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With ammonia In isopropyl alcohol at 150℃; for 16 h; Sealed tube
Preparation 2. 6-Chloro-4,5-diamino-2-methylpyrimidine. A 200 mL stainless steel Parr vessel was loaded with 5-amino-4,6-dichloro-2-methylpyrimidine (7.2 g, 40 mmol) and 2 M ammonia in isopropanol (100 mL), and then was sealed and heated at 150° C. for 16 h. HPLC analysis indicated complete conversion. The mixture was concentrated in vacuo, and the residue was suspended in a mixture of H2O (10 mL) and isopropanol (35 mL). This was stirred at 50° C. for 1 h and then was cooled to room temperature. The precipitate was collected by suction filtration, washed sparingly with isopropanol, then air dried on the filter to afford 6-chloro-4,5-diamino-2-methylpyrimidine (5.8 g, 91percent) as a brown powder, which was used without further purification in the next step.
63%
With ammonia In water at 70 - 100℃;
Preparation 19; 6-Chloro-2-methyl-pyrimidine-4,5-diamine; 2-methyl-4,6-dichloro-5-aminopyrinnidine (2. g , 11.235 mmol) was suspended in 20 ml of 37percent aqueous ammonia. The mixture was shared between 4 high pressure vials and they were heated at 100°C for 10 min. The temperature was then reduced to 7O0C and maintained overnight. LCMS indicates 80percent conversion by TIC. Upon cooling the precipitated product was filtered and washed with water to yield the title product as a yellow solid (1.125g, 63percent): LCMS (System 2): 0.30 mins (2 min run) m/z (APCI) = 159 [MH+], m/z (ES) = 159 [MH+]
38%
With ammonia In ethanol at 160℃; for 4 h; Microwave irradiation
Dichloropyrimidine (compound 9, Scheme 1E) was subjected to nucleophilic displacement with 4-methoxy-N-methylaniline and a catalytic amount of concentrated HC1 in the presence of i-PrOH to afford compound 2, Section E. Compound 2, section E., was hydrogenated under Pd/C at 50 psi for 3 hours (h) to afford compound 3, Section E. The synthesis of compounds 4 and 5, Section E., used trialkylaluminium in the presence of Pd catalyst and THF under reflux conditions. Compound 7, Section E., was obtained from 2 using aqueous hydriodic acid at 0 °C-rt. Compound 7 was then heated at 120 °C in the presence of DMF and copper cyanide to yield compound 8, Section E. One of the chloro groups of compound 9, Section E, was substituted with the amino group under SNAr conditions with ethanolic ammonia to produce compound 10, Section E., which was then subjected to nucleophilic displacement with 4-methoxy-N-methylaniline and a catalytic amount of concentrated HC1 in the presence of butanol to afford compound 6, Section E.
Reference：
[1] Patent: US2011/54173, 2011, A1, . Location in patent: Page/Page column 21
[2] Patent: WO2009/144632, 2009, A1, . Location in patent: Page/Page column 62
[3] Patent: WO2016/22890, 2016, A1, . Location in patent: Page/Page column 64; 65
[4] Patent: WO2010/132598, 2010, A1, . Location in patent: Page/Page column 75
[5] Patent: WO2011/25505, 2011, A1, . Location in patent: Page/Page column 49
[6] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5188 - 5219
[7] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 4962 - 4966
[8] Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5722 - 5733
[9] Patent: WO2015/187684, 2015, A1, . Location in patent: Page/Page column 167
[10] Patent: WO2018/237145, 2018, A1, . Location in patent: Paragraph 0271
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