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【结 构 式】 
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【药物名称】RPR-100579, AMP-579 【化学名称】(1S,2R,3S,4R)-4-[7-[1(R)-(3-Chloro-2-thienylmethyl)propylamino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-1-carboxamide 【CA登记号】143395-98-6, 213453-89-5 (error in CA) 【 分 子 式 】C22H28ClN5O3S 【 分 子 量 】478.01716 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Acute Myocardial Infarction, Treatment of, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Adenosine A1 Agonists, Adenosine A2A Agonists |
合成路线1
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
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
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 |
合成路线4
An efficient synthesis of AMP-579 has been reported: Reaction of the chiral amine (I) with tosyl chloride and NaOH in methyl tert-butyl ether (MTBE) gives the tosyl aziridine (II), which is condensed with 3-chlorothiophene (III) by means of n-BuLi to yield the tosyl amide (IV). Condensation of amide (IV) with 2,4-difluoro-3-nitropyridine (V) obtained by reaction of 2,4-dichloro-3-nitropyridine (VI) with KF and 18-crown-6 (18-C-6) in hot 1-methyl-2-pyrrolidinone (NMP) by means of t-BuOK in THF affords the disubstituted tosyl amide (VII). Condensation of compound (VII) with the cyclopentanecarboxamide (VIII) by means of K2CO3 in NMP provides the corresponding adduct (IX), which is hydrogenated with H2 over Pt in methanol/ethyl acetate to give the aminopyridine (X). Cyclization of (X) with HC(OEt)3 by means of hot Ac2O yields the imidazopyridine (XI), which is detosylated with Mg in MeOH or LiEt3BH in THF to afford the protected deazapurine (XII). Finally, the acetonide group of (XII) is eliminated by treatment with concentrated HCl in THF.
| 【1】 O'Brien, M.K.; Powner, T.H.; Truesdale, L.K.; Kubiak, G.G.; Sledeski, A.W.; Powers, M.R.; Efficient synthesis of AMP579, a novel adenosine A1/A2 receptor agonist. J Org Chem 2000, 65, 23, 8114. |
| 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) | 48572 | (S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol | 5856-62-2 | C4H11NO | 详情 | 详情 |
| (II) | 48573 | (2R)-2-ethyl-1-[(4-methylphenyl)sulfonyl]aziridine | C11H15NO2S | 详情 | 详情 | |
| (III) | 48574 | 3-Chlorothiophene; 3-Thienyl chloride | 17249-80-8 | C4H3ClS | 详情 | 详情 |
| (IV) | 48575 | N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]-4-methylbenzenesulfonamide | C15H18ClNO2S2 | 详情 | 详情 | |
| (V) | 48576 | 2,4-difluoro-3-nitropyridine | C5H2F2N2O2 | 详情 | 详情 | |
| (VI) | 23847 | 2,4-dichloro-3-nitropyridine | C5H2Cl2N2O2 | 详情 | 详情 | |
| (VII) | 48577 | N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]-N-(2-fluoro-3-nitro-4-pyridinyl)-4-methylbenzenesulfonamide | C20H19ClFN3O4S2 | 详情 | 详情 | |
| (VIII) | 48578 | (3aS,4R,6S,6aR)-6-[(ethylamino)carbonyl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-aminium benzoate | C18H26N2O5 | 详情 | 详情 | |
| (IX) | 48579 | (3aR,4S,6R,6aS)-6-[(4-[[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl][(4-methylphenyl)sulfonyl]amino]-3-nitro-2-pyridinyl)amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C31H38ClN5O7S2 | 详情 | 详情 | |
| (X) | 48580 | (3aR,4S,6R,6aS)-6-[(3-amino-4-[[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl][(4-methylphenyl)sulfonyl]amino]-2-pyridinyl)amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C31H40ClN5O5S2 | 详情 | 详情 | |
| (XI) | 48581 | (3aR,4S,6R,6aS)-6-(7-[[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl][(4-methylphenyl)sulfonyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl)-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C32H38ClN5O5S2 | 详情 | 详情 | |
| (XII) | 48582 | (3aR,4S,6R,6aS)-6-[7-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C25H32ClN5O3S | 详情 | 详情 |