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【结 构 式】 
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【分子编号】38389 【品名】4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile 【CA登记号】 |
【 分 子 式 】C12H11N3O 【 分 子 量 】213.23896 【元素组成】C 67.59% H 5.2% N 19.71% O 7.5% |
合成路线1
该中间体在本合成路线中的序号：(XV)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.
| 【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：(XVIII)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.
| 【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：(XVIII)In a further procedure, bromide (XV) was reacted with hexamethylenetetramine in refluxing EtOH followed by acid hydrolysis to produce the benzyl amine (XX). Mercapto imidazole (XXII) was then obtained by condensation of amine (XX) with dihydroxyacetone (XXI) and KSCN. Subsequent oxidative desulfuration gave the hydroxymethyl imidazole (XVIII). This was converted to the corresponding chloride (XXIII) by treatment with either SOCl2 in DMF or the Vilsmeier reagent. Finally, chloride (XXIII) was condensed with piperazinone (VIII) in the presence of diisopropylethylamine.
| 【1】 Cowen, J.A.; Askin, D.; McWilliams, J.C.; Maligres, P.E.; McCauley, J.A. (Merck & Co., Inc.); Process for making farnesyl-protein transferase inhibitors. WO 0001691 . |
| 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 | |
| (XV) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (XVIII) | 38389 | 4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile | C12H11N3O | 详情 | 详情 | |
| (XX) | 47293 | 4-(aminomethyl)benzonitrile | C8H8N2 | 详情 | 详情 | |
| (XXI) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (XXII) | 47294 | 4-[[5-(hydroxymethyl)-2-sulfanyl-1H-imidazol-1-yl]methyl]benzonitrile | C12H11N3OS | 详情 | 详情 | |
| (XXIII) | 47295 | 4-[[5-(chloromethyl)-1H-imidazol-1-yl]methyl]benzonitrile | C12H10ClN3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVI)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.
| 【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5
该中间体在本合成路线中的序号：(VI)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.
| 【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 |