Methanol → HCID 78210253, compound

HRID 876746Notes

Reaction equation

HRID 876746 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:33][C:34]([C:36]3[CH:41]=[N:40][C:39]([O:42][CH3:43])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1)(=O)C1C=CC=CC=1.CO.[ClH:46].CON.N1C=CC=CC=1>C1COCC1.C(O)C>[ClH:46].[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:33][C:34]([C:36]3[CH:41]=[N:40][C:39]([O:42][CH3:43])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1

Participants

7

Reactant 4

HCID 887MethanolHCID 1049PyridineHCID 521874O-Methylhydroxylamine hydrochlorideHCID 86762774N-[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-methoxy-pyrazine-2-carboxamide

Product 1

HCID 78210253HCID 78210253, compound

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

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-methoxy-pyrazine-2-carboxamide (0.350 g, 0.58 mmol, isomer 1) is dissolved in THF (2 mL) and then methanol (4 mL) and ethanol (4 mL) are added. O-Methylhydroxylamine hydrochloride (495 mg, 5.81 mmol) and pyridine (470 μL, 5.81 mmol) are added to the mixture and the reaction is warmed to 50° C. and stirred overnight. Silica gel (˜10 g) is added to the reaction and the mixture is concentrated. The sample, dried onto silica gel, is loaded onto an empty cartridge and purified eluting with a 0-10% gradient of 7 N ammonia methanol in dichloromethane. The product 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 product 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 (0.20 mL, 660 μmol) is added. The solvent is removed in vacuo to give the title compound (71 mg, 23%). ES/MS (m/e): 498 (M+H).

Workup

  1. additionSilica gel (˜10 g) is added to the reaction
  2. concentrationthe mixture is concentrated
  3. customThe sample, dried onto silica gel
  4. custompurified
  5. washeluting with a 0-10% gradient of 7 N ammonia methanol in dichloromethane
  6. customThe product is purified a second time on a SCX column
  7. customThe product is purified a final time over silica gel with a 0% to 10% gradient of 7 N ammonia methanol in dichloromethane

Sources & evidence

ORD record
ord-d730d067775b463f9a3af1d76a0d2d19
Source dataset
uspto-grants-2015_03
Patent number
US08987254B2

Reaction notes

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