Ethyl cyanoacetate → [6-{[4-(Trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]acetonitrile

HRID 1691481Notes

Reaction equation

HRID 1691481 reaction equation
[H-].[Na+].[C:3]([CH2:5]C(OCC)=O)#[N:4].I[C:12]1[CH:13]=[CH:14][C:15]2[NH:21][C:20]3[N:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:19]=3[CH2:18][N:17]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:16]=2[CH:44]=1.[OH-].[Na+]>CS(C)=O.[Cu]I.O.C(OCC)(=O)C>[F:41][C:40]([F:42])([F:43])[O:39][C:36]1[CH:37]=[CH:38][C:33]([S:30]([N:17]2[C:16]3[CH:44]=[C:12]([CH2:5][C:3]#[N:4])[CH:13]=[CH:14][C:15]=3[NH:21][C:20]3[N:22]=[C:23]([C:26]([F:28])([F:27])[F:29])[CH:24]=[CH:25][C:19]=3[CH2:18]2)(=[O:31])=[O:32])=[CH:34][CH:35]=1

Participants

9

Reactant 4

HCID 7764Ethyl cyanoacetateHCID 14798Sodium HydroxideHCID 24758Sodium hydrideHCID 596187318-Iodo-6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine2×

Product 1

HCID 86649045[6-{[4-(Trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]acetonitrile

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolvent2×HCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A sample of NaH (23.4 mg, 0.585 mmol) was put in a dried flask and 1.5 mL of DMSO (anhydrous) was added. Then ethyl cyanoacetate (0.062 ml, 0.585 mmol) was added slowly and stirred under N2 for 20 minutes. Then a solution of 8-iodo-6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (240 mg, 0.390 mmol, intermediate 61) in DMSO (2.0 ml) was added, followed by copper (I) iodide (111 mg, 0.585 mmol). The mixture was stirred for 2 hr at 90-95° C. Then 4 mL of water and 0.3 mL of 1N NaOH were added and the reaction mixture was stirred at 80-85° C. for 1 hr. The reaction mixture was poured into 50 mL of ethyl acetate and 10 mL of water, and the aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with hexane/acetone (6:1-4:1) to give the title compound.

Workup

  1. stirringThe mixture was stirred for 2 hr at 90-95° C
  2. stirringthe reaction mixture was stirred at 80-85° C. for 1 hr
  3. extractionthe aqueous layer was extracted with ethyl acetate (20 mL×2)
  4. dry with materialThe combined organic layers were dried over Na2SO4
  5. concentrationconcentrated
  6. customThe resulting residue was purified by column chromatography on silica gel
  7. washeluting with hexane/acetone (6:1-4:1)

Sources & evidence

ORD record
ord-d68db23343af4fd9b5ea87ae4cba684f
Source dataset
uspto-grants-2012_04
Patent number
US08153626B2

Reaction notes

Loading…