HCID 59507518, compound → HCID 178494244, compound

Participants

Reaction Conditions

Reaction Steps

A mixture of tert-butyl 4-(6-chloro-2-morpholinopyrimidin-4-yloxy)piperidine-1-carboxylate (500 mg, 1.26 mmol), 4-methoxy-2-aminopyrimidyl boronate ester (prepared as in Method 8, 630 mg, 2.51 mmol) and Pd(dppf)Cl2—CH2Cl2 (51 mg, 0.063 mmol) in dimethoxyethane and 2 M Na2CO3 (3:1, 12 mL) was heated under microwave irradiation for 15 minutes at 120° C. The reaction mixture was partitioned between EtOAc (200 mL) and Na2CO3(sat.) (50 mL), the organic layer was separated and washed with brine (50 mL). The combined aqueous layers were extracted further with EtOAc (2×100 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated. To this material was added 4 M HCl/dioxane (20 mL) to remove the Boc group. After standing for 12 hours, the volatiles were removed in vacuo, and the residue was partitioned between CH2Cl2 (200 mL) and 1N NaOH (50 mL). Upon separating, the aqueous layer was extracted further with CH2Cl2 (200 mL) and then CHCl3 (2×150 mL). The combined organic layers were concentrated yielding 1,6-dihydro-6-methoxy-5-(2-morpholino-6-(piperidin-4-yloxy)pyrimidin-4-yl)pyrimidin-2-amine (464 mg). The crude compound and morpholine (0.9 mL, 10.45 mmol) in NMP (10 mL) were heated under microwave irradiation for 15 minutes at 200° C. to convert the methoxy pyrimidine to the pyrimidone. Additional morpholine (0.9 mL, 10.45 mmol) was added and the solution was heated under microwave irradiation for 15 minutes and than 10 minutes at 200° C. Upon cooling the material was directly purified by reverse-phase HPLC. After lyophilization, the bis TFA salt of the 2-amino-5-(2-morpholino-6-(piperidin-4-yloxy)pyrimidin-4-yl)pyrimidin-4(3H)-one was isolated as an off-white solid (325 mg, 45%). LCMS (m/z): 374.1 (MH+). The title compound was prepared by acylation of the secondary amino group as shown in Example 19, step 4. LCMS (m/z): 416.0 (MH+), Rt 1.67.

Provenance & Evidence