Ammonia → (4aR*,6R*,8aS*)-8a-[2-fluoro-5-({[(2R)-1-methoxypropan-2-yl]amino}methyl)phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine
Reaction equation
[NH2:1][C:2]1[S:3][CH2:4][C@@H:5]2[CH2:11][C@H:10]([CH:12]3[CH2:14][CH2:13]3)[O:9][CH2:8][C@:6]2([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[F:23])[C:18]#[N:19])[N:7]=1.[NH3:24].[C:25](#[N:27])C>>[F:23][C:22]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C@H:6]([CH3:5])[CH2:8][O:9][CH3:10])=[CH:16][C:15]=1[C@:6]12[CH2:8][O:9][C@@H:10]([C:12]3[CH:13]=[N:24][N:27]([CH3:25])[CH:14]=3)[CH2:11][C@H:5]1[CH2:4][S:3][C:2]([NH2:1])=[N:7]2Participants
Reactant 3
Product 1
Procedure
Compound C87 was converted to the product according to the method described for synthesis of 13 in Example 13. In this case, reversed phase HPLC (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: aqueous ammonia, pH 10; Mobile phase B: acetonitrile; Gradient: 30% to 50% B) afforded the product as a white gum. By 1H NMR analysis, this was judged to consist of a mixture of the expected diastereomers. Yield: 37 mg, 83 μmol, 25%. LCMS m/z 448.3 [M+H+]. 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 7.60 (s, 1H), 7.33 (s, 1H), 7.24-7.32 (m, 2H), 7.12 (dd, J=12, 8 Hz, 1H), 6.14 (br s, 2H), 4.55 (d, J=11.0 Hz, 1H), 4.46 (br s, 1H), 4.06 (d, J=11 Hz, 1H), 3.79 (s, 3H), 3.58-3.75 (m, 3H), 3.21 and 3.22 (2 s, total 3H), 2.80-2.88 (m, 1H), 2.63-2.79 (m, 3H), 1.85-1.98 (m, 1H), 1.71-1.80 (m, 1H), 0.96 (d, J=6.3 Hz, 3H).
Sources & evidence
- ORD record
- ord-a56ee59ce79d4deb8e1222040f76bab8
- Source dataset
- uspto-grants-2015_12
- Patent number
- US09198917B2
Reaction notes
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