Reaction #164775

Reaction equation

Dimethyl sulfoxide

N-[3-[(4aR,7aS)-2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-methoxy-pyrazine-2-carboxamide

O-methylhydroxylamine hydrochloride

pyridine

→

N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-methoxy-pyrazine-2-carboxamide

Solvents

ethanol

Conditions

Workup

1. 1
   Temperaturethe mixture is heated to 70° C. for 4 hours
2. 2
   Otherto obtain a solution
3. 3
   TemperatureThe reaction is cooled and most of the solvent
4. 4
   Otheris removed in vacuo
5. 5
   workup.ADDITIONWater is added
6. 6
   ExtractionThe mixture is extracted with ethyl acetate (5×)
7. 7
   DryingThe combined organic extracts are dried over sodium sulfate
8. 8
   Filtrationfiltered
9. 9
   Otherthe solvent removed in vacuo
10. 10
    OtherThe crude product is purified over silica gel with a 30 minute 0.5% to 10% gradient of 7 N ammonia methanol in dichloromethane gradient
11. 11
    OtherThe mixture is purified again on a SCX column
12. 12
    Othermethanol and then 2:1 dichloromethane:7 N ammonia in methanol to remove residual dimethyl sulfoxide
13. 13
    OtherThe mixture is purified a final time over silica gel with a 20 minute 0.5% to 10% gradient of 7 N ammonia methanol in dichloromethane

Procedure

A mixture of N-[3-[(4aR,7aS)-2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-methoxy-pyrazine-2-carboxamide (479 mg, 819 μmol), O-methylhydroxylamine hydrochloride (709 mg, 8.19 mmol) and pyridine (663 μL, 8.19 mmol) in ethanol (20 mL) is heated at 50° C. in a capped flask overnight. Dimethyl sulfoxide (4 mL) is added and the mixture is heated to 70° C. for 4 hours to obtain a solution. The reaction is cooled and most of the solvent is removed in vacuo. Water is added and the pH is adjusted to ˜12 with 1 N sodium hydroxide. The mixture is extracted with ethyl acetate (5×). The combined organic extracts are dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 30 minute 0.5% to 10% gradient of 7 N ammonia methanol in dichloromethane gradient. The mixture is purified again on a SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol to remove residual dimethyl sulfoxide. The mixture is purified a final time over silica gel with a 20 minute 0.5% to 10% gradient of 7 N ammonia methanol in dichloromethane to give N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-methoxy-pyrazine-2-carboxamide. This material is dissolved in dichloromethane (1 mL) and methanol (0.5 mL) and 1 M hydrogen chloride in diethyl ether (0.66 mL, 660 μmol) is added. The solvent is removed in vacuo to give the title compound (329 mg, 78%). ES/MS (m/e): 481 (M+H).

Source