Diisopropylethylamine → Ethyl 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinate

HRID 2044078Notes

Reaction equation

HRID 2044078 reaction equation
Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C)C(=O)C>[Cl:13][C:4]1[CH:3]=[C:2]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:22])=[CH:19][CH:20]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 5778154-(Morpholine-4-carbonyl)anilineHCID 600045Ethyl 4,6-dichloropyridine-3-carboxylate

Product 1

HCID 57489629Ethyl 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinateYield 33.9%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of ethyl 4,6-dichloronicotinate (500 mg, 2.272 mmol) and (4-aminophenyl)(morpholino)methanone (469 mg, 2.272 mmol) in N,N-Dimethylacetamide (5 mL) was treated with DIEA (0.794 mL, 4.54 mmol) and sealed in a large microwave vial and heated in a heating block at 120° C. overnight. The reaction mixture is removed from heating block, cooled to rt and diluted with water and extracted into CH2Cl2. Washed with water and concentrated to give dark oil which was chromatographed (ISCO Companion 40 g silica gel column and eluted with EtOAc/Hexane gradient (0-100%) to give 300 mg of ethyl 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinate as a light yellow solid. LCMS: (M+H)+=390.02, 392.02 (Cl pattern). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (t, J=7.14 Hz, 3H) 3.74 (br. s, 8H) 4.41 (q, J=7.03 Hz, 2H) 7.00 (s, 1H) 7.30 (d, J=8.35 Hz, 2H) 7.51 (d, J=8.35 Hz, 2H) 8.80 (s, 1H) 9.99 (s, 1H).

Workup

  1. customsealed in a large microwave vial
  2. customThe reaction mixture is removed
  3. temperaturefrom heating block
  4. temperaturecooled to rt
  5. additiondiluted with water
  6. extractionextracted into CH2Cl2
  7. washWashed with water
  8. concentrationconcentrated
  9. customto give dark oil which
  10. customwas chromatographed (ISCO Companion 40 g silica gel column
  11. washeluted with EtOAc/Hexane gradient (0-100%)

Sources & evidence

ORD record
ord-45995b6e76174156bb7e8c1a02013f12
Source dataset
uspto-grants-2013_11
Patent number
US08586751B2

Reaction notes

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