4-Methylmorpholine → HCID 68605046, compound

HRID 1593266Notes

Reaction equation

HRID 1593266 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:14][O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C>[CH3:14][O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 1454243,5-Difluorophenylacetic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2733257Alanine methyl ester hydrochloride

Product 1

HCID 68605046HCID 68605046, compoundYield 88%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To a stirred solution of 3,5-difluorophenylacetic acid (6.02 g, 34.97 mmol), L-alanine methyl ester hydrochloride (4.88 g, 34.96 mmol) and HOBt (5.20 g, 38.48 mmol) in dichloromethane (200 mL) under nitrogen at 0° C. was added NMM (8.84 g, 87.39 mmol) and EDAC-HCl (7.38 g, 38.49 mmol). The mixture was allowed to warm gradually to ambient temperature and stir overnight. The reaction was diluted with ethyl acetate and extracted sequentially with aqueous sodium bicarbonate, 1N aqueous HCl and brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexanes: ethyl acetate to afford N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.91 g, 88% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (d, 3H, J=7.0 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 4.59 (m, 1H), 6.02 (br 1H), 6.67-6.87 (m, 3H). MS APCI, m/z=258 (M+1). LC/MS: 1.68 Lithium hydroxide (1.40 g, 33.33 mmol) in water (60 mL) was added dropwise to a solution of N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.79 g, 30.28 mmol) in 1,4-dioxane (150 mL). After 2 h the solvent was evaporated. The residue was dissolved in water and the solution extracted with diethyl ether. The aqueous phase was acidified with 1N aqueous HCl and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried, filtered and evaporated to afford the title compound (7.16 g, 97% yield) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.28 (d, 3H, J=7.4 Hz), 3.51 (s, 2H), 4.20 (m, 1H), 6.93-7.12 (m, 3H), 8.44 (d, 1H, J=7.0 Hz), 12.46 (br, 1H). HPLC Method A: 2.12 min.

Workup

  1. extractionextracted sequentially with aqueous sodium bicarbonate, 1N aqueous HCl and brine
  2. customThe organic phase was dried
  3. filtrationfiltered
  4. customevaporated
  5. customThe residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexanes

Sources & evidence

ORD record
ord-46347fe71caa473f8cb83c8130280dd8
Source dataset
uspto-grants-2007_11
Patent number
US07294622B2

Reaction notes

Loading…