Acetic Acid → [2-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-[4-(3,3-difluoro-azetidin-1-yl)-3,4-dihydro-2H-quinolin-1-yl]-methanone

HRID 1877395Notes

Reaction equation

HRID 1877395 reaction equation
[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=O)[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.C(O)(=O)C.C(N(C(C)C)C(C)C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]([N:33]3[CH2:34][C:31]([F:35])([F:30])[CH2:32]3)[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 81531DiisopropylethylamineHCID 27582473,3-Difluoroazetidine hydrochlorideHCID 5049666Sodium triacetoxyborohydrideHCID 59294467HCID 59294467, compound

Product 1

HCID 59294506[2-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-[4-(3,3-difluoro-azetidin-1-yl)-3,4-dihydro-2H-quinolin-1-yl]-methanoneYield 68%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
100 °C

Procedure

To a suspension of 1-[2-(2,5-dichloro-phenoxy)-pyridine-3-carbonyl]-2,3-dihydro-1H-quinolin-4-one (50 mg, 0.12 mmol, 1.0 equiv; Example 128) in ethanol (1.2 mL) was added 3,3-difluoroazetidine hydrochloride (31 mg, 0.24 mmol, 2.0 equiv; [CAS RN 288315-03-7]), acetic acid (27 mg, 26 μL, 0.48 mmol, 4.0 equiv; [CAS RN 64-19-7]) and N-ethyldiisopropylamine (31 mg, 42 μL, 0.24 mmol, 2.0 equiv; [CAS RN 7087-68-5]). The reaction mixture was heated by microwave irradiation to 100° C. for 10 min. Sodium triacetoxyborohydride (33 mg, 0.16 mmol, 1.3 equiv; [CAS RN 56553-60-7]) was added and heating at 100° C. continued for 15 min. The reaction mixture was extraction from a sat. solution of NaHCO3 (50 mL) with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. Purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate afforded 0.04 g (7%) of the title compound as a light yellow solid. MS (ISP): 490.0 [M+H]+.

Workup

  1. temperatureheating at 100° C.
  2. extractionextraction from a sat. solution of NaHCO3 (50 mL) with ethyl acetate (3×50 mL)
  3. dry with materialthe combined organic phases dried over MgSO4
  4. customPurification by silica column chromatography
  5. washeluting with a gradient of heptane/ethyl acetate

Sources & evidence

ORD record
ord-3db6e8785f9b4b3c8f52a83355d7e819
Source dataset
uspto-grants-2012_11
Patent number
US08309734B2

Reaction notes

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