TWI683823B - 製備環縮肽之方法 - Google Patents
製備環縮肽之方法 Download PDFInfo
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- TWI683823B TWI683823B TW104117108A TW104117108A TWI683823B TW I683823 B TWI683823 B TW I683823B TW 104117108 A TW104117108 A TW 104117108A TW 104117108 A TW104117108 A TW 104117108A TW I683823 B TWI683823 B TW I683823B
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- Prior art keywords
- alkyl
- group
- cycloalkyl
- compound
- heterocycloalkyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title abstract description 35
- 108010002156 Depsipeptides Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 180
- 125000000217 alkyl group Chemical group 0.000 claims description 117
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 94
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 70
- 229910052799 carbon Inorganic materials 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 150000001408 amides Chemical class 0.000 claims description 22
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 150000002148 esters Chemical group 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 150000001412 amines Chemical class 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 10
- 150000001413 amino acids Chemical class 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 5
- 101100347605 Arabidopsis thaliana VIII-A gene Proteins 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims 11
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 203
- -1 amino Acid ester Chemical class 0.000 description 110
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 27
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- 0 C[C@@](*)(C(O[C@@](CC(*)=O)C=CCCCl)=O)NC(*)=O Chemical compound C[C@@](*)(C(O[C@@](CC(*)=O)C=CCCCl)=O)NC(*)=O 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- 239000002253 acid Substances 0.000 description 22
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 20
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 19
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 125000000623 heterocyclic group Chemical group 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 13
- 125000005843 halogen group Chemical group 0.000 description 13
- 239000012038 nucleophile Substances 0.000 description 13
- ASFCWAMAQOUEFY-UHFFFAOYSA-N tert-butyl 1,3-thiazole-4-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CSC=N1 ASFCWAMAQOUEFY-UHFFFAOYSA-N 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- 150000007970 thio esters Chemical group 0.000 description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 11
- 229940011051 isopropyl acetate Drugs 0.000 description 11
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 239000007821 HATU Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 8
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- GIMDYEZZNCXDLJ-HNQUOIGGSA-N (e)-5-chloropent-2-enal Chemical compound ClCC\C=C\C=O GIMDYEZZNCXDLJ-HNQUOIGGSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000012190 activator Substances 0.000 description 6
- 125000005907 alkyl ester group Chemical group 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 238000011065 in-situ storage Methods 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- UBLMADIZVCGVFU-UHFFFAOYSA-N tert-butyl 2-(aminomethyl)-1,3-thiazole-4-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CSC(CN)=N1 UBLMADIZVCGVFU-UHFFFAOYSA-N 0.000 description 6
- HPMFJRLPVVXUNT-HNQUOIGGSA-N (e)-5-chloropent-2-en-1-ol Chemical compound OC\C=C\CCCl HPMFJRLPVVXUNT-HNQUOIGGSA-N 0.000 description 5
- SZXBQTSZISFIAO-ZETCQYMHSA-N CC(C)[C@@H](C(O)=O)NC(OC(C)(C)C)=O Chemical compound CC(C)[C@@H](C(O)=O)NC(OC(C)(C)C)=O SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 5
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 5
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 5
- 125000004185 ester group Chemical group 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 229910052707 ruthenium Inorganic materials 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 4
- HMVYYTRDXNKRBQ-UHFFFAOYSA-N 1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSC=N1 HMVYYTRDXNKRBQ-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 4
- LRDIEHDJWYRVPT-UHFFFAOYSA-N 4-amino-5-hydroxynaphthalene-1-sulfonic acid Chemical compound C1=CC(O)=C2C(N)=CC=C(S(O)(=O)=O)C2=C1 LRDIEHDJWYRVPT-UHFFFAOYSA-N 0.000 description 4
- WKEVRZCQFQDCIR-UHFFFAOYSA-N 4-chlorobut-1-ene Chemical compound ClCCC=C WKEVRZCQFQDCIR-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- AGJSNMGHAVDLRQ-IWFBPKFRSA-N methyl (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-IWFBPKFRSA-N 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 150000003141 primary amines Chemical class 0.000 description 4
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- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
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- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
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- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
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- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
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- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
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- 230000009257 reactivity Effects 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical class O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
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- GHPHCACQRYSXSS-UHFFFAOYSA-N ruthenium;tricyclohexylphosphane Chemical compound [Ru].C1CCCCC1P(C1CCCCC1)C1CCCCC1 GHPHCACQRYSXSS-UHFFFAOYSA-N 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
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- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical class *S* 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
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- MLMGCRZFVZRURX-UHFFFAOYSA-N tert-butyl 2-(aminomethyl)-1,3-thiazole-4-carboxylate hydrochloride Chemical compound Cl.NCC=1SC=C(N1)C(=O)OC(C)(C)C MLMGCRZFVZRURX-UHFFFAOYSA-N 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
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- 229940124597 therapeutic agent Drugs 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
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- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
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- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
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- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
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- 239000011992 zhan catalyst-1B Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 230000004572 zinc-binding Effects 0.000 description 1
Images
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- C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
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Abstract
本發明闡述用於製備式(1)及式(2)化合物之方法,其中X、Y、Z、R1-R7、L及n定義於本文中。本發明亦闡述可用於製備式(1)及式(2)化合物之中間體。
Description
本發明係關於經取代之環縮肽之製備及可用於其製備之中間體。如本文所述製備之環縮肽揭示於WO/2011/150283中,其全文以引用方式併入本文中。
已知根據本發明製備之環縮肽係如例如U.S.20130203681中所揭示之組蛋白去乙醯酶(HDAC)抑制劑,且已知可用於治療由HDAC失調介導之疾病,例如癌症、發炎性疾病、自體免疫疾病、過敏性疾病及中樞神經系統疾病。
或其醫藥上可接受之鹽之方法,其中:X、Y及Z獨立地係碳或氮,或另一選擇為Y係直接鍵,且X及Z獨立地係碳、氮、氧或硫;
R1及R2獨立地選自由H、C1-C10烷基及C3-C7環烷基組成之群,或R1與R2一起形成C3-C7環烷基或C3-C7雜環烷基,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR8R9、-NR8C(O)R9、NR8C(O)OR9、-NR8CO2R9及-C(O)NR8R9;R3及R4獨立地選自由H、C1-C10烷基及C3-C7環烷基組成之群,或R3及R4一起形成C3-C7環烷基或C3-C7雜環烷基,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR8R9、-NR8C(O)R9、NR8C(O)OR9、-NR8CO2R9及-C(O)NR8R9;R5及R6獨立地選自由H、C1-C10烷基及C3-C7環烷基組成之群,或R5及R6一起形成C3-C7環烷基或C3-C7雜環烷基,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR8R9、-NR8C(O)R9、NR8C(O)OR9、-NR8CO2R9及-C(O)NR8R9;R7獨立地選自由H、C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基組成之群,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-
NR8R9、-NR8C(O)R9、NR8C(O)OR9、-NR8CO2R9及-C(O)NR8R9;R8及R9獨立地選自由H、C1-C10烷基及C3-C7環烷基組成之群,或R8及R9一起形成C3-C7環烷基或C3-C7雜環烷基,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR10R11、-NR10C(O)R11、-NR10C(O)OR11及-C(O)NR10R11;R10及R11獨立地選自由H、C1-C10烷基及C3-C7環烷基組成之群,或R10及R11一起形成C3-C7環烷基或C3-C7雜環烷基;L係Cl或SR12;R12獨立地選自由以下組成之群:H、三苯基甲基、C(O)R13、CO2R13、C(O)NR13R14、C(O)CR13R14NR13R14、胺基酸、P(O)(OR15)2及SR16;R13及R14獨立地選自由H、C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基及雜芳基組成之群,或R13及R14一起形成C3-C7環烷基或C3-C7雜環烷基,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR10R11及-NR10C(O)R11,其中R10及R11係如上文所定義;R15係第三丁基或-(CH2)2Si(CH3)3;R16係C1-C10烷基或C3-C7環烷基;n係2或3,其包含:將醇(VI-A)
其中TDx係對掌性助劑,轉化成胺基甲酸酯(VIII-A)
其中R18選自由-CH2CH2Si(CH3)3、(9H-茀-9-基)甲基及第三丁基組成之群;且n、R5、R6及TDx係如上文所定義;其係藉由以下方式來實施:使醇(VI-A)與受保護之胺基酸(VII)反應
其中R5、R6及R18係如上文所定義,然後使胺基甲酸酯(VIII-A)與雜環化合物(IX)反應
其中R19選自由-CH2CH2Si(CH3)3、(9H-茀-9-基)甲基及第三丁基組成之群;且n、X、Y及Z係如上文所定義,以提供化合物(X-A)
其中n、R1、R2、R5、R6、R7、R18、R19、X、Y及Z係如上文所定義,然後自化合物(X-A)選擇性地移除胺基甲酸酯保護基團以提供胺(XVII-A)
其中n、R1、R2、R5、R6、R7、R19、X、Y及Z係如上文所定義,然後使化合物(XVII-A)與受保護之胺基酸(VII-A)反應
其中R3、R4及R18係如上文所定義;以提供醯胺(XVIII-A)
其中n、R1至R7、R18、R19、X、Y及Z係如上文所定義,然後由醯胺(XVIII-A)脫除保護基,形成化合物(XIX-A)
其中n、R1至R7、X、Y及Z係如上文所定義,然後環閉合成化合物(XX-A)
其中n、R1至R7、X、Y及Z係如上文所定義,然後使(XX-A)與R12-SH反應以提供式(1)化合物。
在本發明之態樣中,R5係H,且R6選自由H、異丙基及甲基組成之群。
在本發明之態樣中,R5係H且R6係異丙基。
在本發明之態樣中,R12係C(O)C7烷基。
在本發明之態樣中,R12係C(O)(CH2)6CH3。
在本發明之態樣中,R3及R4係甲基。
在本發明之態樣中,R12係C(O)CR13R14NR13R14。
或其醫藥上可接受之鹽之方法,其中:X、Y及Z獨立地係碳或氮,或另一選擇為Y係直接鍵,且X及Z獨立地係碳、氮、氧或硫;R1及R2獨立地選自由H、C1-C10烷基及C3-C7環烷基組成之群,或R1及R2一起形成C3-C7環烷基或C3-C7雜環烷基,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜
芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR8R9、-NR8C(O)R9、-NR8C(O)OR9、-NR8CO2R9及-C(O)NR8R9;R3選自由H、C1-C10烷基及C3-C7環烷基組成之群,或R3及R4一起形成C3-C7環烷基或C3-C7雜環烷基,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR8R9、-NR8C(O)R9、NR8C(O)OR9、-NR8CO2R9及-C(O)NR8R9;R5及R6獨立地選自由H、C1-C10烷基及C3-C7環烷基組成之群,或R5及R6一起形成C3-C7環烷基或C3-C7雜環烷基,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR8R9、-NR8C(O)R9、-NR8C(O)OR9、-NR8CO2R9及-C(O)NR8R9;R7獨立地選自由H、C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基組成之群,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR8R9、-NR8C(O)R9、NR8C(O)OR9、-NR8CO2R9及-C(O)NR8R9;R8及R9獨立地選自由H、C1-C10烷基及C3-C7環烷基組成之群,或R8及R9一起形成C3-C7環烷基或C3-C7雜環烷基,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之
取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR10R11、-NR10C(O)R11、-NR10C(O)OR11及-C(O)NR10R11;R10及R11獨立地選自由H、C1-C10烷基及C3-C7環烷基組成之群,或R10及R11一起形成C3-C7環烷基或C3-C7雜環烷基;且R13選自由C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基及雜芳基組成之群,其中C1-C10烷基、C3-C7環烷基及C3-C7雜環烷基視情況經一或多個選自由以下組成之群之取代基取代:C1-C10烷基、C3-C7環烷基、C3-C7雜環烷基、芳基、雜芳基、鹵基、羥基、-CN、-COOH、-CF3、-OCH2F、-OCHF2、-OC1-C10烷基、O-芳基、O-雜芳基、-NR10R11及-NR10C(O)R11,其中R10及R11係如上文所定義,其包含使胺基甲酸酯(VIII)
其中R18選自由-CH2CH2Si(CH3)3、(9H-茀-9-基)甲基及第三丁基組成之群;TDx係對掌性助劑;且R5及R6係如上文所定義,與雜環化合物(XXVI)反應
其中R1、R2、R3、R7、X、Y及Z係如上文所定義,以提供化合物(XXVII)
其中R1、R2、R3、R5、R6、R7、R18、X、Y及Z係如上文所定義,然後自化合物(XXVII)移除胺基甲酸酯保護基團以提供胺(XXVIII)
其中R1、R2、R5、R6、R7、X、Y及Z係如上文所定義,然後環閉合以提供醯胺(XXIX)
其中R1、R2、R5、R6、R7、X、Y及Z係如上文所定義,然後使(XXIX)與R13-CO-SH(XXI)反應
其中R13係如上文所定義,以提供式(2)化合物。
在本發明之態樣中,為製備式(2)化合物,R5係H且R6係異丙基。
在本發明之態樣中,為製備式(2)化合物,R13係-(CH2)6CH3。
在本發明之態樣中,為製備式(2)化合物,R1及R2係H。
圖1繪示拉格唑拉(largazole)及若干拉格唑拉類似物之化學結構。
「部分」或「基團」係由式、化學名稱或結構指定之任何類型之分子排列。在某些實施例之上下文中,認為偶聯物包含一或多個部分或化學基團。此意味著該部分之式在某些位置經取代以經連接且成為偶聯物之分子排列的一部分。儘管部分可直接共價連接,但兩個或更多個部分並不欲必須直接彼此連接。鏈接基團、交聯基團或連接基團係指藉由共價鍵(例如(但不限於)一或多個可連接部分之醯胺基團)連結部分之任何分子排列。另外,儘管偶聯物可未經取代,但偶聯物可具有多個連結至鏈接基團及/或連結至部分之額外取代基。
「聚合物」或「聚合物群」係指由重複鏈接部分構成之化學物質或群。在某些實施例中,重複部分之數量較佳為3或更大或大於10。所鏈接部分之結構可相同或可具有部分結構之變化形式。「單體聚合物」或「均聚物」係含有相同重複不對稱亞單位之聚合物。「共聚物」係源自兩種或更多種類型之單體物質、即兩個或更多個不同的化學不對稱亞單位之聚合物。「嵌段共聚物」係由兩種或更多種藉由共價鍵鏈接之聚合物亞單位構成之聚合物。
如本文所使用,術語「經取代」係指分子排列之至少一個氫原子經取代基替代。在側氧基取代基(「=O」)之情形下,兩個氫原子經替代。當經取代時,以下基團中之一或多者為「取代基」。取代基包括(但不限於)鹵素、羥基、側氧基、氰基、硝基、胺基、烷基胺基、二烷基胺基、烷基、烷氧基、烷硫基、鹵烷基、芳基、芳基烷基、雜芳基、雜芳基烷基、雜環基及雜環烷基以及-NRaRb、-NRaC(O)Rb、-NRaC(O)NRaNRb、-NRaC(=O)ORb、-NRaSO2Rb、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)NRaRb、-ORa、-SRa、-SORa、-S(=O)2Ra、-OS(=O)2Ra及-S(=O)ORa。另外,上述取代基可進一步經一或多個上述取代基取代,使得取代基包含經取代烷基、經取代芳基、經取代芳基烷基、經取代雜環或經取代雜環烷基。Ra及Rb在此上下文中可相同或不同,且獨立地係氫、烷基、鹵烷基、經取代烷基、芳基、經取代芳基、芳基烷基、經取代芳基烷基、雜環基、經取代雜環基、雜環烷基或經取代雜環烷基。
如本文所使用,術語「未經取代」係指不含附接至化合物之額外取代基之任何化合物。未經取代之化合物係指不含額外取代基之化合物之化學成分,例如化合物不含保護基團。舉例而言,未經取代之脯胺酸係脯胺酸胺基酸,即使脯胺酸之胺基可視為經烷基二取代。
如本文所使用,術語「烷基」係指含有1至10個碳原子之任何直
鏈或具支鏈、非環狀或環狀、不飽和或飽和脂肪族烴,而術語「低碳烷基」具有與烷基相同之含義但含有1至6個碳原子。術語「高碳烷基」具有與烷基相同之含義但含有7至10個碳原子。代表性飽和直鏈烷基包括(但不限於)甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基及諸如此類;而飽和具支鏈烷基包括(但不限於)異丙基、第二丁基、異丁基、第三丁基、異戊基及諸如此類。環狀烷基可藉由連接結合至同一原子之兩個烷基或藉由連接各自結合至鄰接原子之兩個烷基來獲得。代表性飽和環狀烷基包括(但不限於)環丙基、環丁基、環戊基、環己基及諸如此類;而不飽和環狀烷基包括(但不限於)環戊烯基及環己烯基及諸如此類。環狀烷基在本文中亦稱為「雜環」或「同素環」。不飽和烷基在毗鄰碳原子之間含有至少一個雙鍵或三鍵(分別稱為「烯基」或「炔基」)。代表性直鏈及具支鏈烯基包括(但不限於)乙烯基、丙烯基、1-丁烯基、2-丁烯基、異丁烯基、1-戊烯基、2-戊烯基、3-甲基-1-丁烯基、2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基及諸如此類;而代表性直鏈及具支鏈炔基包括(但不限於)乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基及諸如此類。
如本文所使用,術語「芳基」係指任何芳香族碳環部分,例如(但不限於)苯基或萘基。
如本文所使用,術語「芳基烷基」或「芳烷基」係指至少一個烷基氫原子經芳基部分替代之任何烷基,例如(但不限於)苄基、-(CH2)2-苯基、-(CH2)3-苯基、-CH(苯基)2及諸如此類。
如本文所使用,術語「鹵素」係指任何氟、氯、溴及碘部分。
如本文所使用,術語「鹵烷基」係指至少一個氫原子經鹵素替代之任何烷基,例如三氟甲基及諸如此類。
如本文所使用,術語「雜芳基」係指具有5至10個成員且具有至
少一個選自氮、氧及硫之雜原子且含有至少1個碳原子的任何芳香族雜環,包括(但不限於)單環及二環系統二者。代表性雜芳基包括(但不限於)呋喃基、苯并呋喃基、苯硫基、苯并苯硫基、吡咯基、吲哚基、異吲哚基、氮雜吲哚基、吡啶基、喹啉基、異喹啉基、噁唑基、異噁唑基、苯并噁唑基、吡唑基、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、異噻唑基、嗒嗪基、嘧啶基、吡嗪基、三嗪基、啉基、呔嗪基或喹唑啉基。
如本文所使用,術語「雜芳基烷基」係指至少一個烷基氫原子經雜芳基部分替代之任何烷基,例如-CH吡啶基、-CH2嘧啶基及諸如此類。
如本文所使用,術語「雜環」或「雜環狀環」係指任何4至7員單環雜環或7至10員二環雜環,其為飽和、不飽和或芳香族,且含有1至4個獨立地選自氮、氧及硫之雜原子,且其中氮及硫雜原子可視情況發生氧化,且氮雜原子可視情況經四級銨化,包括任一上述雜環與苯環稠合之二環。雜環可經由任一雜原子或碳原子附接。雜環可包括例示為上文所定義之彼等之雜芳基。因此,除上文所列示之雜芳基外,雜環亦可包括(但不限於)嗎啉基、吡咯啶酮基、吡咯啶基、六氫吡啶基、乙內醯脲基、戊內醯胺基、環氧乙烷基、環氧丙烷基、四氫呋喃基、四氫吡喃基、四氫吡啶基、四氫嘧啶基、四氫苯硫基、四氫硫吡喃基、四氫嘧啶基、四氫噻吩基及諸如此類。
如本文所使用,術語「雜環烷基」係指至少一個烷基氫原子經雜環替代之任何烷基,例如-CH2-嗎啉基及諸如此類。
如本文所使用,術語「雜環」或「環烷基」係指含有3-7個碳原子之任何飽和或不飽和(而非芳香族)碳環,例如(但不限於)環丙烷、環丁烷、環戊烷、環己烷、環庚烷、環己烯及諸如此類。
如本文所使用,術語「烷基胺基」係指至少一個經由氮橋(例
如,-N-烷基或-N-(烷基)-N-)附接之烷基部分,包括(但不限於)甲基胺基、乙基胺基、二甲基胺基、二乙基胺基及諸如此類。
如本文所使用,術語「烷基氧基」或「烷氧基」係指經由氧橋(例如,-O-烷基)附接之任何烷基部分,例如(但不限於)甲氧基、乙氧基及諸如此類。
如本文所使用,術語「烷硫基」係指經由硫橋(例如,-S-烷基)附接之任何烷基部分,例如(但不限於)甲硫基、乙硫基及諸如此類。
術語「烯基」係指其中具有一或多個雙鍵之不具支鏈或具支鏈烴鏈。烯基之雙鍵可未經偶聯或偶聯至另一不飽和基團。適宜烯基包括(但不限於)乙烯基、烯丙基、丁烯基、戊烯基、己烯基、丁二烯基、戊二烯基、己二烯基、2-乙基己烯基、2-丙基-2-丁烯基、4-(2-甲基-3-丁烯)-戊烯基。烯基可未經取代或經一或兩個適宜取代基取代。
術語「炔基」係指其中具有一或多個三鍵之不具支鏈或具支鏈烴鏈。炔基之三鍵可未經偶聯或偶聯至另一不飽和基團。適宜炔基包括(但不限於)乙炔基、丙炔基、丁炔基、戊炔基、己炔基、甲基丙炔基、4-甲基-1-丁炔基、4-丙基-2-戊炔基-及4-丁基-2-己炔基。炔基可未經取代或經一或兩個適宜取代基取代。
如本文所使用,術語「鹽」係指與其中所含之經鑑別化合物複合之任何鹽,例如醫藥上可接受之鹽。該等鹽之實例包括(但不限於)與無機酸(例如,鹽酸、氫溴酸、硫酸、磷酸、硝酸及諸如此類)形成之酸加成鹽及與有機酸形成之鹽,該等有機酸係例如(但不限於)乙酸、草酸、酒石酸、琥珀酸、蘋果酸、反丁烯二酸、順丁烯二酸、抗壞血酸、苯甲酸、鞣酸、撲酸、海藻酸、聚麩胺酸、萘磺酸、萘二磺酸及聚半乳糖醛酸。鹽化合物亦可以熟習此項技術者已知之醫藥上可接受之四級鹽形式投與,該等醫藥上可接受之四級鹽包括式-NR,R',R"+Z-之四級銨鹽,其中每一R、R'、R"獨立地係氫、烷基或苄
基,且Z係相對離子,包括(但不限於)氯離子、溴離子、碘離子、烷醇離子、甲苯磺酸根離子、甲基磺酸根離子、磺酸根離子、磷酸根離子或羧酸根離子(例如苯甲酸根離子、琥珀酸根離子、乙酸根離子、羥乙酸根離子、馬來酸根離子、蘋果酸根離子、富馬酸根離子、檸檬酸根離子、酒石酸根離子、抗壞血酸根離子、肉桂酸根離子、扁桃酸根離子及二苯基乙酸根離子)。鹽化合物亦可以醫藥上可接受之具有經取代或未經取代之部分式之吡啶陽離子鹽形式投與:其中Z係相對離子,包括(但不限於)氯離子、溴離子、碘離子、烷醇離子、甲苯磺酸根離子、甲基磺酸根離子、磺酸根離子、磷酸根離子或羧酸根離子(例如苯甲酸根離子、琥珀酸根離子、乙酸根離子、羥乙酸根離子、馬來酸根離子、蘋果酸根離子、富馬酸根離子、檸檬酸根離子、酒石酸根離子、抗壞血酸根離子、肉桂酸根離子、扁桃酸根離子及二苯基乙酸根離子)。
如本文所使用,術語「前藥」係指可水解、氧化或以其他方式在生物條件下(活體外或活體內)反應以提供本發明化合物之化合物衍生物。前藥僅可在生物條件下發生某種反應時變得有活性,但其在呈其未反應形式時可具有活性。本文所涵蓋前藥之實例包括(但不限於)本發明化合物之類似物或衍生物及/或其鹽(在可形成鹽時),但尤其鋅結合硫醇部分之衍生物。前藥部分之實例包括經取代及未經取代、具支鏈或不具支鏈之低碳烷基酯部分(例如,丙酸酯)、低碳烯基酯、二-低碳烷基-胺基低碳烷基酯(例如,二甲基胺基乙基酯)、醯基胺基低碳烷基酯(例如,乙醯基氧基甲基酯)、醯氧基低碳烷基酯(例如,特戊醯基氧基甲基酯)、芳基酯(苯基酯)、芳基-低碳烷基酯(例如,苄基酯)、雜芳基酯(菸酸酯)、經取代(例如,經甲基、鹵基或甲氧基取代基)芳基及芳基-低碳烷基酯、醯胺、低碳烷基醯胺、二-低碳烷基醯胺及羥基醯胺。天然胺基酸酯或其鏡像異構物、二肽酯、磷酸酯、甲氧
基磷酸酯、二硫化物及二硫化物二聚體。前藥及其用途為業內所熟知(例如,參見Berge等人,Pharmaceutical Salts,J.Pharm.Sci.66,1-19(1977))。前藥通常可使用熟知方法、例如Burger's Medicinal Chemistry and Drug Discovery(Manfred E.Wolff編輯(1995))及(Rautio,Nat.Rev.Drug Discov.7,255-270(2008))中所述之彼等來製備。
如本文所使用,「反應性基團」係指親核劑,親電子劑或自由基活性基團,即在自由基存在下反應之基團。親核劑係藉由提供兩個鍵結電子與其反應配偶體(親電子劑)形成化學鍵之部分。親電子劑接受該等電子。親核劑可參與親核取代,藉此親核劑變得吸引至元素上之完全或部分正電荷且置換與其鍵結之基團。另一選擇為,親核劑可參與羰基之取代。通常藉由產生琥珀醯基酯且使該等酯與胺基烷基反應形成醯胺來使羧酸親電子。其他常見親核基團包括硫醇烷基、羥基烷基、一級及二級胺以及碳親核劑(例如烯醇及烷基金屬錯合物)。使用反應性基團連接蛋白質、寡糖及細胞之其他較佳方法揭示於(Lemieux及Bertozzi(1998))中,該文獻以引用方式併入本文中。在另一較佳方法中,一者提供反應性基團用於與包含疊氮化物之部分及炔基反應性基團進行施陶丁格連接(Staudinger ligation,即「點擊化學」)以形成三唑。亦可利用碳親核劑烯醇化物與親電子羰基之麥克加成(Michael addition),或親核一級或二級胺與醛或酮之席夫鹼形成。其他生物偶聯方法提供於(Hang及Bertozzi,J.Am.Chem.Soc.123,1242-1243(2001))及(Kiick等人(2002))中,該兩者之全文皆以引用方式併入本文中。
用於製備本發明化合物(例如由式(1)及式(2)表示之彼等)之本發明方法圖解說明於以下方案中。除非另外指示,否則變量R1-R21、X、Y、Z、M、TDx及n係如上文所定義。具體而言,下文之方案及論
述闡述由式I至XXIX表示之化合物之製備。
方案1之步驟1中所述之反應涉及化合物I與化合物II之間的釕碳烯(ruthenium carbene)催化之交叉烯烴置換反應以產生化合物III,且係在與Voigtritter,K.等人,J.Org.Chem.76,4697-4702(2011)中所述之彼等類似之條件下實施。
具體而言,當化合物I與化合物II(烯丙基醇,其中R20係H且R21係CH2OH,或R20及R21皆為CH2OH)在介於約0.1mol%至約5mol%範圍內、較佳約0.5mol%之量的釕碳烯觸媒(例如(但不限於)亞苄基-雙(三環己基膦)二氯釕(第一代格拉布(Grubbs)觸媒)、(1,3-雙(2,4,6-三甲基苯基)-2-咪唑啶亞基)二氯(苯基亞甲基)(三環己基膦)釕(第二代格拉布觸媒)、(1,3-雙-(2,4,6-三甲基苯基)-2-咪唑啶亞基)二氯(鄰-異丙氧基苯基亞甲基)釕(胡維達-格拉布(Hoveyda-Grubbs)觸媒)或1,3-雙(2,4,6-三甲基苯基)-4,5-二氫咪唑-2-亞基[2-(異丙氧基)-5-(N,N-二甲基胺基磺醯基)苯基]亞甲基二氯化釕(II)(詹氏觸媒(Zhan catalyst)1B))與介於約1mol%至約20mol%範圍內、較佳約6mol%之量的碘化銅(I)之組合存在下,在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷、二乙醚、甲基第三丁基醚、二異丙基醚、二-正丁基醚、四氫呋喃或甲苯,較佳二氯甲烷)中,在約0℃至約100℃之溫度範圍下、較佳在室溫(約25℃)下反應時,獲得化合物III((E)-5-氯戊-2-烯-1-醇)且其直接用於下一步驟中。
如方案1之步驟2中所述,藉由在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷或甲苯,較佳二氯乙烷)中,在約0℃至約100℃之溫
度範圍下、較佳在室溫(約25℃)下,用氧化劑(例如(但不限於)氧化錳(IV)、錳酸鋇、1,1,1-參(乙醯基氧基)-1,1-二氫-1,2-苯并碘氧雜環戊烯-3-(1H)-酮(戴斯-馬丁過碘烷(Dess-Martin periodinane))或催化性四丁基高釕酸銨(TPAP))與化學計量氧化劑(例如(但不限於)過碘酸鈉或(2,2,6,6-四甲基六氫吡啶-1-基)氧烷(oxidanyl)(TEMPO))組合、與化學計量氧化劑(例如(但不限於)次氯酸鈉或氧化錳(IV),較佳氧化錳(IV))組合處理,將化合物III((E)-5-氯戊-2-烯-1-醇)氧化成相應的醛化合物IV((E)-5-氯戊-2-烯醛)。過濾(例如經由CeliteTM墊)及溶劑蒸發後,由此獲得之產物未經純化即直接用於下一步驟中。經由急速管柱層析純化獲得化合物IV之分析純樣品。
在如方案2中所繪示用於製備化合物IV之替代性及較佳方法中,使化合物I與化合物II(其中R20係氫或低碳烷基且R21係CHO,較佳地其中R20係CH3(巴豆醛))在以下條件下反應:在介於約0.1mol%至約5mol%範圍內、較佳約0.5mol%之量的釕碳烯觸媒(例如(但不限於)亞苄基-雙(三環己基膦)二氯釕(第一代格拉布觸媒)、(1,3-雙(2,4,6-三甲基苯基)-2-咪唑啶亞基)二氯(苯基亞甲基)(三環己基膦)釕(第二代格拉布觸媒)、(1,3-雙-(2,4,6-三甲基苯基)-2-咪唑啶亞基)二氯(鄰-異丙氧基苯基亞甲基)釕(胡維達-格拉布觸媒)或1,3-雙(2,4,6-三甲基苯基)-4,5-二氫咪唑-2-亞基[2-(異丙氧基)-5-(N,N-二甲基胺基磺醯基)苯基]亞甲基二氯化釕(II)(詹氏觸媒1B),較佳(1,3-雙(2,4,6-三甲基苯基)-2-咪唑啶亞基)二氯(苯基亞甲基)(三環己基膦)釕(第二代格拉布觸媒))與介於約1mol%至約20mol%範圍內、較佳約6mol%之量的碘化銅(I)之組合
存在下,在約0℃至約100℃之溫度下、較佳在約40℃下。完成後,將反應混合物冷卻且過濾,並藉由在減壓下蒸餾及加熱(例如(但不限於)約30℃)移除通常包括未反應之4-氯-1-戊烯、未反應之巴豆醛及二氯甲烷之揮發性組份。移除大部分揮發性組份後,重構(通常於溶劑(例如(但不限於)二氯甲烷)中)殘餘產物(通常含有少量起始材料),且然後再在減壓下濃縮並加熱(例如(但不限於)約30℃),以獲得(E)-5-氯戊-2-烯醛作為化合物IV,其直接用於下一步驟中。經由急速管柱層析純化獲得化合物IV之分析純樣品。
使用本文所述釕碳烯催化之交叉烯烴置換反應合成化合物III代表優於更通俗的傳統合成途徑之顯著優點,該等傳統合成途徑涉及使用有機磷試劑(例如乙酸(二烷氧基磷醯基)酯(「霍納-沃茲沃思-埃蒙斯(Horner-Wadsworth-Emmonds)」試劑)或2-(三苯基正膦亞基)乙醛),其需要額外合成步驟且亦可產生包括鋁及磷氧化物之廢流。舉例而言,在本合成中,廢流包括相對揮發性、未反應之起始材料(例如4-氯-2-戊烯及巴豆醛)及可自產物蒸餾並再循環之溶劑、可回收且再循環之催化量之釕物質、可過濾且再循環之錳氧化物及丙烯氣體。
下表1說明方案1中所述製備化合物III(由化合物2c表示)或化合物IV(由化合物2a表示)之反應之轉化率如何隨著化合物II(由化合物1表示,其中R1、R2及R3具有1a、1b及1c中之每一者所顯示之值)、溶劑、溫度、添加劑、觸媒、觸媒載量及時間之選擇而變化。
DCM=二氯甲烷
THF=四氫呋喃
MTBE=甲基第三丁基醚
DIE=二乙醚
方案3中所述之合成反應涉及化合物IV之醛與化合物V之噻唑啶
硫酮之間的不對稱醛醇反應(拿告醛醇反應(Nagao-Aldol reaction))且係在與Ren,Q.等人,Synlett 2008,第15期,2379-2383中所述之彼等類似之條件下實施。
拿告醛醇反應尤其可用於製備以立體化學方式富集之β-羥基羰基化合物,其在相對於帶有對掌性助劑之羰基之α碳上不含除氫外之取代基。另外,與更傳統的「Evans」對掌性噁唑啶酮對掌性助劑不同,噻唑啶硫酮助劑用於朝向胺化合物、具體而言一級胺之親核加成活化其所附接之羰基,以無需額外活化即直接獲得相應的醯胺。具體而言,用路易斯酸(Lewis acid)、鹼及化合物IV之醛處理方案3之乙醯化對掌性助劑V(其中TDx包括(但不限於)(R)-4-異丙基噻唑啶-2-硫酮、(R)-4-苄基噻唑啶-2-硫酮、(R)-4-苯基噻唑啶-2-硫酮或(R)-4-(第三丁基)噻唑啶-2-硫酮),以產生具有高度非鏡像選擇性之化合物VI。化合物IV在5位經氯基團取代,該氯基團用作離去基團以經由涉及硫代S-酸之鹽之親核置換反應引入硫酯基團,如方案XIII及IX中所述。先前已利用拿告醛醇反應合成與方案3之化合物VI相關之中間體,其進而用於合成天然產物拉格唑拉。(Taori,K.等人,J.Am.Chem.Soc.,(2008),130,1806;Leusch,H.等人,Nat.Prod.Rep.,(2012),29,449)。在大多數所報導合成中,使用硫醇(以其三苯基甲基衍生物形式受保護)最終遞送納入天然產物拉格唑拉及其合成類似物中之硫酯基團。(Ying,Y.等人,J.Am.Chem.Soc.(2008),130,8457;Bowers,A.等人,J.Am.Chem.Soc.,(2008),130,11221;Xiao,Q.等人,Journal of Asian Natural Products Research,(2010),12:11,940;
Benelkebir,H.等人,Bioorg.Med.Chem.(2011),19,3650;Bhansali,P.等人,J.Med.Chem.(2011),54,7453)。除將硫醇遮蔽為三苯基甲基硫醚外,亦已報導三烷基矽基醚之使用。(Ren,Q.等人,Synlett(2008),第15期,2379-2383)。在此情形中,保護基團與計劃化學不相容,此需要在後期合成中將保護基團更換為二硫化物基團。在其他報導中,所需硫酯基團係在最終步驟中使用交叉烯烴置換反應引入。(Nasveschuk,C.G.等人,J.,Org.Lett.(2008),10,3595;Seiser,T.等人,Angew.Chem.Int.Ed.(2008),47,6483;Souto,J.A.等人,J.Med.Chem.(2010),53,4654)。在該等公開實例中,針對此轉變闡述之化學產率均勻地低,且觸媒載量均勻地高。因此,此具體鍵構築並非大規模合成之具吸引力的選擇。
本發明展示使用氯原子作為三苯基甲硫基之低分子量「原子經濟性」替代以經由方案3之化合物VI製備與拉格唑拉相關之縮肽衍生物,該方案3之化合物VI係經由化合物IV與V之間之拿告醛醇反應來製備。為製備醛醇產物化合物VI,在以下條件下用路易斯酸(例如(但不限於)鹵化鈦(IV),較佳地四氯化鈦)處理N-醯基化對掌性助劑化合物V(包含對掌性噻唑啶二酮,較佳(R)-1-(4-苄基-2-硫基噻唑啶-3-基)乙酮或(R)-1-(4-異丙基-2-硫基噻唑啶-3-基)乙酮):在非質子溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷或甲苯,較佳地二氯甲烷)中,在約-78℃至約0℃、較佳約-5℃下經約30分鐘之時段,然後在三級胺鹼(例如(但不限於)三乙胺、(-)-鷹爪豆鹼或二異丙基乙胺,較佳二異丙基乙胺)中在約-78℃至約0℃、較佳約-40℃之溫度下同時攪拌約2小時,此時將所得溶液冷卻至約-90℃至約-40℃、較佳-78℃,且添加化合物IV之醛於非質子溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷或甲苯,較佳二氯甲烷)中之溶液。
方案4闡述化合物X之合成。在步驟1中,用受保護之胺基酸衍生物將化合物VI之二級羥基醯基化,其中保護基團係例如第三丁基氧基羰基(Boc)、(9H-茀-9-基)甲基氧基羰基(Fmoc)或2-(三甲基矽基)乙基氧基羰基,較佳第三丁基氧基羰基。
方案4之步驟1闡述化合物VI與化合物VII之間之酯形成以獲得化合物VIII,其中化合物VII之R18包括(但不限於)-CH2CH2Si(CH3)3、(9H-茀-9-基)甲基(Fmoc)或第三丁基(Boc),較佳第三丁基,且係使用活化劑(例如(但不限於)1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(EDCI)、二環己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)、羰基二咪唑(CDI)、2,4,6-三氯苯甲醯氯,較佳1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(EDCI))與約5mol%至約30mol%、較佳約10mol%之胺基吡啶觸媒(例如(但不限於)二甲基胺基吡啶或4-吡咯啶基吡啶,較佳4-二甲基胺基吡啶),在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷、乙
腈、四氫呋喃、甲苯、庚烷、甲基第三丁基醚、二異丙基醚、乙酸乙酯或乙酸異丙酯、二甲基甲醯胺、二甲基乙醯胺或N-甲基吡咯啶酮,較佳二氯甲烷)中,在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下實施。
方案4之步驟2係醯胺形成反應,其中化合物VIII之對掌性噻唑啶硫酮基團用於朝向一級胺之親核置換活化其所附接之羰基,如先前所論述。在此反應中,化合物IX係5員或6員雜環部分,其含有至少一個雜環中之氮與適宜地保護為酯、附接至與氮原子相同之碳的羧基酯基團及附接至氮所附接之另一碳原子之經取代或未經取代之甲基胺基。因此,每一基團、酯及經取代或未經取代之甲基胺基位於雜環中氮原子之鄰位及彼此之間位。化合物IX之5員或6員雜環部分包括(但不限於)吡啶、嘧啶、吡嗪、三嗪、噁唑、噻唑、噁二唑或噻二唑。在實例性實施例中,此部分係噻唑或2-(胺基甲基)噻唑-4-甲酸第三丁基酯。該反應通常係藉由以下方式來實施:將方案4之化合物VIII溶解於非質子溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷、乙腈、四氫呋喃、甲苯、庚烷、甲基第三丁基醚、二異丙基醚、乙酸乙酯或乙酸異丙酯、二甲基甲醯胺、二甲基乙醯胺或N-甲基吡咯啶酮,較佳二氯甲烷)中,然後添加化合物VI且在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下攪拌約1小時至約48小時、較佳約24小時。
方案5闡述化合物X之替代及更佳合成。在方案5之步驟1中,將化合物VI之拿告醛醇產物溶解於非質子
溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷、乙腈、四氫呋喃、甲苯、庚烷、甲基第三丁基醚、二異丙基醚、乙酸乙酯、乙酸異丙酯、二甲基甲醯胺、二甲基乙醯胺或N-甲基吡咯啶酮,較佳二氯甲烷)中,用化合物IX(其中R19係例如第三丁基或CH2CH2Si(CH3)3,較佳第三丁基)處理,且在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下攪拌約1小時至約48小時、較佳約24小時。添加水,分離有機層,且用二氯甲烷將水層萃取一次。合併有機層,用鹽水洗滌並在真空下濃縮。與乙酸乙酯一起研磨提供化合物XI(70%-80%產率)。藉由管柱層析純化母液,提供額外化合物XI以及所回收之對掌性助劑,該對掌性助劑可再用於合成化合物V,如表2中所顯示。
在方案5之步驟2中,用化合物VII之受保護之胺基酸衍生物將化合物XI之二級羥基醯基化,其中保護基團係例如第三丁基氧基羰基(Boc)、(9H-茀-9-基)甲基氧基羰基(Fmoc)或2-(三甲基矽基)乙基氧基羰基,較佳第三丁基氧基羰基,以提供化合物X。該反應係使用活化劑(例如(但不限於)二環己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)或1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(EDCI),較佳1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(EDCI)),在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷、乙腈、四氫呋喃、甲苯、庚烷、甲基第三丁基醚、二異丙基醚、乙酸乙酯或乙酸異丙酯、二甲基甲醯胺、二甲基乙
醯胺或N-甲基吡咯啶酮,較佳二氯甲烷)中,使用約5mol%至約30mol%、較佳約10mol%之胺基吡啶觸媒(例如(但不限於)二甲基胺基吡啶或4-吡咯啶基吡啶,較佳4-二甲基胺基吡啶),在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下實施。將水添加至反應混合物中,且分離有機層,並用水洗滌一次。將有機層乾燥且濃縮以獲得化合物X,其未經進一步純化即使用。
方案6闡述例示方案4及5之化合物IX之化合物XV之雜環胺基酸衍生物之製備。
將化合物XII及化合物XIII合併於溶劑(例如(但不限於)1,2-二甲氧基乙烷(DME)、四氫呋喃(THF)或1,4-二噁烷,較佳1,2-二甲氧基乙烷(DME))中,且在約-40℃至約25℃、較佳約-10℃之溫度下添加鹼(例如(但不限於)碳酸氫鈉或碳酸氫鉀,較佳碳酸氫鉀)。攪拌約10min至約24小時、較佳約1小時後,在約-40℃至約25℃、較佳約-20℃之溫度下,添加三氟乙酸酐及鹼(例如(但不限於)吡啶、2-甲基吡啶、2,6-二甲基吡啶、2,3,5-三甲基吡啶或2,4,6-三甲基吡啶,較佳2,6-二甲基吡啶)於溶劑(例如(但不限於)1,2-二甲氧基乙烷(DME)、四氫呋喃(THF)或1,4-二噁烷,較佳1,2-二甲氧基乙烷)中之溶液。攪拌約10min至約24小時、較佳約2小時後,將混合物傾倒至水中且後續萃取處理提供固體狀化合物XIV。
在用於製備方案6之化合物XV之替代及較佳方法中,將方案6之化合物XII與方案6之化合物XIII合併於溶劑(例如(但不限於)甲醇、乙醇、異丙醇、第二丁醇、二氯甲烷、1,2-二氯乙烷、乙腈、四氫呋喃、甲苯、庚烷、甲基第三丁基醚、二異丙基醚、1,2-二甲氧基乙烷、1,4-二噁烷、乙酸乙酯、乙酸異丙酯、二甲基甲醯胺、二甲基乙醯胺或N-甲基吡咯啶酮,較佳異丙醇)中,且在約0℃至約100℃、較佳約25℃之溫度下在鹼(例如(但不限於)氫氧化鈉水溶液、氫氧化鉀水溶液、氫氧化鋰水溶液或碳酸鈣,較佳氫氧化鈉水溶液)不存在或存在下攪拌約1小時至約72小時、較佳約24小時之時段。用水稀釋反應物,且在後續萃取處理後獲得化合物XIV。
方案7a闡述在帶有R19之酯基團存在下選擇性移除化合物XVI內帶有R18之胺基甲酸酯保護基團以提供化合物XVII。
因此,在化合物XVI內帶有R18之胺基甲酸酯保護基團及帶有R19之酯基團關於其結構或反應性係正交保護基團。化合物XVI之R18包括(但不限於)-CH2CH2Si(CH3)3、(9H-茀-9-基)甲基(Fmoc)或第三丁基(Boc)。化合物XVI之R19包括(但不限於)-CH2CH2Si(CH3)3或第三丁基
(Boc)。當化合物XVI之R18係-CH2CH2Si(CH3)2時,藉由以下方式實施方案7a之步驟1:在溶劑(例如(但不限於)四氫呋喃、乙腈、二甲基甲醯胺、N-甲基吡咯啶酮、N,N-二甲基乙醯胺或二甲基亞碸,較佳四氫呋喃)中,在約0℃至約65℃之溫度下、較佳在室溫(約25℃)下,用氟化物來源(例如(但不限於)氟化鉀、氟化銫、四丁基氟化銨或四氟硼酸鋰,較佳四丁基氟化銨)處理化合物XVI。
當化合物XVI之R18係(9H-茀-9-基)甲基(Fmoc)時,藉由以下方式實施方案7a之步驟1:在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷、二甲基甲醯胺、n-甲基吡咯啶酮或N,N-二甲基乙醯胺,較佳二氯甲烷)中,在約-20℃至約40℃之溫度下、較佳在室溫(約25℃)下,用胺鹼(例如(但不限於)嗎啉、六氫吡啶、六氫吡嗪、1,4-雙-(3-胺基丙基六氫吡嗪、二環己基胺、二異丙基乙基胺、4-二甲基胺基吡啶、1,8-二氮雜二環[5.4.0]十一碳-7-烯、吡咯啶、環己基胺、乙醇胺、二乙胺、三乙胺、氨、三丁基胺或三乙二胺,較佳六氫吡啶)處理化合物XVI。
當化合物XVI之R18係第三丁基(Boc)時,藉由以下方式實施方案7a之步驟1:在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下,用溶解於有機溶劑(例如二氯甲烷、甲苯、乙酸乙酯、THF、DME、MTBE或二噁烷)中之酸(例如三氟乙酸或HCl)處理化合物XVI。較佳地,化合物XVI之R18係第三丁基,且步驟1較佳係使用二噁烷中之HCl、更佳在室溫下(約25℃)實施。將反應混合物傾倒至碳酸氫鈉之冷卻飽和溶液(約pH 8-9)中,且用乙酸乙酯將所得混合物萃取兩次,用鹽水萃取一次,乾燥並濃縮至乾燥,以提供化合物XVII(約95%產率),且其未經進一步純化即直接用於下一步驟中。
在方案7a之步驟2中,藉由用化合物VII及活化劑(例如(但不限於)二環己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)或1-乙基-3-(3-
二甲基胺基丙基)碳二亞胺(EDCI),較佳1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(EDCI))自身或在添加劑(例如(但不限於)羥基苯并三唑(HOBt)或1-羥基、7-氮雜苯并三唑,較佳羥基苯并三唑(HOBt))存在下,在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷、乙腈、四氫呋喃、甲苯、庚烷、甲基第三丁基醚、二異丙基醚、乙酸乙酯或乙酸異丙酯、二甲基甲醯胺、二甲基乙醯胺或N-甲基吡咯啶酮,較佳二氯甲烷)中,在約-20℃至約60℃之溫度下、較佳在室溫(約25℃)下處理,將化合物XVII轉化成化合物XVIII。
在方案7a之步驟3中,藉由同時水解化合物XVIII內分別帶有R18及R19之胺基甲酸酯及酯基團產生化合物XIX。因此,例如當R18及R19各自為-CH2CH2Si(CH3)3時,藉由以下方式實施步驟3:在溶劑(例如(但不限於)四氫呋喃、乙腈、二甲基甲醯胺、N-甲基吡咯啶酮、N,N-二甲基乙醯胺或二甲基亞碸,較佳四氫呋喃)中,在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下,用例如氟化鉀、氟化銫、四丁基氟化銨、四氟硼酸鋰或三氟乙酸、較佳四丁基氟化銨處理化合物XVIII。
另一選擇為且較佳地,當R18及R19皆為第三丁基時,藉由以下方式實施方案7a之步驟3:在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷或甲苯,較佳二氯甲烷)中,在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下,用酸(例如(但不限於)三氟乙酸或HCl,較佳三氟乙酸)處理化合物XVIII。
方案7b闡述同步移除化合物XVI內帶有R18之胺基甲酸酯保護基團及帶有R19之酯基團,以提供化合物XVII-A。較佳地,當R18及R19皆為第三丁基時,藉由以下方式實施方案7b之步驟1:在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷或甲苯,較佳二氯甲烷)中,在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下,用酸(例如(但不限
於)三氟乙酸或HCl,較佳三氟乙酸)處理化合物XVI。
在方案7b之步驟2中,藉由用化合物VII及活化劑(例如(但不限於)二環己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)或1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(EDCI),較佳1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(EDCI))自身或在添加劑(例如(但不限於)羥基苯并三唑(HOBt)或1-羥基、7-氮雜苯并三唑,較佳羥基苯并三唑(HOBt))存在下,在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷、乙腈、四氫呋喃、甲苯、庚烷、甲基第三丁基醚、二異丙基醚、乙酸乙酯或乙酸異丙酯、二甲基甲醯胺、二甲基乙醯胺或N-甲基吡咯啶酮,較佳二氯甲烷)中,在約-20℃至約60℃之溫度下、較佳在室溫(約25℃)下處理,將化合物XVII-A轉化成化合物XVIII-A。
在方案7b之步驟3中,藉由水解化合物XVIII-A內帶有R18之胺基甲酸酯基團產生化合物XIX。因此,例如當R18係第三丁基時,藉由以下方式實施方案7b之步驟3:在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷或甲苯,較佳二氯甲烷)中,在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下,用酸(例如(但不限於)三氟乙酸或HCl,
較佳三氟乙酸)處理化合物XVIII-A。
方案8之步驟1係巨內醯胺化反應,藉此藉由化合物XIX中之羧酸基團以分子內方式將化合物XIX之胺基醯基化以提供化合物XX。
藉由以下方式實施步驟1:用活化劑(例如(但不限於)N-[(二甲基胺基)-1H-1,2,3-三唑并-[4,5-b]吡啶-1-基亞甲基]-N-甲基甲銨六氟磷酸鹽N-氧化物(HATU)、(O-(7-氮雜苯并三唑-1-基)-1,1,3,3-雙(四亞甲基)鈾六氟磷酸鹽)(HBTU)、N,N,N,N'-四甲基-O-(1H-苯并三唑-1-基)脲鎓六氟磷酸鹽、O-(苯并三唑-1-基)-N,N,N,N'-四甲基脲鎓六氟磷酸鹽、DCC、DIC、EDCI、BDDC、BOP、PyBOP、BOMP、AOP、PyAOP、PyDOP、PyNOP、PyFOP、PyNFOP、NOP、NSBt、N-NSBt、N-HBTU、N-HATU或(HAPyU),較佳N-[(二甲基胺基)-1H-1,2,3-三唑并-[4,5-b]吡啶-1-基亞甲基]-N-甲基甲銨六氟磷酸鹽N-氧化物(HATU))自身或在添加劑(例如(但不限於)(HOSuc)、(HODhbt)、(HOt)、(HOCt)、(Oxama)、(6-CF3-HOBt)、(6-NO2-HOBt)、羥基-1,2,3-三唑、羥基苯并三唑(HOBt)或1-羥基-7-氮雜苯并三唑(HOAt),較佳羥基苯并三唑(HOBt))存在下,在溶劑(例如(但不限於)二氯甲
烷、1,2-二氯乙烷、乙腈、四氫呋喃、甲苯、庚烷、甲基第三丁基醚、二異丙基醚、乙酸乙酯或乙酸異丙酯、二甲基甲醯胺、二甲基乙醯胺或N-甲基吡咯啶酮,較佳係比率為約20:1至約1:1、較佳約10:1之二氯甲烷及二甲基甲醯胺之組合)中,在相對於化合物XIX約5體積至約50體積、較佳10體積之濃度下,在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下處理化合物XIX。
在方案8之步驟2中,化合物XX轉化成化合物XXII。該反應係藉由以下方式來實施:在溶劑(例如(但不限於)丙酮、乙腈、四氫呋喃、二異丙基醚、甲基第三丁基醚、1,2-二甲氧基乙烷、1,4-二噁烷、甲苯、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、乙酸異丙酯、甲醇、乙醇、水、二甲基甲醯胺、N-甲基吡咯啶酮、N,N-二甲基乙醯胺或二甲基亞碸,較佳乙腈)中,在約-10℃至約100℃、較佳約60℃之溫度下,用硫代酸酯(thioate)親核劑處理化合物XX,該硫代酸酯親核劑係自用鹼(例如(但不限於)氫氧化鉀、氫氧化鈉、氫氧化鋰、碳酸銫、碳酸鉀、碳酸鈉、碳酸鋰、碳酸氫鉀、碳酸氫鈉、甲醇鈉、第三丁醇鉀、三乙胺、N,N-二異丙基乙胺或1,8-二氮雜二環[5.4.0]十一碳-7-烯,較佳碳酸鉀)處理化合物XXI來製備。硫代酸酯中間體係自身形成後添加至反應混合物中,或在原位形成,較佳在碘化鈉或碘化鉀不存在或存在下,較佳在約5mol%至約300mol%、較佳約100mol%之碘化鉀存在下,在原位形成。
在方案9之步驟1中,化合物XX轉化成化合物XXIV。
該反應係藉由以下方式來實施:在溶劑(例如(但不限於)丙酮、乙腈、四氫呋喃、二異丙基醚、甲基第三丁基醚、1,2-二甲氧基乙烷、1,4-二噁烷、甲苯、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、乙酸異丙酯、甲醇、乙醇、水、二甲基甲醯胺、N-甲基吡咯啶酮、N,N-二甲基乙醯胺或二甲基亞碸,較佳乙腈)中,在約-10℃至約100℃、較佳約60℃之溫度下,用硫代酸酯親核劑處理化合物XX,該硫代酸酯親核劑係自用鹼(例如(但不限於)氫氧化鉀、氫氧化鈉、氫氧化鋰、碳酸銫、碳酸鉀、碳酸鈉、碳酸鋰、碳酸氫鉀、碳酸氫鈉、甲醇鈉、第三丁醇鉀、三乙基胺、N,N-二異丙基乙胺或1,8-二氮雜二環[5.4.0]十一碳-7-烯,較佳碳酸鉀)處理化合物XXIII來製備。硫代酸酯中間體係由自身形成後添加至反應混合物中,或在原位形成,較佳在碘化鈉或碘化鉀不存在或存在下,較佳在約5mol%至約300mol%、較佳約100mol%之碘化鉀存在下,在原位形成。
在方案9之步驟2中,化合物XXIV轉化成化合物XXV。該反應係藉由用酸處理化合物XXIV來實施。
除用於製備式(1)治療劑外,方案10之化合物VIII(其中R18闡述
於上文中)可用於製備例如授予Williams等人之美國公開申請案第20100029731號中所述之拉格唑拉及拉格唑拉類似物。
如在方案10之步驟1中已知,以與Xiao,Q.等人,Journal of Asian Nat.Prod.Res.(2010),12,940-949中所述之條件類似之方式用化合物XXVI處理化合物VIII,以提供化合物XXVII。
在方案10之步驟2中,化合物XXVII經由Boc基團脫除保護基,轉化成相應的胺基酸,以獲得化合物XXVIII。
在方案10之步驟3中,化合物XXVIII經由巨內醯胺化反應藉由以下方式轉化成化合物XXIX:用活化劑(例如(但不限於)N-[(二甲基胺基)-1H-1,2,3-三唑并-[4,5-b]吡啶-1-基亞甲基]-N-甲基甲銨六氟磷酸鹽N-氧化物(HATU)、(O-(7-氮雜苯并三唑-1-基)-1,1,3,3-雙(四亞甲基)鈾六氟磷酸鹽)(HBTU)、N,N,N,N'-四甲基-O-(1H-苯并三唑-1-基)脲鎓六
氟磷酸鹽、O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽、DCC、DIC、EDCI、BDDC、BOP、PyBOP、BOMP、AOP、PyAOP、PyDOP、PyNOP、PyFOP、PyNFOP、NOP、NSBt、N-NSBt、N-HBTU、N-HATU或(HAPyU),較佳N-[(二甲基胺基)-1H-1,2,3-三唑并-[4,5-b]吡啶-1-基亞甲基]-N-甲基甲銨六氟磷酸鹽N-氧化物(HATU))自身或在添加劑(例如(但不限於)(HOSuc)、(HODhbt)、(HOt)、(HOCt)、(Oxama)、(6-CF3-HOBt)、(6-NO2-HOBt)、羥基-1,2,3-三唑、羥基苯并三唑(HOBt)或1-羥基-7-氮雜苯并三唑(HOAt),較佳羥基苯并三唑(HOBt))存在下,在溶劑(例如(但不限於)二氯甲烷、1,2-二氯乙烷、乙腈、四氫呋喃、甲苯、庚烷、甲基第三丁基醚、二異丙基醚、乙酸乙酯或乙酸異丙酯、二甲基甲醯胺、二甲基乙醯胺或N-甲基吡咯啶酮,較佳係比率為約20:1至約1:1、較佳約10:1之二氯甲烷及二甲基甲醯胺之組合)中,在相對於化合物XIX約5體積至約50體積、較佳10體積之濃度下,在約0℃至約40℃之溫度下、較佳在室溫(約25℃)下處理。
在方案10之步驟4中,化合物XXIX轉化成式(2)化合物。該反應係藉由以下方式來實施:在溶劑(例如(但不限於)丙酮、乙腈、四氫呋喃、二異丙基醚、甲基第三丁基醚、1,2-二甲氧基乙烷、1,4-二噁烷、甲苯、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、乙酸異丙酯、甲醇、乙醇、水、二甲基甲醯胺、N-甲基吡咯啶酮、N,N-二甲基乙醯胺或二甲基亞碸,較佳乙腈)中,在約-10℃至約100℃、較佳約60℃之溫度下,用硫代酸酯親核劑處理化合物XXIX,該硫代酸酯親核劑之製法係使用鹼(例如(但不限於)氫氧化鉀、氫氧化鈉、氫氧化鋰、碳酸銫、碳酸鉀、碳酸鈉、碳酸鋰、碳酸氫鉀、碳酸氫鈉、甲醇鈉、第三丁醇鉀、三乙基胺、N,N-二異丙基乙胺或1,8-二氮雜二環[5.4.0]十一碳-7-烯,較佳碳酸鉀)處理化合物XXI。硫代酸酯中間體係自身形
成後添加至反應混合物中,或在原位形成,較佳係在碘化鈉或碘化鉀不存在或存在下,較佳在約5mol%至約300mol%、較佳約100mol%之碘化鉀存在下,在原位形成。
實例1:自((7S,10S)-10-((E)-4-氯丁-1-烯-1-基)-7-異丙基-4,4-二甲基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-2,5,8,12-四酮)(化合物XX)製備S-硫代辛酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯(化合物XXII).
在室溫下,將((7S,10S)-10-((E)-4-氯丁-1-烯-1-基)-7-異丙基-4,4-二甲基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-2,5,8,12-四酮)(1.0g,2.07mmol)、硫代辛S-酸(0.66g,4.13mmol)、碳酸鉀(0.57g,4.13mmol)及碘化鉀(0.067g,0.41mmol)溶解於乙腈(20mL)中。在室溫下在氮下將混合物攪拌16小時。將混合物過濾,濃縮且藉由矽膠(石油醚/乙酸乙酯/甲醇,20/20/1)上之急速層析純化,以獲得1.13g(90%)黃褐色固體狀S-硫代辛酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯。 1 H NMR:(CDCl3,400MHz):δ 8.02(s,1H),7.65(s,1H),6.63(d,J=9.6Hz,1H),6.46(m,1H),5.79-5.73(m,2H),5.60(m,1H),5.15(dd,J=17.6,8.2Hz,1H),4.63(m,1H),4.36(dd,J=17.2,4.0Hz,
1H),2.86(t,J=7.2Hz,2H),2.71(m,2H),2.51(t,J=7.6Hz,2H),2.30(m,3H),1.89(s,3H),1.61(s,3H),1.28(bs,10H),0.88(m,6H),0.69(d,J=6.8Hz,3H)。
實例2:自(7S,10S)-10-((E)-4-氯丁-1-烯-1-基)-7-異丙基-4,4-二甲基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-2,5,8,12-四酮)(化合物XX)及(S)-2-((第三丁氧基羰基)胺基)-3-甲基硫代丁S-酸(化合物XXIII)製備(S)-S-2-((第三丁氧基羰基)胺基)-3-甲基硫代丁酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯(化合物XXIV).
將(7S,10S)-10-((E)-4-氯丁-1-烯-1-基)-7-異丙基-4,4-二甲基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-2,5,8,12-四酮)(15g,0.031mmol)、(S)-2-((第三丁氧基羰基)胺基)-3-甲基硫代丁S-酸(Boc-(D)Val-SH)(12.5g,0.054mmol)、碳酸鉀(11.2g,0.081)及碘化鉀(0.50g,0.003mmol)溶解於10mL乙腈中,且將所得混合物升溫至60℃-65℃並在氮下攪拌18hr。將反應混合物冷卻至室溫,添加水(50mL),且用乙酸乙酯(50mL)將所得混合物萃取兩次。用40mL水洗滌合併之有機層,用無水硫酸鈉乾燥並濃縮,且藉由矽膠(石油醚/乙酸乙酯,80/20)上之急速層析純化,以獲得16.90g
(80%)泡沫固體狀(S)-S-2-((第三丁氧基羰基)胺基)-3-甲基硫代丁酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯。 1 H NMR:(CDCl3,400MHz):δ 8.02(s,1H),7.64(s,1H),6.62(bs,1H),6.50(d,J=9.6Hz,1H),5.70-5.69(m,3H),5.18(dd,J=17.6,8.0Hz,1H),5.06(d,J=9.6Hz,1H),4.63(m,1H),4.38(dd,J=9.6Hz,6Hz,1H),4.24(dd,J=9.2,4.8Hz,1H),2.92(t,J=7.0Hz,2H),2.70-2.65(m,2H),2.31(m,4H),2.30(m,3H),1.90(s,3H),1.61(s,3H),1.45(s,9H),0.99(d,J=6.4Hz,3H),0.89(d,J=7.2Hz,3H),0.86(d,J=6.8Hz,3H),0.69(d,J=7.2Hz,3H)。
實例3a:自((S)-S-2-((第三丁氧基羰基)胺基)-3-甲基硫代丁酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯)(化合物XXIV)製備(S)-S-2-胺基-3-甲基硫代丁酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯鹽酸鹽(化合物XXV-A).
將((S)-S-2-((第三丁氧基羰基)胺基)-3-甲基硫代丁酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯)(8.0g,11.7mmol)溶解於160mL二氯甲烷中,且在10℃在氮下
添加三氟乙酸(24ml)。添加後,在室溫下將混合物攪拌5小時,此時將其濃縮至乾燥。將殘餘物溶解於乙酸乙酯(50ml)中,且逐滴緩慢添加HCl於乙酸乙酯中之溶液(10.0ml,4.0M),並在完成添加後將所得混合物攪拌10分鐘。然後添加石油醚(50ml)且藉由過濾收集沈澱固體並在真空下乾燥,以提供6.88g(95%)白色固體狀(S)-S-2-胺基-3-甲基硫代丁酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯鹽酸鹽。 1 H NMR:(DMSO-d6,400MHz):δ 8.55(bs,4H),8.16(s,1H),7.90(m,2H),5.63(m,3H),4.97(dd,J=17.6,8.2Hz,1H),4.34-4.30(m,2H),4.08(m,1H),3.04(m,1H),2.96(m,1H),2.76(m,1H),2.20-2.08(m,4H),1.71(s,3H),1.46(s,3H),0.99(d,J=6.4Hz,3H),0.96(d,J=6.4Hz,3H),0.78(d,J=6.8Hz,3H),0.57(d,J=6.8Hz,3H)。
實例3b:自((S)-S-2-((第三丁氧基羰基)胺基)-3-甲基硫代丁酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯)(化合物XXIV)製備(S)-S-2-胺基-3-甲基硫代丁酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯苯磺酸鹽(化合物XXV-B).
在室溫下,向((S)-S-2-((第三丁氧基羰基)胺基)-3-甲基硫代丁酸
((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯)(3.0g,4.41mmol)於50mL乙腈中之溶液中添加苯磺酸(2.70g,17.10mmol),且將所得混合物攪拌5小時,此時將其濃縮至乾燥。將殘餘物懸浮於庚烷(100ml)中,且攪拌30分鐘,此時藉由傾析移除庚烷。然後用THF(5ml)處理油性殘餘物且在室溫下攪拌16hr.,以提供1.6g(50%)白色固體狀(S)-S-2-胺基-3-甲基硫代丁酸((E)-4-((7S,10S)-7-異丙基-4,4-二甲基-2,5,8,12-四側氧基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-10-基)丁-3-烯-1-基)酯苯磺酸鹽。
實例4:自(7S,10S)-10-((E)-4-氯丁-1-烯-1-基)-7-異丙基-4,4-二甲基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-2,5,8,12-四酮)(化合物XIX)製備(7S,10S)-10-((E)-4-氯丁-1-烯-1-基)-7-異丙基-4,4-二甲基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-2,5,8,12-四酮)(化合物XX).
將HATU(26g,0.067mol)溶解於乙腈(300mL)中,且冷卻至0-5℃。在0-5℃下經5-6小時,將2-(((S,E)-3-(((S)-2-(2-胺基-2-甲基丙醯胺基)-3-甲基丁醯基)氧基)-7-氯庚-4-烯醯胺基)甲基)噻唑-4-甲酸三氟乙酸鹽(來自實例5之28g粗製物)及二異丙基乙胺(40ml,0.225mol)於二氯甲烷(600mL)中之溶液逐滴緩慢添加至HATU溶液中。添加後,
在0-5℃下將混合物再攪拌2小時,此時添加水(600ml)。分離層後,用乙酸乙酯(200mL)將水層萃取兩次,且用鹽水洗滌合併之有機層,用無水硫酸鈉乾燥並濃縮。使用矽膠(石油醚/乙酸乙酯,50/50)之急速層析提供14.5g(總共75%來自2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-11,11,15,15-四甲基-3,7,10,13-四側氧基-6,14-二氧雜-2,9,12-三氮雜十六烷基)噻唑-4-甲酸第三丁基酯)(來自實例5)白色固體狀(7S,10S)-10-((E)-4-氯丁-1-烯-1-基)-7-異丙基-4,4-二甲基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-2,5,8,12-四酮)。 1 H NMR:(CDCl3,400MHz):δ 8.05(s,1H),7.69(s,1H),6.61(d,J=9.6Hz,1H),6.41(m,1H),5.83-5.73(m,3H),5.19(dd,J=17.2,8.0Hz,1H),4.67(dd,J=9.6,4.2Hz,1H),4.36(dd,J=17.6,4.0Hz,1H),3.56(m,2H),2.75(m,2H),2.52(m,2H),2.34(m,1H),1.91(s,3H),1.64(s,3H),0.93(d,J=6.8Hz,3H),0.75(d,J=6.8Hz,3H)。
實例5:自2-(((S,E)-3-(((S)-2-(2-胺基-2-甲基丙醯胺基)-3-甲基丁醯基)氧基)-7-氯庚-4-烯醯胺基)甲基)噻唑-4-甲酸三氟乙酸鹽(化合物XVIII)製備(7S,10S)-10-((E)-4-氯丁-1-烯-1-基)-7-異丙基-4,4-二甲基-9-氧雜-16-硫雜-3,6,13,18-四氮雜二環[13.2.1]十八-1(17),15(18)-二烯-2,5,8,12-四酮)(化合物XIX).
將2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-11,11,15,15-四甲基-3,7,10,13-四側氧基-6,14-二氧雜-2,9,12-三氮雜十六烷基)噻唑-4-甲
酸第三丁基酯(28g,0.04mol)溶解於二氯甲烷(300ml)中,且添加三氟乙酸(150mL)。在室溫下將混合物攪拌20小時,且然後濃縮至乾燥。由此獲得之粗製物2-(((S,E)-3-(((S)-2-(2-胺基-2-甲基丙醯胺基)-3-甲基丁醯基)氧基)-7-氯庚-4-烯醯胺基)甲基)噻唑-4-甲酸三氟乙酸鹽未經純化即直接用於下一步驟(實例4)中。
實例6:自2-(((S,E)-3-(((S)-2-胺基-3-甲基丁醯基)氧基)-7-氯庚-4-烯醯胺基)甲基)噻唑-4-甲酸第三丁基酯(化合物XVII)及2-((第三丁氧基羰基)胺基)-2-甲基丙酸(化合物VII)製備2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-11,11,15,15-四甲基-3,7,10,13-四側氧基-6,14-二氧雜-2,9,12-三氮雜十六烷基)噻唑-4-甲酸第三丁基酯三氟乙酸鹽(化合物XVIII).
將2-(((S,E)-3-(((S)-2-胺基-3-甲基丁醯基)氧基)-7-氯庚-4-烯醯胺基)甲基)噻唑-4-甲酸第三丁基酯(20.0g,0.045mol)及2-((第三丁氧基羰基)胺基)-2-甲基丙酸(8.4g,0.010mol)溶解於二氯甲烷(200mL)中。在10℃-15℃下將HATU(17.6g,0.048mol)及二異丙基乙胺(12g,0.096mol)相繼添加至溶液中,且持續攪拌1小時。然後將100mL水添加至反應混合物中。分離各相且用100mL二氯甲烷萃取水相。合併有機相,用無水硫酸鈉乾燥,過濾且濃縮,以獲得26.7g(90%)2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-11,11,15,15-四甲基-3,7,10,13-四側氧基-6,14-二氧雜-2,9,12-三氮雜十六烷基)噻唑-4-甲酸
第三丁基酯三氟乙酸鹽,其未經進一步純化即使用。 1 H NMR:(CDCl3,400MHz):δ 7.99(s,1H),7.34(bs,1H),7.15(bs,1H),6.00(bs,1H),5.80(m,1H),5.65(m,1H),此區域中之一個額外質子,去除一個質子4.94(s,1H),4.75(d,J=6.0Hz,2H),4.23(t,J=6.7Hz,1H),3.50(t,J=6.7Hz,2H),2.65(bs,2H),2.48(q,J=6.7Hz,2H),2.11(m,1H),1.58(s,9H),1.48-1.39(m,15H),0.94(d,J=6.8Hz,3H),0.89(d,J=6.8Hz,3H)。
實例7:自2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)噻唑-4-甲酸第三丁基酯(化合物XVI)製備2-(((S,E)-3-(((S)-2-胺基-3-甲基丁醯基)氧基)-7-氯庚-4-烯醯胺基)甲基)噻唑-4-甲酸第三丁基酯(化合物XVII).
在5℃-10℃下,向2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)噻唑-4-甲酸第三丁基酯(27.0g,8mmol)於二噁烷(20mL)中之溶液中添加二噁烷中之4M HCl(20mL)。在5℃-10℃下將混合物攪拌3小時,且緩慢傾倒至冷卻飽和碳酸鈉溶液中。用100mL乙酸乙酯將所得混合物萃取兩次,且用鹽水洗滌合併之有機層,用無水硫酸鈉乾燥且濃縮,以獲得22.3g(100%)淺黃色油狀2-(((S,E)-3-(((S)-2-胺基-3-甲基丁醯基)氧基)-7-氯庚-4-烯醯胺基)甲基)噻唑-4-甲酸第三丁基酯,其未經進一步純化即直接用於下一步驟(實例6)中。
實例8:自(S,E)-2-((7-氯-3-羥基庚-4-烯醯胺基)甲基)噻唑-4-甲酸
第三丁基酯(化合物VI-B)及2-((第三丁氧基羰基)胺基)-2-甲基丙酸(化合物VII)製備2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)噻唑-4-甲酸第三丁基酯(化合物VIII).
在10℃-15℃下,經3小時向(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-3-羥基庚-4-烯-1-酮(2.0g,5.4mmol)於二氯甲烷(20mL)中之溶液中添加(S)-2-((第三丁氧基羰基)胺基)-3-甲基丁酸(1.41g;6.5mmol)、二環己基碳二亞胺(1.34g;6.5mmol)及二甲基胺基吡啶(66mg;0.54mmol)。然後將反應物過濾以移除固體,且用水(10mL)洗滌濾液,用無水硫酸鈉乾燥並濃縮。藉由管柱層析使用矽膠(石油醚/乙酸乙酯,25/1)純化粗產物,以獲得1.8g(59%)黃色泡沫固體狀(S)-2-((第三丁氧基羰基)胺基)-3-甲基丁酸(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-1-側氧基庚-4-烯-3-基酯。 1 H NMR:(CDCl3,400MHz):δ 7.37-7.27(m,5H),5.93-5.83(m,2H),5.62(dd,J=15.8,8.6Hz,1H),5.37(m,1H),5.04(d,J=9.1Hz,1H),4.19(dd,J=9.0,4.5Hz,1H),3.68(dd,J=17.4,8.6Hz,1H),3.57(dd,J=18.8,4.7Hz,1H),3.54(t,J=6.8Hz,2H),3.45(dd,J=11.5,7.2Hz,1H),3.21(dd,J=13.1,3.5Hz,1H),3.02(dd,J=13.0,10.7Hz,1H),2.89(d,J=11.6Hz,1H),2.51(q,J=6.8Hz,2H),2.12(m,1H),1.42(s,9H),0.95(d,J=6.8Hz,3H),0.85(d,J=6.9Hz,3H)。
實例9:自2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)噻唑-4-甲酸第三丁基酯(化合物VIII)及2-(胺基甲基)噻唑-4-甲酸第三丁基酯(化合物XV)製備(S)-2-((第三丁氧基羰基)胺基)-3-甲基丁酸(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-1-側氧基庚-4-烯-3-基酯(化合物XVI).
向(S)-(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-1-側氧基庚-4-烯-3-基2-((第三丁氧基羰基)胺基)-3-甲基丁酸酯(0.5g,0.88mmol)於DMF(5mL)中之溶液中添加2-(胺基甲基)噻唑-4-甲酸第三丁基酯鹽酸鹽(0.19g,0.88mmol)及二異丙基乙胺(340mg,2.64mmol),且在10℃-15℃下將所得混合物攪拌3小時。然後添加H2O(20mL),且用乙酸乙酯(50mL)萃取所得混合物。分離有機相,用無水硫酸鈉乾燥且濃縮。藉由管柱層析使用矽膠(石油醚/乙酸乙酯,2/1)純化粗產物,以獲得0.40g(80%)白色泡沫固體狀2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)噻唑-4-甲酸第三丁基酯。 1 H NMR:(CDCl3,400MHz):δ 7.98(s,1H),7.48(bs,1H),7.13(bs,1H),5.80(m,1H),5.62(m,2H),4.97(s,1H),4.75(d,J=5.9Hz,2H),4.24(t,J=6.7Hz,1H),3.49(t,J=6.7Hz,2H),2.65(d,J=4.9Hz,2H),2.47(q,J=6.7Hz,2H),2.08(m,1H)1.57(s,9H),1.41(s,9H),0.92(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H)。
實例10:自2-(((第三丁氧基羰基)胺基)甲基)噻唑-4-甲酸第三丁
基酯(化合物XIV)製備2-((胺基)甲基)噻唑-4-甲酸第三丁基酯(化合物XV).
在室溫下,向20.0g(0.064mol)2-(((第三丁氧基羰基)胺基)甲基)噻唑-4-甲酸第三丁基酯於二噁烷(160ml)中之溶液中添加二噁烷中之120ml 4M HCl。在室溫下攪拌過夜後,添加160ml石油醚且過濾所得沈澱,用庚烷洗滌並在真空下乾燥,以獲得15.9g(100%)2-(胺基甲基)噻唑-4-甲酸第三丁基酯鹽酸鹽,其未經進一步純化即使用。 1 H NMR:(CD3OD,400MHz):δ 8.20(s,9H),4.84(bs,1H),4.13(s,2H),1.61(s,9H)。
實例11:自溴丙酮酸第三丁基酯(化合物XII)及(2-胺基-2-硫基乙基)胺基甲酸第三丁基酯(化合物XIII)製備2-(((第三丁氧基羰基)胺基)甲基)噻唑-4-甲酸第三丁基酯(化合物XIV).
將28.0g(0.126mol)溴丙酮酸乙酯及25.0g(0.131mol)(2-胺基-2-硫基乙基)胺基甲酸第三丁基酯合併於異丙醇(250ml)中。將混合物攪拌16h.,此時添加28.6g 20%氫氧化鈉水溶液,然後添加500ml H2O。用EA(500ml,250ml)萃取產物。用飽和氯化鈉溶液洗滌有機層,用無水硫酸鈉乾燥,過濾並乾燥。使用矽膠(石油醚/乙酸乙酯,85/15)之急速層析獲得32g(72%)白色固體狀2-(((第三丁氧基羰基)胺基)甲基)噻唑-4-甲酸第三丁基酯。 1 H NMR:(CD2Cl2,400MHz):δ
7.92(s,1H),5.23(bs,1H),1.37(s,9H),1.53(s,9H)
實例12:自(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-3-羥基庚-4-烯-1-酮(化合物VI-B)及2-(胺基甲基)噻唑-4-甲酸第三丁基酯(化合物XV)製備(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-3-羥基庚-4-烯-1-酮(化合物XI).
向(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-3-羥基庚-4-烯-1-酮(10.0g,0.027mol)於二氯甲烷(80mL)中之溶液中添加2-(胺基甲基)噻唑-4-甲酸第三丁基酯(8.0g,0.032mol)。然後逐滴添加二異丙基乙胺(9.0g,0.07mol),同時將溫度維持在20℃-30℃之間。添加後,在室溫下將所得溶液攪拌8小時,此時添加水(80mL)。分離各層,並用二氯甲烷(40mL)將水層萃取一次。用鹽水洗滌合併之有機層,用無水硫酸鈉乾燥且濃縮。將殘餘物溶解於乙酸乙酯(20mL)中,且過濾沈澱固體。濃縮母液,將殘餘物溶解於乙酸乙酯(20mL)中,且過濾沈澱固體。在真空下乾燥合併之固體,以獲得7.8g(77%)(S,E)-2-((7-氯-3-羥基庚-4-烯醯胺基)甲基)噻唑-4-甲酸第三丁基酯。藉由濃縮最終母液並藉由使用矽膠(石油醚/二氯甲烷:80/20-50/50)之急速層析純化殘餘物獲得額外1.3g產物。 1 H NMR:(CDCl3,400MHz):δ 7.98(s,1H),7.38(bt,J=5.7Hz,1H),5.72(dt,J=15.6,5.6Hz,1H),5.61(dd,J=15,6,5.8Hz,1H),4.75(dq,J=15.6,6.0Hz,2H),4.54(bs,1H),3.93(s,1H),3.50(t,J=6.8Hz,2H),2.57-2.43(m,4H),1.57(s,9H)。
實例13:自(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-3-羥基庚-4-烯-1-酮(化合物XI)及2-((第三丁氧基羰基)胺基)乙酸(化合物VII)
製備(S)-2-((第三丁氧基羰基)胺基)-3-甲基丁酸(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-1-側氧基庚-4-烯-3-基酯(化合物XVI).
將(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-3-羥基庚-4-烯-1-酮(17.0g,0.045mol)及(S)-2-((第三丁氧基羰基)胺基)-3-甲基丁酸(11.8g,0.045mol)溶解於二氯甲烷(250mL)中,將混合物冷卻至0-5℃,且添加二甲基胺基吡啶(0.55g,4.5mmol)及1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(17.3g,0.054mol)。在0-5℃下將反應物攪拌20小時,此時添加二氯甲烷(100mL)、水(200mL)。分離有機層並用水(150mL)洗滌。用無水硫酸鈉乾燥有機層且濃縮,以獲得25.8g(100%)泡沫固體狀(S)-2-((第三丁氧基羰基)胺基)-3-甲基丁酸(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-1-側氧基庚-4-烯-3-基酯,其未經進一步純化即使用。 1 H NMR:(CD2Cl2,400MHz):δ 7.98(s,1H),7.49(bs,1H),7.13(bs,1H),5.78(m,1H),5.65(m,1H),4.98(s,1H),4.75(d,J=2.8Hz,2H),4.25(t.J=6.4Hz,1H),3.49(t,J=6.8Hz,2H),2.65(d,J=6.8Hz,2H),2.47(q,J=6.4Hz,4H),1.57(s,9H),1.41(s,9H),0.92(d,J=6.8Hz,3H)0.88(d,J=6.8Hz,3H)。
實例14a:自(E)-5-氯戊-2-烯醛(化合物IV)及(R)-1-(4-異丙基-2-硫基噻唑啶-3-基)乙酮(化合物V-A;表2)(來自方案3)製備(S,E)-7-氯-3-羥基-1-((R)-4-異丙基-2-硫基噻唑啶-3-基)庚-4-烯-1-酮(化合物VI-A-1,表2).
將(R)-1-(4-異丙基-2-硫基噻唑啶-3-基)乙酮(4.0g,19.6mmol)溶解於二氯甲烷(150ml)中,且冷卻至-40℃。添加TiCl4(6.0g,31.62mmol),同時將反應溫度維持在-40℃以下。攪拌1h後,逐滴添加二異丙基乙胺(4.1g,31.62mmol),且將反應溫度維持在-40至-50℃之間。添加後,在-40℃下將混合物攪拌2小時,此時將反應物冷卻至-78℃,且逐滴緩慢添加二氯甲烷(10ml)中之(E)-5-氯戊-2-烯醛(2.21g,18.6mmol),同時將反應溫度維持在-65℃以下。添加後,在-70℃至-65℃下將所得混合物攪拌1小時,且然後傾倒至飽和氯化銨水溶液(100ml)及飽和氯化鈉水溶液(100ml)之混合物中。用二氯甲烷(400ml)將所得混合物萃取兩次,且用飽和氯化鈉水溶液(100mL)洗滌合併之有機層並濃縮至乾燥。藉由管柱層析純化獲得4.8g(80%)(S,E)-7-氯-3-羥基-1-((R)-4-異丙基-2-硫基噻唑啶-3-基)庚-4-烯-1-酮(化合物VI-A,表2)。 1 H NMR:(CDCl3,400MHz):δ 5.76(dt,J=15.6,6.5Hz,1H),5.66(dd,J=15.6,5.6Hz,1H),5.15(t,J=7.0Hz,1H),4.65(m,1H),3.64(dd,J=17.6,3.0Hz,1H),3.56-3.50(m,3H),3.29(dd,J=17.7,8.8Hz,1H)3.03(d,J=11.5Hz,1H),2.90(bs,1H),2.51(q,J=6.8Hz,2H),2.36(m,1H),1.06(d,J=6.8Hz,3H),0.98(d,J=6.9Hz,3H)。
實例14b:自(E)-5-氯戊-2-烯醛(化合物IV)及(R)-1-(4-苄基-2-硫基噻唑啶-3-基)乙酮(化合物V-B)(來自方案3)製備(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-3-羥基庚-4-烯-1-酮(化合物VI-B-1;表2).
將(R)-1-(4-苄基-2-硫基噻唑啶-3-基)乙酮(36g,0.143mol)溶解於二氯甲烷(1L)中,且冷卻至-40℃。添加TiCl4(29g,0.153mol),同時將反應溫度維持在-40℃以下。攪拌1h後,逐滴添加二異丙基乙胺(20g,0.153mol),同時將反應溫度維持在-40至-50℃之間。添加後,在-40℃下將混合物攪拌2小時,此時將反應物冷卻至-78℃,且逐滴緩慢添加二氯甲烷(40ml)中之(E)-5-氯戊-2-烯醛(10.0g,0.084mol),同時將反應溫度維持在-65℃以下。添加後,在-70℃至-65℃下將所得混合物攪拌1小時,且然後傾倒至飽和氯化銨水溶液(500ml)及飽和氯化鈉水溶液(500ml)之混合物中。用二氯甲烷(400ml)將所得混合物萃取兩次,且用飽和氯化鈉水溶液(500mL)洗滌合併之有機層並濃縮至乾燥。將乙酸乙酯(50mL)添加至殘餘物中,然後緩慢添加石油醚(150mL)。藉由過濾收集沈澱固體且濃縮母液。將乙酸乙酯(50mL)添加至殘餘物中,然後緩慢添加石油醚(150mL)。藉由過濾收集沈澱固體,與第一批所收集固體合併,並在真空下乾燥,以獲得22g(71%)(S,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-3-羥基庚-4-烯-1-酮(化合物VI-B-1,表2),其含有2%次要非鏡像異構物(R,E)-1-((R)-4-苄基-2-硫基噻唑啶-3-基)-7-氯-3-羥基庚-4-烯-1-酮(化合物VI-B,表2)。 1 H NMR:(CDCl3,400MHz):δ 7.38-7.27(m,5H),5.78(dt,1H,J=16.1,6.3Hz,1H),5.69(dd,J=15.5,5.6Hz,1H),5.39(ddd,J=10.4,6.9,3.8Hz,1H),4.68(m,1H),3.65(dd,J=17.7,2.9Hz,1H),3.57(t,J=6.8Hz,2H),3.41(dd,J=11.5,7.2Hz,1H),3.31(dd,J=17.7,8.9Hz,1H),3.23(dd,J=13.2,3.9Hz,1H),3.05(dd,J=13.2,10.5Hz,1H),2.91(d,J
=11.6Hz,1H),2.81(d,J=4.4Hz,1H),2.54(q,J=6.7Hz,2H)。
實例15:自4-氯-丁-1-烯(化合物I)及巴豆醛(化合物II)製備(E)-5-氯戊-2-烯醛(化合物IV).
將4-氯-丁-1-烯(20g,0.22mol)、巴豆醛(23g,1.5當量)及CuI(2.5g,0.06當量)合併於二氯甲烷(400mL)中,且一次性添加(1,3-雙(2,4,6-三甲基苯基)-2-咪唑啶亞基)二氯(苯基亞甲基)(三環己基膦)釕)(第2代格拉布烯烴置換觸媒)(0.011mol,0.93g,0.5mol%),同時用氮吹掃。在40℃下在攪拌的同時將混合物加熱至回流並保持16小時,此時藉由1H NMR分析反應物指示65%-70%轉化率。然後將反應混合物冷卻,過濾且濃縮。將殘餘物溶解於二氯甲烷(150ml)中,且在真空下蒸發二氯甲烷以移除未反應之起始材料。將此重複4次。由此產生之產物未經任何進一步純化即用於後續醛醇縮合反應中。經由急速層析使用矽膠(石油醚/二氯甲烷,50/50)獲得分析純樣品。 1 H NMR:(CD2Cl2,400MHz):δ 9.51(d,J=8.0Hz,1H),6.82(dt,J=15.6,6.8Hz,1H),6.16(ddt,J=15.6,6.8,1.6Hz,1H),3.68(t,J=6.4Hz,2H),2.78(qd,J=5.2,1.2Hz,2H)
實例16:自4-氯-丁-1-烯(化合物I)及(E)-丁-2-烯-1,4-二醇(來自方案1之化合物II)製備(E)-5-氯戊-2-烯-1-醇(化合物III).
將4-氯-丁-1-烯(3.4g,0.037mol)、(E)-丁-2-烯-1,4-二醇(5.0g,0.055mol)及CuI(0.42g,2.22mmol)合併於二氯甲烷(70mL)中,且一次性添加(1,3-雙(2,4,6-三甲基苯基)-2-咪唑啶亞基)二氯(苯基亞甲
基)(三環己基膦)釕(第2代格拉布烯烴置換觸媒)(0.185mmol,0.157g),同時用氮吹掃。在40℃下在攪拌的同時將混合物加熱至回流並保持16小時,此時藉由1H NMR分析反應物指示82%轉化率。然後將反應混合物冷卻,過濾,且濃縮以獲得粗(E)-5-氯戊-2-烯-1-醇,其直接用於下一反應中。 1 H NMR:(DMSO-d6,400MHz):δ 5.69-5.52(m,2H),4.70(t,J=5.4Hz,1H),3.91(m,2H),3.64(t,J=6.8Hz,2H),2.54(m,2H)。
實例17:自(E)-5-氯戊-2-烯-1-醇(化合物III)製備(E)-5-氯戊-2-烯-1-醛(化合物IV).
向(E)-5-氯戊-2-烯-1-醇(0.40g,3.33mmol)於二氯甲烷(5mL)中之溶液中添加二氧化錳(0.87g,10.0mmol),且在室溫下將所得混合物攪拌20小時。然後將混合物過濾且濃縮,以獲得(E)-5-氯戊-2-烯-1-醛(基於1H NMR之90%轉化率)。 1 H NMR:(CD2Cl2,400MHz):δ 9.51(d,J=8.0Hz,1H),6.82(dt,J=15.6,6.8Hz,1H),6.16(ddt,J=15.6,6.8,1.6Hz,1H),3.68(t,J=6.4Hz,2H),2.78(qd,J=5.2,1.2Hz,2H)
實例18:自(5R,8S,11S)-11-((E)-4-氯丁-1-烯-1-基)-8-異丙基-5-甲基-10-氧雜-3,17-二硫雜-7,14,19,20-四氮雜三環[14.2.1.12,5]二十-1(18),2(20),16(19)-三烯-6,9,13-三酮(化合物XXIX)製備S-硫代辛酸((E)-4-((5R,8S,11S)-8-異丙基-5-甲基-6,9,13-三側氧基-10-氧雜-3,17-二硫雜-7,14,19,20-四氮雜三環[14.2.1.12,5]二十-1(18),2(20),16(19)-三烯-11-基)丁-3-烯-1-基)酯(拉格唑拉,式(2)化合物).
在室溫下,將(5R,8S,11S)-11-((E)-4-氯丁-1-烯-1-基)-8-異丙基-5-甲基-10-氧雜-3,17-二硫雜-7,14,19,20-四氮雜三環[14.2.1.12,5]二十-1(18),2(20),16(19)-三烯-6,9,13-三酮(化合物XXIX)(0.23g,0.46mmol)、硫代辛S-酸(0.44g,2.75mmol)、碳酸鉀(0.40g,2.90mmol)及碘化鉀(0.067g,0.41mmol)溶解於乙腈(20mL)中。在室溫下在氮下將混合物攪拌16小時。將混合物過濾,濃縮且藉由製備型矽膠層析(二氯甲烷/甲醇,50/1)純化,以獲得0.12g(42%)白色固體狀S-硫代辛酸((E)-4-((5R,8S,11S)-8-異丙基-5-甲基-6,9,13-三側氧基-10-氧雜-3,17-二硫雜-7,14,19,20-四氮雜三環[14.2.1.12,5]二十-1(18),2(20),16(19)-三烯-11-基)丁-3-烯-1-基)酯。 1 H NMR:(CDCl3,400MHz):δ 7.76(s,1H),7.16(d,J=9.4Hz,1H),6.43(d,J=10.4Hz,1H),5.83(dt,J=15.8,7.3Hz,1H),5.66(m,1H),5.51(dd,J=15.5,6.9Hz,1H),5.29(dd,J=17.7,9.3Hz,1H),4.60(dd,J=9.4,3.3Hz,1H),4.27(dd,J=17.6,3.0Hz,1H),4.04(d,J=11.4Hz,1H),3.28(d,J=11.4Hz,1H),2.90(t,J=7.2Hz,2H),2.87(dd,J=16.4,10.4Hz,1H),2.68(dd,J=16.3,2.7Hz,1H),2.53(t,J=7.5Hz,1H),2.31(q,J=7.0Hz,2H),2.11(m,1H),1.87(s,3H),1.62(m,2H),1.27(m,8H),0.87(m,3H),0.69(d,J=6.7Hz,3H),0.51(d,J=6.8Hz,3H)。
實例19:自(R)-2'-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)-4-甲基-4,5-二氫-[2,4'-二噻唑]-4-甲酸(化合物XXVII)製備(5R,8S,11S)-11-((E)-4-氯丁-1-烯-1-基)-8-異丙基-5-甲基-10-氧雜-3,17-二硫雜-
7,14,19,20-四氮雜三環[14.2.1.12,5]二十-1(18),2(20),16(19)-三烯-6,9,13-三酮(化合物XXIX).
將(R)-2'-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)-4-甲基-4,5-二氫-[2,4'-二噻唑]-4-甲酸(化合物XXVII)(1.5g,2.4mmol)溶解於二氯甲烷(20ml)中,且添加三氟乙酸(2.9g,25.4mmol),同時在20℃-25℃下攪拌。在20℃-25℃下將所得混合物攪拌3小時後,再添加一等份三氟乙酸(0.80g,7.0mmol),並將所得混合物再攪拌3.5小時,此時藉由HPLC確定反應完成。向含有(R)-2'-(((S,E)-3-(((S)-2-胺基-3-甲基丁醯基)氧基)-7-氯庚-4-烯醯胺基)甲基)-4-甲基-4,5-二氫-[2,4'-二噻唑]-4-甲酸三氟乙酸鹽(化合物XXVIII)之粗反應混合物中添加二異丙基乙胺(4.7g,41.2mmol)。然後在0-5℃下經5-6小時時段,將所得混合物逐滴緩慢添加至HATU(2.9g,7.63mmol)溶解於乙腈(50mL)中之預形成溶液中。添加後,在0-5℃下將混合物再攪拌2小時,此時添加水(100mL)。分離層後,用乙酸乙酯(50mL)將水層萃取兩次,且用鹽水洗滌合併之有機層,用無水硫酸鈉乾燥並濃縮。使用矽膠(二氯甲烷/甲醇,40/1)之急速層析提供白色固體狀(5R,8S,11S)-11-((E)-4-氯丁-1-烯-1-基)-8-異丙基-5-甲基-10-氧雜-3,17-二硫雜-7,14,19,20-四氮雜三環[14.2.1.12,5]二十-1(18),2(20),16(19)-三烯-6,9,13-三酮(0.26g)(總共23%來自化合物XXVII)。 1 H NMR:(CDCl3,400MHz):δ 7.76(s,1H),7.19(d,J=7.4Hz,1H),6.49(d,J=8.6Hz,1H),5.89(dt,J=15.7,7.3
Hz,1H),5.70(m,1H),5.60(dd,J=15.6,6.5Hz,1H),5.28(dd,J=17.0,9.1Hz,1H),4.61(dd,J=9.0,3.5Hz,1H),4.27(dd,J=17.5,2.9Hz,1H),4.04(d,J=11.2Hz,1H),3.54(t,J=6.6Hz,2H),3.28(d,J=11.3Hz,1H),2.85(m,1H),2.72(dd,J=16.3,2.7Hz,1H),2.51(q,J=6.7Hz,2H),2.10(m,1H),1.86(s,3H),0.70(d,J=6.9Hz,3H),0.53(d,J=6.8Hz,3H)。
實例20:自2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)噻唑-4-甲酸第三丁基酯(化合物VIII)及(R)-2'-(胺基甲基)-4-甲基-4,5-二氫-[2,4'-二噻唑]-4-甲酸(化合物XXVI)製備(R)-2'-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)-4-甲基-4,5-二氫-[2,4'-二噻唑]-4-甲酸(化合物XXVII).
將2-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)噻唑-4-甲酸第三丁基酯(化合物VIII)(1.0g,1.8mmol)添加至(R)-2'-(胺基甲基)-4-甲基-4,5-二氫-[2,4'-二噻唑]-4-甲酸三氟乙酸鹽(化合物XXVI)(0.51g,2.0mmol)(經由以下文獻中所述方法之修改製備:Xiao,Q.等人,Journal of Asian Natural Products Research,(2010),12:11,940)及二異丙基乙胺(2.5g,0.025mmol)於二氯甲烷(10mL)中之預形成溶液
中。在25℃下攪拌16小時後,添加H2O(20mL)且分離各層。用二氯甲烷(20mL)將水相萃取一次,且用無水硫酸鈉乾燥合併之有機相,過濾並濃縮。藉由急速層析(二氯甲烷/MeOH=40:1→10:1)純化提供1.6g(88%)泡沫狀(R)-2'-((5S,8S)-5-((E)-4-氯丁-1-烯-1-基)-8-異丙基-12,12-二甲基-3,7,10-三側氧基-6,11-二氧雜-2,9-二氮雜十三烷基)-4-甲基-4,5-二氫-[2,4'-二噻唑]-4-甲酸。質譜(m/z):617.9
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Claims (17)
- 一種用於製備式(1)化合物
- 如請求項1之方法,其中R5係H且R6選自由H、異丙基及甲基組成之群。
- 如請求項1之方法,其中R5係H且R6係異丙基。
- 如請求項1之方法,其中R12係C(O)C7烷基。
- 如請求項1之方法,其中R12係C(O)(CH2)6CH3。
- 如請求項1之方法,其中R3及R4係甲基。
- 如請求項1之方法,其中R12係C(O)CR13R14NR13R14。
- 一種用於製備式(2)化合物
- 如請求項12之方法,其中R5係H且R6係異丙基。
- 如請求項12之方法,其中R13係-(CH2)6CH3。
- 如請求項12之方法,其中R1及R2係H。
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