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【结 构 式】 
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【分子编号】39654 【品名】methyl 2-methyl-5-nitrophenyl ether; 2-methoxy-1-methyl-4-nitrobenzene 【CA登记号】13120-77-9 |
【 分 子 式 】C8H9NO3 【 分 子 量 】167.1644 【元素组成】C 57.48% H 5.43% N 8.38% O 28.71% |
合成路线1
该中间体在本合成路线中的序号：(I)The oxidation of 3-methoxy-4-methylnitrobenzene (I) with CrO3, H2SO4 and AC2O in acetic acid gives the gem-diacetate (II), which is hydrolyzed with HCl in refluxing dioxane to yield 2-methoxy-4-nitrobenzaldehyde (III). Cyclization of (III) with tosylmethyl isocyanide and K2CO3 in refluxing methanol affords 3-methoxy-4-(5-oxazolyl)nitrobenzene (IV), which is reduced with H2 over Pd/C in ethyl acetate to provide the corresponding aniline (V). The activation of (V) with carbonyldiimidazole (CDI) in THF gives the carboxamide (VI), which is condensed with 3-(tert-butoxycarbonylaminomethyl)aniline (VII), obtained by reaction of 3-aminobenzylamine with Boc2O, and DMAP in refluxing THF to yield the urea (IX). Deprotection of (IX) with TFA in dichloromethane affords the free benzylamine (X), which is finally condensed with the 3-furyl ester of the succinimidyl-activated carbonate (XI) by means of TEA in dichloromethane/DMF.
| 【1】 Martín, L.; Sorbera, L.A.; Castañer, J.; Silvestre, J.S.; VX-497. Drugs Fut 2000, 25, 8, 809. |
| 【2】 Armistead, D.M.; Badia, M.C.; Bemis, G.W.; Bethiel, R.S.; Frank, C.A.; Novak, P.M.; Ronkin, S.M.; Saunders, J.O. (Vertex Pharmaceuticals Inc.); Urea derivs. as inhibitors of IMPDH enzyme. EP 0902782; US 5807876; US 6054472; WO 9740028 . |
| 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) | 39654 | methyl 2-methyl-5-nitrophenyl ether; 2-methoxy-1-methyl-4-nitrobenzene | 13120-77-9 | C8H9NO3 | 详情 | 详情 |
| (II) | 39655 | (acetoxy)(2-methoxy-4-nitrophenyl)methyl acetate | C12H13NO7 | 详情 | 详情 | |
| (III) | 39656 | 2-methoxy-4-nitrobenzaldehyde | C8H7NO4 | 详情 | 详情 | |
| (IV) | 39657 | methyl 5-nitro-2-(1,3-oxazol-5-yl)phenyl ether; 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole | C10H8N2O4 | 详情 | 详情 | |
| (V) | 39658 | C10H10N2O2 | 详情 | 详情 | ||
| (VI) | 39659 | N-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]-1H-imidazole-1-carboxamide | C14H12N4O3 | 详情 | 详情 | |
| (VII) | 39660 | tert-butyl 3-aminobenzylcarbamate | C12H18N2O2 | 详情 | 详情 | |
| (VIII) | 39661 | 3-(aminomethyl)aniline; 3-aminobenzylamine | 4403-70-7 | C7H10N2 | 详情 | 详情 |
| (IX) | 39662 | tert-butyl 3-([[3-methoxy-4-(1,3-oxazol-5-yl)anilino]carbonyl]amino)benzylcarbamate | C23H26N4O5 | 详情 | 详情 | |
| (X) | 39663 | N-[3-(aminomethyl)phenyl]-N'-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]urea | C18H18N4O3 | 详情 | 详情 | |
| (XI) | 39664 | 1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C9H11NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Oxidation of 2-methoxy-4-nitrotoluene (I) with CrO3 in the presence of sulfuric acid and acetic anhydride produced acylal (II), which was further hydrolyzed to the benzaldehyde (III) under acidic conditions. The isoxazole derivative (IV) was obtained by treatment of aldehyde (III) with tosylmethyl isocyanide in the presence of K2CO3 in refluxing methanol. Then, catalytic hydrogenation of the nitro group of (IV) over Pd/C afforded aniline (V).
| 【1】 Murali Dhar, T.G.; Pitts, W.J.; Guo, J.; et al.; Rapid synthesis of novel inosine monophosphate dehydrogenase (IMPDH) inhibitors. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 214. |
| 【2】 Liu, C.; Leftheris, K.; Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H. (Bristol-Myers Squibb Co.); Cpds. derived from an amine nucleus that are inhibitors of IMPDH enzyme. EP 1126843; US 6399773; WO 0025780 . |
| 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) | 39654 | methyl 2-methyl-5-nitrophenyl ether; 2-methoxy-1-methyl-4-nitrobenzene | 13120-77-9 | C8H9NO3 | 详情 | 详情 |
| (II) | 39655 | (acetoxy)(2-methoxy-4-nitrophenyl)methyl acetate | C12H13NO7 | 详情 | 详情 | |
| (III) | 39656 | 2-methoxy-4-nitrobenzaldehyde | C8H7NO4 | 详情 | 详情 | |
| (IV) | 39657 | methyl 5-nitro-2-(1,3-oxazol-5-yl)phenyl ether; 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole | C10H8N2O4 | 详情 | 详情 | |
| (V) | 39658 | C10H10N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Intermediate (VII) is prepared by the following route. Oxidation of 2-methoxy-4-nitrotoluene (I) by means of chromic acid in the presence of Ac2O affords acylal (II), which is further hydrolyzed to aldehyde (III) under acidic conditions. Treatment of benzaldehyde (III) with TOSMIC reagent in the presence of K2CO3 gives rise to the phenyl oxazole derivative (IV). Nitro group reduction in (IV) with H2 and Pd/C yields aniline (V). This is then converted into isothiocyanate (VII) employing 1,1'-thiocarbonyldi-2(2H)-pyridone (VI).
| 【1】 Liu, C.; Leftheris, K.; Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H. (Bristol-Myers Squibb Co.); Cpds. derived from an amine nucleus that are inhibitors of IMPDH enzyme. EP 1126843; US 6399773; WO 0025780 . |
| 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) | 39654 | methyl 2-methyl-5-nitrophenyl ether; 2-methoxy-1-methyl-4-nitrobenzene | 13120-77-9 | C8H9NO3 | 详情 | 详情 |
| (II) | 39655 | (acetoxy)(2-methoxy-4-nitrophenyl)methyl acetate | C12H13NO7 | 详情 | 详情 | |
| (III) | 39656 | 2-methoxy-4-nitrobenzaldehyde | C8H7NO4 | 详情 | 详情 | |
| (IV) | 39657 | methyl 5-nitro-2-(1,3-oxazol-5-yl)phenyl ether; 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole | C10H8N2O4 | 详情 | 详情 | |
| (V) | 39658 | C10H10N2O2 | 详情 | 详情 | ||
| (VI) | 61696 | 1-{[2-oxo-1(2H)-pyridinyl]carbothioyl}-2(1H)-pyridinone | C11H8N2O2S | 详情 | 详情 | |
| (VII) | 61697 | 3-methoxy-4-(1,3-oxazol-5-yl)phenyl isothiocyanate; 5-(4-isothiocyanato-2-methoxyphenyl)-1,3-oxazole | C11H8N2O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Oxidation of 4-nitro-2-methoxytoluene (I) by means of chromic anhydride and sulfuric acid in the presence of acetic anhydride gives rise to acylal (II), which is further hydrolyzed to aldehyde (III) under acidic conditions. Reaction of aldehyde (III) with tosylmethyl isocyanide produces the 5-aryl oxazole (IV). Reduction of the nitro group of (IV) by catalytic hydrogenation yields aniline (V). Then, electrophilic iodination of amine (V) with iodine and silver triflate furnishes the aryl iodide (VI).
| 【1】 Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H.; Watterson, S.H. (Bristol-Myers Squibb Co.); Heterocycles that are inhibitors of IMPDH enzyme. EP 1276739; JP 2003531205; WO 0181340 . |
| 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) | 39654 | methyl 2-methyl-5-nitrophenyl ether; 2-methoxy-1-methyl-4-nitrobenzene | 13120-77-9 | C8H9NO3 | 详情 | 详情 |
| (II) | 39655 | (acetoxy)(2-methoxy-4-nitrophenyl)methyl acetate | C12H13NO7 | 详情 | 详情 | |
| (III) | 39656 | 2-methoxy-4-nitrobenzaldehyde | C8H7NO4 | 详情 | 详情 | |
| (IV) | 39657 | methyl 5-nitro-2-(1,3-oxazol-5-yl)phenyl ether; 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole | C10H8N2O4 | 详情 | 详情 | |
| (V) | 39658 | C10H10N2O2 | 详情 | 详情 | ||
| (VI) | 64043 | 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)aniline; 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)phenylamine | C10H9IN2O2 | 详情 | 详情 |