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【结 构 式】 
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【分子编号】15050 【品名】ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester 【CA登记号】626-35-7 |
【 分 子 式 】C4H7NO4 【 分 子 量 】133.10392 【元素组成】C 36.1% H 5.3% N 10.52% O 48.08% |
合成路线1
该中间体在本合成路线中的序号：(VI)This compound can be prepared by two related ways: 1) The condensation of methoxyacetaldehyde (I) with isopropylamine (II) gives methoxyacetaldehyde isopropylimine (III), which is treated with 4-benzyloxyindole (IV) in acetic acid yielding 4-benzyloxy-3-(1-isopropylamino-2-ethoxyethyl)indole (V). The reaction of (V) with ethyl nitroacetate (VI) in hot toluene affords ethyl 3-(4-benzyloxyindol-3-yl)-2-nitro-5-oxahexanoate (VII), which is reduced with H2 over Raney-Ni in ethanol giving ethyl 3-(4-benzyloxyindol-3-yl)-2-amino-5-oxahexanoate (VIII). Finally, this compound is cyclized with paraformaldehyde (IX) in refluxing benzene. 2) Compound (VIII) can also be cyclized with glyoxylic acid (X) yielding a mixture of the tetrahydrocarboline (XI) and the dihydrocarboline (XII), which, without separation, are decarboxylated and dehydrogenated with sulfur at 140 C.
| 【1】 Neef, G.; Schmiechen, R.; Huth, A.; Eder, U.; Rathz, D.; Seidelmann, D.; Synthesis of 4-sibstituted beta-carbolines. Heterocycles 1983, 20, 7, 1295-1313. |
| 【2】 Neef, G.; Eder, U.; Schmiechen, R.; Huth, A.; Rathz, D.; Seidelmonn, D.; Kehr, W.; Palenschat, D.; Braestrup, C.T.; et al. (Schering AG); Pharmacologically active 3-substituted beta-carbolines. DD 161210; EP 0054507; ES 8301984; US 4435403; US 4596808 . |
| 【3】 Castaner, J.; Serradell, M.N.; ZK-91296. Drugs Fut 1984, 9, 10, 761. |
| 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) | 34354 | 2-methoxyacetaldehyde | 10312-83-1 | C3H6O2 | 详情 | 详情 |
| (II) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
| (III) | 34355 | N-[(E)-2-methoxyethylidene]-2-propanamine; N-isopropyl-N-[(E)-2-methoxyethylidene]amine | C6H13NO | 详情 | 详情 | |
| (IV) | 31535 | 4-Benzyloxyindole; 4-(benzyloxy)-1H-indole; benzyl 1H-indol-4-yl ether | 20289-26-3 | C15H13NO | 详情 | 详情 |
| (V) | 34356 | N-[1-[4-(benzyloxy)-1H-indol-3-yl]-2-methoxyethyl]-2-propanamine; N-[1-[4-(benzyloxy)-1H-indol-3-yl]-2-methoxyethyl]-N-isopropylamine | C21H26N2O2 | 详情 | 详情 | |
| (VI) | 15050 | ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester | 626-35-7 | C4H7NO4 | 详情 | 详情 |
| (VII) | 34357 | ethyl 3-[4-(benzyloxy)-1H-indol-3-yl]-4-methoxy-2-nitrobutanoate | C22H24N2O6 | 详情 | 详情 | |
| (VIII) | 34358 | ethyl 2-amino-3-[4-(benzyloxy)-1H-indol-3-yl]-4-methoxybutanoate | C22H26N2O4 | 详情 | 详情 | |
| (X) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (XI) | 34359 | 5-(benzyloxy)-3-(ethoxycarbonyl)-4-(methoxymethyl)-2,3,4,9-tetrahydro-1H-beta-carboline-1-carboxylic acid | C24H26N2O6 | 详情 | 详情 | |
| (XII) | 34360 | 5-(benzyloxy)-3-(ethoxycarbonyl)-4-(methoxymethyl)-2,4a,9,9a-tetrahydro-1H-beta-carboline-1-carboxylic acid | C24H26N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The condensation of 6-chloropurine-2-amine (I) with epoxide (II) by means of Pd(PPh3)4 in DMSO gives the cyclopentenol derivative (III), which is treated with dimethyl dicarbonate and DMAP in dichloromethane to yield the carbonate (IV). The condensation of (IV) with ethyl 2-nitroacetate (V) by means of Pd in THF affords the adduct (VI), which is decarboxylated by means of NaCl in DMSO/water at 150 C to provide the nitromethylcyclopentene derivative (VII). The reaction of (VII) with tBuOK, O3 and NaBH4 in methanol gives the corresponding hydroxymethyl derivative (VIII), which is finally hydrolyzed with NaOH in refluxing water to afford the target guanine as a racemic compound. Alternatively, the nitromethyl-cyclopentene derivative (VII) can also be obtained by condensation of carbonate (IV) with 2-(trimethylsilyl)ethyl 2-nitroacetate (IX) by means of Pd in THF to give the adduct (X), which is decarboxylated by means of CsF in hot acetonitrile, affording (VII).
| 【1】 Peel, M.R.; et al.; A short, enantioselective synthesis of the carbocyclic nucleoside carbovir. J Org Chem 1991, 56, 16, 4990. |
| 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) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (II) | 45367 | 6-oxabicyclo[3.1.0]hex-2-ene | C5H6O | 详情 | 详情 | |
| (III) | 45368 | (1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-ol | C10H10ClN5O | 详情 | 详情 | |
| (IV) | 45369 | (1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl methyl carbonate | C12H12ClN5O3 | 详情 | 详情 | |
| (V) | 15050 | ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester | 626-35-7 | C4H7NO4 | 详情 | 详情 |
| (VI) | 45370 | ethyl (2S)-2-[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]-2-nitroethanoate | C14H15ClN6O4 | 详情 | 详情 | |
| (VII) | 45371 | 6-chloro-9-[(1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl]-9H-purin-2-ylamine; 6-chloro-9-[(1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl]-9H-purin-2-amine | C11H11ClN6O2 | 详情 | 详情 | |
| (VIII) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (IX) | 45372 | 2-(trimethylsilyl)ethyl 2-nitroacetate | C7H15NO4Si | 详情 | 详情 | |
| (X) | 45373 | 2-(trimethylsilyl)ethyl (2S)-2-[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]-2-nitroethanoate | C17H23ClN6O4Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The condensation of 6-chloropurine-2-amine (III) with the chiral monoacetate (II) (obtained by enzymatic desymmetrization of diacetate (I)) by means of Pd(PPh3)4 in DMSO gives the cyclopentenol derivative (IV), which is treated with dimethyl dicarbonate and DMAP in dichloromethane to yield the carbonate (V). The condensation of (V) with ethyl 2-nitroacetate (VI) by means of Pd in THF affords the adduct (VII), which is decarboxylated by means of NaCl in DMSO/water at 150 C to provide the nitromethylcyclopentene derivative (VIII). The reaction of (VIII) with tBuOK, O3 and NaBH4 in methanol gives the corresponding hydroxymethyl derivative (IX), which is finally hydrolyzed with NaOH in refluxing water to afford the target guanine as a racemic compound. Alternatively, the nitromethyl-cyclopentene derivative (VIII) can also be obtained by condensation of carbonate (V) with 2-(trimethylsilyl)ethyl 2-nitroacetate (X) by means of Pd in THF to give the adduct (XI), which is decarboxylated by means of CsF in hot acetonitrile, affording (VIII).
| 【1】 Peel, M.R.; et al.; A short, enantioselective synthesis of the carbocyclic nucleoside carbovir. J Org Chem 1991, 56, 16, 4990. |
| 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) | 45374 | (1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate | C9H12O4 | 详情 | 详情 | |
| (II) | 33169 | (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate | C7H10O3 | 详情 | 详情 | |
| (III) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (IV) | 45368 | (1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-ol | C10H10ClN5O | 详情 | 详情 | |
| (V) | 45369 | (1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl methyl carbonate | C12H12ClN5O3 | 详情 | 详情 | |
| (VI) | 15050 | ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester | 626-35-7 | C4H7NO4 | 详情 | 详情 |
| (VII) | 45370 | ethyl (2S)-2-[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]-2-nitroethanoate | C14H15ClN6O4 | 详情 | 详情 | |
| (VIII) | 45371 | 6-chloro-9-[(1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl]-9H-purin-2-ylamine; 6-chloro-9-[(1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl]-9H-purin-2-amine | C11H11ClN6O2 | 详情 | 详情 | |
| (IX) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (X) | 45372 | 2-(trimethylsilyl)ethyl 2-nitroacetate | C7H15NO4Si | 详情 | 详情 | |
| (XI) | 45373 | 2-(trimethylsilyl)ethyl (2S)-2-[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]-2-nitroethanoate | C17H23ClN6O4Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)L-697,661 was prepared via a convergent route: Formylation of 2-pentanone (I) with ethyl formate and sodium methoxide gave the ketoaldehyde sodium salt (II). When a mixture of anhydrous diethyl ether and absolute ethanol, 6:1 v/v, was used as solvent, the desired regioisomer precipitated out of solution. Treatment of ethyl nitroacetate (III) with ethanol saturated with ammonia provided nitroacetamide ammonium salt (IV). The nitroacetamide was then condensed with (II) in an aqueous solution of piperidinium acetate to afford the 3-nitropyridinone (V). Catalytic reduction of (V) provided the 3-aminopyridinone (VI). Treatment of chloroacetonitrile (VII) with hydrogen chloride and absolute ethanol gave ethyl chloroiminoacetate hydrochloride (VIII). Nitration of 2,4-dichlorophenol (IX), followed by catalytic reduction of the resultant product, led to the aminophenol (X). Coupling of (X) with (VIII) yielded the chloromethylbenzoxazole (XI), which was converted to the corresponding iodomethyl derivative (XII). Alkylation of the 3-aminopyridinone (VI) with the iodomethylbenzoxazole (XII) furnished L-697,661.
| 【1】 Saari, W.S.; Hoffman, J.M.; Wai, J.S.; et al.; 2-Pyridinone derivatives: A new class of nonnucleoside, HIV-1-specific reverse transcriptase inhibitors. J Med Chem 1991, 34, 9, 2922. |
| 【2】 Goldmann, M.E.; Wai, J.S.; L-697,661. Drugs Fut 1992, 17, 4, 283. |
| 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) | 15048 | 2-pentanone | 107-87-9 | C5H10O | 详情 | 详情 |
| (II) | 15049 | sodium (Z)-2-ethyl-3-oxo-1-buten-1-olate | C6H9NaO2 | 详情 | 详情 | |
| (III) | 15050 | ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester | 626-35-7 | C4H7NO4 | 详情 | 详情 |
| (IV) | 15051 | 1-Carbamoyl-1-nitromethanide ammonium salt | C2H7N3O3 | 详情 | 详情 | |
| (V) | 15052 | 5-ethyl-6-methyl-3-nitro-2(1H)-pyridinone | C8H10N2O3 | 详情 | 详情 | |
| (VI) | 15053 | 3-amino-5-ethyl-6-methyl-2(1H)-pyridinone | C8H12N2O | 详情 | 详情 | |
| (VII) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (VIII) | 15055 | 1-chloro-2-pentanimine hydrochloride | C5H11Cl2N | 详情 | 详情 | |
| (IX) | 11953 | 2,5-Dichlorophenol | 583-78-8 | C6H4Cl2O | 详情 | 详情 |
| (X) | 15057 | 2-amino-3,6-dichlorophenol | C6H5Cl2NO | 详情 | 详情 | |
| (XI) | 15058 | 4,7-dichloro-2-(chloromethyl)-1,3-benzoxazole | C8H4Cl3NO | 详情 | 详情 | |
| (XII) | 15059 | 4,7-dichloro-2-(iodomethyl)-1,3-benzoxazole | C8H4Cl2INO | 详情 | 详情 |