Sodium hydride → N-[2-({6-[Cyano(2,6-dichlorophenyl)methyl]pyridazin-3-yl}sulfanyl)benzyl]-3-fluoro-5-(morpholin-4-yl)benzamide

HRID 2096249Notes

Reaction equation

HRID 2096249 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[SH:15])=[O:6].[H-].[Na+].Cl[C:28]1[N:33]=[N:32][C:31]([CH:34]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:44])[C:35]#[N:36])=[CH:30][CH:29]=1>CN(C=O)C>[C:35]([CH:34]([C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44])[C:31]1[N:32]=[N:33][C:28]([S:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:16]=[C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:18]=[C:2]([F:1])[CH:3]=2)=[CH:29][CH:30]=1)#[N:36]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 27550402-(6-Chloropyridazin-3-yl)-2-(2,6-dichlorophenyl)acetonitrileHCID 668222283-Fluoro-5-(morpholin-4-yl)-N-(2-sulfanylbenzyl)benzamide

Product 1

HCID 66822461N-[2-({6-[Cyano(2,6-dichlorophenyl)methyl]pyridazin-3-yl}sulfanyl)benzyl]-3-fluoro-5-(morpholin-4-yl)benzamideYield 25%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
100 °C

Procedure

A solution of 3-fluoro-5-(morpholin-4-yl)-N-(2-sulfanylbenzyl)benzamide (80 mg, 0.23 mmol) in DMF (3 mL) was treated with sodium hydride (60% in mineral oil, 8.8 mg, 0.22 mmol). The mixture was stirred for 5 min and treated with a solution of (6-chloro-pyridazin-3-yl)-(2,6-dichloro-phenyl)-acetonitrile (63 mg, 0.21 mmol) in DMF (1 mL). The reaction mixture was heated at 100° C. for 45 min, cooled to RT and partitioned between aqueous saturated NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc, the combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. Purification by reverse phase preparative HPLC (water/acetonitrile+0.1% HCO2H 50% isocratic), afforded the title compound (32 mg, 25%) as a yellow oil. LCMS (Method 3): Rt 11.77 min, m/z 608 [MH+]. 1H NMR (400 MHz, CDCl3): 7.67-7.58 (2H, m), 7.53-7.47 (1H, m), 7.45-7.32 (4H, m), 7.31-7.20 (2H, m), 7.09 (1H, t, J 1.7), 6.75 (1H, br t, J 5.6), 6.71-6.61 (2H, m), 6.33 (1H, s), 4.76 (2H, m), 3.86 (4H, t, J 4.8), 3.21 (4H, t, J 4.8).

Workup

  1. temperaturecooled to RT
  2. custompartitioned between aqueous saturated NaHCO3 and EtOAc
  3. extractionThe aqueous layer was extracted with EtOAc
  4. dry with materialthe combined organic layers were dried over MgSO4
  5. filtrationfiltered
  6. concentrationthe filtrate was concentrated in vacuo
  7. customPurification by reverse phase preparative HPLC (water/acetonitrile+0.1% HCO2H 50% isocratic)

Sources & evidence

ORD record
ord-2e706a27af12460a9ca06a0bb8f93406
Source dataset
uspto-grants-2013_05
Patent number
US08450314B2

Reaction notes

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