Diisopropylethylamine → 3-((3S,9aS)-8-(2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile

HRID 1502178Notes

Reaction equation

HRID 1502178 reaction equation
[F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C@@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][NH:18][CH2:19][CH2:20][N:13]3[CH2:12]2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([F:33])([F:32])[C:29](O)=[O:30])=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[NH2:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([F:33])([F:32])[C:29]([N:18]2[CH2:19][CH2:20][N:13]3[C@H:14]([CH2:15][O:16][C@@H:11]([C:5]4[C:6]([CH3:10])=[C:7]([C:2]([F:1])=[CH:3][CH:4]=4)[C:8]#[N:9])[CH2:12]3)[CH2:17]2)=[O:30])=[CH:26][N:27]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 712721096-fluoro-2-methyl-3-((3S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrileHCID 896192612-(2-Aminopyrimidin-5-yl)-2,2-difluoroacetic acid

Product 1

HCID 1176902733-((3S,9aS)-8-(2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 6-fluoro-2-methyl-3-((3S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile (60 mg, 0.218 mmol) and 2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetic acid (60.3 mg, 0.218 mmol) in anhydrous DMF (2724 μL) was added DIEA (133 μL, 0.763 mmol) followed by HATU (149 mg, 0.392 mmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with methanol and purified on mass-directed preparative HPLC, Polar method (Column: Sunfire Prep C18, OBD 5 um, 30×100 mm). LC/MS: [(M+1)]+=447.08; 1H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 2H), 8.11-8.17 (m, 1H), 7.30-7.39 (m, 3H), 4.83-4.92 (m, 1H), 4.07-4.27 (m, 1H), 3.43-3.76 (m, 2H), 3.00-3.37 (m, 4H), 2.72-2.96 (m, 2H), 2.58-2.68 (m, 1H), 2.16-2.55 (m, 4H).

Workup

  1. custompurified on mass-directed preparative HPLC, Polar method (Column: Sunfire Prep C18, OBD 5 um, 30×100 mm)

Sources & evidence

ORD record
ord-bdc746e352394ad590daf9b298982a93
Source dataset
uspto-grants-2015_12
Patent number
US09206199B2

Reaction notes

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