4-Methylmorpholine → [2-({1-[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester

HRID 1062304Notes

Reaction equation

HRID 1062304 reaction equation
[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN1CCOCC1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:43]([O:47][C:48](=[O:55])[N:49]([CH2:51][CH2:52][O:53][NH2:54])[CH3:50])([CH3:46])([CH3:45])[CH3:44]>O1CCCC1.C(OCC)(=O)C>[C:43]([O:47][C:48](=[O:55])[N:49]([CH2:51][CH2:52][O:53][NH:54][C:5]([C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20])=[O:7])[CH3:50])([CH3:46])([CH3:44])[CH3:45]

Participants

7

Reactant 4

HCID 79724-Methylmorpholine2×HCID 73910Diphenylphosphinic chlorideHCID 220256632-(2-Fluoro-4-iodoanilino)-3,4-difluorobenzoic acidHCID 23398498tert-butyl N-[2-(aminooxy)ethyl]-N-methylcarbamate

Product 1

HCID 86591461[2-({1-[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl esterYield 73.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (3.11 g, 7.91 mmol) in tetrahydrofuran (20 mL) was cooled with a −40° C. bath and treated with N-methylmorpholine (0.87 mL, 7.9 mmol). Diphenylphosphinic chloride (2.00 mL, 10.5 mmol) was added dropwise over 5 min and the reaction mixture was stirred for 90 min, during which time the temperature of the cooling bath slowly warmed to 0° C. The reaction mixture was again cooled to −40° C. and (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.00 g, 10.5 mmol) was added as a solution in tetrahydrofuran (6 mL). After an additional 10 min, N-methylmorpholine (1.33 mL, 12.1 mmol) was added. The temperature of the cooling bath was allowed to warm to ambient temperature over 4 h and the reaction mixture was further stirred overnight. The reaction was diluted with ethyl acetate (40 mL) and washed with saturated aqueous ammonium chloride (2×10 mL). The organics were dried over magnesium sulfate, concentrated and purified by silica gel chromatography. Elution with 35% ethyl acetate-hexanes afforded [2-({1-[3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (3.28 g, 73% yield) as an off-white foam: 1H NMR (400 MHz, DMSO-d6) δ 11.84 and 11.75 (br s, 1H total), 8.66 (br s, 1H), 7.54 (dd, J=10.9, 1.6 Hz, 1H), 7.36 (br t, J=8.8 Hz, 1H), 7.33 (br d, J=8.8 Hz), 7.20 (m, 1H), 6.64 (m, 1H), 3.85 (t, J=5.2 Hz, 2H), 3.34 (br s, 2H), 2.81 and 2.79 (br s, 3H total), 1.34 and 1.32 (s, 9H total); 19F NMR (376 MHz, DMSO-d6) δ −128.0 (d, J=32.9 Hz), −133.0, −144.2 (d, J=17.7 Hz); MS (APCI−)=564.1.

Workup

  1. temperatureThe reaction mixture was again cooled to −40° C.
  2. waitAfter an additional 10 min
  3. temperatureto warm to ambient temperature over 4 h
  4. waitthe reaction mixture was further stirred overnight
  5. washwashed with saturated aqueous ammonium chloride (2×10 mL)
  6. dry with materialThe organics were dried over magnesium sulfate
  7. concentrationconcentrated
  8. custompurified by silica gel chromatography
  9. washElution with 35% ethyl acetate-hexanes

Sources & evidence

ORD record
ord-2ab023caa29640c09e4ac235ce8a28b1
Source dataset
uspto-grants-2005_11
Patent number
US06960614B2

Reaction notes

Loading…