Dimethylformamide → 5-(2-Cyclopropylmethylamino-thiazol-4-yl)-pyridine-2-carbonitrile

HRID 1191085Notes

Reaction equation

Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:18][N:19](C=O)C>CCOC(C)=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:15]1([CH2:14][NH:13][C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([C:18]#[N:19])=[N:7][CH:6]=3)[N:9]=2)[CH2:17][CH2:16]1

Participants

Conditions

Temperature: 115 °C

Procedure

Slurry 6-bromo-3-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine (1.1 g, 3.6 mmol), 1,1′-bis-(diphenylphosphino)ferrocene (320 mg, 0.6 mmol), zinc cyanide (337 mg, 2.9 mmol) and tris(dibenzylideneacetone)dipalladium(0) (231 mg, 0.25 mmol) in wet DMF (6 mL). Stir the mixture in a sealed tube at 115° C. for 6 h. Cool the mixture to room temperature, dilute with EtOAc (50 mL) and wash with 5% aqueous sodium chloride (3×30 mL). Collect the organic layer and concentrate in vacuo. Purify the residue by chromatography on silica gel (40 g) eluting with hexane/(THF with 1% methanol) (4:1) to obtain the desired intermediate (350 mg, 38%). MS (ES+) m/z: 257.3 (M+H)+.

Workup

temperatureCool the mixture to room temperature
washwash with 5% aqueous sodium chloride (3×30 mL)
customCollect the organic layer
concentrationconcentrate in vacuo
customPurify the residue by chromatography on silica gel (40 g)
washeluting with hexane/(THF with 1% methanol) (4:1)

Sources & evidence

ORD record: ord-d31dcfd8b2e440fb89eaabd5ea49520c
Source dataset: uspto-grants-2014_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08680091B2

Reaction notes

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