[00511 (Starting Material Synthesis) As described above, the compound of the formula (I) or a salt thereof can be produced using an FR901459 substance as a starting material in accordance with Patent Citation 1.
The FR901459 substance can be obtained by, for example, the method described in Patent Citation 2 from a culture of a Stachybotrys spp. microorganism (Stachybotrys chartarum No. 19292), deposited at International Patent Organism Depositary National Institute of Advanced Industrial Science and Technology, Tsukuba Central 6, 1-1-1, Higashi, Tsukuba-shi, Ibaraki-ken, (Postal Code) 305-8566, JAPAN on April 16, with deposit No. FERM BP-3364.
[0052]
Example Compounds are isolated and purified as free compounds, salts thereof, hydrates, solvates, or polymorphic crystal substances thereof. The salt of Example Compounds can also be produced in accordance with a conventional method for a salt formation reaction. Isolation and purification are carried out by employing extraction or fractional crystallization.
Examples [0053]
Hereinbelow, the methods for producing the compounds of the formulae (I) to (VIII) will be described in detail with reference to Examples. The structures of Example Compounds are shown in Table 4.
[0054]
Example 1 (Production of the compound of the formula (I), wherein Prot is Boc) 93.8 mg of (6S,12S,15S,18S,21S,24R,27S,30S,33S,36S)-6-[(1R)-1-hydroxyethyl] -3 6-[(1 R,2R,4E)-1-hydroxy-2-methyl-4-hexen- l -yl] -12,15,18,27,30-pentaisobutyl-33-isopropyl-2,2,8,11,17,21,24,26,32,35-decamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20,23,26,29,32,35-undecaazaheptatriacontan-37-oic acid was obtained in accordance with the method described in Patent Citation 1.
[0055]
Example 2 (Production of the compound of the formula (II)) 50.0 g of Example Compound 1 was dissolved in 500 mL of methylene chloride, followed by cooling to 5 C, and 213.2 g of TFA was added dropwise thereto, followed by stirring for 4 hours. Thereafter, 500 mL of cooled tap water was added thereto, followed by adjustment to pH 6.5 with a 10 (w/v) % aqueous Na2CO3 solution. After liquid separation, to the organic layer was added 500 mL of cooled tap water again, followed by adjustment to pH 6.5 to 7 with a 10 (w/v) % aqueous Na2CO3 solution. After liquid separation, the organic layer was collected by separation, and the lower layer was concentrated to about 250 mL, followed by addition of 500 mL of CPME and concentration to about 250 mL again. 500 mL of CPME was added thereto, followed by concentration under reduced pressure to about 250 mL. About 250 mL of a solution of Example Compound 2 in CPME was obtained.
[0056]
HR-ESIMS Found m/z 1236.8547 (M+H)+
Calcd for C62H114N11014, 1236.8546 [0057]
Example 3 (Production of the compound of the formula (III)) To about 250 mL of the solution of Example Compound 2 in CPME were added 500 mL of CPME and 500 mL of an aqueous phosphate buffer solution at pH 7.6 (the aqueous Na2HPO4 solution was adjusted to pH 7.6 with an aqueous KH2PO4 solution; the aqueous Na2HPO4 solution was prepared by dissolving 6.26 g of Na2HPO4.12H20in mL of water; the aqueous KH2PO4 solution was prepared by dissolving 0.377 g of KH2PO4 in 81 mL of water), followed by elevating the temperature to 80 to 85 C, stirring for 5 hours, and then cooling to 25 C. The organic layer obtained by liquid separation was washed with 500 mL of tap water twice. The organic layer was concentrated to about 105 mL, and then 115 mL of acetonitrile was added dropwise thereto.
Thereafter, 75 mg of the seed crystal of Example Compound 3 was added thereto at an inner temperature of 22 C, and 345 mL of acetonitrile was further added dropwise thereto.
The precipitated crystal liquid was collected by filtration and then dried under reduced pressure to obtain (2 S,3 R,4R,6E)-3-hydroxy-4-methyl-2-[methyl(N-methyl-L-leucyl-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl)amino]octa-6-enoic acid as a white powder. Amount: 22.7 g, Yield: 56.9%
[0058]
'3C-NMR (125 MHz, CDC13, 8):175.7 (s), 174.1 (s), 173.1 (s), 172.8 (s), 172.3 (s), 171.6 (s), 171.0 (s), 170.6 (s), 168.1 (s), 129.0 (d), 126.9 (d), 75.5 (d), 61.2 (d), 60.2 (d), 58.4 (d), 55.3 (d), 54.4 (d), 48.1 (d), 47.8 (d), 47.2 (d), 45.5 (d), 41.3 (t), 41.1 (t), 38.6 (t), 36.1 (t), 36.1 (d), 36.0 (t), 35.9 (t), 34.3 (q), 31.2 (q), 30.8 (q), 30.2 (q), 30.1 (q), 27.0 (d), 25.1 (d), 25.1 (d), 24.9 (d), 24.8 (d), 24.8 (d), 23.6 (q), 23.4 (q), 23.3 (q), 22.9 (q), 22.9 (q), 22.4 (q), 21.9 (q), 21.6 (q), 21.4 (q), 21.3 (q), 19.5 (q), 18.1 (q), 18.0 (q), 16.8 (q), 16.2 (q), 15.4 (q). (main conformers) HR-ESIMS Found m/z 1064.7697 (M+H)+
Calcd for C55H102N9011, 1064.7698 [0059]
Further, a part of the reaction liquid of Example 3 was collected, and by the following analysis results, it was confirmed that 3 -(1-hydroxyethyl)-1-methylpiperazine-2,5-dione was produced.
Column: Waters Atlantis HILIC Silica Column, 2.1 x50mm, 3 m; Gradient:
CH3CN-HCOOH=1000-1-CH3CN-H2O-HCOOH=500-500-1(0 min->5 min), CH3CN-H20-HCOOH=500-500-1(5 min->7 min), CH3CN-H2O-HCOOH=500-500-1)-->CH3CN-HCOOH=1000-1(7 min-+7.1 min), CH3CN-HCOOH=1000:1 (7.1 min--> 10 min), flow rate: 0.5 mL/min, Detector: diode array (210 nm to 600 nm), Retention Time:
1.51 min.
13C-NMR (100MHz, DMSO-d6):166.3, 166.2, 68.5, 60.6, 51.2, 32.9, 19.8 'H-NMR (400MHz, DMSO-d6):1.08 (3H, d, J=6.6Hz), 2.82 (3H, s), 3.52 (1H, brs), 3.66 (1 H, d, J=16.8Hz), 3.96 (1 H, d, J=16.8Hz), 3.99 to 4.04 (1 H, m), 8.26 (1 H, brs), MS: ESI (+)/TOF-MS, Found 173.0922 (M+H)+, Calcd for C7H13N203, 173.0921 [0060]
Example 3-1 (Method for Producing Amorphous Substance) To a solution of Example Compound 2 in CPME (corresponding to 40.0 g/800 mL) was added 400 mL of an aqueous phosphate buffer solution at pH 7.6 (the pH
of the aqueous Na2HPO4 solution was adjusted to pH 7.6 with the aqueous KH2PO4 solution;
the aqueous Na2HPO4 solution was prepared by dissolving 6.26 g of Na2HPO4.12H2O in 522 mL of water; the aqueous KH2PO4 solution was prepared by dissolving 0.377 g of KH2PO4 in 81 mL of water), followed by elevating the temperature to 80 to 85 C, stirring for 5 hours and 30 minutes, and then cooling to room temperature. The organic layer obtained by liquid separation was washed sequentially with 400 mL of tap water and 400 mL of 20 (w/v) % brine. The organic layer was concentrated to about 280 mL, and then 1800 mL of n-heptane was added dropwise thereto. The precipitated powder was collected by filtration and then dried under reduced pressure to obtain (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-[methyl(N-methyl-L-leucyl-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl)amino]octa-6-enoic acid as powder. Amount: 32.17 g, Yield: 93.4%
[0061]
(Method for Producing Seed Crystal) 25.0 g of the powder of Example Compound 3 was dissolved in a mixed solvent of 40 mL of CPME and 160 mL of acetonitrile at 25 to 45 C. Thereafter, the mixture was cooled slowly to 20 C over 1 hour, and stirred at 20 C for 18 hours. The precipitated crystal was collected by filtration and then dried under reduced pressure to obtain (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-[methyl(N-methyl-L-leucyl-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl)amino]octa-6-enoic acid as a crystal. Amount: 13.02 g, Yield: 52.1%
[0062]
Example 4 (Production of the compound of the formula (IV)) 10.0 g of Example Compound 3 was dissolved in 150 mL of EtOAc, and then 50 mL of a phosphate buffer at pH 7.6 (the pH of the aqueous Na2HPO4 solution was adjusted to pH 7.6 with the aqueous KH2PO4 solution; the aqueous Na2HPO4 solution was prepared by dissolving 1.04 g of Na2HP04- 12H2O in 87.5 L of water; the aqueous KH2PO4 solution was prepared by dissolving 0.568 g of KH2PO4 in 12.5 L of water) and 2.54 g of phenylisothiocyanate were added thereto, followed by stirring for 4 hours.
Thereafter, the pH was adjusted to 2.3 with 1 M hydrochloric acid. After liquid separation, the organic layer was collected by separation, washed with 100 mL
of 20 (w/v) % brine, and then concentrated to about 40 mL. Thus, about 40 mL of a solution of Example Compound 4 in EtOAc was obtained.
LR-ESIMS: 1222.0 (M+Na)+, 1198.1 (M-H)-[0063]
Example 5 (Production of the compound of the formula (V)) To about 40 mL of Example Compound 4 in EtOAc was further added dropwise 200 mL of n-heptane. The precipitated powder was collected by filtration, and then dissolved in 100 mL of acetonitrile, and 94 mL of 1 M hydrochloric acid was added thereto, followed by stirring at 20 C for 3 hours and 15 minutes. It was confirmed that Example Compound 5 was obtained.
HR-ESIMS Found m/z 937.6712 (M+H)+
Calcd for C481-189N8010, 937.6701 [0064]
Example 6 (Production of the compound of the formula (VI), wherein Prot, is Boc) A 10 (w/v) % aqueous Na2CO3 solution was further added to the reaction liquid of Example Compound 5 so as to adjust the pH to about 7. 2.25 g of DIBOC was added thereto, followed by stirring at 25 C for 3 hours and 20 minutes, and then adjustment to pH 2.5 with 1 M hydrochloric acid. The organic layer was collected by separation and 100 mL of 20 (w/v) % brine was added thereto, followed by extraction with 100 mL of EtOAc. The organic layer was collected by separation and then concentrated to about mL and 150 mL of EtOAc was added again thereto, followed by concentration to about 40 mL. To this concentrated liquid was added again 150 mL of EtOAc, followed by concentration to about 40 mL. Then, the mixture was cooled to 5 C and added dropwise to 40 mL of n-heptane that had been cooled to 5 C in advance. The precipitated powder was filtered and then dried under reduced pressure to obtain (2S ,3 R,4R,6E)-2- { [N-(tert-butoxycarbonyl)-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl] (methyl)amino } -3-hydroxy-methylocta-6-enoic acid as white powder. Amount: 7.6 g, Yield: 77.9%
[0065]
13C-NMR (125 MHz, CDC13, S) 175.2 (s), 174.4 (s), 173.3 (s), 173.2 (s), 172.8 (s), 172.1 (s), 170.7 (s), 169.9 (s), 155.7 (s), 128.8 (d), 127.1 (d), 79.6 (s), 75.3 (d), 59.2 (d), 57.5 (d), 55.2 (d), 54.6 (d), 49.1 (d), 48.5 (d), 48.2 (d), 45.8 (d), 41.7 (t), 41.1 (t), 36.6 (t), 36.4 (d), 36.0 (t), 36.0 (t), 34.7 (q), 30.8 (q), 30.7 (q), 29.9 (q), 28.2 (q)x3, 27.2 (d), 25.0 (d), 24.9 (d), 24.8 (d), 24.6 (d), 23.4 (q), 23.4 (q), 23.2 (q), 23.0 (q), 22.0 (q), 21.7 (q), 21.5 (q), 21.4 (q), 19.1 (q), 18.2 (q), 18.0 (q), 17.5 (q), 16.8 (q), 15.3 (q). (main conformers) HR-ESIMS Found m/z 1037.7219 (M+H)+
Calcd for C53H97N8012, 1037.7225 [0066]
Example 7 (Production of the compound of the formula (VII) wherein Prot, is Boc and Prot2 is methyl) 7.5 g of Example Compound 6 was dissolved in 75 mL of methylene chloride, and 1.47 g of L-threonine methyl ester hydrochloride and 1.47 g of HOBt=monohydrate were added thereto, followed by cooling to 0 to 10 C. Further, 1.12 g of WSC
was added thereto, followed by stirring at 5 C for about 20 hours, and then the organic layer was washed with 75 mL of tap water. The aqueous layer was re-extracted with 38 mL of methylene chloride and the organic layer was combined. The organic layer was washed with 68 mL of 0.3 M hydrochloric acid and the aqueous layer was re-extracted with 38 mL of methylene chloride again. The organic layer was combined, then washed sequentially with 76 mL of a 5(w/v) % aqueous NaHCO3 solution and 55 mL of 20 (w/v) % brine, and concentrated to about 30 mL. The concentrated liquid was added dropwise to 300 mL of heptane. The precipitated powder was collected by filtration and then dried under reduced pressure to obtain (N-[(2S,3R,4R,6E)-2-{[N-(tert-butoxycarbonyl)-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl](methyl)amino}-3-hydroxy-4-methylocta-6-enoyl]-L-threoninemethyl ester as white powder. Amount: 7.12 g, Yield: 85.5%
[0067]
'3C-NMR (125 MHz, CDC13, 8):174.1 (s), 174.0 (s), 173.5 (s), 172.5 (s), 172.4 (s), 171.4 (s), 171.2 (s), 170.8 (s), 170.4 (s), 155.7 (s), 128.5 (d), 127.3 (d), 79.5 (s), 74.5 (d), 67.7 (d), 58.3 (d), 58.3 (d), 57.3 (d), 55.1 (d), 54.9 (d), 52.6 (q), 49.1 (d), 48.0 (d), 47.7 (d), 45.8 (d), 42.0 (t), 40.8 (t), 36.4 (t), 36.1 (t), 35.5 (t), 35.4 (d), 34.6 (q), 30.9 (q), 30.7 (q), 30.3 (q), 28.3 (q) x3, 27.0 (d), 25.0 (d), 25.0 (d), 24.9 (d), 24.7 (d), 23.4 (q), 23.4 (q), 23.3 (q), 23.1 (q), 22.1 (q), 21.8 (q), 21.4 (q), 21.3 (q), 20.2 (q), 19.4 (q), 18.1 (q), 18.0 (q), 17.0 (q), 17.0 (q), 15.7 (q). (main conformers) HR-ESIMS Found m/z 1152.7864 (M+H)+
Calcd for C58H106N9014, 1152.7859 [0068]
Example 8 (Production of the compound of the formula (VIII), wherein Prot2 is methyl) 20.0 g of Example Compound 7 was dissolved in 120 mL of methylene chloride, followed by cooling to -5 C. 98.9 g of TFA was added dropwise thereto, followed by stirring for 2 hours and 40 minutes and then washing with 200 mL of cooled tap water.
The organic layer obtained by liquid separation was further washed with 200 mL
of cooled tap water. To the organic layer was added 200 mL of cooled tap water, followed by further adjustment to pH 6.5 to 7 using a 10 (w/v) % aqueous Na2CO3 solution. To the organic layer obtained by liquid separation was added 200 mL of cooled tap water again, followed by adjustment to pH 6.5 to 7 with a 10 (w/v) % aqueous Na2CO3 solution. The organic layer obtained by liquid separation was added to 200 mL
of cooled tap water again, followed by adjustment to pH 6.5 to 7 with a 10 (w/v) % aqueous Na2CO3 solution. The organic layer obtained by liquid separation was concentrated under reduced pressure to about 50 mL. The concentrated liquid was added dropwise to 1500 mL of heptane. The precipitated powder was collected by filtration and then dried under reduced pressure to obtain N-{(2 S,3 R,4R,6E)-3-hydroxy-2-[(L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl) (methyl)amino] -4-methylocta-6-enoyl}-L-threoninemethyl ester as white powder. Amount: 16.82 g, Yield: 92.1%.
As a result of comparison of the obtained Example Compound 8 with the compound of Prep 3 of Patent Citation 1 in terms of NMR and MS data, it was confirmed that they have the same structures.
[0069]
HR-ESIMS Found m/z 1052.7347 (M+H)+
Calcd for C53H98N9012, 1052.7335 [Table 2]
Me HO
Me iBu Me 0 HN'J"rN N R
iBu` ~O O Pr Me 0 O~NMOe H iBu O H
IT N N. 2 Me N ~N R
H Me O Me iBu Example Compound R' R2 iBu 0 Me NHBoc 1 -OH N -If1 Me O MeO OH
iBu O Me NH2 2 -OH N Me O MeO OH
iBu O Me iBu S
4 -OH yN~NHPh O Me 6 -OH -Boc Me 7 0 -Boc Me "'OH
H O
8 ,, OMe -H
Me "'OH
Industrial Applicability [0070]
The present production method is superior in operability from the viewpoints that a diamino acid can be eliminated in a single step. According to the present production method, for example, since the compound of the formula (III) or a salt thereof of the present invention does not cause by-production of thiohydantoins or the like in a step in which an Edman degradation reaction can be omitted, even without purification by means of chromatography, the compound of the formula (A), an intermediate for producing the same, or a salt of each thereof can be obtained at a high purity by crystallization. Accordingly, it can be scaled up to the industrial level.
The present step is a step in which the N-terminal of a chained peptide as an intermediate is protected, a protected threonine is condensed to a C-terminal, and then the N-terminal is deprotected.
Examples of Prot2 include lower alkyl which may be substituted with phenyl, lower alkyl which may be substituted with aryl, and the like. In another embodiment, examples thereof include lower alkyl, benzyl, and tert-butyl.
Examples of Prot' include carbamate, toluenesulfonyl, nitrobenzenesulfonyl, and the like. In another embodiment, examples thereof include Boc, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl.
In order to condense a protected threonine to the C-terminal of the chained peptide of the substrate, the condensation can be carried out in the same manner as a so-called amidation reaction. Specifically, the compound of the formula (VII) or a salt thereof can be obtained by reacting the compound of the formula (VI) or a salt thereof with the protected threonine of the formula (B2). In this reaction, the compound of the formula (VI) or a salt thereof and the protected threonine of the formula (B2) are used in equal amounts or with an excess amount of either, and the mixture is stirred under any temperature condition from cooling to heating in a solvent which is inert to the reaction, preferably at -20 C to 60 C, usually for 0.1 hours to 5 days. Examples of the solvent used herein are not particularly limited, but the examples include aromatic hydrocarbons such as toluene, xylene, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, ethers such as diethyl ether, THF, dioxane, dimethoxyethane, and the like, DMF, DMSO, EtOAc, MeCN, water, and a mixture thereof. Examples of the condensing agent include, but are not limited to, WSC, DPPA, and phosphorous oxychloride. It may be preferable for the reaction to use an additive (for example, HOBt) in some cases. It may be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of organic bases such as TEA, DIPEA, N-methylmorpholine, and the like, or inorganic bases such as K2CO3, Na2CO3, KOH, and the like.
Furthermore, a method in which the compound of the formula (VII) or a salt thereof is converted to its reactive derivative, followed by performing a reaction with the protected threonine of the formula (B2) may be used. Examples of the reactive derivative of the carboxylic acid include acid halides that can be obtained by the reaction of a halogenating agent such as phosphorus oxychloride, thionyl chloride, and the like, mixed acid anhydrides obtained by the reaction of isobutyl chloroformate or the like, active esters obtained by the condensation with HOBt or the like, etc. The reaction of the reactive derivative and the protected threonine of the formula (B2) can be carried out at a temperature from under cooling to heating, preferably at -20 C to 60 C, in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like.
[Citation] "Organic Functional Group Preparations", S. R. Sandler and W. Karo, 2a edition, Vol. 1, Academic Press Inc., 1991 "Courses in Experimental Chemistry (5th edition)", edited by The Chemical Society of Japan, vol. 16 (2005) (Maruzen Company, Limited) [0050]
(Fourth Step) The compound of the formula (III) or a salt thereof, the compound of the formula (V) or a salt thereof, or the compound of the formula (VIII) or a salt thereof can be protected or deprotected using a suitable protective group in a suitable process, and condensed with an amino acid or peptide, thereby producing the compound of the formula (A) or a salt thereof. The cyclization reaction is amidation, and thus, it can be carried out according to the method as in the above-described third step, and accordingly, reference may be made to the third step for the reagent and reaction conditions used (for example, a solvent, a reaction temperature, and the like).
[00511 (Starting Material Synthesis) As described above, the compound of the formula (I) or a salt thereof can be produced using an FR901459 substance as a starting material in accordance with Patent Citation 1.
The FR901459 substance can be obtained by, for example, the method described in Patent Citation 2 from a culture of a Stachybotrys spp. microorganism (Stachybotrys chartarum No. 19292), deposited at International Patent Organism Depositary National Institute of Advanced Industrial Science and Technology, Tsukuba Central 6, 1-1-1, Higashi, Tsukuba-shi, Ibaraki-ken, (Postal Code) 305-8566, JAPAN on April 16, with deposit No. FERM BP-3364.
[0052]
Example Compounds are isolated and purified as free compounds, salts thereof, hydrates, solvates, or polymorphic crystal substances thereof. The salt of Example Compounds can also be produced in accordance with a conventional method for a salt formation reaction. Isolation and purification are carried out by employing extraction or fractional crystallization.
Examples [0053]
Hereinbelow, the methods for producing the compounds of the formulae (I) to (VIII) will be described in detail with reference to Examples. The structures of Example Compounds are shown in Table 4.
[0054]
Example 1 (Production of the compound of the formula (I), wherein Prot is Boc) 93.8 mg of (6S,12S,15S,18S,21S,24R,27S,30S,33S,36S)-6-[(1R)-1-hydroxyethyl] -3 6-[(1 R,2R,4E)-1-hydroxy-2-methyl-4-hexen- l -yl] -12,15,18,27,30-pentaisobutyl-33-isopropyl-2,2,8,11,17,21,24,26,32,35-decamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20,23,26,29,32,35-undecaazaheptatriacontan-37-oic acid was obtained in accordance with the method described in Patent Citation 1.
[0055]
Example 2 (Production of the compound of the formula (II)) 50.0 g of Example Compound 1 was dissolved in 500 mL of methylene chloride, followed by cooling to 5 C, and 213.2 g of TFA was added dropwise thereto, followed by stirring for 4 hours. Thereafter, 500 mL of cooled tap water was added thereto, followed by adjustment to pH 6.5 with a 10 (w/v) % aqueous Na2CO3 solution. After liquid separation, to the organic layer was added 500 mL of cooled tap water again, followed by adjustment to pH 6.5 to 7 with a 10 (w/v) % aqueous Na2CO3 solution. After liquid separation, the organic layer was collected by separation, and the lower layer was concentrated to about 250 mL, followed by addition of 500 mL of CPME and concentration to about 250 mL again. 500 mL of CPME was added thereto, followed by concentration under reduced pressure to about 250 mL. About 250 mL of a solution of Example Compound 2 in CPME was obtained.
[0056]
HR-ESIMS Found m/z 1236.8547 (M+H)+
Calcd for C62H114N11014, 1236.8546 [0057]
Example 3 (Production of the compound of the formula (III)) To about 250 mL of the solution of Example Compound 2 in CPME were added 500 mL of CPME and 500 mL of an aqueous phosphate buffer solution at pH 7.6 (the aqueous Na2HPO4 solution was adjusted to pH 7.6 with an aqueous KH2PO4 solution; the aqueous Na2HPO4 solution was prepared by dissolving 6.26 g of Na2HPO4.12H20in mL of water; the aqueous KH2PO4 solution was prepared by dissolving 0.377 g of KH2PO4 in 81 mL of water), followed by elevating the temperature to 80 to 85 C, stirring for 5 hours, and then cooling to 25 C. The organic layer obtained by liquid separation was washed with 500 mL of tap water twice. The organic layer was concentrated to about 105 mL, and then 115 mL of acetonitrile was added dropwise thereto.
Thereafter, 75 mg of the seed crystal of Example Compound 3 was added thereto at an inner temperature of 22 C, and 345 mL of acetonitrile was further added dropwise thereto.
The precipitated crystal liquid was collected by filtration and then dried under reduced pressure to obtain (2 S,3 R,4R,6E)-3-hydroxy-4-methyl-2-[methyl(N-methyl-L-leucyl-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl)amino]octa-6-enoic acid as a white powder. Amount: 22.7 g, Yield: 56.9%
[0058]
'3C-NMR (125 MHz, CDC13, 8):175.7 (s), 174.1 (s), 173.1 (s), 172.8 (s), 172.3 (s), 171.6 (s), 171.0 (s), 170.6 (s), 168.1 (s), 129.0 (d), 126.9 (d), 75.5 (d), 61.2 (d), 60.2 (d), 58.4 (d), 55.3 (d), 54.4 (d), 48.1 (d), 47.8 (d), 47.2 (d), 45.5 (d), 41.3 (t), 41.1 (t), 38.6 (t), 36.1 (t), 36.1 (d), 36.0 (t), 35.9 (t), 34.3 (q), 31.2 (q), 30.8 (q), 30.2 (q), 30.1 (q), 27.0 (d), 25.1 (d), 25.1 (d), 24.9 (d), 24.8 (d), 24.8 (d), 23.6 (q), 23.4 (q), 23.3 (q), 22.9 (q), 22.9 (q), 22.4 (q), 21.9 (q), 21.6 (q), 21.4 (q), 21.3 (q), 19.5 (q), 18.1 (q), 18.0 (q), 16.8 (q), 16.2 (q), 15.4 (q). (main conformers) HR-ESIMS Found m/z 1064.7697 (M+H)+
Calcd for C55H102N9011, 1064.7698 [0059]
Further, a part of the reaction liquid of Example 3 was collected, and by the following analysis results, it was confirmed that 3 -(1-hydroxyethyl)-1-methylpiperazine-2,5-dione was produced.
Column: Waters Atlantis HILIC Silica Column, 2.1 x50mm, 3 m; Gradient:
CH3CN-HCOOH=1000-1-CH3CN-H2O-HCOOH=500-500-1(0 min->5 min), CH3CN-H20-HCOOH=500-500-1(5 min->7 min), CH3CN-H2O-HCOOH=500-500-1)-->CH3CN-HCOOH=1000-1(7 min-+7.1 min), CH3CN-HCOOH=1000:1 (7.1 min--> 10 min), flow rate: 0.5 mL/min, Detector: diode array (210 nm to 600 nm), Retention Time:
1.51 min.
13C-NMR (100MHz, DMSO-d6):166.3, 166.2, 68.5, 60.6, 51.2, 32.9, 19.8 'H-NMR (400MHz, DMSO-d6):1.08 (3H, d, J=6.6Hz), 2.82 (3H, s), 3.52 (1H, brs), 3.66 (1 H, d, J=16.8Hz), 3.96 (1 H, d, J=16.8Hz), 3.99 to 4.04 (1 H, m), 8.26 (1 H, brs), MS: ESI (+)/TOF-MS, Found 173.0922 (M+H)+, Calcd for C7H13N203, 173.0921 [0060]
Example 3-1 (Method for Producing Amorphous Substance) To a solution of Example Compound 2 in CPME (corresponding to 40.0 g/800 mL) was added 400 mL of an aqueous phosphate buffer solution at pH 7.6 (the pH
of the aqueous Na2HPO4 solution was adjusted to pH 7.6 with the aqueous KH2PO4 solution;
the aqueous Na2HPO4 solution was prepared by dissolving 6.26 g of Na2HPO4.12H2O in 522 mL of water; the aqueous KH2PO4 solution was prepared by dissolving 0.377 g of KH2PO4 in 81 mL of water), followed by elevating the temperature to 80 to 85 C, stirring for 5 hours and 30 minutes, and then cooling to room temperature. The organic layer obtained by liquid separation was washed sequentially with 400 mL of tap water and 400 mL of 20 (w/v) % brine. The organic layer was concentrated to about 280 mL, and then 1800 mL of n-heptane was added dropwise thereto. The precipitated powder was collected by filtration and then dried under reduced pressure to obtain (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-[methyl(N-methyl-L-leucyl-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl)amino]octa-6-enoic acid as powder. Amount: 32.17 g, Yield: 93.4%
[0061]
(Method for Producing Seed Crystal) 25.0 g of the powder of Example Compound 3 was dissolved in a mixed solvent of 40 mL of CPME and 160 mL of acetonitrile at 25 to 45 C. Thereafter, the mixture was cooled slowly to 20 C over 1 hour, and stirred at 20 C for 18 hours. The precipitated crystal was collected by filtration and then dried under reduced pressure to obtain (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-[methyl(N-methyl-L-leucyl-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl)amino]octa-6-enoic acid as a crystal. Amount: 13.02 g, Yield: 52.1%
[0062]
Example 4 (Production of the compound of the formula (IV)) 10.0 g of Example Compound 3 was dissolved in 150 mL of EtOAc, and then 50 mL of a phosphate buffer at pH 7.6 (the pH of the aqueous Na2HPO4 solution was adjusted to pH 7.6 with the aqueous KH2PO4 solution; the aqueous Na2HPO4 solution was prepared by dissolving 1.04 g of Na2HP04- 12H2O in 87.5 L of water; the aqueous KH2PO4 solution was prepared by dissolving 0.568 g of KH2PO4 in 12.5 L of water) and 2.54 g of phenylisothiocyanate were added thereto, followed by stirring for 4 hours.
Thereafter, the pH was adjusted to 2.3 with 1 M hydrochloric acid. After liquid separation, the organic layer was collected by separation, washed with 100 mL
of 20 (w/v) % brine, and then concentrated to about 40 mL. Thus, about 40 mL of a solution of Example Compound 4 in EtOAc was obtained.
LR-ESIMS: 1222.0 (M+Na)+, 1198.1 (M-H)-[0063]
Example 5 (Production of the compound of the formula (V)) To about 40 mL of Example Compound 4 in EtOAc was further added dropwise 200 mL of n-heptane. The precipitated powder was collected by filtration, and then dissolved in 100 mL of acetonitrile, and 94 mL of 1 M hydrochloric acid was added thereto, followed by stirring at 20 C for 3 hours and 15 minutes. It was confirmed that Example Compound 5 was obtained.
HR-ESIMS Found m/z 937.6712 (M+H)+
Calcd for C481-189N8010, 937.6701 [0064]
Example 6 (Production of the compound of the formula (VI), wherein Prot, is Boc) A 10 (w/v) % aqueous Na2CO3 solution was further added to the reaction liquid of Example Compound 5 so as to adjust the pH to about 7. 2.25 g of DIBOC was added thereto, followed by stirring at 25 C for 3 hours and 20 minutes, and then adjustment to pH 2.5 with 1 M hydrochloric acid. The organic layer was collected by separation and 100 mL of 20 (w/v) % brine was added thereto, followed by extraction with 100 mL of EtOAc. The organic layer was collected by separation and then concentrated to about mL and 150 mL of EtOAc was added again thereto, followed by concentration to about 40 mL. To this concentrated liquid was added again 150 mL of EtOAc, followed by concentration to about 40 mL. Then, the mixture was cooled to 5 C and added dropwise to 40 mL of n-heptane that had been cooled to 5 C in advance. The precipitated powder was filtered and then dried under reduced pressure to obtain (2S ,3 R,4R,6E)-2- { [N-(tert-butoxycarbonyl)-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl] (methyl)amino } -3-hydroxy-methylocta-6-enoic acid as white powder. Amount: 7.6 g, Yield: 77.9%
[0065]
13C-NMR (125 MHz, CDC13, S) 175.2 (s), 174.4 (s), 173.3 (s), 173.2 (s), 172.8 (s), 172.1 (s), 170.7 (s), 169.9 (s), 155.7 (s), 128.8 (d), 127.1 (d), 79.6 (s), 75.3 (d), 59.2 (d), 57.5 (d), 55.2 (d), 54.6 (d), 49.1 (d), 48.5 (d), 48.2 (d), 45.8 (d), 41.7 (t), 41.1 (t), 36.6 (t), 36.4 (d), 36.0 (t), 36.0 (t), 34.7 (q), 30.8 (q), 30.7 (q), 29.9 (q), 28.2 (q)x3, 27.2 (d), 25.0 (d), 24.9 (d), 24.8 (d), 24.6 (d), 23.4 (q), 23.4 (q), 23.2 (q), 23.0 (q), 22.0 (q), 21.7 (q), 21.5 (q), 21.4 (q), 19.1 (q), 18.2 (q), 18.0 (q), 17.5 (q), 16.8 (q), 15.3 (q). (main conformers) HR-ESIMS Found m/z 1037.7219 (M+H)+
Calcd for C53H97N8012, 1037.7225 [0066]
Example 7 (Production of the compound of the formula (VII) wherein Prot, is Boc and Prot2 is methyl) 7.5 g of Example Compound 6 was dissolved in 75 mL of methylene chloride, and 1.47 g of L-threonine methyl ester hydrochloride and 1.47 g of HOBt=monohydrate were added thereto, followed by cooling to 0 to 10 C. Further, 1.12 g of WSC
was added thereto, followed by stirring at 5 C for about 20 hours, and then the organic layer was washed with 75 mL of tap water. The aqueous layer was re-extracted with 38 mL of methylene chloride and the organic layer was combined. The organic layer was washed with 68 mL of 0.3 M hydrochloric acid and the aqueous layer was re-extracted with 38 mL of methylene chloride again. The organic layer was combined, then washed sequentially with 76 mL of a 5(w/v) % aqueous NaHCO3 solution and 55 mL of 20 (w/v) % brine, and concentrated to about 30 mL. The concentrated liquid was added dropwise to 300 mL of heptane. The precipitated powder was collected by filtration and then dried under reduced pressure to obtain (N-[(2S,3R,4R,6E)-2-{[N-(tert-butoxycarbonyl)-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl](methyl)amino}-3-hydroxy-4-methylocta-6-enoyl]-L-threoninemethyl ester as white powder. Amount: 7.12 g, Yield: 85.5%
[0067]
'3C-NMR (125 MHz, CDC13, 8):174.1 (s), 174.0 (s), 173.5 (s), 172.5 (s), 172.4 (s), 171.4 (s), 171.2 (s), 170.8 (s), 170.4 (s), 155.7 (s), 128.5 (d), 127.3 (d), 79.5 (s), 74.5 (d), 67.7 (d), 58.3 (d), 58.3 (d), 57.3 (d), 55.1 (d), 54.9 (d), 52.6 (q), 49.1 (d), 48.0 (d), 47.7 (d), 45.8 (d), 42.0 (t), 40.8 (t), 36.4 (t), 36.1 (t), 35.5 (t), 35.4 (d), 34.6 (q), 30.9 (q), 30.7 (q), 30.3 (q), 28.3 (q) x3, 27.0 (d), 25.0 (d), 25.0 (d), 24.9 (d), 24.7 (d), 23.4 (q), 23.4 (q), 23.3 (q), 23.1 (q), 22.1 (q), 21.8 (q), 21.4 (q), 21.3 (q), 20.2 (q), 19.4 (q), 18.1 (q), 18.0 (q), 17.0 (q), 17.0 (q), 15.7 (q). (main conformers) HR-ESIMS Found m/z 1152.7864 (M+H)+
Calcd for C58H106N9014, 1152.7859 [0068]
Example 8 (Production of the compound of the formula (VIII), wherein Prot2 is methyl) 20.0 g of Example Compound 7 was dissolved in 120 mL of methylene chloride, followed by cooling to -5 C. 98.9 g of TFA was added dropwise thereto, followed by stirring for 2 hours and 40 minutes and then washing with 200 mL of cooled tap water.
The organic layer obtained by liquid separation was further washed with 200 mL
of cooled tap water. To the organic layer was added 200 mL of cooled tap water, followed by further adjustment to pH 6.5 to 7 using a 10 (w/v) % aqueous Na2CO3 solution. To the organic layer obtained by liquid separation was added 200 mL of cooled tap water again, followed by adjustment to pH 6.5 to 7 with a 10 (w/v) % aqueous Na2CO3 solution. The organic layer obtained by liquid separation was added to 200 mL
of cooled tap water again, followed by adjustment to pH 6.5 to 7 with a 10 (w/v) % aqueous Na2CO3 solution. The organic layer obtained by liquid separation was concentrated under reduced pressure to about 50 mL. The concentrated liquid was added dropwise to 1500 mL of heptane. The precipitated powder was collected by filtration and then dried under reduced pressure to obtain N-{(2 S,3 R,4R,6E)-3-hydroxy-2-[(L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl) (methyl)amino] -4-methylocta-6-enoyl}-L-threoninemethyl ester as white powder. Amount: 16.82 g, Yield: 92.1%.
As a result of comparison of the obtained Example Compound 8 with the compound of Prep 3 of Patent Citation 1 in terms of NMR and MS data, it was confirmed that they have the same structures.
[0069]
HR-ESIMS Found m/z 1052.7347 (M+H)+
Calcd for C53H98N9012, 1052.7335 [Table 2]
Me HO
Me iBu Me 0 HN'J"rN N R
iBu` ~O O Pr Me 0 O~NMOe H iBu O H
IT N N. 2 Me N ~N R
H Me O Me iBu Example Compound R' R2 iBu 0 Me NHBoc 1 -OH N -If1 Me O MeO OH
iBu O Me NH2 2 -OH N Me O MeO OH
iBu O Me iBu S
4 -OH yN~NHPh O Me 6 -OH -Boc Me 7 0 -Boc Me "'OH
H O
8 ,, OMe -H
Me "'OH
Industrial Applicability [0070]
The present production method is superior in operability from the viewpoints that a diamino acid can be eliminated in a single step. According to the present production method, for example, since the compound of the formula (III) or a salt thereof of the present invention does not cause by-production of thiohydantoins or the like in a step in which an Edman degradation reaction can be omitted, even without purification by means of chromatography, the compound of the formula (A), an intermediate for producing the same, or a salt of each thereof can be obtained at a high purity by crystallization. Accordingly, it can be scaled up to the industrial level.
Claims (6)
- [Claim 1]
A method for producing a compound of the formula (III) or a salt thereof:
(wherein R X means -H or a protective group, iBu means isobutyl, iPr means isopropyl, and Me means methyl), which comprises eliminating a diamino acid from a compound of the formula (II) or a salt thereof:
- [Claim 2]
A method for producing a compound of the formula (VI) or a salt thereof:
[Chem. 25]
(wherein R X means -H or a protective group, iBu means isobutyl, iPr means isopropyl, Me means methyl, and Prot0 and Prot1 mean protective groups), which comprises subjecting a compound of the formula (I) or a salt thereof:
to a deprotection reaction to obtain a compound of the formula (II) or a salt thereof, and introducing a protective group to the compound of the formula (III) or a salt thereof obtained by the step described in claim 1. - [Claim 3]
A method for producing a compound of the formula (A) or a salt thereof:
(wherein X is or R1 is -H, or lower alkyl;
R2 is -H, aryl, or lower alkyl, wherein the lower alkyl may be substituted with one suitable substituent selected from the group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, aralkoxy, carbamoyloxy which may be substituted, and amino which may be substituted;
is a nitrogen-containing heterocycle; and Y is or R3 is cycloalkyl, aryl, a heterocycle which may be substituted, or lower alkyl, wherein the lower alkyl may be substituted with one suitable substituent selected from the group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, aralkoxy, lower alkoxy-lower alkylene-O-, amino which may be substituted, and -OC(O)NR6R7, (wherein R6 and R7 each independently represent -H or lower alkyl, or R6 and R7, together with a nitrogen atom to which they bind, represent a nitrogen-containing heterocycle, which may be substituted with lower alkyl);
R4 and R5 each independently represent -H or lower alkyl;
~ represents a single bond or a double bond.
(provided that if R2 is -H, R3 is cycloalkyl, aryl, a heterocycle which may be substituted, lower alkoxymethyl, aralkyl, t-butyl, sec-butyl, cycloalkyl, or ethyl, wherein the ethyl may be substituted with one suitable substituent selected from the group consisting of lower alkyl, or hydroxy, lower alkyl-O-, aryl-lower alkylene-O-, lower alkyl-O-lower alkylene-O-, amino which may be substituted, and -OC(O) NR6R)), from the compound of the formula (VI) or a salt thereof obtained from the compound of the formula (I) or a salt thereof by the production method of claim 2. - [Claim 4]
A method for producing a compound of the formula (VIII) or a salt thereof:
(wherein iBu means isobutyl, iPr means isopropyl, Me means methyl, and Prot2 means a protective group), which comprises subjecting the compound of the formula (VI) or a salt thereof obtained from the compound of the formula (I) or a salt thereof according to the production method of claim 2 to condensation with a protected threonine at the carboxylic acid terminal, and deprotecting the amino terminal. - [Claim 5]
A method for producing a compound of the formula (A) or a salt thereof, which comprises subjecting the compound of the formula (VIII) or a salt thereof obtained from the compound of the formula (I) or a salt thereof according to the method described in claim 3 to condensation with a diamino acid at the amino terminal, carrying out deprotection, and then carrying out cyclization. - [Claim 6]
A compound or a salt thereof selected from the group consisting of:
(wherein iBu means isobutyl, iPr means isopropyl, Boc means tertiary butoxycarbonyl, Me means methyl, and Ph means phenyl).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008-244410 | 2008-09-24 | ||
| JP2008244410 | 2008-09-24 | ||
| PCT/JP2009/066449 WO2010035722A1 (en) | 2008-09-24 | 2009-09-18 | Peptide compound and method for producing same |
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| Publication Number | Publication Date |
|---|---|
| CA2738280A1 true CA2738280A1 (en) | 2010-04-01 |
Family
ID=42059721
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| CA2738280A Abandoned CA2738280A1 (en) | 2008-09-24 | 2009-09-18 | Peptide compound and method for producing the same |
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|---|---|
| JP (1) | JP5625910B2 (en) |
| KR (1) | KR20110073473A (en) |
| CN (1) | CN102164947A (en) |
| CA (1) | CA2738280A1 (en) |
| MX (1) | MX2011003259A (en) |
| WO (1) | WO2010035722A1 (en) |
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| GB0320638D0 (en) * | 2003-09-03 | 2003-10-01 | Novartis Ag | Organic compounds |
| JP2007015926A (en) * | 2003-10-06 | 2007-01-25 | Fujisawa Pharmaceut Co Ltd | Hepatitis C therapeutic agent |
| PL1957518T3 (en) * | 2005-10-26 | 2016-07-29 | Astellas Pharma Inc | New cyclic peptide compounds |
| MX2009011512A (en) * | 2007-05-02 | 2009-11-12 | Astellas Pharma Inc | New cyclic peptide compounds. |
-
2009
- 2009-09-18 MX MX2011003259A patent/MX2011003259A/en active IP Right Grant
- 2009-09-18 CA CA2738280A patent/CA2738280A1/en not_active Abandoned
- 2009-09-18 KR KR1020117006749A patent/KR20110073473A/en not_active Withdrawn
- 2009-09-18 WO PCT/JP2009/066449 patent/WO2010035722A1/en active Application Filing
- 2009-09-18 CN CN2009801381065A patent/CN102164947A/en active Pending
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| KR20110073473A (en) | 2011-06-29 |
| WO2010035722A1 (en) | 2010-04-01 |
| MX2011003259A (en) | 2011-04-21 |
| CN102164947A (en) | 2011-08-24 |
| JPWO2010035722A1 (en) | 2012-02-23 |
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