Synthesis for heteroarylamine compounds

#This invention relates to the synthesis of heteroarylamine compounds which are useful in the production of heteroaryl ureas a key component in pharmaceutically active compounds possessing a heteroaryl urea group.

#Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production. These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory and autoimmune diseases. Examples of such compounds are reported in WO 99/23091 and in WO 98/52558.

#A key step in the synthesis of these compounds is the formation of the urea bond. Various methods have been reported to accomplish this. For example, as reported in the above references, an aromatic or heteroaromatic amine, Ar1NH2, may be reacted with an aromatic or heteroaromatic isocyanate, Ar2NCO, to generate the urea Ar1HC(O)NHAr2.

#Preparation of chloride: A solution of alcohol shown above (18.0 g, 100 mmol) in 200 mL of CH2Cl2 was prepared and cooled in an ice-water bath. A solution of SOCl2 (22 mL, 300 mmol) in 100 mL of CH2Cl2 was added to the above solution at the rate to keep the internal temperature below 10° C. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature over 2 h. The reaction mixture was evaporated to remove all volatile by rotavap. The residue was dissolved in 150 mL of CH2Cl2 and saturated sodium bicarbonate solution was added until pH=9. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated to give 20.0 g (100%) of the desired chloride. 1H NMR (CDCL3): δ9.15 (s, 1H), 8.33 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz), 4.73 (s, 2H), 4.42 (q, J=7 Hz, 2H), 1.42 (t, J=7 Hz, 3H).

#Preparation of morpholine moiety: A solution of chloride from Example 1 above (20 g, 100 mmol) and triethylamine (15.2 g, 150 mmol) in 125 mL of CH2Cl2 was prepared. 11 g (126 mmol) of morpholine was added and the reaction mixture was stirred at room temperature overnight (18 h). 100 mL of saturated sodium bicarbonate solution was added. The aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried (MgSO4) and concentrated to give 24.3 g (97%) of desired product. 1H NMR (CDCL3): δ9.15 (s, 1H), 8.25 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 4.40 (q, J=7 Hz, 2H), 3.73 (m, 6H), 2.51 (t, J=4 Hz, 4H), 1.40 (t, J=7 Hz, 3H).

#Diester (2). To a mixture of ester 1 (10.0 g, 40 mmol), diethyl succinate (7.0 g, 40 mmol) and sodium hydride (60% dispersion in mineral oil, 3.20 g, 80 mmol) in dry THF (200 ml) was added DMPU (20 ml) and methanol (0.10 ml) and the mixture was refluxed for 2.5 h. Additional diethyl succinate (10.50 g, 60 mmol) and sodium hydride (4.80 g, 120 mmol) were added in five equal portions to the refluxing reaction mixture at 0.75 h intervals. Refluxing was continued for additional 1.5 h. The cooled reaction mixture was poured into a stirring mixture of 2N HCl (200 ml) and ethyl acetate (200 ml). The aqueous phase was separated, the pH was adjusted to 8.5 with saturated sodium bicarbonate and it was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. Evaporation of ethyl acetate gave almost pure 2 as yellowish brown oil (10.65 g, 70.4%). 1H NMR (CDCl3) δ1.16 (t, J-=7.2 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H), 2.51-2.53 (m, 4H), 3.02-3.20 (m, 2H), 3.72-3.75 (m, 6H), 4.10-4.15 (m, 4H), 4.78-4.80 (m, 1H), 7.58 (d, J=8.0 Hz, 1H), 8.27 (d, J=6.0 Hz, 1H), and 9.18 (d, J=2.1 Hz, 1H).