Reaction #164780

Reaction equation

N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-cyano-pyridine-2-carboxamide

O-Methylhydroxylamine hydrochloride

pyridine

→

title compound

N-[3-[(4aR,7aS)-2-Amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-cyano-pyridine-2-carboxamide hydrochloride

Solvents

THF

methanol

ethanol

Conditions

Workup

1. 1
   ConcentrationThe mixture is concentrated onto silica gel (˜10 g)
2. 2
   Otherpurified via silica gel chromatography
3. 3
   Washeluting with a 0-10% gradient of 7 N ammonia methanol in dichloromethane
4. 4
   OtherThe material is purified a second time on a SCX column
5. 5
   OtherThe mixture is purified a final time over silica gel with a 0% to 10% gradient of 7 N ammonia methanol in dichloromethane

Procedure

N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-cyano-pyridine-2-carboxamide (133 mg, 0.22 mmol, isomer 1) is dissolved in THF (1 mL) and diluted with methanol (3 mL) and ethanol (3 mL). O-Methylhydroxylamine hydrochloride (190 mg, 2.2 mmol) and pyridine (180 μL, 2.2 mmol) are added. The reaction is warmed to 50° C. and stirred overnight. The mixture is concentrated onto silica gel (˜10 g) and purified via silica gel chromatography eluting with a 0-10% gradient of 7 N ammonia methanol in dichloromethane. The material is purified a second time on a SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol. The mixture is purified a final time over silica gel with a 0% to 10% gradient of 7 N ammonia methanol in dichloromethane to give the free base of the title compound. This material is dissolved in dichloromethane (5 mL) and 1 M hydrogen chloride in diethyl ether (0.27 mL, 270 μmol) is added. The solvent is removed in vacuo to give the title compound (114 mg, 97%). ES/MS (m/e): 493 (M+H).

Source