Diisopropylamine → 2-(3,5-Dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanol

HRID 1825387Notes

Reaction equation

HRID 1825387 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([C:33]([F:38])=[CH:34][C:35]=2[O:36][CH3:37])[CH:31]=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH2:20][CH:31]([C:30]1[C:33]([F:38])=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:29]=1)[OH:32]

Participants

7

Reactant 5

HCID 7912DiisopropylamineHCID 25517Ammonium ChlorideHCID 109538273,5-Dichloro-4-methylpyridineHCID 221457953-Cyclopentyloxy-6-fluoro-4-methoxybenzaldehydeHCID 178418339Butyllithium

Product 1

HCID 221459052-(3,5-Dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanolYield 52.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-1 °C

Procedure

To a solution of diisopropylamine (0.16 g) in tetrahydrofuran (2 mL) at −78° C. is added a 2.5 N solution of n-butyl lithium in hexanes (0.62 mL). The solution is allowed to warm to −1° C. and cooled back to −78° C. A solution of 3,5-dichloro-4-methylpyridine (0.25 g) in dry tetrahydrofuran (4 mL) is added, stirred for 0.5 hours at −60° C. and treated with 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (0.25 g) in dry tetrahydrofuran (4 mL). The reaction mixture is allowed to warm to room temperature over 1 hour and stirred overnight. The mixture is treated with 2N ammonium chloride (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts are washed with brine (50 mL), dried (magnesium sulfate) and evaporated to give 2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanol (0.22 g). [NMR (CDCl3):—8.44 (s, 2H), 6.97 (d, 1H, J=7 Hz), 6.56 (d, 1H, J=12 Hz), 5.34 (m, 1H), 4.74 (m, 1H), 3.83 (s, 3H), 3.5 (dd, 1H, J=8 Hz, 8 Hz), 3.32 (dd, 1H, J=5 Hz, 6 Hz), 2.07 (d, 1H, J=6 Hz), 1.93–1.55 (m, 8H)].

Workup

  1. temperaturecooled back to −78° C
  2. temperatureto warm to room temperature over 1 hour
  3. stirringstirred overnight
  4. extractionextracted with ethyl acetate (3×50 mL)
  5. washThe combined organic extracts are washed with brine (50 mL)
  6. dry with materialdried (magnesium sulfate)
  7. customevaporated

Sources & evidence

ORD record
ord-7c10107816e746c28ce007f0957936c3
Source dataset
uspto-grants-2006_05
Patent number
US07045660B2

Reaction notes

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