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Dichloromethane → Tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate

HRID 595955
Notes
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Reaction equation

HRID 595955 reaction equation
[NH2:1][C:2]1[C:3]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([F:22])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH2:40][CH2:39][C:34]3([O:38][CH2:37][CH2:36][O:35]3)[CH2:33][CH:32]=2)O1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([F:22])[CH:10]=2)=[N:4][C:5]([C:31]2[CH2:40][CH2:39][C:34]3([O:38][CH2:37][CH2:36][O:35]3)[CH2:33][CH:32]=2)=[CH:6][N:7]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 36970768-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro(4.5)dec-7-eneHCID 118045500tert-Butyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate

Product 1

HCID 118045818Tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate
Yield 99%

Reagents, catalysts & solvents 4

HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To tert-butyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (5.17 g, 46.2 mmol) in DME (115 mL) were added 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (15.36 g, 57.7 mmol), PdCl2(dppf).CH2Cl2 adduct (1.885 g, 2.309 mmol), and then 2 M aqueous solution sodium carbonate (19.57 g, 185 mmol). The reaction mixture was heated at 100° C. overnight. LCMS indicated the reaction was completed. The reaction was cooled down. To the mixture was added 1000 mL of EtOAc and 300 mL of water. The resulting mixture was stirred for 30 min, and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×200 mL). The organic layers were combined, washed with water three times and brine, dried over sodium sulfate, filtered off, and concentrated in vacuo. The crude product was triturated by ether to provide tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate (19.5 g, 45.6 mmol, 99%) as a light yellow solid. LCMS (m/z): 428.1 (MH+), 1.02 min.

Workup

  1. temperatureThe reaction was cooled down
  2. customthe organic layer was separated
  3. extractionThe aqueous layer was extracted with EtOAc (3×200 mL)
  4. washwashed with water three times and brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered off
  7. concentrationconcentrated in vacuo
  8. customThe crude product was triturated by ether

Sources & evidence

ORD record
ord-4c4ead5d3e0a4add9684362a832ac27b
Source dataset
uspto-grants-2016_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09242996B2

Reaction notes

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