1H-imidazol-5-ylmethanol -Drug Synthesis Database

【结构式】

【分子编号】42116

【品名】1H-imidazol-5-ylmethanol

【CA登记号】

【分子式】C₄H₆N₂O

【分子量】98.10452

【元素组成】C 48.97% H 6.16% N 28.55% O 16.31%

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：(X)

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

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(XII)

Protection of 4-(hydroxymethyl)imidazole (XII) with chlorotriphenylmethane provided the 1-tritylimidazole (XIII). Acetylation of (XIII) with acetic anhydride in pyridine gave acetate ester (XIV). The imidazole ring of (XIV) was then alkylated with alpha-bromo-p-tolunitrile (XV) to yield the imidazolium salt (XVI), from which the N-trityl group was removed upon heating with MeOH. The resulting acetoxymethyl imidazole (XVII) was then hydrolyzed to alcohol (XVIII) using LiOH, and further Swern oxidation of (XVIII) furnished aldehyde (XIX). Finally, reductive condensation of aldehyde (XIX) with piperazinone (VIII) in the presence of sodium triacetoxyborohydride produced the title compound.

参考文献中间体

合成目标

【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 .
【2】 Williams, T.M.; Dinsmore, C.J.; Hutchinson, J.H. (Merck & Co., Inc.); Inhibitors of prenyl-protein transferase. EP 1014984; WO 9909985 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	47289	1-(3-chlorophenyl)-2-piperazinone		C₁₀H₁₁ClN₂O	详情	详情
(XII)	42116	1H-imidazol-5-ylmethanol		C₄H₆N₂O	详情	详情
(XIII)	38392	(1-trityl-1H-imidazol-4-yl)methanol		C₂₃H₂₀N₂O	详情	详情
(XIV)	38391	(1-trityl-1H-imidazol-4-yl)methyl acetate		C₂₅H₂₂N₂O₂	详情	详情
(XV)	14200	4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile	17201-43-3	C₈H₆BrN	详情	详情
(XVI)	47292	4-[(acetoxy)methyl]-3-(4-cyanobenzyl)-1-trityl-1H-imidazol-3-ium bromide		C₃₃H₂₈BrN₃O₂	详情	详情
(XVII)	38390	[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl acetate		C₁₄H₁₃N₃O₂	详情	详情
(XVIII)	38389	4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile		C₁₂H₁₁N₃O	详情	详情
(XIX)	38388	4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile		C₁₂H₉N₃O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

4-(Hydroxymethyl)imidazole (I) was protected as the 1-trityl derivative (II) by treatment with triphenylmethyl chloride. The hydroxyl group of (II) was then esterified with Ac2O in pyridine to yield acetate (III). After N-alkylation of (III) with 4-cyanobenzyl bromide (IV), the intermediate imidazolium bromide was deprotected by refluxing in MeOH to give (V). Subsequent hydrolysis of the acetate ester with LiOH provided alcohol (VI), which was oxidized to aldehyde (VII) under Swern conditions employing DMSO in the presence of SO3-pyridine complex.

参考文献中间体

合成目标

【1】 Beshore, D.C.; Bell, I.M.; Gallicchio, S.N.; Sisko, J.T.; Zartman, C.B.; Lumma, W.C. Jr. (Merck & Co., Inc.); Inhibitors of prenyl-protein transferase. WO 0117992 .

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)	42116	1H-imidazol-5-ylmethanol		C₄H₆N₂O	详情	详情
(II)	38392	(1-trityl-1H-imidazol-4-yl)methanol		C₂₃H₂₀N₂O	详情	详情
(III)	38391	(1-trityl-1H-imidazol-4-yl)methyl acetate		C₂₅H₂₂N₂O₂	详情	详情
(IV)	14200	4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile	17201-43-3	C₈H₆BrN	详情	详情
(V)	38390	[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl acetate		C₁₄H₁₃N₃O₂	详情	详情
(VI)	38389	4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile		C₁₂H₁₁N₃O	详情	详情
(VII)	38388	4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile		C₁₂H₉N₃O	详情	详情

Extended Information