Tetrahydrofuran → Dicyclopropyl-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-6-yl]-methanol

HRID 2111188Notes

Reaction equation

HRID 2111188 reaction equation
CO[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:14]3[C:15]4[S:21][CH:20]=[CH:19][C:16]=4[NH:17][N:18]=3)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH:22]1([Mg]Br)[CH2:24][CH2:23]1.O1[CH2:31][CH2:30][CH2:29]C1>>[CH:22]1([C:3]([CH:29]2[CH2:30][CH2:31]2)([C:5]2[CH:13]=[C:12]3[C:8]([CH:9]=[C:10]([C:14]4[C:15]5[S:21][CH:20]=[CH:19][C:16]=5[NH:17][N:18]=4)[NH:11]3)=[CH:7][CH:6]=2)[OH:4])[CH2:24][CH2:23]1

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 1354711942-(1H-Thieno[3,2-c]pyrazol-3-yl)-1H-indole-6-carboxylic acid methyl esterHCID 178418630HCID 178418630, compound

Product 1

HCID 135457833Dicyclopropyl-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-6-yl]-methanol

Procedure

To a mixture of 2-(1H-Thieno[3,2-c]pyrazol-3-yl)-1H-indole-6-carboxylic acid methyl ester (180 mg, 0.605 mmol, Example 43) in anhydrous tetrahydrofuran (8 mL) is added cyclopropylmagnesium bromide (6.0 mL, 0.5 M in tetrahydrofuran) at 0° C. The ice bath is removed and the reaction mixture stirred at room temperature for 4 hours. To it is added an additional cyclopropylmagnesium bromide (6 mL, 0.5 M in tetrahydrofuran) and stirred at room temperature overnight. The reaction is not completed (TLC) and added cyclopropylmagnesium bromide (6.0 mL). The solublized reaction mixture is then stirred overnight. The reaction is quenched at 0° C. by the addition of saturated ammonium chloride. The reaction mixture is partitioned between diethyl ether and water. The diethyl ether layer is washed with brined and dried over magnesium sulfate. The crude is chromatographed on 10 g silica gel cartridge (30-50% ethyl acetate gradient in heptane) to afford product (120 mg). The product is recrystallized as follows: In a Smith vial, a mixture of solid (120 mg) and ethyl acetate (2 mL) is heated at 70° C. using microwave (Personal chemistry optimizer) for 240 seconds at normal absorption. Upon cooling dicyclopropyl-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-6-yl]-methanol crystallized as a white solid. mp 110-112° C.; 1H NMR [(CD3)2SO)]: δ 13.189 (1H, s), 11.440 (1H, s), 7.747 (1H, d, J=5.1 Hz), 7.631 (1H, s), 7.467 (1H, d, J=8.4 Hz), 7.249 (2H, m), 6.579 (1H, s), 4.304 (1H, s), 1.225 (2H), 0.581 (2H, m), 0.387 (4H, m), 0.195 (2H, m); LC/MS: 350 (M+H).

Workup

  1. customThe ice bath is removed
  2. additionTo it is added an additional cyclopropylmagnesium bromide (6 mL, 0.5 M in tetrahydrofuran)
  3. stirringstirred at room temperature overnight
  4. additionadded cyclopropylmagnesium bromide (6.0 mL)
  5. stirringThe solublized reaction mixture is then stirred overnight
  6. customThe reaction is quenched at 0° C. by the addition of saturated ammonium chloride
  7. customThe reaction mixture is partitioned between diethyl ether and water
  8. washThe diethyl ether layer is washed with brined and
  9. dry with materialdried over magnesium sulfate
  10. customThe crude is chromatographed on 10 g silica gel cartridge (30-50% ethyl acetate gradient in heptane)

Sources & evidence

ORD record
ord-3fb94a0ad2c94d6c98e75009b45a0b63
Source dataset
uspto-grants-2009_04
Patent number
US07518000B2

Reaction notes

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