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【结 构 式】 
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【分子编号】38388 【品名】4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile 【CA登记号】 |
【 分 子 式 】C12H9N3O 【 分 子 量 】211.22308 【元素组成】C 68.24% H 4.29% N 19.89% O 7.57% |
合成路线1
该中间体在本合成路线中的序号：(XIX)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2
该中间体在本合成路线中的序号：(XIV)The reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot ethanol/water gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII). The protection of the amino group of (VII) with Boc2O and K2CO3 in methyl tert-butyl ether yields the carbamate (VIII), which is debenzylated with ammonium formate over Pd/C in methanol affording the amino compound (IX). The condensation of (IX) with 2-(2,6-dimethylphenoxy)acetic acid (X) by means of EDAC in DMF provides the corresponding amide (XI), which is deprotected at the carbamate group with TFA in dichloromethane to give (XII) with a free amino group. Finally, this compound is condensed with 3-methyl 2(S)-(2-oxoperhydropyrimidin-1-yl)butyric acid (XIII) by means of EDAC in DMF or SOCl2 and imidazole to furnish the target compound. The intermediate 2-(2,6-dimethylphenoxy)acetic acid (X) has been obtained by condensation of 2,6-dimethylphenol (XIV) with ethyl 2-bromoacetate (XV) by means of Cs2CO3 in refluxing dioxane to give the acetate ester (XVI), which is hydrolyzed with LiOH ethanol/water to afford the target intermediate (X).
| 【1】 Stoner, E.J.; et al.; Synthesis of ABT-378, an HIV protease inhibitor candidate: Avoiding the use of carbodiimides in a difficult peptide coupling. Org Process Res Dev 1999, 3, 2, 145. |
| 【2】 Sham, H.L.; Stewart, K.D.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. EP 0876353; JP 2000502997; WO 9721683 . |
| 【3】 Retroviral protease inhibiting cpds.. EP 0882024; JP 2000502085; US 5914332; WO 9721685 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (III) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IV) | 38263 | (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile | C25H24N2O | 详情 | 详情 | |
| (V) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (VI) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (VII) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 | |
| (VIII) | 38542 | tert-butyl (1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentylcarbamate | C37H44N2O3 | 详情 | 详情 | |
| (IX) | 38543 | tert-butyl (1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentylcarbamate | C23H32N2O3 | 详情 | 详情 | |
| (X) | 38270 | 2-(2,6-dimethylphenoxy)acetic acid | C10H12O3 | 详情 | 详情 | |
| (XI) | 38545 | tert-butyl (1S,3S,4S)-1-benzyl-4-[[2-(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenylpentylcarbamate | C33H42N2O5 | 详情 | 详情 | |
| (XII) | 38546 | N-[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]-2-(2,6-dimethylphenoxy)acetamide | C28H34N2O3 | 详情 | 详情 | |
| (XIII) | 38264 | (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid | C9H16N2O3 | 详情 | 详情 | |
| (XIV) | 38388 | 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile | C12H9N3O | 详情 | 详情 | |
| (XV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (XVI) | 38544 | ethyl 2-(2,6-dimethylphenoxy)acetate | C12H16O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)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4
该中间体在本合成路线中的序号：(VII)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 |
合成路线5
该中间体在本合成路线中的序号：(VII)Coupling of N-Boc-L-methionine (VIII) with 3-chlorobenzylamine (IX) using PyBOP provided amide (X). Methylation of the sulfide group of (X) with iodomethane gave rise to the sulfonium salt (XI), which was further cyclized to pyrrolidinone (XII) by treatment with lithium bis(trimethylsilyl)amide in cold THF. Acid deprotection of the Boc group of (XII) furnished amine (XIII). This was finally subjected to reductive alkylation with aldehyde (VII) in the presence of sodium cyanoborohydride to provide the corresponding (imidazolylmethyl)amine.
| 【1】 Bell, I.M.; et al.; Design and biological activity of (S)-4-(5-{[1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency. J Med Chem 2001, 44, 18, 2933. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (VII) | 38388 | 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile | C12H9N3O | 详情 | 详情 | |
| (VIII) | 34459 | (3-chlorophenyl)methanamine; 3-chlorobenzylamine | 4152-90-3 | C7H8ClN | 详情 | 详情 |
| (IX) | 17634 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid; N-alpha-t-BOC-L-methionine | 2488-15-5 | C10H19NO4S | 详情 | 详情 |
| (X) | 49995 | tert-butyl (1S)-1-[[(3-chlorobenzyl)amino]carbonyl]-3-(methylsulfanyl)propylcarbamate | C17H25ClN2O3S | 详情 | 详情 | |
| (XI) | 49996 | [(3S)-3-[(tert-butoxycarbonyl)amino]-4-[(3-chlorobenzyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide | C18H28ClIN2O3S | 详情 | 详情 | |
| (XII) | 49997 | tert-butyl (3S)-1-(3-chlorobenzyl)-2-oxopyrrolidinylcarbamate | C16H21ClN2O3 | 详情 | 详情 | |
| (XIII) | 49998 | (3S)-3-amino-1-(3-chlorobenzyl)-2-pyrrolidinone | C11H13ClN2O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The target compound has been obtained by reductocondensation of 1-(4-cyanobenzyl)-1H-imidazole-5-carbaldehyde (I) with N2-(4-amino-3,4-dihydro-2H-1-benzopyran-8-ylcarbonyl)-4-chlorophenylalaninamide (II) by means of NaBH3CN and HOAc in acetonitrile.
| 【1】 Jimonet, P.; Dereu, N.; Le Brun, A.; Baudoin, B.; Clerc, F.; El-Ahmad, Y.; Hardy, J.-C. (Aventis Pharma SA); Condensed heterocyclic system derivs., preparation, pharmaceutical compsns. containing them. EP 1054882; FR 2774987; WO 9941248 . |