Cesium carbonate → 2-(3-(3-Chloropyrazin-2-yl)azetidin-1-yl)quinoline

HRID 1850243Notes

Reaction equation

HRID 1850243 reaction equation
Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Br[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:12][C:11]1[C:6]([CH:4]2[CH2:5][N:2]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:3]2)=[N:7][CH:8]=[CH:9][N:10]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 27627562-BromoquinolineHCID 717437842-(Azetidin-3-YL)-3-chloropyrazine hydrochloride

Product 1

HCID 585467412-(3-(3-Chloropyrazin-2-yl)azetidin-1-yl)quinolineYield 45%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 2-(azetidin-3-yl)-3-chloropyrazine hydrochloride (8) (163 g, 0.79 mol), 2-bromoquinoline (164 g, 0.79 mol, 1 eq., Combi-Blocks) and cesium carbonate (772 g, 2.37 mol, 3 eq., Aldrich) in anhydrous DMF (6.5 L) was heated to 110° C. and stirred for 19 h. After cooling to RT, the mixture was transferred to 50 L separatory funnel and diluted with water (13 L). Then it was extracted with ethyl acetate (20 L×2) and the organic extracts were combined, washed with water (8 L), brine (8 L), dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 3:1). All fractions containing desired compound were combined and concentrated. The obtained solid was triturated with MTBE (250 mL), washed with MTBE (100 mL×2) and dried to obtain 100 g of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity. The mother liquor was concentrated and purified by column chromatography and trituration with MTBE again to give 4.5 g of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity. Yield: 45% for two steps.

Workup

  1. temperatureAfter cooling to RT
  2. customthe mixture was transferred to 50 L separatory funnel
  3. extractionThen it was extracted with ethyl acetate (20 L×2)
  4. washwashed with water (8 L), brine (8 L)
  5. customdried
  6. concentrationconcentrated
  7. customThe resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 3:1)
  8. additionAll fractions containing desired compound
  9. concentrationconcentrated
  10. customThe obtained solid was triturated with MTBE (250 mL)
  11. washwashed with MTBE (100 mL×2)
  12. customdried

Sources & evidence

ORD record
ord-e68a1d1ab4374645914e72c7ae57b9e6
Source dataset
uspto-grants-2015_02
Patent number
US08957073B2

Reaction notes

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