Hydrochloric Acid → 2-{4-[2-(2-Cyclopentyl-4-hydroxy-5-{[1-methyl-3-(6-methylpyridin-2-yl)-1H-1,2,4-triazol-5-yl]methyl}-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile

HRID 2387131Notes

Reaction equation

HRID 2387131 reaction equation
[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl.[CH3:30][N:31]1[C:35]([CH:36]=O)=[N:34][C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)=[N:32]1.C(N(CC)CC)C.Cl>C(O)(C)C.O>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:36][C:35]3[N:31]([CH3:30])[N:32]=[C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=4)[N:34]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 587624232-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl)-2-methylpropanenitrileHCID 866053711-Methyl-3-(6-methylpyridin-2-yl)-1H-1,2,4-triazole-5-carbaldehyde hydrochloride hydrate

Product 1

HCID 587641922-{4-[2-(2-Cyclopentyl-4-hydroxy-5-{[1-methyl-3-(6-methylpyridin-2-yl)-1H-1,2,4-triazol-5-yl]methyl}-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrileYield 38%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3776IsopropanolSolvent2×

Conditions

Temperature
48.5 °C

Procedure

A solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile (1.0 g, 2.70 mmol, from step 3 of example A(84) in hot (50° C.) isopropanol (7 mL) was treated with (CH3)2NHBH3 (175 mg, 2.97 mmol, 1.1 equiv), then with a solution of 1-methyl-3-(6-methylpyridin-2-yl)-1H-1,2,4-triazole-5-carbaldehyde hydrochloride hydrate (762 mg, 2.97 mmol, 1.1 equiv, from Step 4 below) in isopropanol (4 mL) containing triethylamine (301 mg, 2.97 mmol, 1.1 equiv). The reaction mixture was stirred heated at 47-50° C. for 18 h. The reaction mixture was treated with 1.1 equiv of 1 M aqueous HCl and concentrated in vacuo to afford an oily resin. This was diluted with water and extracted with dichloromethane containing 10% methanol (3×30 mL). The extract was dried over Na2SO4, filtered, and concentrated. The residue was triturated with hot ethyl acetate/methylene chloride, filtered, washed with cold ether, and dried, affording 584 mg (38%) of the title product. 1H NMR (400 MHz, DMSO-d6): δ 1.36-1.71 (m, 14 H), 2.05 (m, 2 H), 2.48 (m, 1 H), 2.46 (s, 3 H), 2.63 (m, 3 H), 2.78 (d, J=17.9 Hz, 1 H), 3.67 (d, J=15.7 Hz, 1 H), 3.74 (d, J=15.7 Hz, 1 H), 3.91 (s, 3 H), 6.99 (d, J=8.1 Hz, 1 H), 7.10-7.20 (m, 3 H), 7.57 (m, 2 H), 11.22 (s, 1 H). LC-MS (APCI) calcd for C32H36FN5O3: 557.28, found (M+H+): 558.40 m/z.

Workup

  1. concentrationconcentrated in vacuo
  2. customto afford an oily resin
  3. extractionextracted with dichloromethane containing 10% methanol (3×30 mL)
  4. dry with materialThe extract was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was triturated with hot ethyl acetate/methylene chloride
  8. filtrationfiltered
  9. washwashed with cold ether
  10. customdried

Sources & evidence

ORD record
ord-50e5b630968d4a61b29980fad4090480
Source dataset
uspto-grants-2012_09
Patent number
US08268835B2

Reaction notes

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