Acetic Acid → HCID 131727219, compound

HRID 1670329Notes

Reaction equation

HRID 1670329 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:31])[N:20]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:21]=[CH:22][CH:23]=2)=[O:17])=[CH:11][C:10]=1[F:32].C(OC([N:40]1[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41]1)=O)(C)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:65]>ClCCCl.O1CCOCC1.CO.CCOC(C)=O>[ClH:65].[F:32][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2[C:19](=[O:31])[N:20]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)=[O:17])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][CH2:45][CH:42]1[CH2:43][CH2:44][NH:40][CH2:41]1

Participants

9

Reactant 5

HCID 176Acetic AcidHCID 313Hydrochloric AcidHCID 4692112(+-)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxaldehydeHCID 5049666Sodium triacetoxyborohydride2×HCID 11654977HCID 11654977, compound

Product 1

HCID 131727219HCID 131727219, compoundYield 60%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 312751,4-DioxaneSolventHCID 21584119Ethylacetate methanolSolvent

Procedure

To N-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 120, 30 mg, 0.07 mmol) in DCE (1 mL) was added 3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CB Research and Development Inc., 28 mg, 0.14 mmol), acetic acid (5 uL, 0.084 mmol), then sodium triacetoxyborohydride (23 mg, 0.104 mmol). After stirring at rt for 6 h, a second portion (23 mg) of sodium triacetoxyborohydride was added. After stirring at rt for 2 h, the reaction mixture was charged with 4N HCl in dioxane (5 mL) and stirred an additional 1 h at rt. The reaction was diluted with 10% MeOH/EtOAc (10 mL) and washed with saturated sodium bicarbonate solution (10 mL). The aqueous phase was back-extracted with 10 mL of 10% MeOH/EtOAc and the combined organic layers were dried over anhydrous Na2SO4 and then concentrated in vacuo. The resulting crude product was purified by prep HPLC. The appropriate fractions were concentrated to remove methanol and then made basic with saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with 10% MeOH/EtOAc (3×20 mL) and the pooled organic extracts were dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was lyophilized from acetonitrile (1 mL)/water (3 mL)/1N aq HCl (0.2 mL) to give the HCl salt of the title compound (25 mg, 60%) as a white solid. 1H NMR (DMSO-d6) δ 12.17 (s, 1H), 8.59 (dd, 1H, J=7.6, 2 Hz), 8.30 (s, 1H), 8.16 (dd, 1H, J=6.4, 2 Hz), 8.10 (dd, 1H, J=12.8, 2 Hz), 8.00 (d, 1H, J=6.4 Hz), 7.64-7.58 (m, 3H), 7.52 (t, 1H, J=9.2 Hz), 7.46-7.42 (m, 2H), 7.00 (d, 1H, J=6 Hz), 6.75 (t, 1H, J=7.2 Hz), 3.72-3.64 (m, 3H), 3.37-3.26 (m, 1H), 3.17-3.10 (m, 1H), 2.97-2.92 (m, 1H), 2.74-2.66 (m, 1H), 2.10-2.03 (m, 1H), 1.75-1.68 (m, 1H); MS (ESI+) m/z 518.29 (M+H)+.

Workup

  1. stirringAfter stirring at rt for 2 h
  2. stirringstirred an additional 1 h at rt
  3. washwashed with saturated sodium bicarbonate solution (10 mL)
  4. extractionThe aqueous phase was back-extracted with 10 mL of 10% MeOH/EtOAc
  5. dry with materialthe combined organic layers were dried over anhydrous Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe resulting crude product was purified by prep HPLC
  8. concentrationThe appropriate fractions were concentrated
  9. customto remove methanol
  10. extractionThe aqueous solution was extracted with 10% MeOH/EtOAc (3×20 mL)
  11. dry with materialthe pooled organic extracts were dried over anhydrous Na2SO4
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-b17bf445508b406cb8da299418b0c123
Source dataset
uspto-grants-2011_08
Patent number
US07989477B2

Reaction notes

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