Ethyl 2-(n-Butylamino)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

Ethyl 2-cyano-3,3-bis(methylthio)acrylate 1 [1] (3.255 g; 15.0 mmol) was dissolved in anhydrous ethanol (100 mL), n-butylamine (1.100 g; 15.0 mmol) was added and the solution was heated to reflux for 2 h in a flask equipped with a gas outlet to remove the evolving methanethiol (hood). The reaction mixture was evaporated and the product (2, 3.59 g, 99 %) was obtained as a yellowish oil. Tlc (light petroleum : ethyl acetate 8 : 2): single spot (R_f 0.67). ¹H NMR (200 MHz, CDCl₃): 0.97 (t, J 7.0 Hz, 3 H, CH₃CH₂O); 1.29-1.46 (m, 4 H, 2 x CH₂); 1.63 (t, J 7.4 Hz, 3 H, CH₃); 2.70 (s, 3 H, SCH₃); 3.53 (m, 2 H, CH₂); 4.23 (q, J 7.0 Hz, 2 H, CH₃CH₂O); 10.08 (br s, 1 H, NH). This intermediate (ethyl 2-cyano-3-n-butylamino-3-methylthioacrylate, 2) was again dissolved in anhydrous ethanol (100 mL), hydrazine hydrate (0.74 mL; 15.0 mmol) was added and the solution was heated to reflux for 3 h (hood). The reaction mixture was evaporated and the resulting oil was triturated with hexane. After the ensuing crystallization, filtration, and washing with hexane, the product (ethyl 5-amino-3-n-butylamino-1H-pyrazole-4-carboxylate, 3) was obtained (3.235 g; 97 %) as white crystals, mp. 103-104 °C. Tlc (CHCl₃ : MeOH 9 : 1): single spot (R_f 0.42). Compound 3 (3.215 g, 14.21 mmol) was dissolved in glacial acetic acid (5 mL), a solution of ethyl acetoacetate (1.811 mL, 14.21 mmol) in glacial acetic acid (2 mL) was added and the reaction mixture was heated to reflux for 3 h. The solution was placed in a refrigerator for 16 h. The crystals formed were filtered off and washed with ethanol (10 mL) to give the title compound 4 (2.88 g, 69 %). From the mother liquor further crops were obtained, altogether 3.619 g (87 %).

Yield: 84 % (over 3 steps).

R_f = 0.65 (CH₂Cl₂ : MeOH = 9 : 1).

Mp. 189-190 ^-C.

Solubility: in water: 0.23 mg/mL (25 ^-C), 1.45 mg/mL (100 ^-C); in 40 % aq. DMF: 2.8 mg/mL (25 ^-C).

¹H NMR (DMSO-d₆, 500 MHz, for numbering see the figure): 0.90 (t, J 7.4 Hz, 3 H, CH₃); 1.30 (t, J 7.0 Hz, 3 H, CH₃CH₂O); 1.35 (m, 2 H, CH₂); 1.56 (m, 2 H, CH₂); 2.33 (s, 3 H, 5-CH₃); 3.25 (t, J 6.6 Hz, 2 H, NHCH₂); 4.30 (q, J 7.0 Hz, 2 H, CH₃CH₂O); 5.71 (s, 1 H, H-6); 5.79 (t, J 5.8 Hz, deut. with D₂O, 1H, NH); 11.15 (s, deut. with D₂O, 1 H, OH).

¹³C NMR (DMSO-d₆, 125 MHz, assignment based on a HMBC experiment [2,3]): 13.93 (aliph. CH₃); 14.74 (aliph. CH₃); 18.98 (5-CH₃); 19.83 (CH₂); 31.26 (CH₂); 41.69 (NCH₂); 59.92 (OCH₂); 83.07 (C-5); 99.66 (C-6); 143.76; 149.70; 155.08; 156.86 (C-2, C-3, C-3a, C-7); 163.07 (COO).

APCI-MS (isobutane, m/z): 293 ([M+H]⁺).

Anal calcd. for C₁₄H₂₀N₄O₃ (292.334): N, 19.17; found N 19.17 %.