【结 构 式】 |
【分子编号】17646 【品名】2-amino-4,6-dichloro-5-pyrimidinylformamide 【CA登记号】 |
【 分 子 式 】C5H4Cl2N4O 【 分 子 量 】207.01852 【元素组成】C 29.01% H 1.95% Cl 34.25% N 27.06% O 7.73% |
合成路线1
该中间体在本合成路线中的序号:(V)1) The reaction of 4,6-dihydroxypyrimidine-2,5-diamine (I) with (chloromethylene)dimethylammonium chloride (II) in refluxing chloroform gives 4,6-dichloro-2,5-bis(dimethylaminomethyleneamino)pyrimidine (III), which by reaction with aqueous HCl in hot ethanol yields monoamine (IV). The reaction of (IV) with a refluxing phosphate buffer (pH 3.2) affords N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (V). The condensation of (V) with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) (which was obtained by optical resolution of the cis-racemate (VII) with D-dibenzoyltartaric acid, and elimination of the acid with ion exchange resin Amberlite IA-400, by means of triethylamine and NaOH in refluxing ethanol) gives N-[2-amino-4-chloro-6-[4(S)-(hydroxymethyl)-2-cyclopenten-1(R)-ylamino]pyrimidin-5-yl]formamide (VIII). The cyclization of (VIII) with refluxing diethoxymethyl acetate or triethyl orthoformate yields the corresponding purine derivative (IX), which is finally treated with cyclopropylamine (X) in refluxing n-butanol. 2) The formylation of N-(5-amino-4,6-dichloropyrimidin-2-yl)acetamide (XI) with 95% formic acid in acetic anhydride gives the expected formamide (XII), which is condensed with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) by means of triethylamine in hot ethanol to yield the substituted pyrimidine (XIII). Finally, the cyclization of (XIII) with diethoxymethyl acetate as before affords the purine intermediate (IX).
【1】 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167. |
【2】 Daluge, S.M. (Glaxo Wellcome plc); Therapeutic nucleosides. EP 0434450; JP 1996092252; JP 1999158160; JP 1999343292 . |
【3】 Daluge, S.M. (Glaxo Wellcome plc); Therapeutic nucleosides. AU 8937025; EP 0349242; JP 1990045486; JP 1999139976; US 5034394; US 5089500 . |
【4】 Daluge, S.M.; Martin, M.T.; Fugett, M.J.F.; Chloropyrimide intermediates. WO 9521161 . |
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) | 17642 | 2,5-diamino-4,6-pyrimidinediol | C4H6N4O2 | 详情 | 详情 | |
(II) | 17643 | (Chloromethylene)dimethylammonium chloride; N-(chloromethylene)-N-methylmethanaminium chloride | 3724-43-4 | C3H7Cl2N | 详情 | 详情 |
(III) | 17644 | N'-(4,6-dichloro-2-[[(E)-(dimethylamino)methylidene]amino]-5-pyrimidinyl)-N,N-dimethyliminoformamide | C10H14Cl2N6 | 详情 | 详情 | |
(IV) | 17645 | N'-(2-amino-4,6-dichloro-5-pyrimidinyl)-N,N-dimethyliminoformamide | C7H9Cl2N5 | 详情 | 详情 | |
(V) | 17646 | 2-amino-4,6-dichloro-5-pyrimidinylformamide | C5H4Cl2N4O | 详情 | 详情 | |
(VI) | 17647 | [(1S,4R)-4-amino-2-cyclopenten-1-yl]methanol | C6H11NO | 详情 | 详情 | |
(VII) | 63843 | (rac)-[(1R*,4S*)-4-amino-2-cyclopenten-1-yl]methanol | C6H11NO | 详情 | 详情 | |
(VIII) | 17649 | 2-amino-4-chloro-6-[[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-5-pyrimidinylformamide | C11H14ClN5O2 | 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) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
(XI) | 17652 | N-(5-amino-4,6-dichloro-2-pyrimidinyl)acetamide | C6H6Cl2N4O | 详情 | 详情 | |
(XII) | 17653 | N-[4,6-dichloro-5-(formylamino)-2-pyrimidinyl]acetamide | C7H6Cl2N4O2 | 详情 | 详情 | |
(XIII) | 17654 | N-(4-chloro-5-(formylamino)-6-[[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-2-pyrimidinyl)acetamide | C13H16ClN5O3 | 详情 | 详情 |