Tetrahydrofuran → HCID 136348457, compound

HRID 1748815Notes

Reaction equation

HRID 1748815 reaction equation
[Si:1]([O:8][CH2:9][C@@H:10]1[NH:16][C:15]2[N:17]([CH3:26])[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:14]=2[C@H:13](OC(=O)C2C=CC=C(C)C=2)[S:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:37][C:38]1[C:43]([NH2:44])=[CH:42][CH:41]=[CH:40][N:39]=1.[CH3:45][Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60].C1C[O:64][CH2:63]C1>>[Si:1]([O:8][CH2:9][C@@H:10]1[NH:16][C:15]2[N:17]([CH3:26])[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:14]=2[C@@H:13]([C:57]2[C:56]([CH3:45])=[CH:55][CH:60]=[CH:59][C:58]=2[C:63]([NH:44][C:43]2[C:38]([CH3:37])=[N:39][CH:40]=[CH:41][CH:42]=2)=[O:64])[S:12][CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]

Participants

6

Reactant 5

HCID 8028TetrahydrofuranHCID 8058HexaneHCID 5726163-Amino-2-methylpyridineHCID 2733832Lithium HexamethyldisilazideHCID 136348458HCID 136348458, compound

Product 1

HCID 136348457HCID 136348457, compoundYield 85%

Procedure

To a solution of rac-methyl 4-((4R,7S)-(7-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoate (0.300 g, 0.56 mmol) and 2-methylpyridin-3-amine (0.181 g, 1.67 mmol, Appollo) in THF (6 ml) at about 0° C. was added 1 M lithium bis(trimethylsilyl)amide in hexane (2.78 ml, 2.78 mmol). About 5 min after the complete addition, the cold bath was removed and the reaction was stirred for about 2 h at rt. The reaction was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 50-100% EtOAc/heptane) to give rac-4-((4R,7S)(7-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.29 g, 0.47 mmol, 85%) as a pale yellow film: LC-MS (Table 1, Method g) Rt=2.83 min, m/z 615 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 9.84 (s, 1H), 8.48-8.44 (m, 1H), 8.30 (d, J=4.6 Hz, 1H), 7.81-7.78 (m, 1H), 7.73-7.66 (m, 2H), 7.64-7.60 (m, 1H), 7.39-7.36 (m, 1H), 7.28-7.16 (m, 2H), 6.87 (d, J=3.1 Hz, 1H), 6.80 (s, 1H), 5.86 (d, J=5.2 Hz, 1H), 4.96 (s, 1H), 3.78-3.61 (m, 4H), 3.52 (s, 1H), 2.87-2.74 (m, 2H), 2.57 (s, 3H), 2.40 (s, 3H), 0.83 (s, 9H), 0.12-−0.15 (m, 6H).

Workup

  1. additionAbout 5 min after the complete addition
  2. customthe cold bath was removed
  3. customThe reaction was quenched with saturated NH4Cl (50 mL)
  4. extractionextracted with EtOAc (50 mL)
  5. washThe organic layer was washed with brine (50 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationwas concentrated in vacuo
  9. customThe residue was purified by column chromatography (SiO2, 50-100% EtOAc/heptane)

Sources & evidence

ORD record
ord-2e3aea183ebb4fd48fc7b817dff6e7ba
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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