morpholin-3-ylmethanol;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,4,6-trichloro-5-methoxy-pyrimidine (1 g, 4.68 mmol), morpholin-3-yl-methanol hydrochloride (0.86 g, 5.6 mmol) and triethylamine (0.9 mL, 6.5 mmol) in IMS (30 mL) was stirred at RT for 3 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording [4-(2,6-Dichloro-5-methoxy-pyrimidin-4-yl)-morpholin-3-yl]-methanol (614 mg, 45%). LCMS (method A): RT=2.63 min, [M+H]+=294/296. concentrated in vacuo The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.74 g, 1.3 mmol) was reacted with morpholin-3-ylmethanol hydrochloride (0.23 g, 1.5 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.34 g, 43%). The compound was characterized by the following spectroscopic data:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.74 g, 1.3 mmol) was reacted with morpholin-3-ylmethanol hydrochloride (0.23 g, 1.5 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.34 g, 43%). The compound was characterized by the following spectroscopic data:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methoxythiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.53 g, 1 mmol) was reacted with morpholin-3-ylmethanol hydrochloride (0.18 g, 1.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.27 g, 48%). The compound was characterized by the following spectroscopic data:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,4,6-trichloro-5-methoxy-pyrimidine (1 g, 4.68 mmol), morpholin-3-yl-methanol hydrochloride (0.86 g, 5.6 mmol) and triethylamine (0.9 mL, 6.5 mmol) in IMS (30 mL) was stirred at RT for 3 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording [4-(2,6-Dichloro-5-methoxy-pyrimidin-4-yl)-morpholin-3-yl]-methanol (614 mg, 45%). LCMS (method A): RT=2.63 min, [M+H]+=294/296. concentrated in vacuo The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,4,6-trichloro-5-methoxy-pyrimidine (1 g, 4.68 mmol), morpholin-3-yl-methanol hydrochloride (0.86 g, 5.6 mmol) and triethylamine (0.9 mL, 6.5 mmol) in IMS (30 mL) was stirred at RT for 3 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording [4-(2,6-Dichloro-5-methoxy-pyrimidin-4-yl)-morpholin-3-yl]-methanol (614 mg, 45%). LCMS (method A): RT=2.63 min, [M+H]+=294/296. concentrated in vacuo The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2,6-dichloropyrimidine-4-carboxamide (0.384 g, 2.00 mmol) in acetonitrile (10 mL) was added morpholin-3-ylmethanol hydrochloride (0.310 g, 2.02 mmol) and iPr2NEt (0.77 mL, 4.4 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 25-75% acetone in hexanes. The product fractions were evaporated in vacuo to yield 2-chloro-6-(3-(hydroxymethyl)morpholino)pyrimidine-4-carboxamide as a pale tan solid (0.501 g, 1.84 mmol, 92% yield). LC/MS: m/z=273.2 [M+H]+. then concentrated in vacuo The residue was chromatographed over silica gel with 25-75% acetone in hexanes The product fractions were evaporated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.74 g, 1.3 mmol) was reacted with morpholin-3-ylmethanol hydrochloride (0.23 g, 1.5 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.34 g, 43%). The compound was characterized by the following spectroscopic data:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methoxythiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.53 g, 1 mmol) was reacted with morpholin-3-ylmethanol hydrochloride (0.18 g, 1.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.27 g, 48%). The compound was characterized by the following spectroscopic data:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,4,6-trichloro-5-methoxy-pyrimidine (1 g, 4.68 mmol), morpholin-3-yl-methanol hydrochloride (0.86 g, 5.6 mmol) and triethylamine (0.9 mL, 6.5 mmol) in IMS (30 mL) was stirred at RT for 3 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording [4-(2,6-Dichloro-5-methoxy-pyrimidin-4-yl)-morpholin-3-yl]-methanol (614 mg, 45%). LCMS (method A): RT=2.63 min, [M+H]+=294/296. concentrated in vacuo The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane)