4-Methylmorpholine → HCID 59293921, compound

HRID 1930790Notes

Reaction equation

HRID 1930790 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[CH2:28]([O:30][C:31](=[O:46])[C@@H:32]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:33][CH2:34][C:35](O)=[O:36])[CH3:29].CN1CCOCC1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O>O.C(#N)C>[CH2:28]([O:30][C:31](=[O:46])[C@@H:32]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:33][CH2:34][C:35](=[O:36])[NH:25][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:26]=[CH:27][C:9]([CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:29]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 13819298(4S)-4-[(tert-Butoxycarbonyl)amino]-5-ethoxy-5-oxopentanoic acidHCID 16719049E-1210HCID 21864398Tetramethyluronium hexafluorophosphate

Product 1

HCID 59293921HCID 59293921, compoundYield 9.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester 1-ethyl ester (390 mg, 0.67 mmol; 63% purity) described in Manufacturing Example 4-1 and ethanol (4 mL) was added palladium-carbon (40 mg, 0.19 mmol; 50% water content) at room temperature, which was stirred overnight under a hydrogen atmosphere (1 atm) at room temperature. The reaction mixture was replaced with nitrogen and filtered through a Celite pad. The solvent was evaporated from the filtrate under a reduced pressure, so as to obtain (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-ethyl ester (330 mg) in a crude form. The crude product thus obtained was used directly in the next reaction. To a mixture of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (150 mg, 80.42 mmol) described in Reference Example 1 and acetonitrile (3 mL) were added (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-ethyl ester (crude, 230 mg), N-methylmorpholine (46 μL, 0.42 mmol), and 180 mg (0.46 mmol) of 047-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (180 mg, 0.46 mmol) were added in this order at 0° C., which was stirred overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1), so as to obtain the titled compound (47 mg).

Workup

  1. customwas used directly in the next reaction
  2. additionwere added in this order at 0° C.
  3. extractionwas extracted with ethyl acetate
  4. washThe organic layer was washed with saturated brine
  5. customthe solvent was evaporated under a reduced pressure
  6. customThe residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1)

Sources & evidence

ORD record
ord-7f5393e772a144d987e9d26ae6abee1a
Source dataset
uspto-grants-2012_05
Patent number
US08188119B2

Reaction notes

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