2,3,4,5,6-pentafluorophenol -Drug Synthesis Database

【结构式】

【分子编号】22662

【品名】2,3,4,5,6-pentafluorophenol

【CA登记号】771-61-9

【分子式】C₆HF₅O

【分子量】184.065356

【元素组成】C 39.15% H 0.55% F 51.61% O 8.69%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(A)

b) Large scale preparation of L-pyro-2-aminoadipic acid (IX) is accomplished by oxidation of the N-protected L-lysine derivative (VI) with KMnO4 followed by deprotection to (VIII) and cyclization.

参考文献中间体

合成目标

【1】 Szirtes, T.; Szporny, L.; Pálosi, É.; Kisfaludy, L.; Synthesis of thyrotropin releasing hormone analogu. J Med Chem 1984, 27, 741.
【2】 Kisfaludy, L.; Szporny, L.; Pálosi, É.; Szirtes, T.; Synthesis of thyrotropin-releasing hormone analogu. J Med Chem 1986, 29, 1654.
【3】 Nogradi, M.; RGH-2202. Drugs Fut 1988, 13, 5, 420.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	22662	2,3,4,5,6-pentafluorophenol	771-61-9	C₆HF₅O	详情	详情
(V)	22656	1-[2-(aminocarbonyl)-1-pyrrolidinyl]-4-methyl-1-oxo-2-pentanaminium chloride		C₁₁H₂₂ClN₃O₂	详情	详情
(VI)	22658	N(6)-[(benzyloxy)carbonyl]lysine		C₁₄H₂₀N₂O₄	详情	详情
(VII)	22659	N(6)-[(benzyloxy)carbonyl]-6-oxolysine		C₁₄H₁₈N₂O₅	详情	详情
(VIII)	22660	2-aminohexanedioic acid		C₆H₁₁NO₄	详情	详情
(IX)	22661	(2S)-6-oxo-2-piperidinecarboxylic acid		C₆H₉NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Treatment of butanedioate derivative (I) with methallyl iodide (II) and LDA in THF affords alkene (III), which is then reduced by hydrogenation over Pd/C and subjected to saponification by means of KOH in dioxane to yield succinic acid (IV). Protection of (IV) with 2,2-dimethoxypropane (V) and p-TsOH in DMF provides derivative (VI), which is then coupled with pentafluorophenol (VII) by using EDC in CH2Cl2 to furnish activated ester (VIII). Displacement of the pentafluorophenol moiety of (VIII) by treatment with L-tert-leucine methylamide (IX) in DMF gives methylamide derivative (X), which is deprotected with THF and HCl and condensed with O-benzylhydroxylamine (XI) by means of EDC to afford derivative (XII). Finally, (XII) is debenzylated by hydrogenation over Pd/C in EtOH to give the target compound.

参考文献中间体

合成目标

【1】 Davenport, R.J.; Watson, R.J.; An improved synthesis of the broad spectrum matrix metalloprotease inhibitor marimastat. Tetrahedron Lett 2000, 41, 41, 7983.
【2】 Dickens, J.P.; Crimmin, M.J.; Beckett, R.P. (British Biotech plc); Natural amino acid derivs. as metalloproteinase inhibitors. EP 0651738; EP 0651739; GB 2268933; GB 2268934; JP 1995509460; JP 1998204081; WO 9402446; WO 9402447 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	43782	diisopropyl (2S)-2-hydroxybutanedioate		C₁₀H₁₈O₅	详情	详情
(II)	43783	3-iodo-2-methyl-1-propene		C₄H₇I	详情	详情
(III)	43784	diisopropyl (2S,3R)-2-hydroxy-3-(2-methyl-2-propenyl)butanedioate		C₁₄H₂₄O₅	详情	详情
(IV)	43785	(2S,3R)-2-hydroxy-3-isobutylbutanedioic acid		C₈H₁₄O₅	详情	详情
(V)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(VI)	43786	(2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid		C₁₁H₁₈O₅	详情	详情
(VII)	22662	2,3,4,5,6-pentafluorophenol	771-61-9	C₆HF₅O	详情	详情
(VIII)	43787	2,3,4,5,6-pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate		C₁₇H₁₇F₅O₅	详情	详情
(IX)	18843	(2S)-2-amino-N,3,3-trimethylbutanamide	89226-12-0	C₇H₁₆N₂O	详情	详情
(X)	43788	(2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanamide		C₁₈H₃₂N₂O₅	详情	详情
(XI)	14640	O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene	622-33-3	C₇H₉NO	详情	详情
(XII)	43789	(2S,3R)-N(1)-(benzyloxy)-N(4)-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-hydroxy-3-isobutylbutanediamide		C₂₂H₃₅N₃O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Condensation of alpha-methyl tryptophan methyl ester (I) with benzylchloroformate (II) in the presence of Et3N in THF yields urethane (III), which is hydrolyzed with LiOH in THF/MeOH/H2O and then activated with DCCI and pentafluorophenol (IV) to furnish ester (V). Treatment of (V) with alpha-methyl-benzylamine (VI) gives derivative (VII), which is then debenzylated by hydrogenation over Pd(OH)2 in EtOH to afford (VIII). Finally, amine (VIII) reacts in DMF with DMAP and carbonate (IX), which has been previously prepared from 2-benzofuranylmethanol (X), 4-nitrophenylchloroformate (XI) and pyridine in CH2Cl2.

参考文献中间体

合成目标

【1】 Boyle, S.; et al.; Rational design of high affinity tachykinin NK1 receptor antagonists. Bioorg Med Chem 1994, 2, 5, 357.
【2】 Horwell, D.C.; Howson, W.; Rees, D.C.; Roberts, E.; Pritchard, M.C. (Pfizer Inc.); Tachykinin antagonists. EP 0655055; EP 1000930; US 5594022; WO 9404494 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	44166	methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate		C₁₃H₁₆N₂O₂	详情	详情
(II)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(III)	44167	methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate		C₂₁H₂₂N₂O₄	详情	详情
(IV)	22662	2,3,4,5,6-pentafluorophenol	771-61-9	C₆HF₅O	详情	详情
(V)	44168	2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate		C₂₆H₁₉F₅N₂O₄	详情	详情
(VI)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(VII)	44169	benzyl (1R)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[(1S)-1-phenylethyl]amino]ethylcarbamate		C₂₈H₂₉N₃O₃	详情	详情
(VIII)	44170	(2R)-2-amino-3-(1H-indol-3-yl)-2-methyl-N-[(1S)-1-phenylethyl]propanamide		C₂₀H₂₃N₃O	详情	详情
(IX)	44171	1-benzofuran-2-ylmethyl 4-nitrophenyl carbonate		C₁₆H₁₁NO₆	详情	详情
(X)	38335	1-benzofuran-2-ylmethanol		C₉H₈O₂	详情	详情
(XI)	16605	4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene	7693-46-1	C₇H₄ClNO₄	详情	详情

Extended Information