4-Methylmorpholine → HCID 89123998, compound

HRID 1192735Notes

Reaction equation

HRID 1192735 reaction equation
[CH:1]1([CH2:4][C:5]([F:25])([F:24])[CH2:6][C@H:7]([NH:11][C@@H:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])[C:8]([OH:10])=O)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:49][C@@H:50]([CH2:59][CH3:60])[CH:51]([OH:58])[C:52]([NH:54][CH:55]1[CH2:57][CH2:56]1)=[O:53].CN1CCOCC1>ClCCl>[CH:1]1([CH2:4][C:5]([F:25])([F:24])[CH2:6][C@H:7]([NH:11][C@@H:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([F:15])([F:14])[F:16])[C:8]([NH:49][C@@H:50]([CH2:59][CH3:60])[CH:51]([OH:58])[C:52]([NH:54][CH:55]2[CH2:56][CH2:57]2)=[O:53])=[O:10])[CH2:2][CH2:3]1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 67385246HCID 67385246, compoundHCID 86673300HCID 86673300, compound

Product 1

HCID 89123998HCID 89123998, compoundYield 66.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of (S)-5-cyclopropyl-4,4-difluoro-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)-pentanoic acid (0.5 g; 1.35 mmol) in dry dichloromethane (16 mL) under nitrogen was treated with HOBt (228 mg; 1.49 mmol; 110 mol %), EDC hydrochloride (286 mg; 1.49 mmol; and (3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide hydrochloride (311 mg; 1.49 mmol; 110 mole %). N-methylmorpholine (NMM; 210 μL; 301 mg; 2.97 mmol; 220 mole %) was added and resulting mixture was stirred for 20 h at ambient temperature. The dichloromethane was removed by distillation and the residue partitioned between ethyl acetate (50 mL) and washed in sequence with 10% aqueous citric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated aqueous sodium chloride (20 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give 740 mg of the crude product which was chromatographed on silica gel (5 g), eluting with ethyl acetate/hexane, 1:2 followed by 1:1, to give 469 mg (66.2%) of (25)-5-cyclopropyl-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxopentan-3-yl)-4,4-difluoro-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)pentanamide. LC-MS, positive ion mode: m/z=524 [M+H]+ (100%). Methods for the preparation of starting materials are disclosed in U.S. Pat. Nos. 7,488,848 and 7,893,112.

Workup

  1. customresulting mixture
  2. customThe dichloromethane was removed by distillation
  3. customthe residue partitioned between ethyl acetate (50 mL)
  4. washwashed in sequence with 10% aqueous citric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated aqueous sodium chloride (20 mL)
  5. dry with materialThe organic phase was dried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customto give 740 mg of the crude product which
  8. customwas chromatographed on silica gel (5 g)
  9. washeluting with ethyl acetate/hexane, 1:2

Sources & evidence

ORD record
ord-57bd7afcee9a4f6f8ca8ed2f4c7ffa4e
Source dataset
uspto-grants-2014_03
Patent number
US08680152B2

Reaction notes

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