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【结 构 式】 
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【分子编号】19106 【品名】2-nitrophenol 【CA登记号】88-75-5 |
【 分 子 式 】C6H5NO3 【 分 子 量 】139.11064 【元素组成】C 51.8% H 3.62% N 10.07% O 34.5% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of 2-nitrophenol (I) with 2,2,2-trrifluoroethyl p-toluenesulfonate (II) by means of K2CO3 in DMF gives 2-(2,2,2-trifluoroethoxy) nitrobenzene (III), which isreduced with H2 over PtO2 in ethanol yiedling the aniline (IV). The cyclization of (IV) with bis (2-chloroethyl)amine (V) and K2CO3 affords the piperazine (VI), which is condensed with 1-benzyl-3-(3-chloro-propyl)-5-methylpyrimidine-2,4(1H,3H)-dione (VII) by means of K2CO3 in refluxing acetonitrile to give the benzylated target compound (VIII). Finally, this compound is deprotected by hydrogenation with ammonium formate and Pd/C. The intermediate pyrimidine (VII) has been obtained by benzylation of thymine (IX) with benzyl bromide and K2CO3 to give the 1-benzylthymine (X), which is alkylated with 1-bromo-3-chloropropane and K2CO3 to the target intemediate (VII).
| 【1】 Bantle, G.W.; Elworthy, T.R.; Guzman, A.; Jaime-Figueroa, S.; Lopez-Tapia, F.J.; Morgans, D.J. Jr.; Perez-Medrano, A.; Pfister, J.R.; Sjogren, E.B.; Talamas, F.X. (F. Hoffmann-La Roche AG); Pyrimidinedione, pyrimidinetrione, triazinedione, tetrahydroquinazolinedione derivs. as alpha1-adrenergic receptor antagonists. EP 0748800; JP 1997100269 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 | |
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (I) | 19106 | 2-nitrophenol | 88-75-5 | C6H5NO3 | 详情 | 详情 |
| (II) | 29561 | 2,2,2-trifluoroethyl 4-methylbenzenesulfonate | 433-06-7 | C9H9F3O3S | 详情 | 详情 |
| (III) | 29562 | 2-nitrophenyl 2,2,2-trifluoroethyl ether; 1-nitro-2-(2,2,2-trifluoroethoxy)benzene | C8H6F3NO3 | 详情 | 详情 | |
| (IV) | 29563 | 2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine | C8H8F3NO | 详情 | 详情 | |
| (V) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (VI) | 29564 | 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether | C12H15F3N2O | 详情 | 详情 | |
| (VII) | 29565 | 1-benzyl-3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione | C15H17ClN2O2 | 详情 | 详情 | |
| (VIII) | 29566 | 1-benzyl-5-methyl-3-(3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl)-2,4(1H,3H)-pyrimidinedione | C27H31F3N4O3 | 详情 | 详情 | |
| (IX) | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
| (X) | 29567 | 1-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione | C12H12N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Nitrophenoxyacetate (III) (prepared from 2-nitrophenol (I) and tert-butyl bromoacetate), was reduced with H2 in the presence of Pd/C to give aniline (IV). This was condensed with Z-D-Phe (V) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to yield amide (VI), which was deprotected to amine (VII) by hydrogenolysis in the presence of Pd/C. Subsequent coupling with Z-Pro (VIII), followed by hydrogenolytic deprotection produced (IX). This was coupled with methyl oxalyl chloride (X) to afford (XI). Then, treatment with trifluoroacetic acid in CH2Cl2 gave acid (XII). Finally, dipeptide (XV) (obtained by coupling of protected 3-amino-2-hydroxy-4-phenylbutyric acid (XIII) with tert-butyl prolinamide (XIV)), was condensed with acid (XII) to produce the title compound.
| 【1】 Asagarasu, A.; et al.; Synthesis of dipeptide-type human immunodeficiency virus (HIV) protease inhibitors with a binding unit to GP120. Chem Pharm Bull 1998, 46, 5, 867. |
| 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) | 19106 | 2-nitrophenol | 88-75-5 | C6H5NO3 | 详情 | 详情 |
| (II) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (III) | 19108 | tert-butyl 2-(2-nitrophenoxy)acetate | C12H15NO5 | 详情 | 详情 | |
| (IV) | 19109 | tert-butyl 2-(2-aminophenoxy)acetate | C12H17NO3 | 详情 | 详情 | |
| (V) | 19110 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid | C17H17NO4 | 详情 | 详情 | |
| (VI) | 19111 | tert-butyl 2-[2-[((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)amino]phenoxy]acetate | C29H32N2O6 | 详情 | 详情 | |
| (VII) | 19112 | tert-butyl 2-(2-[[(2R)-2-amino-3-phenylpropanoyl]amino]phenoxy)acetate | C21H26N2O4 | 详情 | 详情 | |
| (VIII) | 19113 | (2S)-1-[(benzyloxy)carbonyl]-2-pyrrolidinecarboxylic acid | 1148-11-4 | C13H15NO4 | 详情 | 详情 |
| (IX) | 19114 | tert-butyl 2-[2-[((2R)-3-phenyl-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoyl)amino]phenoxy]acetate | C26H33N3O5 | 详情 | 详情 | |
| (X) | 19115 | [(chlorocarbonyl)oxy](methoxy)methane | C3H5ClO3 | 详情 | 详情 | |
| (XI) | 19116 | methyl 2-((2S)-2-[[((1R)-1-benzyl-2-[2-[2-(tert-butoxy)-2-oxoethoxy]anilino]-2-oxoethyl)amino]carbonyl]pyrrolidinyl)-2-oxoacetate | C29H35N3O8 | 详情 | 详情 | |
| (XII) | 19117 | 2-(2-[[(2R)-2-([[(2S)-1-(2-methoxy-2-oxoacetyl)pyrrolidinyl]carbonyl]amino)-3-phenylpropanoyl]amino]phenoxy)acetic acid | C25H27N3O8 | 详情 | 详情 | |
| (XIII) | 19118 | (2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyric acid | C18H19NO5 | 详情 | 详情 | |
| (XIV) | 19119 | (2S)-N-(tert-butyl)-2-pyrrolidinecarboxamide | C9H18N2O | 详情 | 详情 | |
| (XV) | 19120 | (2S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-N-(tert-butyl)-2-pyrrolidinecarboxamide | C19H29N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The protected (R)-ornithine (I) was converted to the active ester (III) upon coupling with 2-nitrophenol (II) in the presence of DCC and pyridine. Subsequent reaction of the nitrophenyl ester (III) with (R)-4-hydroxy-alpha-methylbenzylamine (IV) produced the corresponding amide (V). After acid cleavage of the Boc protecting group of (V), the resulting amine (VI) was acylated with diphenylacetyl chloride (VII) to give (VIII). Removal of the N-benzyloxycarbonyl group of (VIII) was achieved by catalytic hydrogenation over Pd/C. The resultant amine (IX) was then converted to the protected guanidine (XI) by reaction with N,N'-bis(benzyloxycarbonyl)-S-methylisothiourea (X). The protecting groups of (X) were finally removed by hydrogenation over Pd/C.
| 【1】 Pilling, G.; Bergman, N.-A.; D'Ambra, T. (AstraZeneca plc); New NPY antagonists. EP 1017672; WO 9915498 . |
| 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) | 44215 | (2R)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | C18H26N2O6 | 详情 | 详情 | |
| (II) | 19106 | 2-nitrophenol | 88-75-5 | C6H5NO3 | 详情 | 详情 |
| (III) | 46848 | 2-nitrophenyl (2R)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoate | C24H29N3O8 | 详情 | 详情 | |
| (IV) | 46849 | 4-[(1R)-1-aminoethyl]phenol | 134855-87-1 | C8H11NO | 详情 | 详情 |
| (V) | 46850 | benzyl (4R)-4-[(tert-butoxycarbonyl)amino]-5-[[(1R)-1-(4-hydroxyphenyl)ethyl]amino]-5-oxopentylcarbamate | C26H35N3O6 | 详情 | 详情 | |
| (VI) | 46851 | benzyl (4R)-4-amino-5-[[(1R)-1-(4-hydroxyphenyl)ethyl]amino]-5-oxopentylcarbamate | C21H27N3O4 | 详情 | 详情 | |
| (VII) | 23800 | Diphenylacetyl chloride; 2,2-diphenylacetyl chloride | 1871-76-7 | C14H11ClO | 详情 | 详情 |
| (VIII) | 46852 | benzyl (4R)-4-[(2,2-diphenylacetyl)amino]-5-[[(1R)-1-(4-hydroxyphenyl)ethyl]amino]-5-oxopentylcarbamate | C35H37N3O5 | 详情 | 详情 | |
| (IX) | 46853 | (2R)-5-amino-2-[(2,2-diphenylacetyl)amino]-N-[(1R)-1-(4-hydroxyphenyl)ethyl]pentanamide | C27H31N3O3 | 详情 | 详情 | |
| (X) | 32861 | benzyl (E)-[[(benzyloxy)carbonyl]amino](methylsulfanyl)methylidenecarbamate | C18H18N2O4S | 详情 | 详情 | |
| (XI) | 46854 | benzyl (E)-[[(benzyloxy)carbonyl]amino][((4R)-4-[(2,2-diphenylacetyl)amino]-5-[[(1R)-1-(4-hydroxyphenyl)ethyl]amino]-5-oxopentyl)amino]methylidenecarbamate | C44H45N5O7 | 详情 | 详情 |