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【结 构 式】 
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【分子编号】23850 【品名】(3aR,4S,6R,6aS)-6-amino-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide 【CA登记号】 |
【 分 子 式 】C11H20N2O3 【 分 子 量 】228.29148 【元素组成】C 57.87% H 8.83% N 12.27% O 21.02% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of 2,4-dichloro-3-nitropyridine (I) with the thiophene derivative (II) by means of triethylamine in refluxing ethanol gives the 4-pyridylamino derivative (III), which is allowed to react with the isopropylidenedioxycyclopentanecarboxamide derivative (IV) by means of triethylamine in refluxing nitromethane yielding the pyridine-2,4-diamine derivative (V). The reduction of the niutro group of (V) with H2 over Pd/C in ethanol affords the pyridine-2,3,4-triamine compound (VI), which is finally cyclocondensed with formamidine (VII) acetate in refluxing methoxyethanol and deprotected with hot aqueous formic acid to give the target compound.
| 【1】 Martín, L.; Leeson, P.A.; Castañer, J.; Sorbera, L.A.; AMP-579. Drugs Fut 2000, 25, 9, 900. |
| 【2】 Spada, A.P.; Fink, C.A.; Myers, M.R. (Aventis Pharma SA); Cpds. having antihypertensive, cardioprotective, a. EP 0758897; EP 1006115; JP 1997512020; US 5561134; WO 9528160 . |
| 【3】 Spada, A.P.; Fink, C.A.; Myers, M.R. (Aventis Pharma SA); Cpds. having antihypertensive and anti-ischemic pr. EP 0550631; JP 1993508864; US 5217982; US 5364862; WO 9205177 . |
| 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) | 23847 | 2,4-dichloro-3-nitropyridine | C5H2Cl2N2O2 | 详情 | 详情 | |
| (II) | 23848 | (2R)-1-(3-chloro-2-thienyl)-2-butanamine; (1R)-1-[(3-chloro-2-thienyl)methyl]propylamine | C8H12ClNS | 详情 | 详情 | |
| (III) | 23849 | N-(2-chloro-3-nitro-4-pyridinyl)-N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amine; 2-chloro-N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine | C13H13Cl2N3O2S | 详情 | 详情 | |
| (IV) | 23850 | (3aR,4S,6R,6aS)-6-amino-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C11H20N2O3 | 详情 | 详情 | |
| (V) | 23851 | (3aR,4S,6R,6aS)-6-[[4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-3-nitro-2-pyridinyl]amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C24H32ClN5O5S | 详情 | 详情 | |
| (VI) | 23852 | (3aR,4S,6R,6aS)-6-[[3-amino-4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-2-pyridinyl]amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C24H34ClN5O3S | 详情 | 详情 | |
| (VII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Reaction of 5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-one (VIII) with 2,2-dimethoxypropane (A) and TsOH in acetone gives the acetonide (IX), which is treated with ethylamine at 140 C, followed by optical resolution with di-O-benzoyl-D-tartaric acid, yielding the chiral cyclopentanecarboxamide (IV).
| 【1】 Martín, L.; Leeson, P.A.; Castañer, J.; Sorbera, L.A.; AMP-579. Drugs Fut 2000, 25, 9, 900. |
| 【2】 Spada, A.P.; Fink, C.A.; Myers, M.R. (Aventis Pharma SA); Cpds. having antihypertensive, cardioprotective, a. EP 0758897; EP 1006115; JP 1997512020; US 5561134; WO 9528160 . |
| 【3】 Spada, A.P.; Fink, C.A.; Myers, M.R. (Aventis Pharma SA); Cpds. having antihypertensive and anti-ischemic pr. EP 0550631; JP 1993508864; US 5217982; US 5364862; WO 9205177 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 23850 | (3aR,4S,6R,6aS)-6-amino-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C11H20N2O3 | 详情 | 详情 | |
| (VIII) | 40487 | (1R,4S,5R,6S)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-one | C6H9NO3 | 详情 | 详情 | |
| (IX) | 40488 | (1S,2R,6S,7R)-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.0(2,6)]decan-9-one | C9H13NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Reaction of 2-hydroxy-4-methoxypyridine-3-carbonitrile (X) with 85% phosphoric acid at 180 C gives 2,4-dihydroxypyridine (XI), which is nitrated with HNO3 in hot acetic acid to yield 2,4-dihydroxy-3-nitropyridine (XII). The reaction of (XII) with POCl3 in hot toluene affords 4-chloro-3-nitropyridin-2(1H)-one (XIII), which is condensed with the previously described amine (II) by means of DIEA in isopropanol to afford the aminopyridinol (XIV). Chlorination of (XIV) with POCl3 in toluene gives the previously described 4-amino-2-chloro-3-nitropyridine derivative (III), which is condensed with the described cyclopentanecarboxamide (IV) by means of K2CO3 in toluene, yielding the already known 2,4-diamino-3-nitropyridine (V). The reduction of (V) with ammonium formate over Pt/C or with Zn and ammonium acetate affords the described 2,3,4-triaminopyridine (VI), which is treated with HCl in THF in order to eliminate the acetonide group, providing the deprotected triaminopyridine derivative (XV). Finally, this compound is cyclized with formamidine (VII), triethyl orthoformate (XVI) or dimethylformamide dimethylacetal (XVII) in a suitable solvent.
| 【1】 Martín, L.; Leeson, P.A.; Castañer, J.; Sorbera, L.A.; AMP-579. Drugs Fut 2000, 25, 9, 900. |
| 【2】 Reilly, L.W.; Vanasse, B.J.; Garcia, H.; Shah, H.C.; Leon, P.; O'Brien, M.K.; Walther, F.L.; Powner, T.H.; Tsuei, C.T.; Thompson, M.D. (Aventis Pharmaceuticals, Inc.); Preparation of [1S-[1a,2b,3b,4a(S*)]]-4-[7-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]N-ethyl-2,3-dihydroxycyclopentanecarboxamide. WO 9825921 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 23849 | N-(2-chloro-3-nitro-4-pyridinyl)-N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amine; 2-chloro-N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine | C13H13Cl2N3O2S | 详情 | 详情 | |
| (IV) | 23850 | (3aR,4S,6R,6aS)-6-amino-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C11H20N2O3 | 详情 | 详情 | |
| (V) | 23851 | (3aR,4S,6R,6aS)-6-[[4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-3-nitro-2-pyridinyl]amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C24H32ClN5O5S | 详情 | 详情 | |
| (VI) | 23848 | (2R)-1-(3-chloro-2-thienyl)-2-butanamine; (1R)-1-[(3-chloro-2-thienyl)methyl]propylamine | C8H12ClNS | 详情 | 详情 | |
| (VI) | 23852 | (3aR,4S,6R,6aS)-6-[[3-amino-4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-2-pyridinyl]amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C24H34ClN5O3S | 详情 | 详情 | |
| (VII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (X) | 40489 | 2-hydroxy-4-methoxynicotinonitrile | C7H6N2O2 | 详情 | 详情 | |
| (XI) | 34269 | 2,4-pyridinediol | 626-03-9 | C5H5NO2 | 详情 | 详情 |
| (XII) | 40490 | 3-nitro-2,4-pyridinediol | 89282-12-2 | C5H4N2O4 | 详情 | 详情 |
| (XIII) | 40491 | 4-chloro-3-nitro-2(1H)-pyridinone | C5H3ClN2O3 | 详情 | 详情 | |
| (XIV) | 40492 | 4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-3-nitro-2-pyridinol | C13H14ClN3O3S | 详情 | 详情 | |
| (XV) | 40493 | (1S,2R,3S,4R)-4-[[3-amino-4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-2-pyridinyl]amino]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide | C21H30ClN5O3S | 详情 | 详情 | |
| (XVI) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (XVII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |