Potassium Carbonate → (R)-[4-(3-cyano-1-cyclopropyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester

HRID 506131Notes

Reaction equation

HRID 506131 reaction equation
[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=3)[C:6]([C:14]#[N:15])=[CH:5]2)[CH2:3][CH2:2]1.C(OB(OC(C)C)OC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH:37]1([C@H:40]([O:42][C:43](=[O:52])[NH:44][C:45]2[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=2)[CH3:41])[CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.Cl[Pd]Cl.CN(C=O)C>[CH:37]1([C@H:40]([O:42][C:43](=[O:52])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:5]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[C:12]4[C:7]([C:6]=3[C:14]#[N:15])=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=4)=[CH:47][CH:46]=2)[CH3:41])[CH2:39][CH2:38]1

Participants

9

Reactant 5

HCID 11430Potassium CarbonateHCID 21531Triisopropyl borateHCID 2724682Lithium diisopropylamideHCID 59430460(R)-(4-iodo-phenyl)carbamic acid 1-cyclopropyl-ethyl esterHCID 594306891-cyclopropyl-6-hydroxy-1H-indole-3-carbonitrile

Product 1

HCID 59430464(R)-[4-(3-cyano-1-cyclopropyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl esterYield 97%

Reagents, catalysts & solvents 3

HCID 24290Palladium ChlorideCatalystHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 1-cyclopropyl-6-hydroxy-1H-indole-3-carbonitrile (0.59 g, 3.0 mmol) and triisopropylborate (1.03 mL, 4.5 mmol) in THF (15 mL) at −78° C. was added LDA (1.5M mono THF in cyclohexane, 4.60 mL, 6.9 mmol) with stirring. The mixture was stirred at −78° C. for 10 min and at room temperature for 30 min followed by the addition of (R)-(4-iodo-phenyl)-carbamic acid 1-cyclopropyl-ethyl ester (1.19 g, 3.6 mmol) and PdCl2 (dppf) (0.11 g, 0.15 mmol). The reaction mixture was cooled to −78° C. and flushed with nitrogen whereupon DMF (30 mL) and aq. K2CO3 (2.0M, 4.5 mL, 9.0 mmol) was added. The cooling bath was removed and the mixture was stirred overnight, poured into ice water (100 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water, dried in air and purified on silica gel (CH2Cl2/EtOAc, 9:1) to give (R)-[4-(3-cyano-1-cyclopropyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (1.16 g, 97%).

Workup

  1. stirringThe mixture was stirred at −78° C. for 10 min and at room temperature for 30 min
  2. additionwas added
  3. customThe cooling bath was removed
  4. stirringthe mixture was stirred overnight
  5. additionpoured into ice water (100 mL)
  6. filtrationThe precipitate was filtered
  7. washwashed with water
  8. customdried in air
  9. custompurified on silica gel (CH2Cl2/EtOAc, 9:1)

Sources & evidence

ORD record
ord-6291a6079cb84bd0a72ce447eb9f6cdd
Source dataset
uspto-grants-2010_08
Patent number
US07781478B2

Reaction notes

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