Sodium hydride → 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester

HRID 77496Notes

Reaction equation

HRID 77496 reaction equation
[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:30])([CH3:29])[CH2:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:11][CH:10]=2)[CH3:2].[H-].[Na+].[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39]([C:42]2[CH:53]=[CH:52][C:45]([CH2:46]OS(C)(=O)=O)=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:30])([CH3:29])[CH2:6][C:7]1[N:8]([CH2:46][C:45]2[CH:44]=[CH:43][C:42]([C:39]3[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)=[CH:53][CH:52]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:11][CH:10]=2)[CH3:2]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 444749063-[3-tert-Butylsulfanyl-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl esterHCID 59556522Methanesulfonic acid 4-(6-methoxy-pyridin-3-yl)-benzyl ester

Product 1

HCID 162262693-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
-10 °C

Procedure

3-[3-tert-Butylsulfanyl-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester (A-4; 20.0 g, 45.4 mmol) was dissolved in DMF (150 mL) and cooled to −10° C. under N2. Sodium hydride (60% dispersion in mineral oil; 2.0 g, 50.0 mmol) was added portionwise, and the reaction was stirred at −10° C. for 45 minutes until the foam had disappeared. To this dark brown-reddish solution was added methanesulfonic acid 4-(6-methoxy-pyridin-3-yl)-benzyl ester (Int-72; 16.0 g, 54.5 mmol) in DMF dropwise. The reaction was then stirred at −10° C. for 1 hour and allowed to warm to room temperature slowly. After 16 hours, LCMS confirmed the formation of the product. The reaction was quenched with saturated NH4Cl and diluted with methyl tert-butyl ether (MTBE) and water. The aqueous phase was extracted twice with MTBE. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude product was purified by column chromatography to give the desired product (A-5).

Workup

  1. stirringThe reaction was then stirred at −10° C. for 1 hour
  2. temperatureto warm to room temperature slowly
  3. waitAfter 16 hours
  4. customThe reaction was quenched with saturated NH4Cl
  5. additiondiluted with methyl tert-butyl ether (MTBE) and water
  6. extractionThe aqueous phase was extracted twice with MTBE
  7. dry with materialThe combined organic layers were dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customthe crude product was purified by column chromatography

Sources & evidence

ORD record
ord-0778ee0c079246b486db2f4d81d6e87d
Source dataset
uspto-grants-2014_09
Patent number
US08841295B2

Reaction notes

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