6-Chloronicotinic acid → 4-[(6-Chloro-pyridine-3-carbonyl)-amino]-4-cyano-piperidine-1-carboxylic acid tert-butyl ester

HRID 913337Notes

Reaction equation

HRID 913337 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][N:46]=1>C1COCC1.C(N(C(C)C)C(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:49]([C:48]2[CH:47]=[N:46][C:45]([Cl:44])=[CH:53][CH:52]=2)=[O:50])([C:14]#[N:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 3

HCID 792226-Chloronicotinic acidHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 22091429tert-Butyl 4-amino-4-cyanopiperidine-1-carboxylate

Product 1

HCID 866250164-[(6-Chloro-pyridine-3-carbonyl)-amino]-4-cyano-piperidine-1-carboxylic acid tert-butyl esterYield 74%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 81531DiisopropylethylamineSolvent

Procedure

To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.527 g, 2.34 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in anhydrous THF (12 mL) and N-ethyl diisopropylamine (0.48 mL) was added in the presence of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.138 g, 2.58 mmol, 1.1 equiv; BOP reagent) 6-chloro-nicotinic acid (0.369 g, 2.34 mmol, 1.0 equiv) and the reaction mixture stirred at rt for 12 h. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of ethyl acetate/triethylamine (97:3) providing 0.63 g (74%) of the title compound as off-white solid. MS (ISP): 365.1 [M+H]+

Workup

  1. additionThe reaction mixture was poured
  2. extractionextracted with ethyl acetate (2×200 mL)
  3. washthe combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL)
  4. dry with materialThe organic phase was dried over Na2SO4
  5. concentrationconcentrated by evaporation under reduced pressure
  6. customthe crude material purified by silica column chromatography
  7. washeluting with a mixture of ethyl acetate/triethylamine (97:3)

Sources & evidence

ORD record
ord-bb85cba21d9044e69a0a732942fb99a8
Source dataset
uspto-grants-2011_09
Patent number
US08026365B2

Reaction notes

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