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【结 构 式】

【分子编号】14200

【品名】4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile

【CA登记号】17201-43-3

【 分 子 式 】C8H6BrN

【 分 子 量 】196.04638

【元素组成】C 49.01% H 3.08% Br 40.76% N 7.14%
与该中间体有关的原料药合成路线共 15 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5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

该中间体在本合成路线中的序号：(III)

1) The condensation of 4-(3-hydroxypropyl)-1H-imidazole (I) with dimethylcarbamoyl chloride by means of triethylamine in refluxing acetonitrile followed by reaction with trimethylchlorosilane gives 1-(dimethylcarbamoyl)-4-[3-(trimethylsilyloxy)propyl]imidazole (II), which is condensed with 4-cyanobenzyl bromide (III) in refluxing acetonitrile yielding 1-(4-cyanobenzyl)-5-(3-hydroxypropyl)imidazole (IV). The reaction of (IV) with SOCl2 in refluxing dichloromethane affords the corresponding 3-chloropropyl derivative (V), which is finally cyclized by means of potassium tert-butoxide in THF.

参考文献 中间体
合成目标
【1】 Browne, L.J. (Ciba Geigy Corp.); Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors.. ES 8801262; JP 61012688; US 4617307 .
【2】 Pento, J.T.; Prous, J.; Castaner, J.; CGS-16949A. Drugs Fut 1989, 14, 9, 843.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
13708 N,N'-Dimethylcarbamoyl chloride; Dimethylcarbamoyl chloride; [(Chlorocarbonyl)(methyl)amino]methane 79-44-7 C3H6ClNO 详情 详情
(I) 21245 3-(1H-imidazol-4-yl)-1-propanol C6H10N2O 详情 详情
(II) 21246 N,N-dimethyl-4-[4-(trimethylsilyl)butyl]-1H-imidazole-1-carboxamide C13H25N3OSi 详情 详情
(III) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(IV) 21248 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H15N3O 详情 详情
(V) 21249 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H14ClN3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(III)

The synthesis of [14C]-fadrozole hydrochloride has been described: The reaction of 4-bromotoluene (I) with [14C]-copper cyanide in hot DMF gives [14C]-4-methylbenzonitrile (II), which is brominated with N-bromosuccinimide (NBS) and benzoyl peroxide in CCl4 yields the corresponding bromomethyl derivative (III). The condensation of (III) with N,N-dimethyl-4-[3-(trimethylsilyloxy)propyl]imidazole-1-carboxamide (IV) by means of ammonia, followed by desilylation with HCl affords labeled 4-[5-(3-hydroxypropyl)imidazol-1-ylmethyl]benzonitrile (V). The reaction of (V) with SOCl2 in dichloromethane gives the corresponding chloropropyl derivative (VI), which is finally cyclized by means of potassium tert-butoxide in THF and treated with dry HCl in ethanol/ethyl acetate to obtain the corresponding hydrochloride.

参考文献 中间体
合成目标
【1】 Allentoff, A.J.; Chaudhuri, N.K.; Markus, B.; Duelfer, T.; Desai, M.; Synthesis of 14C--labelled CGS 16949A (fadrozole HCl), a potent aromatase inhibitor. J Label Compd Radiopharm 1997, 39, 11, 885.
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) 14044 4-Bromotoluene; 1-Bromo-4-methylbenzene 106-38-7 C7H7Br 详情 详情
(II) 15458 4-methylbenzonitrile; p-tolunitrile 104-85-8 C8H7N 详情 详情
(II) 45171 4-methylbenzonitrile C8H7N 详情 详情
(III) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(III) 45172 4-(bromomethyl)benzonitrile C8H6BrN 详情 详情
(IV) 27902 N,N-dimethyl-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide C12H23N3O2Si 详情 详情
(V) 21248 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H15N3O 详情 详情
(V) 45173 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H15N3O 详情 详情
(VI) 21249 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H14ClN3 详情 详情
(VI) 45174 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H14ClN3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(IX)

14C-Radiolabeled fadrozole has been obtained by two similar ways: 1) The condensation of 4-[3-(methanesulfonyloxy)propyl]-N,N-dimethylimidazole-1-carboxamide (VI) with 14C-labeled 4-(bromomethyl)benzonitrile (IX) by means of NH3 followed by hydrolysis with HCl gives radiolabeled 4-[5-(3-hydroxypropyl)imidazol-1-ylmethyl]benzonitrile (X), which is treated with SOCl2 yielding the chloropropyl derivative (XI). Finally, this compound is cyclized to the target compound by means of potassium tert-butoxide. The intermediate compounds imidazole (VI) and radiolabeled benzonitrile (IX) have been obtained as follows: a) Imidazole (VI): The esterification of 3-(4-imidazolyl)-2(E)-propenoic acid (I) with SOCl2 and methanol gives the methyl ester (II), which is reduced with H2 over Pd/C yielding the propionic ester (III). The reduction of (III) with LiAlH4 affords 3-(4-imidazolyl)-1-propanol (IV), which is treated with N,N-dimethyl chloroformamide to afford 4-(3-hydroxypropyl)-N,N-dimethylimidazole-1-carboxamide (V). Finally, this compound is mesylated with methanesulfonyl chloride to give the desired intermediate (VI). b) Radiolabeled benzonitrile (IX): The reaction of 4-bromotoluene (VII) with radiolabeled potassium cyanide gives the radiolabeled 4-methylbenzonitrile (VIII), which is brominated with NBS and benzoylperoxide yielding intermediate (IX).

参考文献 中间体
合成目标
【1】 Allentoff, A.J.; et al.; Palladium-catalyzed aryl cynations in radiosynthesis: Synthesis of 14C-labeled fadrozole, a potent aromatase inhibitor. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 49.
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) 27420 Urocanic acid; (E)-3-(1H-imidazol-4-yl)-2-propenoic acid 104-98-3 C6H6N2O2 详情 详情
(II) 39976 methyl (E)-3-(1H-imidazol-4-yl)-2-propenoate C7H8N2O2 详情 详情
(III) 39977 methyl 3-(1H-imidazol-4-yl)propanoate C7H10N2O2 详情 详情
(IV) 21245 3-(1H-imidazol-4-yl)-1-propanol C6H10N2O 详情 详情
(V) 39978 4-(3-hydroxypropyl)-N,N-dimethyl-1H-imidazole-1-carboxamide C9H15N3O2 详情 详情
(VI) 27902 N,N-dimethyl-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide C12H23N3O2Si 详情 详情
(VII) 14044 4-Bromotoluene; 1-Bromo-4-methylbenzene 106-38-7 C7H7Br 详情 详情
(VIII) 15458 4-methylbenzonitrile; p-tolunitrile 104-85-8 C8H7N 详情 详情
(VIII) 45171 4-methylbenzonitrile C8H7N 详情 详情
(IX) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(IX) 45172 4-(bromomethyl)benzonitrile C8H6BrN 详情 详情
(X) 21248 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H15N3O 详情 详情
(X) 45173 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H15N3O 详情 详情
(XI) 21249 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H14ClN3 详情 详情
(XI) 45174 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H14ClN3 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

Reaction of 4-bromomethylbenzonitrile (I) with 1,2,4-triazole (II) in chloroform - acetonitrile gives 1-(4-cyanophenyl)methyl-1,2,4-triazole (III), which is treated with potassium tert-butoxide and 4-fluorobenzonitrile (IV) in DMF.

参考文献 中间体
合成目标
【1】 Bowman, R.M.; Steele, R.E.; Browne, L.J. (Novartis AG); Alpha-heterocycle substd. Tolunitriles. EP 0236940; JP 1987212369 .
【2】 Graul, A.; Castaner, J.; Prous, J.; Letrozole. Drugs Fut 1994, 19, 4, 335.
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) 14132 4-Chloro-1H-pyrazole 15878-00-9 C3H3ClN2 详情 详情
(I) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(II) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(III) 14202 4-(1H-1,2,4-Triazol-1-ylmethyl)benzonitrile C10H8N4 详情 详情
(IV) 14144 4-Fluorobenzonitrile 1194-02-1 C7H4FN 详情 详情

合成路线5

该中间体在本合成路线中的序号：(I)

The reaction of 4-cyanobenzyl bromide (I) with NaN3 in DMF gives 4-cyanobenzyl azide (II), which is treated first with HCl and then with ammonia to yield 4-(azidomethyl)benzamidine (III). Protection of the amidino group of (III) with benzyl chloroformate affords the protected compound (IV), which is finally reduced at the azido group with PPh3 in THF to provide 4-(benzyloxycarbonylamidino)benzylamine (V).

参考文献 中间体
合成目标
【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155.
【2】 Antonsson, K.T.; Bylund, R.E.; Gustafsson, N.D.; Nilsson, N.O.I. (AstraZeneca plc); New peptide derivs.. EP 0701568; JP 1996511018; JP 2001322974; US 5602253; US 5723444; WO 9429336 .
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) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(II) 50383 4-(azidomethyl)benzonitrile C8H6N4 详情 详情
(III) 50384 4-(azidomethyl)benzenecarboximidamide C8H9N5 详情 详情
(IV) 50385 benzyl [4-(azidomethyl)phenyl](imino)methylcarbamate C16H15N5O2 详情 详情
(V) 50386 benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate C16H17N3O2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

Reaction of 4-cyanobenzyl bromide (I) with bis(tert-butoxycarbonyl)imine (XVI) by means of NaH in THF gives the protected benzylamine (XVII), which is treated with hydroxylamine and Na2CO3 in ethanol/water to yield the N-hydroxybenzamidine (XVIII). Reduction of compound (XVIII) with H2 over Pd/C in HOAc/Ac2O affords the protected benzamidine (XIX), which is treated with benzyl chloroformate and NaOH in THF in order to obtain the fully protected compound (XX). Selective deprotection of (XX) with HCl gives 4-(benzyloxycarbonylamidino)benzylamine (V), which is condensed with the protected azetidine-2-carboxylic acid (XXI) to afford the corresponding amide (XXII). Boc-deprotection of (XXII) provides azetidine (XXIII), which is condensed with N-Boc-(R)-cyclohexylglycine (VII) to give the protected dipeptide (XI). Boc-deprotection of (XI) affords intermediate (XII), which is condensed with benzyl 2-bromoacetate (XIV) to give the melagatran precursor (XV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C as before.

参考文献 中间体
合成目标
【2】 Hervé, Y.; Fournier, J.; De Nanteuil, G.; Leborgne, F.; Verbeuren, T.J.; Lila, C.; Gloanec, P.; Cadet, L.; Large scale preparation of protected 4-aminomethylbenzamidine. Application to the synthesis of the thrombin inhibitor melagatran. Synth Commun 1998, 28, 23, 4419.
【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155.
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) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(V) 50386 benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate C16H17N3O2 详情 详情
(VII) 35619 (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid C13H23NO4 详情 详情
(XI) 50376 benzyl [4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methylcarbamate C33H43N5O6 详情 详情
(XII) 50390 benzyl (4-[[([(2S)-1-[(2R)-2-amino-2-cyclohexylethanoyl]azetidinyl]carbonyl)amino]methyl]phenyl)(imino)methylcarbamate C28H35N5O4 详情 详情
(XIV) 12869 benzyl 2-bromoacetate 5437-45-6 C9H9BrO2 详情 详情
(XV) 50392 benzyl 2-[((1R)-2-[(2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]azetidinyl]-1-cyclohexyl-2-oxoethyl)amino]acetate C37H43N5O6 详情 详情
(XVI) 48447 Di-tert-butyl iminodicarboxylate; Iminodicarboxylic acid di-tert-butyl ester 51779-32-9 C10H19NO4 详情 详情
(XVII) 50393 1-[[bis(tert-butoxycarbonyl)amino]methyl]-4-cyanobenzene C18H24N2O4 详情 详情
(XVIII) 50394 1-[amino(hydroxyimino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene C18H27N3O5 详情 详情
(XIX) 50395 1-[amino(imino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene C18H27N3O4 详情 详情
(XX) 50396 1-[[[(benzyloxy)carbonyl]amino](imino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene C26H33N3O6 详情 详情
(XXI) 26205 (2S)-1-(tert-butoxycarbonyl)-2-azetidinecarboxylic acid C9H15NO4 详情 详情
(XXII) 50397 tert-butyl (2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]-1-azetidinecarboxylate C25H30N4O5 详情 详情
(XXIII) 50398 benzyl [4-([[(2S)azetidinylcarbonyl]amino]methyl)phenyl](imino)methylcarbamate C20H22N4O3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(XIII)

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8

该中间体在本合成路线中的序号：(XV)

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9

该中间体在本合成路线中的序号：(XV)

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.

参考文献 中间体
合成目标
【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10

该中间体在本合成路线中的序号：(XII)

Protection of 4-imidazoleacetic acid methyl ester (X) with triphenylmethyl bromide provided the N1-trityl derivative (XI). Subsequent alkylation of (XI) with 4-cyanobenzyl bromide (XII) resulted in the formation of the imidazolium salt (XIII). Deprotection of the trityl group of (XIII) was achieved upon refluxingin MeOH to give (XIV). Hydrolysis of the methyl ester group of (XIV) under either acidic or basic conditions yielded imidazoleacetic acid (XV), which was subsequently coupled with the intermediate amine (IX) using EDC and 3-hydroxy-1,2,3-benzotriazin-4-one (HOOBT) to provide amide (XVI). Finally, saponification of the methyl ester group of (XVI) furnished the title compound.

参考文献 中间体
合成目标
【1】 Gomez, R.P.; Schaber, M.D.; Anthony, N.J.; et al.; Design and in vivo analysis of potent non-thiol inhibitors of farnesyl protein transferase. J Med Chem 1999, 42, 17, 3356.
【2】 Anthony, N.J.; Desolms, S.J.; Gomez, R.P.; Graham, S.L.; Hutchinson, J.H.; Stokker, G.E. (Merck & Co., Inc.); Thio-free inhibitors of farnesyl-protein transferase. JP 1998508005; US 5652257; WO 9610034 .
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) 34738 methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate C25H37N3O3S 详情 详情
(X) 34739 methyl 2-(1H-imidazol-4-yl)acetate C6H8N2O2 详情 详情
(XI) 34740 methyl 2-(1-trityl-1H-imidazol-4-yl)acetate C25H22N2O2 详情 详情
(XII) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(XIII) 34741 3-(4-cyanobenzyl)-4-(2-methoxy-2-oxoethyl)-1-trityl-1H-imidazol-3-ium bromide C33H28BrN3O2 详情 详情
(XIV) 34742 methyl 2-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetate C14H13N3O2 详情 详情
(XV) 34743 2-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid C13H11N3O2 详情 详情
(XVI) 34805 methyl (2S)-2-([2-[[(2S,3S)-2-([2-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetyl]amino)-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate C38H46N6O4S 详情 详情

合成路线11

该中间体在本合成路线中的序号：(XII)

Protection of 4-imidazoleacetic acid methyl ester (X) with triphenylmethyl bromide provided the N1-trityl derivative (XI). Subsequent alkylation with 4-cyanobenzyl bromide (XII) resulted in the formation of the imidazolium salt (XIII). Deprotection of the trityl group of (XIII) was achieved upon refluxingin MeOH to give (XIV). Hydrolysis of the methyl ester group of (XIV) under either acidic or basic conditions yielded imidazoleacetic acid (XV). This was finally coupled with the intermediate amine (IX) using EDC and 3-hydroxy-1,2,3-benzotriazin-4-one (HOOBT) to provide the title compound.

参考文献 中间体
合成目标
【1】 Gomez, R.P.; Schaber, M.D.; Anthony, N.J.; et al.; Design and in vivo analysis of potent non-thiol inhibitors of farnesyl protein transferase. J Med Chem 1999, 42, 17, 3356.
【2】 Anthony, N.J.; Desolms, S.J.; Gomez, R.P.; Graham, S.L.; Hutchinson, J.H.; Stokker, G.E. (Merck & Co., Inc.); Thio-free inhibitors of farnesyl-protein transferase. JP 1998508005; US 5652257; WO 9610034 .
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) 34738 methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate C25H37N3O3S 详情 详情
(X) 34739 methyl 2-(1H-imidazol-4-yl)acetate C6H8N2O2 详情 详情
(XI) 34740 methyl 2-(1-trityl-1H-imidazol-4-yl)acetate C25H22N2O2 详情 详情
(XII) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(XIII) 34741 3-(4-cyanobenzyl)-4-(2-methoxy-2-oxoethyl)-1-trityl-1H-imidazol-3-ium bromide C33H28BrN3O2 详情 详情
(XIV) 34742 methyl 2-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetate C14H13N3O2 详情 详情
(XV) 34743 2-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid C13H11N3O2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XIV)

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13

该中间体在本合成路线中的序号：(IX)

The intermediate 3-(4-cyanobenzyloxy)isoxazole-5-carboxylic acid (VII) has been obtained by condensation of 4-(bromomethyl)benzonitrile (IX) with 3-hydroxyisoxazole-5-carboxylic acid methyl ester (X) by means of K2CO3 in hot DMF to yield the benzyloxy derivative (XI), which is finally hydrolyzed with LiOH in THF to provide the target intermediate (VII).

参考文献 中间体
合成目标
【1】 Xue, C.-B.; Roderick, J.; Mousa, S.; Olson, R.E.; DeGrado, W.F.; Synthesis and antiplatelet effects of an isoxazole series of glycoprotein IIb/IIIa antagonists. Bioorg Med Chem Lett 1998, 8, 24, 3499.
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) 25098 3-[(4-cyanobenzyl)oxy]-5-isoxazolecarboxylic acid C12H8N2O4 详情 详情
(IX) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(X) 25101 methyl 3-hydroxy-5-isoxazolecarboxylate 10068-07-2 C5H5NO4 详情 详情
(XI) 25103 N-omega'-nitro-D-arginine C6H13N5O4 详情 详情

合成路线14

该中间体在本合成路线中的序号：(X)

Amide (III) was prepared by acylation of L-methionine methyl ester (I) with 3-(chloromethyl)benzoyl chloride (II). Displacement of the halogen atom of (III) with LiN3 gave azide (IV), which was reduced to amine (V) by catalytic hydrogenation in the presence of Pd/C. Reductive coupling of (V) with protected imidazole-4-carboxaldehyde (VI) provided the (imidazolylmethyl)amine (VII), and a second reductive coupling of (VII) with benzaldehyde (VIII) furnished the trisubstituted amine (IX). The regioselective imidazole alkylation of (IX) with bromide (X), followed by trityl group deprotection with trifluoroacetic acid yielded (XI). Finally, the methyl ester group of (XI) was hydrolyzed with methanolic NaOH to afford the title carboxylic acid.

参考文献 中间体
合成目标
【1】 Ciccarone, T.M.; MacTough, S.C.; Williams, T.M.; et al.; Non-thiol 3-aminomethylbenzamide inhibitor of farnesyl-protein transferase. Bioorg Med Chem Lett 1999, 9, 14, 1991.
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) 17950 D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride 21691-49-6 C6H13NO2S 详情 详情
(II) 25107 3-(chloromethyl)benzoyl chloride 63024-77-1 C8H6Cl2O 详情 详情
(III) 33729 methyl (2S)-2-[[3-(chloromethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate C14H18ClNO3S 详情 详情
(IV) 33730 methyl (2S)-2-[[3-(azidomethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate C14H18N4O3S 详情 详情
(V) 33731 methyl (2S)-2-[[3-(aminomethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate C14H20N2O3S 详情 详情
(VI) 27712 1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde 33016-47-6 C23H18N2O 详情 详情
(VII) 33732 methyl (2S)-4-(methylsulfanyl)-2-[[3-([[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]butanoate C37H38N4O3S 详情 详情
(VIII) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(IX) 33733 methyl (2S)-2-[[3-([(4-cyanobenzyl)[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]-4-(methylsulfanyl)butanoate C45H43N5O3S 详情 详情
(X) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(XI) 33734 methyl (2S)-2-([3-[((4-cyanobenzyl)[[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl]amino)methyl]benzoyl]amino)-4-(methylsulfanyl)butanoate C34H34N6O3S 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IV)

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