TWI468375B - 製備經保護之l-丙胺酸衍生物之方法 - Google Patents
製備經保護之l-丙胺酸衍生物之方法 Download PDFInfo
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- TWI468375B TWI468375B TW98136147A TW98136147A TWI468375B TW I468375 B TWI468375 B TW I468375B TW 98136147 A TW98136147 A TW 98136147A TW 98136147 A TW98136147 A TW 98136147A TW I468375 B TWI468375 B TW I468375B
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- 238000000034 method Methods 0.000 title claims description 62
- 238000002360 preparation method Methods 0.000 title description 9
- 230000008569 process Effects 0.000 title description 9
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical class C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 152
- 239000000203 mixture Substances 0.000 claims description 67
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 60
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 54
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 39
- 229910052740 iodine Inorganic materials 0.000 claims description 39
- 239000011630 iodine Substances 0.000 claims description 39
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 38
- 239000003960 organic solvent Substances 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 34
- -1 C 1-6 alkane Oxy Chemical group 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 229910052725 zinc Inorganic materials 0.000 claims description 28
- 239000011701 zinc Substances 0.000 claims description 28
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 23
- 229910052763 palladium Inorganic materials 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 18
- 239000003446 ligand Substances 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- 150000007529 inorganic bases Chemical class 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 239000007983 Tris buffer Substances 0.000 claims description 7
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 239000003791 organic solvent mixture Substances 0.000 claims description 5
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical group CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- HPGPEWYJWRWDTP-UHFFFAOYSA-N lithium peroxide Chemical compound [Li+].[Li+].[O-][O-] HPGPEWYJWRWDTP-UHFFFAOYSA-N 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical group COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 claims description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 230000009257 reactivity Effects 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 229940113088 dimethylacetamide Drugs 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 102000003840 Opioid Receptors Human genes 0.000 description 11
- 108090000137 Opioid Receptors Proteins 0.000 description 11
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 9
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
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- 238000010438 heat treatment Methods 0.000 description 6
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- 239000000047 product Substances 0.000 description 6
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- 101100025412 Arabidopsis thaliana XI-A gene Proteins 0.000 description 4
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- 125000003003 spiro group Chemical group 0.000 description 1
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- 238000010561 standard procedure Methods 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 229940124597 therapeutic agent Drugs 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-N trans-4-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- JUDXOKKZTISQDJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 JUDXOKKZTISQDJ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
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Description
本發明為關於受保護L-丙胺酸衍生物之新製造方法,受保護L-丙胺酸衍生物可作為合成作為mu/delta類鴉片調節劑之化合物時的中間物。
類鴉片受體是於1970年代中期被辨認出,且快速被區分出三子集(mu,delta與kappa)。近來,這最初的三種受體類型被更區分出數種亞型。類鴉片受體科(family)亦被認為是G-蛋白偶聯受體(GPCR)總科(super family)之成員。更具生理相關者為已確認類鴉片受體遍佈於許多哺乳類,包括人類,之中樞或末梢神經系統,且對各個受體之調節會招致數種期望或不期望產生之生理效應。(D.S. Fries,止痛劑(Analgesics),《醫藥化學原理(Principles of Medicinal Chemistry)》,第4版;W.O. Foye,T.L. Lemke,與D.A. Williams,Eds.;Williams與Wilkins: Baltimore,Md.,1995;頁247-269;J.V. Aldrich,止痛劑(Analgesics),《包格氏醫藥化學與藥劑發現(Burger’s Medicinal Chemistry and Drug Discovery)》,
第5版,第3冊:治療藥物(Therapeutic Agents),John Wiley & Sons,Inc.,1996,頁321-441)。於最近之文獻中,已報導類鴉片受體亞型的雜二聚體化(heterodimerization),不過其個別生理反應尚未確定。(Pierre J.M. Riviere與Jean-Louis Junien,類鴉片受體:新腸胃藥發展之標的(Opioid receptors: Targets for new gastrointestinal drug development),藥物發展(Drug Development)2000,頁203-238)。
關於類鴉片調節劑經辨明之生物效應,已經導致數種藥物的出現。最重要為,數種市售止痛藥為中樞作用mu類鴉片促效劑調節劑,用以緩解疼痛(例如,嗎啡),末梢作用mu促效劑則被用以調節能動性(例如,羅普醯胺(loperamide))。目前,臨床研究持續評估對delta,mu與kappa具選擇性的調節劑,與具組合之亞型調節能力之化合物的醫療用途。可預見上述探索可找到具新利用性之藥劑,或與目前可得之藥劑相比,不良副作用可減至最小之藥劑(嗎啡之副作用,舉例來說,包含便秘、呼吸窘迫與成癮性)。對於選擇性或混合性類鴉片調節劑,一些目前正在評估之新GI區域,包含對於痢疾症候群、能動性失調(術後腸塞絞痛、便秘)與內臟疼痛(術後疼痛、激躁性結腸症、炎性腸障礙)有發展潛力療法(Pierre J. M. Riviere與Jean-Louis Junien,類鴉片受體:新腸胃藥發展之標的(Opioid receptors: Targets for new gastrointestinal drug development),2000,頁203-238)。
大約與辨認出類鴉片受體同時,腦啡肽被辨認與歸類為一套內源性類鴉片配位體(D.S. Fries,止痛劑(Analgesics),《醫藥化學原理(Principles of Medicinal Chemistry)》,第4版;W.O. Foye;T.L. Lemke,與D.A. Williams,Eds.;Williams與Wilkins: Baltimore,Md.,1995;頁247-269)。Schiller發現截去原五肽腦啡肽,將二肽類簡化後,可得到一系列維持類鴉片活性之化合物(Schiller,P. WO 96/06855)。但是此種化合物的一個可能缺點是先天即不安定(P.W. Schiller等,國際胜肽與蛋白質研究期刊(Int. J. Pept. Protein Res.)1993,41(3),頁313-316)。
最近,已發現一系列含雜芳族或雜脂族核之類鴉片假肽類,但是此系列顯現異於Schiller研究揭示之功能描記(L.H. Lazarus等,《胜肽(Peptides)》2000,21,頁1663-1671)。
最近,Wentland等提出嗎啡相關結構之研究報告,為關於製備羧醯胺衍生物嗎啡及其同系物(M.P. Wentland等,《生物有機與藥物化學通訊(Biorg. Med. Chem. Letters)》2001,11,頁1717-1721;M.P. Wentland等,《生物有機與藥物化學通訊(Biorg. Med. Chem. Letters)》2001,11,頁623-626)。Wentland發現嗎啡相關結構之酚部份有一級羧醯胺取代時,依類鴉片受體及羧醯胺,會導致維持相同活性到40倍不等之活性下降。這也揭示在羧醯胺上出現任何其他N-取代基,會明顯降低所期待的鍵結活性。
類鴉片受體調節劑、促效劑或拮抗劑,可用於治療或預防多種哺乳動物的疾病狀態,例如疼痛及胃腸失調例如腹瀉徵候群,能動性失調,包括術後腸塞絞痛及便秘,及內臟疼痛,包括術後疼痛,激躁性結腸症,炎性腸障礙。
Breslin,H.J.等之美國專利公開案第2005/0203143 Al號(2005年9月15日公開)全文併於本文中,作為交互參照,其揭露類鴉片受器調節劑、包含該調節劑之醫藥組成、與使用該調節劑之治療方法。本發明為關於製造中間物的方法,該中間物可用於合成如美國專利公開案第2005/0203143 A1號所揭露之類鴉片受器調節劑。
本發明為關於一種式(I)化合物的製造方法,
其中PG1
是一種氮保護基團;R0
為選自包含氫原子、C1-4
烷基與苄基之群組;R6
為選自包含氫原子、C1-6
烷基之群組;R4
為芳基或雜芳基;其中芳基或雜芳基可選擇性經1至5個取代基取代,該取代基為獨立選自包含C1-6
烷基、C1-6
烷氧基、芳基C1-6
烷氧基、芳基C1-6
烷基羰氧基、雜芳基C1-6
烷基羰氧基、雜芳基、羥基、鹵素、胺基磺醯基、甲醯胺基、胺羰基、C1-6
烷基胺羰基、二(C1-6
烷基)胺羰基、雜環羰基、羧基與氰基之群組;其中C1-6
烷基為選擇性有胺基,C1-6
烷基胺基、或(C1-6
烷基)2
胺基取代之烷基;其中芳基C1-6
烷基羰氧基之芳基部份為選擇性經1至4個取代基取代,該取代基獨立選自包含C1-6
烷基、C1-6
烷氧基、鹵素、氰基、胺基與羥基之群組;與其醫藥可接受鏡像異構物、其醫藥可接受非鏡像異構物、其醫藥可接受外消旋物與其醫藥可接受鹽類;其包含,包含與/或主要包含
使式(X)反應化合物,其中PG1
為氮保護基團,於碘源存在下,於第一有機溶劑或有機溶劑混合物內,與鋅反應,以產生相對應之式(XI)化合物,其中第一有機溶劑對碘源無反應性;
使式(XI)化合物,其中LG1
是脫離基;於鈀催化劑與膦配位基系統存在下,於第二有機溶劑或有機溶劑混合物內,與式(XII)化合物反應,以產生相對應式(I)化合物;。
本發明更關於式(I-B)化合物之製造方法
其包含,包含與/或主要包含
使式(X-B)反應化合物,於碘源存在下,於第一有機溶劑或有機溶劑混合物內,與鋅反應,以產生相對應之式(XI-B)化合物,其中第一有機溶劑對碘源無反應性;
式(XI-B)化合物,於鈀催化劑與膦配位基系統存在下,於第二有機溶劑或有機溶劑混合物內,與式(XII-B)化合物反應,以產生相對應之式(I-B)化合物。
本發明更關於式(II-B)化合物
或其醫藥上可接受鹽類之製造方法;其包含,包含與/或主要包含
使式(I-B)化合物,於存有無機鹼下,於第三有機溶劑內與氧化劑反應,以產出相對應之式(II-B)化合物。
本發明更關於根據於此所述方法製備之產物。較佳,根據本發明方法製備之化合物近純。
本發明關於一種製造式(I)化合物之新方法
其中PG1
,R0
,R4
與R6
為於此加以定義,並包括其醫藥上可接受鏡像異構物,非鏡像異構物,外消旋物與鹽類。式(I)化合物可作為合成如美國專利公開案第2005/0203143 A1號(2005年9月15日公開)所揭露類鴉片受器調節劑時之中間物。該公開案全文併於本說明書內,作為交互參照。
於一具體實施例,本發明關於式(I-A)化合物之製造方法
與更關於式(I-B)化合物之製造方法
式(I-B)化合物別名為(S)-2-第三-丁氧羰胺-3-(4-氰-2,6-二甲-苯)-丙酸甲酯。
本發明更關於式(II-A)化合物,
或其醫藥上可接受鹽類之製造方法;本發明更關於製造式(II-B)化合物
式(II-B)化合物之別名為(S)-2-第三-丁氧羰胺-3-(4-胺甲醯-2,6-二甲-苯)-丙酸,或其醫藥上可接受鹽類。
於本發明一實施例,PG1
選自包含第三丁氧基羰基(butoxycarbonyl,Boc)與苄氧羰基(carbobenzoxy,Cbz)群組。於本發明另一實施例,PG1
為第三丁氧基羰基。
於本發明一實施例,R0
選自包含C1-4
烷基與苄基之群組。於本發明另一實施例,R0
選自包含甲基,乙基,異丙基,三級丁基與苄基之群組。於本發明另一實施例,R0
為甲基或苄基。於本發明另一實施例,R0
為甲基。於本發明另一實施例,R0
非氫原子。
於本發明一實施例,R6
選自包含氫原子與甲基群組於本發明另一實施例,R6
為氫原子。
於本發明一實施例,R4
選自包含C6-10
芳基與雜芳基之群組;其中雜芳基選自包含呋喃基、噻吩基、呲咯基、噁唑基、噻唑基(thiazolyl)、咪唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、吲哚基、異吲哚基、吲哚啉基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯並噻唑基、苯并噁唑基、喹嗪基(quinolizinyl)、喹啉基(quinolinyl)、異喹啉基與喹唑啉基之群組;其中R4
選擇性有1-3個取代基,該取代基係獨立選自包含C1-6
烷基(其中C1-6
烷基選擇性有胺基、C1-6
烷基胺基、或二(C1-6
烷基)胺基取代);C1-6
烷氧基;苄基C1-6
烷氧基;苄基C1-6
烷基羰氧基(其中C1-6
烷基部份可選擇性有胺基取代;與苄基C1-6
烷基羰氧基中的苄基部份可選擇性有C1-6
烷基、C1-6
烷氧基、鹵素、氰基、胺基或羥基取代);非稠環之5元雜芳基C1-6
烷基羰氧基;非稠環之5元雜芳基;羥基;鹵素;胺基磺醯基;甲醯胺基;胺基羰基;C1-6
烷基胺羰基(其中C1-6
烷基部份選擇性有胺基、C1-6
烷基胺基、或(C1-6
烷基)2
胺基取代);二(C1-6
烷基)胺羰基(其中每一C1-6
烷基部份可選擇性以胺基、C1-6
烷基胺基、或(C1-6
烷基)2
胺基取代);雜環基羰基(其中雜環基為5-7元含氮環,且其中雜環為藉氮原子接於羰基之碳原子);羧基;與氰基之群組。
本發明另一實施例R4
是C6-10
芳基,且其選擇性經一至三個取代基取代,該取代基獨立選自包含(C1-3
)烷基、(C1-6
)烷氧基、苄基(C1-6
)烷氧基;羥基;鹵素;甲醯胺基;胺基羰基;C1-6
烷基胺羰基;(C1-6
烷基)2
胺羰基;雜環基羰基,其中雜環為含氮5-7元環,且該雜環為藉氮原子接於羰基之碳原子;羧基;與氰基之群組;上述選擇之前提為:不多於一個之取代基是醯胺基、胺基羰基、C1-6
烷基胺羰基、(C1-6
烷基)2
胺羰基、雜環基羰基、羥基、羧基、或含苯取代基。
本發明另一實施例R4
為苄基,且其經一至三個取代基取代,該取代基獨立選自包含(C1-3
)烷基、(C1-3
)烷氧基、苄基(C1-3
)烷氧基、羥基、C1-6
烷基胺羰基,與胺基羰基之群組;上述選擇之前提為:不多於一個的取代基為胺基羰基、C1-6
烷基胺羰基、羥基、含苯取代基。
本發明另一實施例,R4
為苄基,且於其位置4為羥基、C1-3
烷基胺羰基或胺基羰基取代,且其可更選擇性有一至二個取代基,該取代基獨立選自包含甲基、甲氧基與苯氧基之群組。於本發明另一實施例R4
為苄基,且其位置4為以羥基、C1-3
烷基胺羰基,或胺羰基取代,其更可選擇性有1至2個甲基取代。於本發明另一實施例,R4
為苄基,且其位置4為以羥基、C1-3
烷基胺羰基或胺羰基取代,其更可選擇性於其位置2與6以甲基取代。
本發明之實施例為關於式(I)化合物之製造方法,其中以“*”表示手性中心,其係表示(R)鏡像異構物屬鏡像異構物過量。本發明之實施例為關於式(I)化合物之製造方法,其中以“*”表示手性中心,其係表示(S)鏡像異構物屬鏡像異構物過量。
除非另有說明,於此使用之術語「烷基」為單獨存在或屬於取代基之一部分,為指直或分枝碳鏈,具有1至8個碳原子或任何在該數目範圍內之碳原子數目。術語「烷氧基」為指含氧之烷基的取代基,其中烷基定義如上。烷基與烷氧鏈可為於單一碳原子上發生取代。具複數烷基之取代基例如二(C1-6
烷基)胺基,其中二烷胺基之C1-6
烷基可相同,也可不同。
術語「雜環」為指5至7元非芳環中,其中1至2元為氮,或是指5至7元非芳環中,其中0、1或2元為氮,與至多2元為氧或硫;其中該環可選擇性包含0至1個不飽和鍵,當為6或7元環時,則包含至多2個不飽和鍵。術語「雜環」包含一5至7元單雜環與苯環稠合(苯稠雜環)、與一5或6元雜芳環(包含氧、硫或氮其中之一,可選擇性另包含一氮)稠合、與一5至7元環烷基或環烯基稠合、與一5至7元雜環(與上述定義同,但不再更包含一稠環)稠合或與環烷基,環烯基或雜環基環上之碳原子稠合,形成具螺狀(spiro)部份。本發明之化合物中,形成雜環之碳所形成之鍵結為飽和鍵。其他發明化合物則可為部份飽和之雜環。術語「雜環」也包含以5至7元單雜環,以架橋方式形成雙環。這種化合物不被認為完全屬於芳香族,也不是雜芳基化合物。雜環基之例子包括,但不限於,吡咯啉基(pyrrolinyl)、(包含2H-吡咯,2-咯啉基或3-咯啉基)、吡咯啶基、2-咪唑基、咪唑烷基(imidazolidinyl)、2-吡唑啉基(2-pyrazolinyl)、吡唑烷基(pyrazolidinyl)、哌啶基(piperidinyl)、嗎福林基、噻嗎啉基(thiomorpholinyl)、與哌嗪基(piperazinyl)。
術語「芳基」指一不飽和芳族六元單碳環,或不飽和芳族10至14元多碳環。此種芳族之例,包含苄基,萘基或蔥基。較佳用以實施本發明之芳基為苄基與萘基。
術語「雜芳基」為指5或6元芳基,其中環包括碳原子與包含至少一元之雜原子(heteroatom)。合適的雜原子包含氮、氧、硫。於5元環,雜芳基之環包含一元之氮、氧、硫,此外還可包含至多三個氮原子。於6元環,雜芳基之環可包含自1至3個氮原子。上述例子,其中6元環有三個氮,最多兩個氮原子為相鄰。選擇性地,雜芳基可為與苯環稠合(苯稠雜芳基)、與一5或6元雜芳基(包含氮、氧或硫,選擇性地可再包含一氮)稠合、與5至7元環烷基稠合,或與5至7元雜環(如上述定義但不再更包含一稠環)稠合。雜芳基例子包含但不限於,呋喃基、噻吩基、呲咯基(pyrrolyl)、噁唑基咪唑基、吡唑基、異噁唑基(isoxazolyl)、異三唑基(isothiazolyl)、氧二氮茂基(oxadiazolyl)、三唑基(triazolyl)、噻二唑基(thiadiazolyl)、吡啶基、噠嗪基(pyridazinyl)、嘧啶基與吡嗪基;稠雜芳基包含吲哚基、異吲哚基、吲哚啉基、苯并呋喃基、苯并噻吩、吲唑基、苯并咪唑基、苯並噻唑基(benzthiazolyl)、苯并唑基、苯異噁唑基(benzisoxazolyl)、苯噻二唑基(benzothiadiazolyl)、苯並三唑基(benzotriazolyl)、喹唑啉基(quinolizinyl)、喹啉基(quinolinyl)、異喹啉基與喹唑啉基。
術語「芳烷基」指於於烷基有芳基取代(例如,苄基與乙酚基)。相似的,術語「芳烷氧基」指於烷氧基有芳基取代(例如苯甲氧基)。
術語「鹵素」為指氟、氯、溴與碘。取代基有複數鹵素取代時,其取代為可使化合物穩定之方式。
當術語「烷基」或「芳基」或其字首命名表示其屬取代基(例如芳基烷基、烷基胺基),其解釋即包含上述關於「烷基」與「芳基」之限制。指定之碳原子數目(例如C1
-C6
)指烷基部份之碳原子數目,或較大取代基中烷基部份,其中烷基表示於字首。烷基與烷氧取代基之指定碳原子數目為單獨給定的範圍,與所有給定範圍內之組合範圍內所包含之所有獨立元。例如C1-6
烷基包含甲基、乙基、丙基、丁基、戊基與己基,也包含其子集(例如C1-2
、C1-3
、C1-4
、C1-5
、C2-6
、C3-6
、C4-6
、C5-6
、C2-5
等)。
當特定基屬「經取代(substituted)
」(例如烷基、環烷基、芳基、雜芳基、雜環烷基等),其可包含一或更多取代基,較佳為1至5個取代基,更較佳為1至3個取代基,最佳為1至2個取代基,獨立自取代基群組中選取。
關於取代基,術語「獨立」指當可能有一個以上之此種取代基,所選取取代基可相同,亦可不同。
如同於此所使用,符號“*”為表示手性中心的存在。當本發明之化合物包含至少一個手性中心其即可能以鏡像異構物存在。當化合物具有二或以上手性中心,其也可能以非鏡像異構物存在。這些異構物與其混合物均為本發明所涵括。較佳為,化合物表示為鏡像異構物時,鏡像異構物為指鏡像異構物過量值高於或等於80%,較佳,鏡像異構物過量值高於或等於約90%,較佳之狀況也包含,鏡像異構物過量值高於或等於約95%,較佳狀況也包含,鏡像異構物過量值高於或等於約98%,最佳為,鏡像異構物過量值高於或等於約99%。相似的,化合物表示為非鏡像異構物時,非鏡像異構物為指非鏡像異構物過量值高於或等於約80%,較佳,非鏡像異構物過量值高於或等於約90%,較佳之狀況也包含,非鏡像異構物過量值高於或等於約95%,較佳之狀況也包含,非鏡像異構物過量值高於或等於約98%,最佳為,非鏡像異構物過量值高於或等於約99%。
此外,一些本發明化合物之晶形為多形,這亦涵蓋於本發明範圍內。此外一些本發明之化合物與水或一般有機溶劑形成溶劑合物(也就是與水形成水合物),這些溶劑合物也涵蓋於本發明範圍內。
本發明揭露內容所使用之標準命名,為由指定側鏈之末端先開始描述,之後依序朝鍵結點方向描述各相鄰官能基。因此,舉例來說,一「苯C1
-C6
烷基胺羰基C1
-C6
烷基」取代基為指具下述結構式之基團:
說明書所使用之縮寫,特別是使用於圖與例子中,表列如下:
除非另有說明,如同於此所使用的,術語「近(substntilly)
純化合物」為指分離後化合物內不純物莫耳比例低於約5莫耳比例,較佳低於約2莫耳比例,較佳,低於約0.5莫耳比例,最佳,低於約0.1莫耳比例。於本發明一實施例,所製備之式(I)化合物為近純化合物。於本發明一實施例,所製備之式(I-A)化合物為近純化合物。本發明另一實施例,所製備之式(I-B)化合物為近純化合物。本發明另一實施例,所製備之式(II-A)化合物為近純化合物。本發明另一實施例,所製備之式(II-B)化合物為近純化合物。
除非另有說明,如同於此所使用的,術語「近乎無相對應鹽類型式」描述式(I)化合物為指於經分離之式(I)之化合物中,其相對應鹽類之莫耳比例低於約5莫耳比例,較佳為低於約2莫耳比例,較佳,低於約0.5莫耳比例,最佳低於約0.1莫耳比例。於一本發明實施例,製備之式(I)化合物近乎無相對應鹽類。於一本發明實施例,所製備之式(II-A)化合物為近乎無相對應鹽類形式。於一本發明實施例,所製備之式(II-B)化合物為近乎無相對應鹽類形式。
在本發明說明中更廣泛提及之術語,例如「反應(reacting)
」與「經反應(reacted)
」為參照下述任一化學個體之而使用:(a)該化學個體實際敘述之形式,與(b)於一媒介中之該化學個體的任一形式,當該化合物被陳述時,表示有將之納入考慮。
若未另為說明,具有通常技藝之人可明瞭,反應步驟為根據已知方法,於適當條件下進行,以得到所預期產物。具有通常技藝之人更可明瞭,於本說明書與請求項中,當其中藥劑或藥劑類別/類型(例如,鹼、溶劑等)於方法中不只於一步驟中被提及時,每一反應步驟使用之藥劑,為獨立挑選,以供每一反應步驟使用,該藥劑於各步驟中可能相同或相異。例如,當一方法之兩步驟使用一有機或無機鹼作為反應藥劑,第一步驟所選之有機或無機鹼,可與第二步驟選用者相同或相異。具通常技藝之人可明瞭其中本發明之反應步驟,可於各種溶劑或溶劑系統中進行,該反應步驟也可於一適當溶劑或溶劑系統之混合物中進行。具通常技藝之人更可明瞭其中兩相繼反應或方法步驟可不將中間產物(換言之,兩相續反應或方法步驟中,第一步驟之產物)分離,即繼續進行,之後第一與第二反應或方法步驟於相同溶劑或溶劑系統進行;或,選擇性地,也可根據已知方法更換溶劑後,於不同溶劑或溶劑系統進行。
為提供更簡明敘述,於此提供之一些量化表示,以術語「約」。表示,以表示未受限。且可瞭解者為,無論是否明確使用術語「約」,任何於此給定之數量,除指實際給定數量,也指該技術領域具通常技術之人,根據該給定數量可思及之約略值,其包含根據實驗與/或對於該數值之測量環境而得之估計值。
為提供更簡明敘述,一些量化表示為以自約X數量至約Y數量之範圍表示。可被瞭解者為,當提及一範圍時,並不只限於所提及範圍之上下界,而是包含自約X數量至約Y數量之全部範圍,或任何其中之範圍。
下述敘述將詳述適當溶劑、鹼、反應溫度與其他反應參數及成份之例子。本技術領域具通常技術之人明瞭下述例子並無意,也非用以限制後述請求項中所述之本發明。
如此所述,除非另加以說明,術語「脫離基」為指帶電荷原子或基團,於取代或置換反應中離開。適當範例包括,但不限於氯、溴、碘、甲磺酸、甲苯磺酸與其相似物。
本發明任何用以製造化合物之方法,對於涉及分子,可能必要且需要保護敏感或反應性基團。上述保護,可利用傳統保護基團,例如於下述書籍所述者,有機化學保護基團(Protective Group in Organic Chemistry),ed. J.F.W. McOmie,Plenum Press,1973;與T.W. Greene& P.G.M. Wuts,有機合成之保護基團(Protective Groups in Organic Synthesis),John Wiley & Sons,1991。保護基團可使用本技術領域已知方法,並可於後續步驟中方便的移除。
如此所述,除非另加以說明,術語「氮保護基團」為指與氮原子鍵結,用於保護氮原子免於參與反應,並可於後續步驟移除之基團。適當氮保護基團包含式-C(O)O-R之胺甲酸酯基,其中R為,例如,甲基、乙基、三級丁基、苄基、苯乙基、丙烯基、CH2
=CH-CH2
-,以及相似物;具化學式C(O)-R’之醯胺基其中R’,舉例,為甲基、苄基、三氟甲基,以及相似物;具化學式-SO2
-R”之N-磺醯基衍生物基,其中R”為,例如,甲苯基、苄基、三氟甲基、2,2,5,7,8-五甲苯并二氫哌喃-6-基-,2,3,6-三甲-4-甲氧苯,以及相似物。其他適當氮保護基團可於其他文書記載中尋得,例如T.W. Greene & P.G.M. Wuts,有機合成之保護基團(Protective Groups in Organic Synthesis),John Wiley & Sons,1991。
具通常技藝之人可明瞭其中本發明之一反應步驟,可於各種溶劑或溶劑系統中進行,該反應步驟也可於一適當溶劑或溶劑系統之混合物中進行。
根據本發明之製造化合物方法會產生鏡像異構物混合物,這些異構物可用傳統方法分離,例如製備級層析法(preprtive chromtogrphy)。製備之化合物可為外消旋形式,或個別鏡像異構物,這可以藉具鏡像異構物專一性合成法或藉分離方法製備。化合物,舉例言之,可使用標準方法分離出個別鏡像異構物成份,例如,藉由與具光學活性酸反應,例如(-)-二-對-甲苯醯-D-酒石酸及/或(+)-二-對-甲苯醯-L-酒石酸,形成鹽類,以生成非鏡像異構物對後,進行分部結晶與並再生成游離鹼。化合物也可以藉由形成非鏡像異構物之酯或醯胺以進行分離後,進行層析分離並移除手性助劑。此外,化合物可使用手性高效液相層析管柱進行分離。
此外,手性高效液相層析管柱配合標準品,可用於確認鏡像異構物過量百分比(%ee)。鏡像異構物過量係以下式計算:
[(R莫耳-S莫耳)/(R莫耳+S莫耳)]×100%
其中R莫耳與S莫耳為混合物中R與S莫耳比例,因此R莫耳+S莫耳=1。鏡像異構物過量也可以根據所期望之鏡像異構物,與所製備混合物之特定旋光度,以下式計算:
ee=([α-obs]/[α-max])×100。
為用於醫藥,本發明之化合物鹽類為指無毒性「醫藥上可接受鹽類」。其他鹽類可根據本發明,用於製造化合物或其醫藥上接受鹽類。適當之醫藥上可接受鹽類包含酸添加鹽類(acid addition salts),舉例言之,其為將化合物溶液與醫藥上可接受酸溶液,例如,氫氯酸、硫酸、反丁烯二酸、順丁烯二酸、琥珀酸、醋酸、苯酸、檸檬酸、酒石酸、碳酸與磷酸混合。更特定言之,本發明化合物可具酸性部份,其適當之醫藥上可接受鹽類可包含鹼金屬鹽類,例如,鈉與鉀鹽類;鹼土金屬鹽類,例如,鈣與鎂鹽類;與具有適當有機配位基之鹽類,例如,四級銨鹽類。因此,具代表性醫藥上可接受鹽類包含醋酸鹽、苯磺酸鹽、苯甲酸鹽、碳酸氫鹽、硫酸氫鹽、酒石酸氫鹽、硼酸鹽、溴化物、依地酸鈣鹽、樟腦磺酸鹽(camsylate)、碳酸鹽、氯化物、克拉維酸鹽(clavulanate)、檸檬酸鹽、二鹽酸鹽、伊地酸鹽(edetate)、乙二磺酸鹽(edisylate)、伊托酸鹽(estolate)、乙磺酸鹽(esylate)、延胡索酸鹽、葡庚糖酸鹽(gluceptate)、葡萄糖酸鹽、麩胺酸鹽、甘苯胂鈉鹽(glycollylarsanilate)、己基苯間二酚鹽(hexylresorcinate)、海巴明鹽(hydrabamine)、氫溴酸鹽、氫氯化物、羥基萘酸鹽、碘化物、羥基乙硫酸鹽(isothionate)、乳酸鹽、乳糖酸鹽、月桂酸鹽、蘋果酸鹽、順丁烯二酸鹽、杏仁酸鹽、甲磺酸鹽、甲基溴化物、甲基硝酸鹽、甲基硫酸鹽、粘酸鹽、萘磺酸鹽(napsylte)、硝酸鹽、N-甲基葡糖胺銨鹽、油酸鹽、巴沫酸鹽(pamoate)、棕櫚酸鹽、泛酸鹽、磷酸鹽/二磷酸鹽、聚半乳糖酸鹽、柳酸鹽、硬酯酸鹽、硫酸鹽、次醋酸鹽、琥珀酸鹽、單寧酸鹽、酒石酸鹽、氯茶鹼鹽(teoclate)、甲苯磺酸鹽、三乙碘化物(triethiodide)、與戊酸鹽。
具代表性用於製造醫藥上可接受鹽類,包括:乙酸、2,2-二氯乳酸、乙醯化的胺基酸類、己二酸、藻酸、抗壞血酸、L-門冬胺酸、苯磺酸、苯甲酸、4-乙醯胺基苯甲酸、(+)-樟腦酸(camphoric cid)、樟腦磺酸(camphosulfonic cid)、(+)-(1S)-樟腦-10-磺酸、癸酸、己酸、辛酸、羥桂皮酸、檸檬酸、環磺酸、十二碳基硫酸、1,2-乙二磺酸、乙磺酸、2-羥-乙磺酸、甲酸、反丁烯二酸、半乳糖二酸、龍膽酸、葡庚糖酸、D-葡糖酸、D-葡糖醛酸(D-glucuronic cid)、L-谷胺酸(L-glutmic cid)、α-氧代-戊二酸、乙醇酸、馬尿酸、氫溴酸、氫氯酸、(+)-L-乳醛、(±)-DL-乳酸、乳糖酸、順丁烯二酸、(-)-L-蘋果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羥-2-萘酸、菸鹼酸、硝酸、油酸、乳清酸、草酸、棕櫚酸、巴沫酸(pamoic cid)、磷酸、L-高谷胺酸、水楊酸、4-胺基-水楊酸、癸二酸、硬脂酸、琥珀酸、硫酸、丹寧酸、(+)-L-酒石酸、硫氰酸、對-甲苯磺酸及十一碳烯酸。
具代表性用於製造醫藥上可接受鹼類包括氨水、L-精胺酸、本沙明(benethamine)、本札辛(benzathine)、氫氧化鈣、膽鹼、二甲胺基乙醇(deanol)、二乙醇胺、二乙基胺、2-(二乙基胺基)-乙醇、乙醇胺、乙二胺、N-甲基-葡萄糖胺、海巴明(hydrabamine)、1H-咪唑、L-離胺酸、氫氧化鎂、4-(2-羥基乙基)-嗎福林、哌嗪(piperazine)、氫氧化鉀、1-(2-羥基乙基)-吡咯啶、二級胺、氫氧化鈉、三乙醇胺、胺基丁三醇(tromethamine)及氫氧化鋅。
如下述反應流程1詳述,本發明為關於式(I)化合物之製造方法。
據此,式(X)適當取代化合物,於有碘源時,於第一有機溶劑或混合物中與鋅反應,以產出相對應式(XI)之化合物;其中式(X)適當取代化合物,為一已知化合物或以已知方法製備;PG1
為適當的選自氮保護基團,例如第三丁氧基羰基、苄氧羰基以及其相似物,較佳為第三丁氧基羰基;鋅較佳為鋅粉末,其中鋅較佳量範圍自約0.5至約3.0莫耳當量,較佳量範圍自約0.5至約1.5莫耳當量,較佳約1.1莫耳當量;較佳碘源為碘,碘源較佳量範圍自約0.1至約1.0莫耳當量,較佳量範圍自約0.1至約0.5莫耳當量,較佳約0.3莫耳當量,較佳量為具催化效果,足以活化鋅;第一有機溶劑包括,對碘源不具反應性,例如,二甲基乙醯胺、二甲基乙醯胺與2-甲基-四氫呋喃混合物、四氫呋喃、甲苯、二甲基甲醯胺以及其相似物,較佳為二甲基乙醯胺;較佳溫度範圍自約-20℃至約10℃,較佳為低於10℃,較佳為約-8℃。較佳為,未分離式(XI)之化合物。較佳為,鋅與碘源於加至式(X)化合物前先混合,以活化鋅。
式(XI)化合物與式(XII)之適當取代化合物,於存有鈀催化劑與膦配位基系統下,在第二有機溶劑或其混合物中反應,以產出相對應式(I)化合物;其中LG1
為適當選擇之脫離基例如,氯、溴、碘與相似物,較佳為溴;其中式(XII)化合物較佳量範圍自約0.1至約3.0莫耳當量,較佳量範圍自約0.25至約1.0莫耳當量,較佳量範圍自約0.5至約1.1莫耳當量;鈀催化劑與膦配位基系統為,例如三(雙苯亞甲基丙酮)二鈀(0)(Pd2
(dba)3
)與三-(鄰甲苯)膦(P(o-tol)3
)之組合,氯化鈀與三苯基膦(PPh3
)、雙(三苯膦)氯化鈀(II)(Pd(PPh3
)2
Cl2
)、四(三苯基膦)鈀(0)(Pd(PPh3
)4
)及其類似物之組合,較佳為三(雙苯亞甲基丙酮)二鈀(0)(Pd2
(dba)3
)與三-(鄰甲苯)膦(P(o-tol)3
)之組合;鈀催化劑與膦配位基系統較佳為以具催化效能之量存在;第二有機溶劑或其混合物包含,例如,二甲基乙醯胺、二甲基乙醯胺與2-甲基-四氫呋喃混合物、四氫呋喃、二甲基甲醯胺、甲苯與相似物,較佳為二甲基乙醯胺;較佳為使用與前步驟相同溶劑;較佳溫度範圍自約50℃至約100℃,較佳約80℃。較佳,式(XI)化合物係加入一式(XII)化合物、鈀催化劑與膦劑構成之混合物。
本發明更關於製造於反應流程2詳述之式(I-A)化合物之方法。
據此,式(X-A)適當取代化合物,於有碘源時,於第一有機溶劑或混合物中與鋅反應,以產出相對應式(XI-A)之化合物;其中式(X-A)適當取代化合物,為一已知化合物或以已知方法製備;PG1
為適當的選自氮保護基團,例如第三丁氧基羰基、苄氧羰基以及其相似物,較佳為第三丁氧基羰基;較佳鋅為鋅粉末;其中鋅較佳量範圍自約0.5至約3.0莫耳當量,較佳量範圍自約0.5至約1.5莫耳當量,較佳約1.1莫耳當量;較佳碘源為碘;其中碘源較佳量範圍自約0.1至約1.0莫耳當量,較佳量範圍自約0.1至約0.5莫耳當量,較佳約0.3莫耳當量,較佳量為足進行催化,用以活化鋅;第一有機溶劑為,對碘源不具反應性,例如,二甲基乙醯胺,二甲基乙醯胺與2-甲基-四氫呋喃混合物、四氫呋喃、甲苯,二甲基甲醯胺,以及其相似物,較佳為二甲基乙醯胺;較佳溫度範圍自約-20℃至約10℃較佳溫度為低於約10℃較佳為約-8℃。較佳為,未分離式(XI-A)之化合物。較佳為,鋅與碘源於加至式(V-A)化合物前先混合,以活化鋅。
式(XI-A)化合物與適當式(XII-A)取代化合物,於存有鈀催化劑與膦配位基系統下,在第二有機溶劑或其混合物中反應,以產出相對應式(I-A)化合物;其中LG1
為選自脫離基例如,氯、溴、碘與相似物,較佳為溴;其中式(XII-A)化合物較佳量範圍自約0.1至約3.0莫耳當量,較佳量範圍自約0.25至約1.0莫耳當量,較佳量範圍自約0.5至約1.1莫耳當量;鈀催化劑與膦配位基系統為,例如三(雙苯亞甲基丙酮)二鈀(0)(Pd2
(dba)3
)與三-(鄰甲苯)膦(P(o-tol)3
)之組合,氯化鈀與三苯基膦(PPh3
)、雙(三苯膦)氯化鈀(II)(Pd(PPh3
)2
Cl2
)、四(三苯基膦)鈀(0)(Pd(PPh3
)4
)及其類似物之組合,較佳為三(雙苯亞甲基丙酮)二鈀(0)(Pd2
(dba)3
)與三-(鄰甲苯)膦(P(o-tol)3
)之組合,其中鈀催化劑與膦配位基系統較佳為以具催化效能之量存在;第二有機溶劑或混合物為,例如,二甲基乙醯胺,二甲基乙醯胺與2-甲基-四氫呋喃混合物、四氫呋喃、二甲基甲醯胺、甲苯、與相似物,較佳為二甲基乙醯胺;較佳為使用與前步驟相同溶劑;較佳溫度範圍自約50℃至約100℃,較佳為約80℃。較佳為,式(XI-A)化合物加入至一式(XII-A)化合物、鈀催化劑與膦劑構成之混合物。
如於反應流程3所詳述,本發明更為關於製造式(I-B)化合物方法
據此,式(X-B)適當取代化合物,於有碘源時,於第一有機溶劑或混合物中與鋅反應,以產出相對應式(XI-B)之化合物;式(X-B)適當取代化合物,為一已知化合物或以已知方法製備;較佳鋅為鋅粉末;其中鋅較佳量範圍自約0.5至約3.0莫耳當量,較佳量範圍自約0.5至約1.5莫耳當量,較佳約1.1莫耳當量;較佳碘源為碘;其中碘源較佳量範圍自約0.1至約1.0莫耳當量,較佳量範圍自約0.1至約0.5莫耳當量,較佳約0.3莫耳當量,較佳量為足進行催化,用以活化鋅;第一有機溶劑對碘源不具反應性,例如,二甲基乙醯胺、二甲基乙醯胺與2-甲基-四氫呋喃混合物、四氫呋喃、甲苯、二甲基甲醯胺,以及其相似物,較佳為二甲基乙醯胺;較佳溫度範圍自約-20℃至約10℃較佳溫度為低於約10℃較佳為約-8℃。較佳,鋅與碘源於加至式(V-B)化合物前先混合,以活化鋅。
式(XI-B)化合物與適當式(XII-B)取代化合物,於存有鈀催化劑與膦配位基系統下,在第二有機溶劑或其混合物中反應,以產出相對應式(I-B)化合物;其中式(XII-B)化合物較佳量範圍自約0.1至約3.0莫耳當量,較佳量範圍自約0.25至約1.0莫耳當量,較佳量範圍自約0.5至約1.1莫耳當量;鈀催化劑與膦配位基系統為,例如三(雙苯亞甲基丙酮)二鈀(0)(Pd2
(dba)3
)與三-(鄰甲苯)膦(P(o-tol)3
)之組合,氯化鈀與三苯基膦(PPh3
)、雙(三苯膦)氯化鈀(II)(Pd(PPh3
)2
Cl2
)、四(三苯基膦)鈀(0)(Pd(PPh3
)4
)及其類似物之組合,較佳為三(雙苯亞甲基丙酮)二鈀(0)(Pd2
(dba)3
)與三-(鄰甲苯)膦(P(o-tol)3
)之組合,其中其中鈀催化劑與膦配位基系統較佳為以具催化效能之量存在;第二有機溶劑或混合物,例如,二甲基乙醯胺、二甲基乙醯胺與2-甲基-四氫呋喃混合物、四氫呋喃、二甲基甲醯胺、甲苯、與相似物,較佳為二甲基乙醯胺;較佳為使用與前步驟相同溶劑;較佳溫度範圍自約50℃至約100℃較佳為約80℃。較佳,式(XI-B)化合物加入至一式(XII-B)化合物、鈀催化劑與膦劑構成之混合物。
如於反應流程4所詳述,本發明更為關於製造式(II-A)化合物方法。
據此,一式(I-A)適當取代化合物,於有無機鹼存在,在第三有機溶劑中,與適當選擇之氧化劑反應,以產出式(II-A)相對應化合物。其中R0
較佳為非氫原子,與其中PG1
為適當選自氮保護基團,例如第三丁氧基羰基,苄氧羰基與其相似物,較佳PG1
為第三丁氧基羰基;氧化劑為,例如,過氧化氫、氫氧化鋰、過氧化鋰(LiOOH)與相似物,較佳為30%過氧化氫;其中氧化劑較佳為過量;無機鹼為,例如碳酸鉀、碳酸鈉、碳酸氫鈉與相似物,較佳碳酸鉀;其中無機鹼較佳量範圍自約1.0至約3.0莫耳當量,較佳量為約1.6莫耳當量;第三有機溶劑為,例如,二甲基亞碸、二甲基甲醯胺、二甲基乙醯胺、N-甲基吡咯酮(NMP)與相似物,較佳二甲基亞碸;溫度範圍自約室溫度至約60℃,較佳約45℃。
如於反應流程5所詳述,本發明更為關於製造式(II-B)化合物方法。
據此,一式(I-B)適當取代化合物,於有無機鹼存在,在第三有機溶劑中,與適當選擇之氧化劑反應,以產出式(II-B)相對應化合物。其中氧化劑為,例如,過氧化氫、氫氧化鋰、過氧化鋰(LiOOH)與相似物,較佳為30%過氧化氫;其中氧化劑較佳為過量;無機鹼為,例如碳酸鉀、碳酸鈉、碳酸氫鈉與相似物,較佳碳酸鉀;其中無機鹼較佳量範圍自約1.0至約3.0莫耳當量,較佳量為約1.6莫耳當量;第三有機溶劑為,例如,二甲基亞碸、二甲基甲醯胺、二甲基乙醯胺、N-甲基吡咯酮與相似物,較佳二甲基亞碸;溫度範圍自約室溫度至約60℃,較佳約45℃。
下述實施例為用以瞭解本發明,無意也不應解釋為限制請求項所述本發明之範圍。
於下述實施例,一些合成產物表示為已經分離為殘留物。I本技術領域具通常知識之人可明瞭術語「殘留物」並非限制分離產物之物理狀態,舉例包含固體,油狀物,泡沫狀物,膠狀物,漿狀物(syrup),與相似物。
製備2-第三-丁氧羰胺-3-(4-胺甲醯-2,6-二甲-苯)-丙酸甲酯
步驟A:
將乾二甲基乙醯胺(DMAc)(300毫升)、2-甲基-四氫呋喃(150毫升),碘(I2
)(25.4克,0.10莫耳)與鋅粉末(294.3克,4.5莫耳),於氮氣環境下,加入3升四頸圓底燒瓶中,該燒瓶裝有漏斗、機械攪拌器、加熱臺、冷凝器與熱電偶。終泥狀物攪拌直到碘(I2
)紅色消失(約2分鐘)。添加時,可觀察到溫度升高(自23℃升至43℃)。使用冰/氯化鈉浴冷卻終混合物至約-5℃至-2℃。於此溫度,將溶於二甲基乙醯胺(250毫升)與2-甲-四氫呋喃
(500毫升)混合物中之Boc-β-iodo-alanine-OCH3
(別名為2-第三-丁氧羰胺-3-碘-丙酸甲酯,658.3克,2.0莫耳)以2小時之時間緩慢加入。終混合物溫度保持低於10℃,將該混合物冰浴約1-2小時待其熟成(aged),之後加熱至約15℃,以產出一混合物。終冷卻混合物不經進一步處理,即用於下一步驟。
步驟B:
4-碘-3,5-二甲-苯甲醯胺(275克,1.0莫耳)、2-甲基-四氫呋喃(500毫升)與二甲基乙醯胺(DMA)(200毫升),加入一5升四頸圓底燒瓶中,該燒瓶裝有機械攪拌器、加熱臺、冷凝器與熱電偶與氮進氣口。加入三-(鄰甲苯)膦(P(o-tol)3
)(24.5克,0.08莫耳)與三(雙苯亞甲基丙酮)二鈀(0)(Pd2
(dba)3
)(36.6克,0.04莫耳)至懸浮液,加熱終泥狀物至45-50℃。於此溫度,步驟A製備之混合物藉插管,以約1.5-2小時之時間加入。終混合物冷卻至環境溫度。加入矽(275克),攪拌泥狀物約30分鐘。過程中矽片以2甲基-四氫呋喃(3×500毫升)與乙酸乙酯(3×1升)加以清洗。終溶液以2升1.0當量濃度之氯化氫水溶液進行驟冷,之後將各層分離。酸性層以乙酸乙酯(2×1升)進行反萃取。有機層,於減壓濃縮機中濃縮至約5.0L,並以水(3×1升)與50%鹽水潤洗(2.0L)。溶劑以減壓濃縮機除去,產出一米白色固體。
如題述化合物為藉乙酸乙酯(EtOAc)(2升)與庚烷(2升)以下述方法結晶。16小時後,終混合物以冰浴冷卻2小時,加入更多庚烷(500毫升)以完成沈澱。過濾固體並於真空烤箱以55℃乾燥48小時,以產出如題述化合物之白色固體。
將乾二甲基乙醯胺(2毫升)、碘(I2
)(38.1毫克,0.15毫莫耳)與活化鋅粉末(以10%氯化氫清洗,並以水與丙酮潤洗)(393毫克,6毫莫耳),在氮氣環境下,裝入一50毫升,裝有漏斗、磁攪拌子、加熱臺、冷凝器三頸圓底燒瓶。終混合物於23℃攪拌直到碘(I2
)紅色消失(2分鐘)。緩緩加入溶於二甲基乙醯胺(2毫升)之第三丁氧羰-β-碘-L-丙胺酸甲酯溶液(1克,3毫莫耳)(溫度自21℃變化至29℃),終混合物於80℃攪拌0.5-1小時,之後冷卻至35℃。接著將溶於二甲基乙醯胺(6毫升)之4-溴-3,5-二甲-苯甲腈(315毫克,1.5毫莫耳)、三-(鄰甲苯)膦(P(o-tol)3
)(36.5毫克,0.12毫莫耳)與三(雙苯亞甲基丙酮)二鈀(0)(Pd2
(dba)3
)(55毫克,0.06毫莫耳)加入上述終混合物。終混合物加熱到70℃,並攪拌1小時,之後冷卻至環境溫度終混合物以乙酸乙酯(15毫升)稀釋,並以STND SUPER-CEL 815520過濾。乙酸乙酯溶液以1當量濃度氯化氫(40毫升)驟冷,並以乙酸乙酯(20毫升)進行萃取。合併之有機相先用水(2×50毫升)之後以50%鹽水潤洗,以硫酸鈉加以乾燥,經過濾後,使用減壓濃縮機於真空環境,以揮發乾燥方法,產出褐色固體。如題述化合物藉乙酸乙酯(5毫升)與庚烷(40毫升)結晶,產出一白色固體。
將無水二甲基乙醯胺(500毫升)與碘(16.8克,0.06莫耳)填裝入裝有氮進氣口、機械攪拌器、漏斗與熱電偶之2升四頸圓底燒瓶,以產出一紅色溶液。加入鋅粉末(143.9克,2.2莫耳)至經攪拌紅色溶液。對該終混合物可觀察到紅色於約2分鐘內消失,與放熱反應(自22℃變化至約36℃)。終混合物冷卻至-8℃,之後將一溶於無水二甲基乙醯胺(500毫升)之N-(第三-丁氧羰)-3-碘-L-丙胺酸甲酯(658克,2.0莫耳)溶液以約2小時時間緩緩加入,混合物不攪拌,並保持溫度低於約10℃。經冷卻之終混合物不經處理,即用於下一步驟。
將4-溴-3,5-二甲-苯甲腈(210克,1.0莫耳)與二甲基乙醯胺(750毫升)裝填入裝有氮進氣口、機械攪拌器、漏斗與熱電偶之5L三頸圓底燒瓶。攪拌終懸浮液並加熱到35℃以溶解固體。加入三-(鄰甲苯)膦(P(o-tol)3
)(6.0克,0.02莫耳)與三(雙苯亞甲基丙酮)二鈀(0)(Pd2
(dba)3
)(9.2克,0.01莫耳)至終混合物,之後並將終混合物加熱至約75-80℃。步驟A製備之經冷卻混合物利用插管,以約75-80℃(約2小時)之條件,加入到反應混合物。終懸浮液冷卻到環境溫度,溫和攪拌過夜,使其熟成。終懸浮液之後加熱至約35-40℃,利用矽(540克)過濾。矽床以二甲基乙醯胺(400毫升×2)清洗,合併之二甲基乙醯胺溶液冷卻至約0-5℃,之後緩緩加至冰與去離子水之混合物中。終混合物保持冷卻2小時,可觀察到白色固體沈澱。終混合物回溫到環境溫度,並過夜熟成。使用布氏漏斗以真空過濾方式使固體沈澱物冷卻。濾餅以去離子水(1升×3)潤洗,過夜風乾,之後在真空烤箱過夜使之乾燥。加入甲醇(1升)至固體,形成之終泥狀物冷卻至約0-5℃,以該溫度攪拌熟成1小時。固體利用過濾收集,以冷甲醇(400毫升)清洗,並於真空烤箱以45℃乾燥產出如題述化合物之米白色固體。
4-溴-3,5-二甲酚(50.0克,0.25莫耳,購自Aldrich 99%)與吡啶(250毫升),加入裝有漏斗、機械攪拌器與熱電偶之2.0升3頸圓底燒瓶,該燒瓶。終溶液冷卻至0℃,三氟甲磺酸酐(80.5克,0.285莫耳購自Aldrich 99%)以2小時時間逐滴加入。加入完畢後,終混合物維持於0℃ 15分鐘,之後於室溫放置過夜。16小時後,終混合物於冰浴冷卻並以水(1.7升)與乙酸乙酯(1.7升)使之驟冷。分離終兩相混合物之各相,有機層以2當量濃度氯化氫(2×1.0升)處理,之後以(1.0升)水與50%鹽水各潤洗一次。有機層以硫酸鈉乾燥,之後以減壓濃縮機使之乾燥,產出三氟甲磺酸4-溴-3,5-二甲-苯酯之濃稠油狀物。
三氟甲磺酸4-溴-3,5-二甲-苯酯(79.8克,0.24莫耳)與氰甲烷(AcCN)(500毫升)加入一裝有機械攪拌器,氮進氣口適配器,加熱臺與熱電偶之2.0L3頸圓底燒瓶。終溶液之後加入四(三苯基膦)鈀(0)(Pd(PPh3
)4
)(27.7克,0.024莫耳)、碘化銅(9.2克,0.048莫耳)與氰化鋅(79.8克,0.24莫耳)。終混合物於50℃攪拌45分鐘,加入二甲基乙醯胺(150毫升)且溫度升至80-88℃。混合物以該溫度放置過夜熟成。終混合物冷卻到環境溫度,以乙酸乙酯(200毫升)稀釋,以STND SUPER-CEL 815520將之過濾。SUPER-CEL餅以乙酸乙酯(200毫升×6)潤洗。乙酸乙酯溶液與飽和氯化銨:濃縮氫氧化銨:水比例為4:1:4(240毫升:60毫升:240毫升)之混合物合併並使之驟冷。分離各層,有機層以水(500毫升)與鹽水(500毫升)各潤洗一次,之後於真空使之乾燥,產出紅色濃稠油狀物。如題述化合物之為藉乙酸乙酯(135毫升)與庚烷(500毫升)結晶,以產出黃白色結晶。
將(S)-2-第三-丁氧基羰基胺基-3-(4-氰-2,6-二甲-苯)-丙酸甲酯(166.2毫克,0.5毫莫耳)、二甲基亞碸(DMSO)(5.0毫升)、與碳酸鉀(75毫克,0.5毫莫耳),於氮氣環境,裝填入一裝有磁攪拌子與熱電偶之50毫升三頸圓底燒瓶,終混合物以冰浴冷卻。以針筒逐滴加入30%過氧化氫(110毫升)至終混合物。使終混合物回溫到環境溫度,可觀察到固體溶解,產出清澈溶液。於45-50℃攪拌2小時後,加入水(10毫升),將之冷卻,以過濾方式分離沈澱產物。分離之白色固體以水清洗(2×25毫升),之後以高真空幫浦乾燥24小時,以產出如題述化合物之白色固體。
2-第三-丁氧羰胺-3-(4-胺甲醯-2,6-二甲-苯)-丙酸甲酯(250克,0.713莫耳)、二甲基亞碸(DMSO)(750毫升)與30%過氧化氫(250毫升),加入至一5升三頸圓底燒瓶,該燒瓶裝有漏斗,機械攪拌器,加熱臺,回流冷凝器,熱電偶與氮進氣口。碳酸鈉(158克,1.14莫耳,1.6當量(eq))溶於水中(750毫升),並以30分鐘時間逐滴加入。加入時,可觀察到溫度增加(自23℃增加至34℃)。終混合物加熱到約42-45℃,反應進程以高效液相層析儀(HPLC)觀察。3小時後,對加溫混合物加入活性碳(ECOSORB-941)(37.5克,15%(重量百分比))。終泥狀物回流1小時後,趁熱以CELITE過濾。以水(1.5L)潤洗CELITE板。終混合物冷卻至約10℃並以2.0當量濃度之氯化氫驟冷(酸鹼值2,1.22升),以產出包含白色固體沈澱物之混合物。混合物在約4小時冰浴與攪拌下熟成,之後經過濾與於真空烤箱經48小時乾燥,產出如題述化合物之白色結晶固體。
雖然本案是以若干最佳實施例做說明,但精於此技藝者能在不脫離本案精神與範疇下做各種不同形式的改變。舉凡不違本案精神所從事的種種修改或變化,俱屬本案申請專利範圍。
Claims (38)
- 一種製造式(I)化合物的方法
- 如申請專利範圍第1項之方法,其中該PG1 為第三丁氧基羰基。
- 如申請專利範圍第1項之方法,其中該R0 是甲基。
- 如申請專利範圍第1項之方法,其中該鋅為鋅粉末。
- 如申請專利範圍第4項之方法,其中該鋅粉末之數量範圍為0.5至1.5莫耳當量。
- 如申請專利範圍第1項之方法,其中該碘源為碘。
- 如申請專利範圍第6項之方法,其中該碘之數量範圍為0.1至0.5莫耳當量。
- 如申請專利範圍第1項之方法,其中該第一溶劑為二甲基乙醯胺。
- 如申請專利範圍第1項之方法,其中該式(X)化合物於低於10℃之溫度與該鋅反應。
- 如申請專利範圍第1項之方法,其中該鋅與該碘源於加入該式(X)化合物前即混合。
- 如申請專利範圍第1項之方法,其中該LG1 為溴。
- 如申請專利範圍第1項之方法,其中該式(XII)化合物之數量範圍為自0.25至1.0莫耳當量。
- 如申請專利範圍第1項之方法,其中該鈀催化劑與膦配位基系統是三(雙苯亞甲基丙酮)二鈀(0)(Pd2 (dba)3 )與三-(鄰甲苯)膦(P(o-tol)3 )之組合。
- 如申請專利範圍第1項之方法,其中該第二有機溶劑是為二甲基乙醯胺。
- 如申請專利範圍第1項之方法,其中該式(X)化合物與該式(XII)化合物於50℃至100℃溫度範圍反應。
- 如申請專利範圍第1項之方法,其中該式(XI)化合物加入包含該式(XII)化合物、該鈀催化劑與該膦配位基系統之混合物。
- 一種用以製造式(I-B)化合物之方法
- 如申請專利範圍第17項之方法,其中該鋅為鋅粉末。
- 如申請專利範圍第18項之方法,其中該鋅粉末之數量範圍為0.5至1.5莫耳當量。
- 如申請專利範圍第17項之方法,其中該碘源為碘。
- 如申請專利範圍第20項之方法,其中該碘之數量範圍為0.1至0.5莫耳當量。
- 如申請專利範圍第17項之方法,其中該第一有機溶劑為二甲基乙醯胺。
- 如申請專利範圍第17項之方法,其中該式(X-B)化合物於低於10℃之溫度與該鋅反應。
- 如申請專利範圍第17項之方法,其中該鋅與該碘源於加入該式(X-B)化合物前即混合。
- 如申請專利範圍第17項之方法,其中該式(XII-B)化合物之數量範圍為自0.25至1.0莫耳當量。
- 如申請專利範圍第17項之方法,其中該鈀催化劑與膦配位基系統是三(雙苯亞甲基丙酮)二鈀(0)(Pd2 (dba)3 )與三-(鄰甲苯)膦(P(o-tol)3 )之組合。
- 如申請專利範圍第17項之方法,其中該第二有機溶劑為二甲基乙醯胺。
- 如申請專利範圍第17項之方法,其中該式(X-B)化合物與該式(XII-B)化合物於50℃至100℃之溫度範圍反應。
- 如申請專利範圍第17項之方法,其中該式(XI)化合物加入包含該式(XII)化合物、該鈀催化劑與該膦配位基系統之混合物。
- 一種以如申請專利範圍第17項方法製造之化合物。
- 一種用以製造式(II-B)化合物或其醫藥上可接受鹽類之方法,
- 如申請專利範圍第31項之方法,其中該氧化劑為選自包含過氧化氫、氫氧化鋰、過氧化鋰之群組。
- 如申請專利範圍第32項之方法,其中該氧化劑為過氧化氫。
- 如申請專利範圍第31項之方法,其中該氧化劑為濃度30%之過氧化氫且為過量。
- 如申請專利範圍第31項之方法,其中該無機鹼為碳酸鉀。
- 如申請專利範圍第31項之方法,其中該無機鹼之數量範圍為1.0至3.0莫耳當量。
- 如申請專利範圍第31項之方法,其中該第三有機溶劑為二甲基亞碸。
- 如申請專利範圍第31項之方法,其中該式(I-B)化合物與該氧化劑於室溫至60℃之溫度範圍反應。
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TWI713889B (zh) | 2011-12-28 | 2020-12-21 | 中外製藥股份有限公司 | 胜肽化合物之環化方法 |
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