吡唑并[1,5-a]嘧啶化合物的常见合成方法

吡唑并嘧啶是一类非常重要的稠杂环，此类化合物具有广泛的生物活性，如抗肿瘤性，多巴胺受体拮抗剂，P38激酶抑制剂等等。

一、3-氨基吡唑和丙二酸酯反应

1. 乙醇钠作用下反应【WO2011/2887; (2011); (A1) English】

To 1H-pyrazol-3-amine (12.3 g, 148.0 mmol) in EtOH (50 mL) was added diethyl malonate (25.0 mL, 164.7 mmol), 21 wt percent NaOEt in EtOH (110 mL, 294.6

mmol) and additional EtOH (50 mL). The resulting reaction mixture was then heated at 80oC under an atmosphere of argon for 16 hours, at which time the reaction was allowed to cool to room temperature. The reaction mixture was

then concentrated in vacuo until almost dry, before H2O (500 mL) was added. Vigorous stirring aided the dissolution of solids, at which time cone. HCl was added until pH~2 was attained (precipitate formed). The precipitate was collected and dried by vacuum filtration giving pyrazolo[l,5-a]pyrimidine-5,7-diol (Int-9a) as a tan solid (17.13 g, 113.4mmol, 77percent).

2. 三丁胺条件下neat反应【US2005/187224;(2005); (A1) English】

With stirring, a mixture of 14.15 g (0.071 mol) of dimethyl cyclopentylmalonate (WO2004/006926), 10 g (0.071mol) of methyl 5-amino-1H-pyrazole-3-carboxylate and 14.4 g (0.078 mol) of tri-n-butylamine was heated at 180° C.

for 6 hours.The methanol released during the reaction was continuously distilled off.The reaction mixture was then concentrated under reduced pressure.

This gave 19.7 g (100percent of theory) of methyl 5,7-dihydroxy-6-cyclopentylpyrazolo[1,5-a]pyrimidine-3-carboxylate. The product was used for further syntheses without additional purification.

二、丙二酸先和3-氨基吡唑形成酰胺后再进行关环反应。

1. DMAP条件下【WO2011/105628; (2011); (A1) English】

To a suspention of ethyl 5-[(3-ethoxy-3-oxopropanoyl)amino]-lH-pyrazole-3- carboxylate (2.60 g, 9.66 mmol) in ethanol (50 mL) and water (50 mL) was added N,N-dimethylaminopyridine (3.54 g, 29.0 mmol) at room temperature.

After being stirred for 22 h, the reaction mixture was concentrated in vacuo. The residue was triturated with ethyl acetate/ethanol to give ethyl 5,7-dihydroxypyrazolo[l,5- a]pyrimidine-2-carboxylate. MS (APCI): m/z 224 (M+H),

123 (M+H, DMAP).

2. 甲醇钠条件下【US2011/294781; (2011); (A1) English】

To a solution of the compound (2.3 g, 6.8 mM) prepared in the preceding step 2 in ethanol (50 mL), there was added a 28percent methanol solution of sodium methoxide (3 mL, 15 mM) and the mixture was stirred at 70° C. for one hour.

After cooling the mixture to room temperature, the precipitated solid was filtered and then washed with ethanol to thus give a crude product in the form of a bis-sodium salt thereof.

下面为氯化

To the crude product, there were added phosphorus oxychloride (10 mL) and pyridine (0.6 mL) and the mixture was stirred at 90° C. for 5 hours.

After cooling the mixture to room temperature, it was concentrated under reduced pressure and the concentrate was neutralized with a saturated aqueous sodium bicarbonate solution.The neutralized concentrate was extracted with dichloromethane, the resulting organic phase was dried over anhydrous

magnesium sulfate, then concentrated under reduced pressure and thereafter the resulting residue was purified by the silica gel column chromatography (SiO2, methanol: dichloromethane=1:9) to thus give the title compound (633 mg, overall yield of these two steps: 34percentpercent).

1H-NMR (300 MHz, DMSO): δ 1.66 (6H, br), 3.40-3.42 (4H, m), 5.94 (1H, s), 6.65 (1H, s) MS (ESI) m/z (M+H)+ 271

3. 3-氨基吡唑和丙二酰氯反应【US2011/294781; (2011); (A1) English】

:There was dissolved, in tetrahydrofuran (4 mL), 3-amino-4-phenyl-pyrazole (208 mg, 1.31 mM), then malonyl chloride (153 μL, 1.57 mM) was added to the solution with ice-cooling and the mixture was stirred at room temperature

for 30 minutes. To the reaction solution, there was added malonyl chloride (15 μL, 0.16 mM) and the mixture was further stirred at room temperature for 30 minutes. This reaction liquid was diluted with a 1M aqueous sodium hydroxide solution, washed with ethyl acetate, the aqueous phase was acidified (pH 2) by the addition of hydrochloric acid and then it was extracted with ethyl acetate.

The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was then distilled off and the resulting solid was washed with diethyl ether.

氯化

Phosphoryl chloride (4 mL) was added to the resulting solid with ice-cooling, and then the resulting suspension was stirred for 6 hours while refluxing the same with heating. The phosphoryl chloride was distilled off from the reaction liquid, ethanol was added to the resulting residue with ice-cooling and the mixture was stirred for 15 minutes. After the reaction liquid was concentrated, the concentrate was diluted with water and then extracted with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:10) to thus give the title compound (47.7 mg, overall yield of these two steps: 14percent).

1H-NMR (300 MHz, CDCl3): δ 7/01 (s, 1H), 7.32 (m, 1H), 7.44-7.49 (m, 2H), 7.97-8.00 (m, 2H), 8.53 (s, H); MS (ESI)m/z 264 (M+H)+.

三、也有文献报道3-氨基吡唑和丙二酸酯在醋酸中加热反应制备产物。

With acetic acid, Time= 3h, Heating

Ammar; Saleh; Micky; Abbas; El-Gaby; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 43; nb. 10; (2004); p. 2203 - 2211。

（印度的，你懂得，有兴趣可以试试）