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-cyano-pyridine-2-carboxamide hydrochloride

HRID 876747Notes

Reaction equation

HRID 876747 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]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1)(=O)C1C=CC=CC=1.[ClH:43].CON.N1C=CC=CC=1>C(O)C.ClCCl>[ClH:43].[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]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1

Participants

6

Reactant 3

HCID 1049PyridineHCID 521874O-Methylhydroxylamine hydrochlorideHCID 86762776N-[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-cyano-pyridine-2-carboxamide

Product 1

HCID 86762782N-[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-cyano-pyridine-2-carboxamide hydrochloride

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6344DichloromethaneSolvent

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]phenyl]-5-cyano-pyridine-2-carboxamide (360 mg, 0.59 mmol) is dissolved in ethanol (10 mL) and dichloromethane (2 mL). O-Methylhydroxylamine hydrochloride (504 mg, 5.91 mmol) and pyridine (478 μL, 5.91 mmol) are added and the reaction is stirred at room temperature over the weekend (70 hrs). The reaction is warmed to 60° C. and stirred for 24 hrs. The reaction is concentrated to give the crude product and purified via silica gel chromatography using a 0-10% 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 (0.54 mL, 540 μmol) is added. The solvent is removed in vacuo to give the title compound (240 mg, 75%). ES/MS (m/e): 475 (M+H).

Workup

  1. temperatureThe reaction is warmed to 60° C.
  2. stirringstirred for 24 hrs
  3. concentrationThe reaction is concentrated
  4. customto give the crude product
  5. custompurified via silica gel chromatography

Sources & evidence

ORD record
ord-8955e7a89a944cfeb4ec235de33775ce
Source dataset
uspto-grants-2015_03
Patent number
US08987254B2

Reaction notes

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