4-Methylmorpholine → HCID 18651459, compound

HRID 1033419Notes

Reaction equation

HRID 1033419 reaction equation
[CH3:1][C:2]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])([CH3:35])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31](O)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[C:8]1=[O:34])=[O:5].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O.C(OCC)(=O)C>[CH2:40]([O:39][C:37]([NH:36][C:2]([CH3:35])([CH3:1])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][OH:32])=[CH:23][CH:24]=2)[C:8]1=[O:34])=[O:5])=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 4311764Sodium borohydrideHCID 67751249HCID 67751249, compound

Product 1

HCID 18651459HCID 18651459, compoundYield 71%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 124 mg (0.20 mmol) of 4'-[[2,3,4,5-tetrahydro-3(R)-[[3-methyl-1-oxo-3-[(benzyloxycarbonyl)amino]butyl]amino]-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxylic acid (Example 72, Step B) in 1.5 mL of dry 1,2-dimethoxyethane at 0° C. was added 0.046 mL (0.421 mmol) of N-methylmorpholine followed by 0.055 mL (0.42 mmol) of isobutyl chloroformate. The reaction mixture was stirred at 0° C. for 1 hour then filtered. Solids were rinsed with 1,2-dimethoxyethane (2×1 mL) and the filtrates combined. To the filtrate at 0° C. was added by syringe a solution of 30.3 mg (0.801 mmol) of sodium borohydride in 0.3 mL of water. The reaction mixture was stirred at 0° C. for 15 minutes then diluted with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous ammonium chloride (25 mL) and brine (25 mL), then dried over magnesium sulfate, filtered and the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (75:25) to afford 86 mg (71%) of the product as a white solid. 1H NMR (200 MHz,CDCl3): 1.35 (s,3H), 1.37 (s,3H), 2.80 (m,2H), 2.50 (m,4H), 4.50 (m,3 H), 4.90 (d,15 Hz,1H), 5.03 (dd;10,12 Hz;2H), 5.18 (d,15 Hz,1H), 5.77 (s,1H), 6.70 (d,8 Hz,1H), 7.10-7.40 (m,16H), 7.53 (m,1H). FAB-MS: calculated for C37H39N3O5 605; found 607 (30%).

Workup

  1. filtrationthen filtered
  2. washSolids were rinsed with 1,2-dimethoxyethane (2×1 mL)
  3. stirringThe reaction mixture was stirred at 0° C. for 15 minutes
  4. washThe organic layer was washed with saturated aqueous ammonium chloride (25 mL) and brine (25 mL)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. customthe solvent was removed under vacuum
  8. customThe residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (75:25)

Sources & evidence

ORD record
ord-5166213e1c954ab7b895b1331c2f7e34
Source dataset
uspto-grants-1994_05
Patent number
US05310737

Reaction notes

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