Dimethyl Sulfoxide → 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

HRID 77593Notes

Reaction equation

HRID 77593 reaction equation
C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[N:39][C:38]([O:41][CH3:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1)(=O)C1C=CC=CC=1.Cl.CON.N1C=CC=CC=1.CS(C)=O>C(O)C>[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[N:39][C:38]([O:41][CH3:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 1049PyridineHCID 521874O-Methylhydroxylamine hydrochlorideHCID 86762772N-[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

Product 1

HCID 86762781N-[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

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
50 °C

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).

Workup

  1. temperaturethe mixture is heated to 70° C. for 4 hours
  2. customto obtain a solution
  3. temperatureThe reaction is cooled and most of the solvent
  4. customis removed in vacuo
  5. additionWater is added
  6. extractionThe mixture is extracted with ethyl acetate (5×)
  7. dry with materialThe combined organic extracts are dried over sodium sulfate
  8. filtrationfiltered
  9. customthe solvent removed in vacuo
  10. customThe 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. customThe mixture is purified again on a SCX column
  12. custommethanol and then 2:1 dichloromethane:7 N ammonia in methanol to remove residual dimethyl sulfoxide
  13. customThe 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

Sources & evidence

ORD record
ord-50910d78aa8e4516b2122893f22fd4a9
Source dataset
uspto-grants-2014_09
Patent number
US08841293B1

Reaction notes

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