Tetrahydrofuran → HCID 136016231, compound

HRID 2111174Notes

Reaction equation

HRID 2111174 reaction equation
C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:20])[CH2:18]C)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:21]1[C:22]2[S:35][CH:34]=[CH:33][C:23]=2[N:24](C(OC(C)(C)C)=O)[N:25]=1)=O)(C)(C)C.C[Mg]Br.O1CC[CH2:41][CH2:40]1>>[NH:24]1[C:23]2[CH:33]=[CH:34][S:35][C:22]=2[C:21]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([C:17]([OH:20])([CH2:40][CH3:41])[CH3:18])=[CH:14][CH:15]=3)=[N:25]1

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 57637290HCID 57637290, compound2×HCID 178418573HCID 178418573, compound2×

Product 1

HCID 136016231HCID 136016231, compoundYield 52%

Conditions

Temperature
-78 °C

Procedure

A solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-propionyl-indole-1-carboxylic acid tert-butyl ester [450 mg, 0.908 mmol, Intermediate (15)] in anhydrous tetrahydrofuran (25 mL) that is cooled to −78° C. is added methylmagnesium bromide (1M in tetrahydrofuran, 3 mL) via syringe under nitrogen. After stirring for 30 minutes cooling bath is removed and brought the reaction to room temperature. The reaction is cooled to −78° C. then additional 5 mL of methyl magnesium bromide is added. After 30 minutes, the cooling bath is removed and reaction temperature is brought to room temperature. After 4 hours, it is quenched by the addition of saturated ammonium chloride (6 mL). After stirring for 10 minutes, water (20 mL) is added and extracted three times with ethyl acetate (40 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate. Purification by chromatography (35 g silica gel cartridge, 1:1 ethyl acetate /heptane) afforded 2-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-butan-2-ol [148 mg, 52%, Example 32 ] as a white solid; 1H NMR [(CD3)2SO)]: δ 13.204 (1H, s), 11.402 (1H, s), 7.743 (1H, d), 7.595 (1H, s), 7.333-7.192 (3H, m), 6.598 (1H, s), 4.658 (1H, s, OH), 1.728 (2H, q), 1.461 (3H, s), 0.702 (3H, t); LC/MS: 312 (M+H).

Workup

  1. temperaturecooling bath
  2. customis removed
  3. customthe reaction to room temperature
  4. waitAfter 30 minutes
  5. customthe cooling bath is removed
  6. customreaction temperature
  7. customis brought to room temperature
  8. waitAfter 4 hours
  9. customit is quenched by the addition of saturated ammonium chloride (6 mL)
  10. stirringAfter stirring for 10 minutes
  11. additionwater (20 mL) is added
  12. extractionextracted three times with ethyl acetate (40 mL)
  13. washThe combined ethyl acetate phases are washed with brine
  14. dry with materialdried over sodium sulfate
  15. customPurification by chromatography (35 g silica gel cartridge, 1:1 ethyl acetate /heptane)

Sources & evidence

ORD record
ord-da7e56c430f949328cfa697c73453c0f
Source dataset
uspto-grants-2009_04
Patent number
US07518000B2

Reaction notes

Loading…