Methylamine → 3-[(4aR,6R,8aS)-2-amino-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile

HRID 1496766Notes

Reaction equation

HRID 1496766 reaction equation
CN.[C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:36])=[C:9]([C@:11]23[CH2:20][O:19][C@@H:18]([C:21]4[O:22][CH:23]=[C:24]([CH3:26])[N:25]=4)[CH2:17][C@H:16]2[CH2:15][S:14][C:13]([NH:27]C(=O)C2C=CC=CC=2)=[N:12]3)[CH:10]=1)#[N:4]>C(O)C>[NH2:27][C:13]1[S:14][CH2:15][C@@H:16]2[CH2:17][C@H:18]([C:21]3[O:22][CH:23]=[C:24]([CH3:26])[N:25]=3)[O:19][CH2:20][C@:11]2([C:9]2[CH:10]=[C:5]([CH:6]=[CH:7][C:8]=2[F:36])[C:3]#[N:4])[N:12]=1

Participants

4

Reactant 2

HCID 6329MethylamineHCID 86762660N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 762818523-[(4aR,6R,8aS)-2-amino-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

Methylamine (8 M in ethanol, 7.1 mL, 57.1 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C41) (0.227 g, 0.48 mmol) in ethanol (12 mL). The resulting solution was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give a yellow oily residue. Purification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) afforded the product as an off-white solid. Yield: 144 mg, 81%. LCMS m/z 374.1 [M+H+]. 1H NMR (400 MHz, CD3OH) δ 7.77 (ddd, J=8.5, 4.5, 2.2 Hz, 1H), 7.68 (dd, J=7.2, 2.3 Hz, 1H), 7.61 (q, J=2.3 Hz, 1H), 7.35 (dd, J=12.1, 8.6 Hz, 1H), 4.82 (dd, J=11.9, 2.5 Hz, 1H), 4.25 (dd, J=11.2, 2.2 Hz, 1H), 3.79 (d, J=11.2 Hz, 1H), 3.06-3.13 (m, 1H), 2.89 (dd, J=12.7, 4.1 Hz, 1H), 2.78 (dd, J=12.7, 2.9 Hz, 1H), 2.33-2.43 (m, 1H), 2.15 (d, J=1.4 Hz, 3H), 1.87-1.91 (m, 1H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customto give a yellow oily residue
  3. customPurification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane)

Sources & evidence

ORD record
ord-3995832f86e54fd0a29f794b5fddf7a9
Source dataset
uspto-grants-2015_12
Patent number
US09198917B2

Reaction notes

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