Hydrochloric Acid → 6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(1-methyl-3-pyrazin-2-yl-1h-1,2,4-triazol-5-yl)methyl]-5,6-dihydro-2h-pyran-2-one

HRID 1438287Notes

Reaction equation

HRID 1438287 reaction equation
[Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)[CH:7]=1.O.Cl.Cl.[CH3:30][N:31]1[C:35]([CH:36]=O)=[N:34][C:33]([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)=[N:32]1.C(N(CC)CC)C.Cl>C(O)(C)C.O>[Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[C:13]([CH2:36][C:35]3[N:31]([CH3:30])[N:32]=[C:33]([C:38]4[CH:43]=[N:42][CH:41]=[CH:40][N:39]=4)[N:34]=3)=[C:12]([OH:17])[CH2:11]2)[CH:7]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 167287016-[2-(5-Chloro-2,4-dimethoxy-phenyl)ethyl]-6-cyclopentyl-tetrahydropyran-2,4-dioneHCID 1317261702-Methyl-5-pyrazin-2-yl-2h-[1,2,4]triazole-3-carbaldehyde dihydrochloride monohydrate

Product 1

HCID 587640146-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(1-methyl-3-pyrazin-2-yl-1h-1,2,4-triazol-5-yl)methyl]-5,6-dihydro-2h-pyran-2-oneYield 24.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3776IsopropanolSolvent2×

Procedure

A solution of 6-[2-(5-chloro-2,4-dimethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (0.300 g, 0.78 mmol, from step 6 below) in hot isopropanol (5 mL) was treated with (CH3)2NHBH3 (48 mg, 0.815 mmol, 1.04 equiv), then with a solution of 2-methyl-5-pyrazin-2-yl-2H-[1,2,4]triazole-3-carbaldehyde dihydrochloride monohydrate (229 mg, 0.819 mmol, 1.05 equiv, from step 3 below) in isopropanol (3 mL) containing triethylamine (0.230 mL, 2 equiv). The reaction mixture was stirred at room temperature, resulting in complete conversion after 1 h. The mixture was acidified with 1 M aqueous HCl to a pH of 2, stirred for 10 min, and concentrated in vacuo to afford a resin. This was diluted with water and extracted with dichloromethane containing 10% methanol (3×15 mL). The extract was dried over Na2SO4, filtered, and concentrated, affording the crude product (410 mg). This material was recrystallized from hot methylene chloride/ether, then the resulting solid triturated with acetone containing petroleum ether, filtered, and dried, affording the title product (107 mg, 24%). 1H NMR (300 MHz, DMSO-d6): δ 1.26-1.75 (m, 8H), 1.78-2.13 (m, 2H), 2.37 (m, 1H), 2.45-2.50 (m, 2H, overlap with DMSO-d5), 2.65 (d, J=17.9 Hz, 1H), 2.73 (d, J=17.9 Hz, 1H), 3.73 (s, m overlap, 5H), 3.80 (s, 3H), 3.95 (s, 3H), 6.63 (s, 1H), 7.05 (s, 1H), 8.6 (m, overlap, 2H), 8.93 (s, 1H), 11.07 (br s, 1H). LC-MS (APCI) calcd for C28H32ClN5O5: 553.21 found (M+H+): 554.4 m/z.

Workup

  1. customresulting in complete conversion after 1 h
  2. stirringstirred for 10 min
  3. concentrationconcentrated in vacuo
  4. customto afford a resin
  5. extractionextracted with dichloromethane containing 10% methanol (3×15 mL)
  6. dry with materialThe extract was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customaffording the crude product (410 mg)
  10. customThis material was recrystallized from hot methylene chloride/ether
  11. customthe resulting solid triturated with acetone
  12. additioncontaining petroleum ether
  13. filtrationfiltered
  14. customdried

Sources & evidence

ORD record
ord-e7e853c1f2024b46818ca63ffc930cb6
Source dataset
uspto-grants-2009_11
Patent number
US07622605B2

Reaction notes

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