Acetonitrile → 2-(cis-2,6-Dimethyl-morpholin-4-yl)-thiazole-4-carbonitrile

HRID 473975Notes

Reaction equation

HRID 473975 reaction equation
Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)[S:5][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](#[N:36])C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C@H:9]1[O:10][C@@H:11]([CH3:13])[CH2:12][N:7]([C:4]2[S:5][CH:6]=[C:2]([C:34]#[N:36])[N:3]=2)[CH2:8]1

Participants

6

Reactant 3

HCID 6342AcetonitrileHCID 11776TriphenylphosphineHCID 672168964-(4-Bromo-thiazol-2-yl)-cis-2,6-dimethyl-morpholine

Product 1

HCID 672160172-(cis-2,6-Dimethyl-morpholin-4-yl)-thiazole-4-carbonitrileYield 60%

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
140 °C

Procedure

A mixture of Intermediate 1 (52.8 g, 190.49 mmol), triphenylphosphine (4.99 g, 19.05 mmol), zinc cyanide (22.37 g, 190.49 mmol) and dry acetonitrile (360 mL) was introduced in a pressure tube and was degassed with nitrogen for 5 min. Tetrakis(triphenylphosphine)palladium (11 g, 9.52 mmol) was added and the mixture was further degassed for 5 min. The tube was sealed and the reaction mixture was stirred at 140° C. for 3 h. The suspension was evaporated and taken up in water/DCM. The combined organic layer was separated, filtered on a plug of diatomaceous earth, dried on MgSO4, filtered off, and evaporated. The residue was purified on an 800 g EasyVarioPrep (Merck) column (eluent: DCM). The desired fractions were concentrated in vacuo and dried in a vacuum oven at 50° C. overnight, yielding 25.6 g (60%) of Intermediate 2 as a yellow solid.

Workup

  1. additionwas introduced in a pressure tube
  2. customwas degassed with nitrogen for 5 min
  3. customthe mixture was further degassed for 5 min
  4. customThe tube was sealed
  5. customThe suspension was evaporated
  6. customThe combined organic layer was separated
  7. filtrationfiltered on a plug of diatomaceous earth
  8. customdried on MgSO4
  9. filtrationfiltered off
  10. customevaporated
  11. customThe residue was purified on an 800 g EasyVarioPrep (Merck) column (eluent: DCM)
  12. concentrationThe desired fractions were concentrated in vacuo
  13. customdried in a vacuum oven at 50° C. overnight

Sources & evidence

ORD record
ord-04197a26a77e45b48e48162075efe4ed
Source dataset
uspto-grants-2014_01
Patent number
US08637510B2

Reaction notes

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