Dimethylformamide → N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-cyano-pyridine-2-carboxamide hydrochloride

HRID 1754873Notes

Reaction equation

HRID 1754873 reaction equation
C(Cl)(=O)C([Cl:4])=O.CN(C)C=O.[C:12]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=1)#[N:13].[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([F:41])=[C:28]([C@:30]23[CH2:38][O:37][CH2:36][C@@:35]2([F:39])[CH2:34][S:33][C:32]([NH2:40])=[N:31]3)[CH:29]=1>C(#N)C.C(O)C.O>[ClH:4].[NH2:40][C:32]1[S:33][CH2:34][C@:35]2([F:39])[CH2:36][O:37][CH2:38][C@:30]2([C:28]2[CH:29]=[C:24]([NH:23][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:19][N:18]=3)=[O:22])[CH:25]=[CH:26][C:27]=2[F:41])[N:31]=1

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 124007345-Cyanopyridine-2-carboxylic acidHCID 117738545(4aR,7aS)-7 a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-2-amine

Product 1

HCID 117739073N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-cyano-pyridine-2-carboxamide hydrochlorideYield 83%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

Scheme 2, step K (amide formation): Oxalyl chloride (60.0 μL, 692 μmol) is added to a solution of dimethylformamide (60.0 μL, 776 μmol) in acetonitrile (4.0 mL), and the resulting reaction is stirred for 16 min 5-Cyanopyridine-2-carboxylic acid (106 mg, 715 μmol) is added to the resulting solution. The reaction is stirred for 33 minutes, and 2.0 mL of this solution is removed via syringe and added drop wise to a solution of (4aR,7aS)-7a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-2-amine (110 mg, 347 μmol) in ethanol (2.0 mL) and water (2.0 mL) at 50° C. The resulting solution is heated at 50° C. for 44 minutes followed by purification by SCX columns (methanol to 7 M ammonia in methanol) to give a residue, which is purified again by silica gel flash chromatography, eluting with 7 M ammonia in methanol/dichloromethane (0/10) to 7 M ammonia in methanol/dichloromethane (1/10) to give a residue as the free base of the desired product (120 mg, 83%). This material is dissolved in 5 mL of dichloromethane/methanol (1/1) and is treated with 1 M HCl in ether (300 μL, 0.30 mmol). The sample is concentrated to give the title compound (128 mg, 81.6%). ES/MS (m/e): 416.1 (M+1).

Workup

  1. customthe resulting reaction
  2. additionis added to the resulting solution
  3. custom2.0 mL of this solution is removed via syringe
  4. customfollowed by purification by SCX columns (methanol to 7 M ammonia in methanol)
  5. customto give a residue, which
  6. customis purified again by silica gel flash chromatography
  7. washeluting with 7 M ammonia in methanol/dichloromethane (0/10) to 7 M ammonia in methanol/dichloromethane (1/10)

Sources & evidence

ORD record
ord-bc7726cba1c14c81b0c4a3ca190b72ad
Source dataset
uspto-grants-2015_10
Patent number
US09169271B2

Reaction notes

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