Potassium Hydroxide → [2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-methanol

HRID 2111166Notes

Reaction equation

HRID 2111166 reaction equation
C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22](C(OC(C)(C)C)=O)[N:23]=1)=O)(C)(C)C.[OH-].[K+]>O1CCCC1>[NH:22]1[C:21]2[CH:31]=[CH:32][S:33][C:20]=2[C:19]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)=[N:23]1

Participants

4

Reactant 2

HCID 14797Potassium HydroxideHCID 576372852-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester2×

Product 1

HCID 135483611[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-methanolYield 74%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-indole-2-boronic acid 1-carboxylic acid tert-butyl ester [3.82 g, 9.42 mmol, Intermediate (8), prepared as described in Example 1-4 of International Patent Application Publication No. WO 02/32861], 3-iodo-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [4.0 g, 11.42 mmol, Example 5B above], tetrakis(triphenylphosphine)palladium(0) (544 mg, 0.470 mmol), potassium carbonate (2M aqueous, 12 mL) in tetrahydrofuran (60 mL) is purged with N2 for 10 minutes then heated to 55-60° C. for 7.5 hours. The reaction is diluted with ethyl acetate (50 mL) and washed with water (20 mL). Water layer is back extracted with ethyl acetate (50 mL). The combined ethyl acetate phases are dried over sodium sulfate. The residue is chromatographed on 35 g silica gel cartridge (5-30% ethyl acetate gradient in heptane) to give 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl ester [3.8 g, 69%, Intermediate (9)]; 1H NMR [(CD3)2SO)]: δ 8.08 (2H, m), 7.64 (1H, s), 7.38 (2H, m), 7.14 (1H, s), 4.81 (2H, s, —OCH2), 1.65 (9H, s), 1.32 (9H, s) 0.92 (9H, s, Si(CH3)3), 0.10 (6H, s, Si(CH2)); LC/MS: 584 (M+H). Step 2. A solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl ester [3.8 g, 6.51 mmol, Intermediate (9)]) in anhydrous tetrahydrofuran (40 mL) is cooled to 0° C. To it is added tetrabutylammonium fluoride (1M in tetrahydrofuran, 10 mL) drop wise. Stirred at 0° C. for 20 minutes then at room temperature for 20 minutes. Water (20 mL) is added and extracted three times with ethyl acetate (30 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate. The residue is chromatographed on 35 g silica gel (10-50% ethyl acetate in heptane) to give 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester [2.63 g, 85%, Intermediate (10)] as white solid; 1H NMR [(CD3)2SO)]: δ 8.05 (2H, m), 7.62 (1H, s), 7.38 (2H, m), 7.02 (1H, s), 5.21 (1H, t), 4.6 (2H, d), 1.64 (9H, s), 1.25 (9H, s); LC/MS: 470 (M+H). Step 3. To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester [200 mg, 0.426 mmol, Intermediate (10)] in tetrahydrofuran (5 mL) is added KOH (1M aqueous, 2.5 mL) and heated to 60° C. for 20 hours. The solvent is removed and dissolved crude in water. The water layer is neutralized with 3N hydrochloric acid then extracted twice with ethyl acetate (20 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate. Purification by chromatography using 10 g silica gel cartridge (50% ethyl acetate in heptane then ethyl acetate) afforded [2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-methanol (84 mg, 74%, Example 23) as a light yellow solid; 1H NMR [(CD3)2SO)]: δ 13.22 (1H, s), 11.43 (1H, s), 7.77 (1H), 7.56 (1H), 7.38 (1H), 7.20 (1H), 7.04 (1H), 6.61 (1H), 5.02 (1H, OH), 4.57 (2H, —CH2OH); LC/MS: 270 (M+H).

Workup

  1. customThe solvent is removed
  2. dissolutiondissolved crude in water
  3. extractionthen extracted twice with ethyl acetate (20 mL)
  4. washThe combined ethyl acetate phases are washed with brine
  5. dry with materialdried over sodium sulfate
  6. customPurification by chromatography

Sources & evidence

ORD record
ord-c68e5e02e53144cb914e8b216abef7af
Source dataset
uspto-grants-2009_04
Patent number
US07518000B2

Reaction notes

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