L-779575, -Drug Synthesis Database

【结构式】

【药物名称】L-779575

【化学名称】4-[5-[4-(3-Chlorophenyl)-2(R)-(ethylsulfonylmethyl)-5-oxopiperazin-1-ylmethyl]-1H-imidazol-1-ylmethyl]benzonitrile

【CA登记号】219553-06-7, 219552-96-2 (diHCl)

【分子式】C₂₅H₂₆ClN₅O₃S

【分子量】512.03467

【开发单位】Merck & Co. (Originator)

【药理作用】Oncolytic Drugs, Farnesyl Transferase Inhibitors, Inhibitors of Signal Transduction Pathways

合成路线1 合成路线2

合成路线1

The reductive alkylation of 3-chloroaniline (I) with L-S-trityl-N-Boc-cysteinal (II) in the presence of sodium triacetoxyborohydride produced amine (III). Chloroacetylation of (III) followed by cesium carbonate-induced cyclization of the resulting chloroacetamide (IV) furnished the protected piperazinone (V). The S-trityl group of (V) was deprotected by treatment with silver nitrate and pyridine, yielding thiol (VI), which was subsequently alkylated with ethyl iodide to give thioether (VII). Sulfur oxidation by means of magnesium monoperoxyphthalate in methanol afforded sulfone (VIII). Then, acid deprotection of the Boc protecting group of (VIII) provided the intermediate piperazinone (IX).

参考文献中间体

【1】 Anthony, N.J.; Ciccarone, T.M.; Gomez, R.P.; Hutchinson, J.H.; Williams, T.M.; Dinsmore, C.J.; Stokker, G.E. (Merck & Co., Inc.); Inhibitors of farnesyl-protein transferase. EP 0820445; JP 1998511098; US 5856326; WO 9630343 .

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)	25239	3-chloroaniline; 3-chlorophenylamine	108-42-9	C₆H₆ClN	详情	详情
(II)	17953	tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate		C₂₇H₂₉NO₃S	详情	详情
(III)	42109	tert-butyl (1R)-2-(3-chloroanilino)-1-[(tritylsulfanyl)methyl]ethylcarbamate		C₃₃H₃₅ClN₂O₂S	详情	详情
(IV)	42110	tert-butyl (1R)-2-[3-chloro(2-chloroacetyl)anilino]-1-[(tritylsulfanyl)methyl]ethylcarbamate		C₃₅H₃₆Cl₂N₂O₃S	详情	详情
(V)	42111	tert-butyl (2R)-4-(3-chlorophenyl)-5-oxo-2-[(tritylsulfanyl)methyl]-1-piperazinecarboxylate		C₃₅H₃₅ClN₂O₃S	详情	详情
(VI)	42112	tert-butyl (2R)-4-(3-chlorophenyl)-5-oxo-2-(sulfanylmethyl)-1-piperazinecarboxylate		C₁₆H₂₁ClN₂O₃S	详情	详情
(VII)	42113	tert-butyl (2R)-4-(3-chlorophenyl)-2-[(ethylsulfanyl)methyl]-5-oxo-1-piperazinecarboxylate		C₁₈H₂₅ClN₂O₃S	详情	详情
(VIII)	42114	tert-butyl (2R)-4-(3-chlorophenyl)-2-[(ethylsulfonyl)methyl]-5-oxo-1-piperazinecarboxylate		C₁₈H₂₅ClN₂O₅S	详情	详情
(IX)	42115	(5R)-1-(3-chlorophenyl)-5-[(ethylsulfonyl)methyl]-2-piperazinone		C₁₃H₁₇ClN₂O₃S	详情	详情

合成路线2

The regioselective protection of 4-hydroxymethylimidazole (X) with trityl chloride gave the 1-trityl imidazole (XI), which was further acetylated to afford acetate (XII). Alkylation of imidazole (XII) with 4-cyanobenzyl bromide (XIII), followed by solvolysis of the resulting imidazolium salt in refluxing methanol, produced the cyanobenzyl imidazole (XIV). Acetate hydrolysis and subsequent oxidation of alcohol (XV) furnished aldehyde (XVI). The title compound was obtained by reductive alkylation of piperazinone (IX) with aldehyde (XVI) in the presence of sodium triacetoxyborohydride.

参考文献中间体

【1】 Anthony, N.J.; Ciccarone, T.M.; Gomez, R.P.; Hutchinson, J.H.; Williams, T.M.; Dinsmore, C.J.; Stokker, G.E. (Merck & Co., Inc.); Inhibitors of farnesyl-protein transferase. EP 0820445; JP 1998511098; US 5856326; WO 9630343 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	42115	(5R)-1-(3-chlorophenyl)-5-[(ethylsulfonyl)methyl]-2-piperazinone		C₁₃H₁₇ClN₂O₃S	详情	详情
(X)	42116	1H-imidazol-5-ylmethanol		C₄H₆N₂O	详情	详情
(XI)	38392	(1-trityl-1H-imidazol-4-yl)methanol		C₂₃H₂₀N₂O	详情	详情
(XII)	38391	(1-trityl-1H-imidazol-4-yl)methyl acetate		C₂₅H₂₂N₂O₂	详情	详情
(XIII)	14200	4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile	17201-43-3	C₈H₆BrN	详情	详情
(XIV)	38390	[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl acetate		C₁₄H₁₃N₃O₂	详情	详情
(XV)	38389	4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile		C₁₂H₁₁N₃O	详情	详情
(XVI)	39388			C₅₄H₆₇N₁₁O₁₃S₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)