Thionyl Chloride → [2-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone

HRID 1877384Notes

Reaction equation

HRID 1877384 reaction equation
[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[NH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH2:34][CH2:33]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1

Participants

5

Reactant 4

HCID 24386Thionyl ChlorideHCID 770281,2,3,4-TetrahydroquinoxalineHCID 81531DiisopropylethylamineHCID 167959962-(2,5-Dichloro-phenoxy)-nicotinic acid

Product 1

HCID 59294486[2-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanoneYield 12.3%

Procedure

A solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (100 mg, 0.35 mmol, 1.0 equiv; Example 31, Step 1) in thionyl chloride (3.28 g, 2 ml, 27.6 mmol, 230 equiv; [CAS RN 7719-09-7]) was heated to 100° C. for 1 h. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (452 mg, 595 μL, 3.5 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 1,2,3,4-tetrahydro-quinoxaline (56 mg, 0.42 mmol, 1.2 equiv; [CAS RN 3476-89-9]) and the reaction mixture was stirred at rt for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 17.3 mg (12%) of the title compound. MS (ISP): 400.0 [M+H]+.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customremoved by azotropic distillation with toluene
  3. dissolutionthe residue dissolved in anhydrous DMF (1 mL)
  4. customRemoval of the solvent mixture
  5. customunder reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column
  6. customequipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps
  7. washa Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water

Sources & evidence

ORD record
ord-9252eb4a85c04d7b89efe8eb5d6430b9
Source dataset
uspto-grants-2012_11
Patent number
US08309734B2

Reaction notes

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