Dichloromethane → HCID 71208483, compound

HRID 1887914Notes

Reaction equation

HRID 1887914 reaction equation
NC1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30]N=2)[CH2:24][CH2:23]1.[CH2:37](Cl)Cl.[CH:40]([N:43](CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:13][C:7]1[CH:6]=[C:5]2[C:10]([C:11](=[O:12])[C:21]([CH2:40][NH:43][C:32](=[O:34])[C:31]3[CH:35]=[CH:36][C:28]([N:25]4[CH2:24][CH2:23][O:22][CH2:27][CH2:26]4)=[CH:37][CH:30]=3)=[CH:3][N:4]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:9][CH:8]=1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 81531DiisopropylethylamineHCID 27764606-Morpholinonicotinic AcidHCID 71208567HCID 71208567, compound2×

Product 1

HCID 71208483HCID 71208483, compoundYield 57%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

While purging with argon, a 25 mL round-bottom flask was charged with 3-amino-methyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one (intermediate G) (50 mg, 0.157 mmol), 6-morpholinonicotinic acid (39.1 mg, 0.188 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphonate (HBTU) (71.3 mg, 0.188 mmol). Methylene chloride (5 mL) and N,N-diisopropylethylamine (202 mg, 274 μL, 1.57 mmol) were added, then the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over MgSO4, filtered, and concentrated. The crude product was purified using flash chromatography (12 g silica gel column, eluted with 100% methylene chloride ramped to 4% methanol in methylene chloride). Due to poor separation, a second purification was performed using a 23 g spherical silica column (100% methylene chloride ramped to 4% methanol in methylene chloride). N-[7-chloro-1-(2-chloro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-4-morpholin-4-yl-benzamide (46.8 mg, 57%) was obtained as a white solid at 97% purity according to reverse-phase HPLC. By analytical SFC, two peaks were present, suggesting possible atropisomers. The product was submitted to preparative SFC (WHELK-O1 R,R 3×25; modifier: ethanol; flow rate: 70 mL/min); however, the two products were only partially resolved. 1H NMR (DMSO-d6) δ ppm 8.45-8.69 (m, 2H) 8.26 (d, J=8.7 Hz, 1H) 7.56-8.07 (m, 6H) 7.45 (dd, J=8.7, 1.8 Hz, 1H) 6.81 (d, J=9.1 Hz, 1H) 6.67 (d, J=1.6 Hz, 1H) 4.34 (qd, J=15.0, 5.6 Hz, 2H) 3.58-3.78 (m, 4H) 3.38-3.58 (m, 4H). MS calcd. for C26H22Cl2N4O3 [(M+H)+] 510.0, obsd. 508.9.

Workup

  1. customWhile purging with argon, a 25 mL round-bottom flask
  2. washwashed with water and brine
  3. dry with materialThe organic phase was dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was purified
  7. washflash chromatography (12 g silica gel column, eluted with 100% methylene chloride ramped to 4% methanol in methylene chloride)
  8. customDue to poor separation
  9. customa second purification

Sources & evidence

ORD record
ord-8b92a6e2ee5843c2850ec743264ea9b5
Source dataset
uspto-grants-2013_08
Patent number
US08501732B2

Reaction notes

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