Hydrochloric Acid → Tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(phenylcarbamoyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

HRID 384637Notes

Reaction equation

HRID 384637 reaction equation
[OH-].[Li+].[C:3]([C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12]2[CH:21]=[C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:15]([C:16](OC)=[O:17])=[CH:14][N:13]=2)=[N:9][CH:10]=1)#[N:4].Cl.C(N(CC)CC)C.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CN([C:48]([O:52]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:67]([OH:71])([CH3:70])([CH3:69])[CH3:68]>O.CN(C=O)C>[C:3]([C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12]2[CH:21]=[C:20]([NH:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:48]([O:71][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:52])[CH2:28][CH2:29]3)[C:15]([C:16](=[O:17])[NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:14][N:13]=2)=[N:9][CH:10]=1)#[N:4]

Participants

10

Reactant 7

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 6115AnilineHCID 6386tert-ButanolHCID 8471TriethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 42610232Methyl 6-[(5-cyano-2-pyrazinyl)amino]-4-[(4-piperidinylmethyl)amino]nicotinate

Product 1

HCID 59613455Tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(phenylcarbamoyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylateYield 42%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

Lithium hydroxide (3 mg, 0.12 mmol) was added to a solution of methyl 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)nicotinate (30 mg, 0.06 mmol) in a mixture of tert-butanol and water (2:1, 0.3 mL). The reaction mixture was stirred for 4 days at room temperature then acidified to pH 3-4 with 1M HCl and extracted with ethyl acetate. The organic extract was dried (Na2SO4) and solvent was evaporated. The crude acid was used in the next step without further purification. Triethylamine (10.0 μL, 0.07 mmol) was added to a solution of the acid (29 mg, 0.06 mmol), aniline (4.8 μL, 0.05 mmol) and TBTU (24 mg, 0.06 mmol) in DMF (0.3 mL). The reaction mixture was stirred overnight at room temperature. The mixture was purified by ion exchange chromatography on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated. Preparative TLC, eluting with ethyl acetate-hexane (1:1) gave tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(phenylcarbamoyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate as a yellow solid (12 mg, 42%).

Workup

  1. extractionextracted with ethyl acetate
  2. extractionThe organic extract
  3. dry with materialwas dried (Na2SO4) and solvent
  4. customwas evaporated
  5. customThe crude acid was used in the next step without further purification
  6. stirringThe reaction mixture was stirred overnight at room temperature
  7. customThe mixture was purified by ion exchange chromatography on SCX-II acidic resin (500 mg)
  8. washeluting with methanol
  9. customsolvent was evaporated
  10. washPreparative TLC, eluting with ethyl acetate-hexane (1:1)

Sources & evidence

ORD record
ord-4dfd243c04304d9c9a84124a0501458c
Source dataset
uspto-grants-2013_02
Patent number
US08367658B2

Reaction notes

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