4-Methylmorpholine → tert-butyl 4-[[(Z)-[amino-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]methylidene]amino]carbamoyl]piperidine-1-carboxylate

HRID 1749675Notes

Reaction equation

HRID 1749675 reaction equation
F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([N:32]1[CH2:40][CH2:39][CH:35]([C:36]([OH:38])=O)[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN1CCOCC1.[NH2:48][C:49]1[N:50]=[CH:51][C:52](/[C:64](=[N:66]/[NH2:67])/[NH2:65])=[N:53][C:54]=1[C:55]1[O:56][C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])=[N:58][N:59]=1>CC(N(C)C)=O>[NH2:65]/[C:64](/[C:52]1[CH:51]=[N:50][C:49]([NH2:48])=[C:54]([C:55]2[O:56][C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])=[N:58][N:59]=2)[N:53]=1)=[N:66]\[NH:67][C:36]([CH:35]1[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:40][CH2:39]1)=[O:38]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 90283262N',5-diamino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carboximidamide

Product 1

HCID 90283740tert-butyl 4-[[(Z)-[amino-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]methylidene]amino]carbamoyl]piperidine-1-carboxylateYield 95.7%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (74.3 g, 195.44 mmol) was added to a solution of N-Boc-isonipecotic acid (41.1 g, 179.15 mmol) and 4-methylmorpholine (35.9 mL, 325.74 mmol) in DMA (800 mL). The mixture was stirred for 10 minutes then (Z)-5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbohydrazonamide (45 g, 162.87 mmol) was added to the solution in one portion (exotherm observed from 22° C. to 27° C.). After a few minutes the product crystallised from the reaction mixture. The reaction mixture was removed from the vessel and filtered through a sinter. Additional DMA was added to wash product from the sides of the vessel (150 mL) and this was poured onto the filter cake. Isopropanol (600 mL) was added to the vessel and the remainder of the product in the vessel was suspended in this solvent using vigorous agitation. The isopropanol suspension was used to wash the filter cake once the DMA had been removed by suction. The filter cake was sucked dry then washed with MTBE and sucked dry once again. The filter cake was dried in vacuo to afford (Z)-tert-butyl 4-(2-(amino(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)methylene)hydrazinecarbonyl)piperidine-1-carboxylate (76 g, 95%) as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.40 (9H, s), 1.46 (9H, s), 1.63-1.9 (2H, m), 2.33-2.6 (2H, m, obscured by DMSO signal), 2.63-3.03 (2H, m), 3.18-3.48 (4H, m, obscured by water signal), 3.88-4.11 (2H, m), 6.43 (2H, s), 7.76 (2H, br), 8.84 (0.5H, s), 8.87 (0.5H, s), 9.85 (1H, s); Mass Spectrum [M+H]+=488

Workup

  1. customAfter a few minutes the product crystallised from the reaction mixture
  2. customThe reaction mixture was removed from the vessel
  3. filtrationfiltered through a sinter
  4. additionAdditional DMA was added
  5. washto wash product from the sides of the vessel (150 mL)
  6. additionthis was poured onto the filter cake
  7. additionIsopropanol (600 mL) was added to the vessel
  8. washto wash the filter cake once the DMA
  9. customhad been removed by suction
  10. customThe filter cake was sucked dry
  11. washthen washed with MTBE
  12. customsucked dry once again
  13. customThe filter cake was dried in vacuo

Sources & evidence

ORD record
ord-852861bae40f46928d31850a1393ad54
Source dataset
uspto-grants-2015_10
Patent number
US09156831B2

Reaction notes

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