2,2-Difluoroethanamine → 6-benzyl-N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

HRID 713218Notes

Reaction equation

HRID 713218 reaction equation
[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[N:11][C:12](Cl)=[C:13]([N:18]3[CH2:23][CH2:22][CH:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:20][CH2:19]3)[N:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][CH:35]([F:38])[CH2:36][NH2:37].CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[N:11][C:12]([NH:37][CH2:36][CH:35]([F:38])[F:34])=[C:13]([N:18]3[CH2:23][CH2:22][CH:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:20][CH2:19]3)[N:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 1362742,2-DifluoroethanamineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 118159323HCID 118159323, compound

Product 1

HCID 1181592756-benzyl-N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

A solution of 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (261.1 mg, 0.554 mmol) and 2,2-difluoroethanamine (156 μL, 2.22 mmol) in toluene (1.85 mL) was treated with sodium tert-butoxide (107 mg, 1.11 mmol), BINAP (69.0 mg, 0.111 mmol), and Pd2(dba)3 (50.8 mg, 0.055 mmol). Nitrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The reaction mixture was sealed and stirred at 90° C. overnight. The reaction mixture was allowed to cool to room temperature and was opened to air, and the solution was concentrated under reduced pressure. The residue was taken up in MeOH, filtered, and purified by HPLC Method B using a 35% to 60% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (181.2 mg, 51.9%). ESI-MS m/z [M+H]+ 516.4.

Workup

  1. customNitrogen gas (balloon) was bubbled through the reaction mixture for 5 min
  2. customThe reaction mixture was sealed
  3. temperatureto cool to room temperature
  4. concentrationthe solution was concentrated under reduced pressure
  5. filtrationfiltered
  6. custompurified by HPLC Method B

Sources & evidence

ORD record
ord-9a1a6b9541f24c8fb70ced5d9958d15b
Source dataset
uspto-grants-2015_11
Patent number
US09181249B2

Reaction notes

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