Tetrahydrofuran → tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate

HRID 1529322Notes

Reaction equation

HRID 1529322 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](S(C1C=CC(C)=CC=1)(=O)=O)[CH:13]=[C:12]2[C:28]1[N:33]=[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:36][CH2:35]2)[CH:31]=[N:30][CH:29]=1.C[O-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28]1[N:33]=[C:32]([N:34]2[CH2:35][CH2:36][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:38][CH2:39]2)[CH:31]=[N:30][CH:29]=1

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 10942334Sodium Methoxide2×HCID 67960004tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate

Product 1

HCID 67959678tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamateYield 72.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent3×

Procedure

To a slurry of tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.186 g, 0.275 mmol) in 2 mL MeOH was added sodium methanolate 25 wt % in MeOH (0.126 mL, 0.550 mmol). 2 mL THF was added. The cloudy mixture was sealed and stirred rapidly. After 1 h, additional sodium methanolate 25 wt % in MeOH (0.126 mL, 0.550 mmol) was added. The reaction became a clear, orange solution. After 2 h, the reaction was concentrated under a stream of N2, and the solid was partitioned between saturated aqueous NH4Cl and DCM. 1 mL 1N HCl was added to acidify the aqueous layer. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM/MeOH and adsorbed onto 1.5 g silica gel, dried, and purified by silica gel chromatography (40 g column) using 20-80% EtOAc/hexane. The product-containing fractions were concentrated to afford tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.104 g, 0.199 mmol, 72.4% yield) as a orange solid. MS (ESI, pos. ion) m/z: 522 (M+1).

Workup

  1. customThe cloudy mixture was sealed
  2. waitAfter 2 h
  3. concentrationthe reaction was concentrated under a stream of N2
  4. customthe solid was partitioned between saturated aqueous NH4Cl and DCM
  5. addition1 mL 1N HCl was added
  6. extractionThe aqueous layer was extracted with DCM 3 times
  7. dry with materialthe combined organics were dried over anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. additionThe material was treated with DCM/MeOH
  11. customdried
  12. custompurified by silica gel chromatography (40 g column)
  13. concentrationThe product-containing fractions were concentrated

Sources & evidence

ORD record
ord-aa5f38fbd9d44b038d9c94f662881d1e
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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