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 68423Notes

Reaction equation

HRID 68423 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-28a5329f7b8241cd80d4b0dced08ac88
Source dataset
uspto-grants-2014_09
Patent number
US08822456B2

Reaction notes

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