Dimethylacetamide → 4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile

HRID 1852871Notes

Reaction equation

HRID 1852871 reaction equation
C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:48]1[N:53]=[C:52]([C:54]2[CH:55]=[N:56][CH:57]=[C:58]([Cl:60])[CH:59]=2)[C:51]2[N:61]([CH2:73][C:74]3[CH:79]=[CH:78][C:77]([C:80]([F:83])([F:82])[F:81])=[CH:76][CH:75]=3)[C:62]([N:64]3[CH2:69][CH2:68][O:67][C@@H:66]4[CH2:70][CH2:71][CH2:72][C@@H:65]34)=[N:63][C:50]=2[CH:49]=1.[CH3:84][N:85](C)C(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:60][C:58]1[CH:59]=[C:54]([C:52]2[C:51]3[N:61]([CH2:73][C:74]4[CH:75]=[CH:76][C:77]([C:80]([F:83])([F:81])[F:82])=[CH:78][CH:79]=4)[C:62]([N:64]4[CH2:69][CH2:68][O:67][C@@H:66]5[CH2:70][CH2:71][CH2:72][C@@H:65]45)=[N:63][C:50]=3[CH:49]=[C:48]([C:84]#[N:85])[N:53]=2)[CH:55]=[N:56][CH:57]=1

Participants

7

Reactant 3

HCID 31374DimethylacetamideHCID 634876Binap, (A+-)-HCID 867246126-chloro-4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine

Product 1

HCID 867246134-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalystHCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
80 °C

Procedure

Palladium(II) acetate (70 mg, 0.312 mmol) and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (195 mg, 0.313 mmol) were placed in a dry flask. N,N-dimethylacetamide (18.7 mL) was added and the mixture was degassed for three minutes with nitrogen. Sulfuric acid (0.015 mL) was added, and the mixture was degassed for an additional three minutes with nitrogen. The flask was sealed and heated to 80° C. for 30 minutes. The mixture was cooled to room temperature and added to a separate nitrogen purged flask containing 6-chloro-4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine (racemic; 0.5 g, 0.9 mmol), zinc cyanide (46 mg, 0.45 mmol), and zinc (6 mg, 0.09 mmol). The flask was purged with nitrogen for five minutes, sealed, and heated to 100° C. for 2 hrs. The reaction mixture was cooled to room temperature, filtered, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (racemic). MS APCI calc'd. for C27H22ClF3N6O [M+H]+ 539. found 539.

Workup

  1. customthe mixture was degassed for three minutes with nitrogen
  2. additionSulfuric acid (0.015 mL) was added
  3. customthe mixture was degassed for an additional three minutes with nitrogen
  4. customThe flask was sealed
  5. temperatureThe mixture was cooled to room temperature
  6. additionadded to a separate nitrogen purged flask
  7. customThe flask was purged with nitrogen for five minutes
  8. customsealed
  9. temperatureheated to 100° C. for 2 hrs
  10. temperatureThe reaction mixture was cooled to room temperature
  11. filtrationfiltered
  12. additiondiluted with ethyl acetate
  13. washwashed with water and brine
  14. dry with materialThe organic layer was dried over sodium sulfate
  15. filtrationfiltered
  16. concentrationconcentrated under reduced pressure
  17. customThe residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient)

Sources & evidence

ORD record
ord-36bc651c4d9d47658ea60d41ba448e5f
Source dataset
uspto-grants-2015_02
Patent number
US08962611B2

Reaction notes

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