1-Ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde → 6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyl-3-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

HRID 1438296Notes

Reaction equation

HRID 1438296 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH2:27]([N:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[C:31]([CH3:37])=[N:30]1)[CH3:28]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[C:17]([CH2:35][C:32]3[C:31]([CH3:37])=[N:30][N:29]([CH2:27][CH3:28])[C:33]=3[CH3:34])=[C:16]([OH:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]

Participants

4

Reactant 2

HCID 31574611-Ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehydeHCID 167287396-[2-(3-Chloro-4-isopropoxy-phenyl)ethyl]-6-cyclopentyl-tetrahydropyran-2,4-dione

Product 1

HCID 587640396-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyl-3-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-oneYield 40%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
40 °C

Procedure

A solution of 6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (379 mg; 1.0 mmol from step 1 below) and 1-ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde (152 mg; 1.1 mmol) in methanol was heated at 40° C. overnight. The reaction mixture was treated with (CH3)2NHBH3 (65 mg, 1.1 equiv), and heated at 40° C. overnight again. The reaction was partitioned between EtOAc and H2O. The EtOAc layer was dried with Na2SO4, concentrated, and purified by reverse phase HPLC using 0.1% HOAc in H2O and CH3CN. (Column: Water's Bondapak, C18, particle size: 37-55 micron column size: 47×300 mm; Flow rate: 70 ml/min; Detector: was set at 254 nm; Buffer A: 0.1% HOAc in H2O; Buffer B: 0.1% HOAc in CH3CN. The column was equilibrated in A for 20 minutes. The sample was dissolved in 5 ml of DMSO, filtered, and injected onto the column. The gradient was held at 75% A/25% for 5 minutes and then increased linearly to 55% A/45% B in 15 minutes and then continued isocratically at 45% B for another 25 minutes. The desired product eluted at 28 minutes.) The product-containing fractions were lyophilized to afford the title compound as a powder (196.2 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 1.13 (t, 3H), 1.26 (d, m overlap, 8H), 1.35-1.63 (m, 6H), 1.75 (m, 2H), 2.02 (s, 3H), 2.10 (s, 3H), 2.21 (m, 1H), 2.39 (m, overlap, 3H), 2.61 (d, J=16.4 Hz, 1H), 3.1 (m, 2H, overlap with H2O peak), 3.81 (q, 2H), 4.56 (7 line pattern, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 7.11 (s, 1H). LC-MS (APCI) calcd for C29H39ClN2O4: 514.26, found (M+H+): 515.3 m/z.

Workup

  1. customThe reaction was partitioned between EtOAc and H2O
  2. dry with materialThe EtOAc layer was dried with Na2SO4
  3. concentrationconcentrated
  4. custompurified by reverse phase
  5. customfor 20 minutes
  6. dissolutionThe sample was dissolved in 5 ml of DMSO
  7. filtrationfiltered
  8. temperatureincreased linearly to 55% A/45% B in 15 minutes
  9. waitcontinued isocratically at 45% B for another 25 minutes
  10. washThe desired product eluted at 28 minutes

Sources & evidence

ORD record
ord-c227f5f2df574a38be4cb608e8bc2d23
Source dataset
uspto-grants-2009_11
Patent number
US07622605B2

Reaction notes

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