4-Methylmorpholine → (S)-4-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-3-oxo-propyl]-3-methyl-piperazin-2-one

HRID 2095583Notes

Reaction equation

HRID 2095583 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21](O)=[O:22])[C:15](=[O:24])[C@@H:14]2[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]([N:32]3[CH2:33][CH2:34][C:29]4([CH2:27][CH2:28]4)[C@H:30]([OH:35])[CH2:31]3)=[O:22])[C:15](=[O:24])[C@@H:14]2[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 44541812(4S)-6-Azaspiro[2.5]octan-4-ol hydrochloride2×HCID 670743863-{(S)-4-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-3-methyl-2-oxo-piperazin-1-yl}-propionic acid

Product 1

HCID 58232109(S)-4-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-3-oxo-propyl]-3-methyl-piperazin-2-oneYield 55.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-{(S)-4-[(E)-3-(3-chloro-4-fluoro-phenyl)-acryloyl]-3-methyl-2-oxo-piperazin-1-yl}-propionic acid (50 mg, 0.14 mmol), (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 24 mg, 0.15 mmol) and 4-methylmorpholine (41 mg, 0.41 mmol) in N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (77 mg, 0.20 mmol) at room temperature, then after 16 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; dichloromethane→dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (37 mg, 54%). White solid, MS: 478.2 (M+H, Cl)+.

Workup

  1. customafter 16 h the reaction mixture was partitioned between water and ethyl acetate
  2. washThe organic layer was washed with brine
  3. dry with materialdried over magnesium sulfate
  4. filtrationfiltered
  5. customevaporated

Sources & evidence

ORD record
ord-01f015a25e314a3d8e0c605fbd2af7ec
Source dataset
uspto-grants-2013_05
Patent number
US08445674B2

Reaction notes

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