3-Amino-2-methylpyridine → HCID 136228365, compound

HRID 1748765Notes

Reaction equation

HRID 1748765 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([O:7]C)=O.[NH2:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([NH:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:7]

Participants

5

Reactant 3

HCID 5726163-Amino-2-methylpyridineHCID 2733832Lithium HexamethyldisilazideHCID 136348416HCID 136348416, compound

Product 1

HCID 136228365HCID 136228365, compoundYield 9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-40 °C

Procedure

To a mixture of methyl 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.14 g, 0.34 mmol, Example #E.1) and 3-amino-2-methylpyridine (0.04 g, 0.37 mmol) in anhydrous THF (10 mL), was added lithium bis(trimethylsilyl)amide solution (1.3 mL, 1 M in THF, 1.3 mmol), at about −40° C. The resulting mixture was stirred for about 30 min, at about −40° C., and then quenched by the addition of water (10 mL) and ethyl acetate (130 mL). The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/methanol 100:0 to 0:100) and preparative HPLC (Table 2, Method a) to afford 3-chloro-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydro-pyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide (0.0162 g, 0.03 mmol, 9%): LC-MS (Table 1, Method b) Rt=3.70 min, m/z 491 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 2.56 (3H, s), 2.70-2.90 (2H, m), 3.26-3.35 (1H, m), 3.63-3.71 (1H, m) 3.60-4.00 (1H, br s) 3.84 (3H, s) 6.91 (1H, s) 7.09 (1H, ddd, J=1.2, 4.8, 7.9 Hz) 7.21 (1H, dd, J=4.8, 8.2 Hz) 7.44 (1H, d, J=8.0 Hz) 7.58-7.64 (3H, m) 7.80 (1H, d, J=8.0 Hz) 7.92 (1H, d, J=2.0 Hz) 8.28-8.34 (2H, m) 8.48-8.51 (1H, m).

Workup

  1. customat about −40° C
  2. customquenched by the addition of water (10 mL) and ethyl acetate (130 mL)
  3. customThe layers were separated
  4. washthe organic layer was washed with water (25 mL)
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe resulting residue was purified by column chromatography (SiO2, ethyl acetate/methanol 100:0 to 0:100) and preparative HPLC (Table 2, Method a)

Sources & evidence

ORD record
ord-052693c8f27f47f89d3d30e562acb45c
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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