Substituted pyrido (2 , 3-d) pyrimidine derivatives useful as medicines for the treatment of autoimmune disorders
A technology of pyrimidine derivatives and derivatives, applied in the field of trisubstituted pyridopyrimidine derivatives, which can solve the problem of few drugs for cachexia
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Embodiment 1
[0183] Example 1: Synthesis of 2-amino-4-isopropoxy-6-bromo-pyrido[2,3-d]pyrimidine
[0184] Sodium (65 mg, 2.82 mmol) was dissolved in isopropanol (30 mL) at 60°C, and 2-pivaloylamino-4-isopropoxy-6-bromo-pyrido[2,3 -d] Pyrimidine (2.56 mmol, 940 mg) (prepared and characterized eg as described by Taylor et al. in Heterocycles (1993) 36:1889). The reaction mixture was stirred at 70°C for 6 hours, then acidified with acetic acid (160 μl) and extracted with dichloromethane. The organic layer was evaporated in vacuo, and the residue was purified by silica gel column chromatography, wherein the mobile phase was CH 3 OH / CH 2 Cl 2 The composition of the mixture (the ratio was gradually changed from 1:99 to 4:96), the pure title compound (515 mg, yield 71%) was obtained, and the mass spectrum of the compound was characterized as follows: MS (m / z): 305, 307 ( [M+Na] + , 45), 283, 285 ([M+H] + , 60), 241, 243 ([M+H-propylene) + , 100).
Embodiment 2
[0185] Example 2: Synthesis of 2-amino-4-isopropoxy-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine
[0186] To a solution of 2-amino-4-isopropoxy-6-bromo-pyrido[2,3-d]pyrimidine (0.7 mmol, 199 mg) in THF (15 mL) was added 3,4-bis Methoxyphenylboronic acid (192 mg, 1.054 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0352 mmol, 41 mg) and 15 mL of 0.4M Na 2 CO 3 aqueous solution. The reaction mixture was refluxed for 16 hours. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography, wherein the mobile phase was CH 3 OH / CH 2 Cl 2 The composition of the mixture (the ratio was gradually changed from 1:99 to 3:97), the pure title compound (98 mg, yield 41%) was obtained, and the mass spectrum of the compound was characterized as follows: MS (m / z): 703 ([2M +Na] + , 100), 363([M+Na] + , 25), 341([M+H] + , 100), 299 ([M+H-propylene] + , 90).
Embodiment 3
[0187] Example 3: 2-pivaloylamino-4-morpholino-6-bromo-pyrido[2,3-d]pyrimidine
[0188] To 2-pivaloylamino-4-(1,2,4-triazolyl)-6-bromo-pyrido[2,3-d]pyrimidine (1.77 g, 4.71 mmol) (e.g. according to Taylor et al. Morpholine (492 μl, 5.65 mmol) was added to a suspension in 1,4-dioxane (100 ml) as described in Heterocycles (1993) 36:1889 (prepared and characterized). After 1 hour, the suspension became a yellow solution and stirring was continued overnight at room temperature. Water was added to the reaction mixture, which was extracted with dichloromethane (3 times). The organic layer was evaporated in vacuo, and the crude product was purified by silica gel column chromatography, wherein the mobile phase was CH 3 OH / CH 2 Cl 2 Composition of the mixture (the ratio gradually changed from 3:97 to 6:94), the title compound (1.37 g, yield 74%) was obtained as a white powder, and the mass spectrometry of the compound was characterized as follows: MS (m / z): 393,395 ([M+H] + , 100...
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