[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl acetate -Drug Synthesis Database

【结构式】

【分子编号】38390

【品名】[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl acetate

【CA登记号】

【分子式】C₁₄H₁₃N₃O₂

【分子量】255.27624

【元素组成】C 65.87% H 5.13% N 16.46% O 12.53%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XIV)

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：(XVII)

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：(XV)

The reaction of N-(tert-butoxycarbonyl)-L-norleucine (I) with N,O-dimethylhydroxylamine (II) by means of EDC, HOBT and TEA in DMF gives the methoxyamide (III), which is reduced with LiAlH4 to the corresponding aldehyde (IV). The reductocondensation of (IV) with 3-(trifluoromethoxy)aniline (V) by means of NaBH(OAc)3 affords the secondary amine (VI), which is acylated with chloroacetyl chloride (VII) and NaHCO3 to the chloroacetamide (VIII). The cyclization of (VIII) by means of Cs2CO3 in DMF gives the piperazinone (IX), which is finally reductocondensed with 1-(4-cyanobenzyl)imidazole-5-carbaldehyde (X) by means of NaBH(OAc)3. The intermediate 1-(4-cyanobenzyl)imidazole-5-carbaldehyde (X) has been obtained as follows: The tritylation of 1H-imidazole-4-methanol (XI) with trityl chloride and TEA in DMF gives the corresponding 1-trityl derivative (XII), which is acetylated with Ac2O and pyridine yielding the acetate (XIII). The condensation of (XIII) with 4-(bromomethyl)benzonitrile (XIV) in hot ethyl acetate affords 4-(5-acetoxyimidazol-1-ylmethyl)benzonitrile (XV), which is hydrolyzed with LiOH in THF/water providing the carbinol (XVI). Finally, this alcohol is oxidized to the target aldehyde (X) by means of SO3 and pyridine in DMSO.

参考文献中间体

合成目标

【1】 Bergman, J.M.; Brashear, K.; Williams, T.M.; et al.; N-Arylpiperazinone inhibitors of farnesyltransferase: Discovery and biological activity. J Med Chem 1999, 42, 19, 3779.

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)	20398	(2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid		C₁₁H₂₁NO₄	详情	详情
(II)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(III)	38382	tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]pentylcarbamate		C₁₃H₂₆N₂O₄	详情	详情
(IV)	38383	tert-butyl (1S)-1-formylpentylcarbamate		C₁₁H₂₁NO₃	详情	详情
(V)	38384	3-(trifluoromethoxy)phenylamine; 3-(trifluoromethoxy)aniline	1535-73-5	C₇H₆F₃NO	详情	详情
(VI)	38385	tert-butyl (1S)-1-[[3-(trifluoromethoxy)anilino]methyl]pentylcarbamate		C₁₈H₂₇F₃N₂O₃	详情	详情
(VII)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(VIII)	38386	tert-butyl (1S)-1-[[(2-chloroacetyl)-3-(trifluoromethoxy)anilino]methyl]pentylcarbamate		C₂₀H₂₈ClF₃N₂O₄	详情	详情
(IX)	38387	tert-butyl (2S)-2-butyl-5-oxo-4-[3-(trifluoromethoxy)phenyl]-1-piperazinecarboxylate		C₂₀H₂₇F₃N₂O₄	详情	详情
(X)	38388	4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile		C₁₂H₉N₃O	详情	详情
(XI)	38393	1H-imidazol-4-ylmethanol		C₄H₆N₂O	详情	详情
(XII)	38392	(1-trityl-1H-imidazol-4-yl)methanol		C₂₃H₂₀N₂O	详情	详情
(XIII)	38391	(1-trityl-1H-imidazol-4-yl)methyl acetate		C₂₅H₂₂N₂O₂	详情	详情
(XIV)	14200	4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile	17201-43-3	C₈H₆BrN	详情	详情
(XV)	38390	[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl acetate		C₁₄H₁₃N₃O₂	详情	详情
(XVI)	38389	4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile		C₁₂H₁₁N₃O	详情	详情

合成路线4

该中间体在本合成路线中的序号：(V)

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