Dimethyl Sulfoxide → N-[3-[2-Amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-fluoro-pyridine-2-carboxamide

HRID 77591Notes

Reaction equation

HRID 77591 reaction equation
C([NH:9][C:10]1[S:11][CH2:12][CH: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:33][C:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[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][CH: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:33][C:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1

Participants

6

Reactant 4

HCID 679Dimethyl Sulfoxide4×HCID 1049Pyridine4×HCID 521874O-Methylhydroxylamine hydrochloride4×HCID 86762773N-[3-[2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-fluoro-pyridine-2-carboxamide2×

Product 1

HCID 86762779N-[3-[2-Amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-fluoro-pyridine-2-carboxamideYield 186.9%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
70 °C

Procedure

A mixture of N-[3-[2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-fluoro-pyridine-2-carboxamide (293 mg, 497 μmol), O-methylhydroxylamine hydrochloride (430 mg, 4.97 mmol) and pyridine (402 μL, 4.97 mmol) is heated in ethanol (13 mL) to 70° C. in a capped flask for 2.5 hours. Dimethyl sulfoxide (3 mL) is added and the mixture is heated at 70° C. overnight. Additional dimethyl sulfoxide (10 mL) is added and heating continued at 70° C. for 4 hours. Additional O-methylhydroxylamine hydrochloride (208 mg, 2.48 mmol) and pyridine (201 μL, 2.48 mmol) is added and the mixture is heated to 60° C. for 3 hours and the mixture is stirred for 3 days at room temperature. In a separate flask, a mixture of N-[3-[2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-fluoro-pyridine-2-carboxamide (276 mg, 468 μmol), O-methylhydroxylamine hydrochloride (405 mg, 4.68 mmol) and pyridine (478 μL, 4.68 mmol) is heated in ethanol (15 mL) and dimethyl sulfoxide (4 mL) at 70° C. in a capped flask overnight. Additional dimethyl sulfoxide (10 mL) is added and heating is continued at 70° C. for 4 hours. Additional O-methylhydroxylamine hydrochloride (195 mg, 2.34 mmol) and pyridine (189 μL, 2.34 mmol) is added and heating continued at 70° C. for 3 hours followed by stirring the mixture for 3 days at room temperature. The two reaction mixtures are combined and most of the solvent removed in vacuo. The crude product is purified on a SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol. The crude product is further purified over silica gel with a 20 minute 0.5% to 10% gradient of 7 N ammonia methanol in dichloromethane gradient to give the title compound (451 mg, 96%). ES/MS (m/e): 486 (M+H).

Workup

  1. temperatureheating
  2. temperaturethe mixture is heated to 60° C. for 3 hours
  3. customat 70° C.
  4. customovernight
  5. temperatureheating
  6. waitis continued at 70° C. for 4 hours
  7. temperatureheating
  8. waitcontinued at 70° C. for 3 hours
  9. stirringby stirring the mixture for 3 days at room temperature
  10. customThe two reaction mixtures
  11. customremoved in vacuo
  12. customThe crude product is purified on a SCX column
  13. customThe crude product is further purified over silica gel with a 20 minute 0.5% to 10% gradient of 7 N ammonia methanol in dichloromethane gradient

Sources & evidence

ORD record
ord-86da8a8b85644e21828c04d9727e33fb
Source dataset
uspto-grants-2014_09
Patent number
US08841293B1

Reaction notes

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