Sodium Bicarbonate → 4-Amino-6-chloro-5-cyano-N-((1-((2-(pyridin-2-yl)thiazol-5-yl)methyl)piperidin-4-yl)methyl)picolinamide

HRID 2407726Notes

Reaction equation

HRID 2407726 reaction equation
[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([C:11]([OH:13])=O)[CH:3]=1.Cl.Cl.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[S:24][C:25]([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]2)=[CH:26][N:27]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([C:11]([NH:36][CH2:35][CH:32]2[CH2:33][CH2:34][N:29]([CH2:28][C:25]3[S:24][C:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)=[N:27][CH:26]=3)[CH2:30][CH2:31]2)=[O:13])[CH:3]=1

Participants

9

Reactant 4

HCID 516892Sodium BicarbonateHCID 2724699PyBOPHCID 66989375(1-((2-(Pyridin-2-yl)thiazol-5-yl)methyl)piperidin-4-yl)methanamine TrihydrochlorideHCID 714642104-Amino-6-chloro-5-cyanopicolinic acid

Product 1

HCID 585040794-Amino-6-chloro-5-cyano-N-((1-((2-(pyridin-2-yl)thiazol-5-yl)methyl)piperidin-4-yl)methyl)picolinamide

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Procedure

4-Amino-6-chloro-5-cyanopicolinic acid (1.053 g, prepared according to the reported preparation in Zhao, Hongyu, et al.; J. Med. Chem. 2006, 49(15), 4455-4458), the compound prepared in Example 214 (2.12 g), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (3.33 g) and triethylamine (7.43 mL) were suspended in N,N-dimethylformamide (100 mL) and stirred at room temperature over weekend. The reaction mixture was poured onto saturated aqueous sodium bicarbonate solution and ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material. The crude material was slurried with dichloromethane and the desired material precipitated out of solution. The solids was filtered and washed with dichloromethane to afford clean material. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (gradient elution: 100% ethyl acetate to 96.5% ethyl acetate, 2.5% triethylamine 1% methanol) to afford pure material, which was combined with the triturated material to give the title compound (1.69 g), with the following physical data.

Workup

  1. customaccording to the reported preparation in Zhao, Hongyu, et al.
  2. washThe organics were washed with brine
  3. dry with materialdried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customto afford the crude material
  7. customthe desired material precipitated out of solution
  8. filtrationThe solids was filtered
  9. washwashed with dichloromethane
  10. customto afford clean material
  11. concentrationThe filtrate was concentrated under reduced pressure
  12. custompurified by flash column chromatography (gradient elution: 100% ethyl acetate to 96.5% ethyl acetate, 2.5% triethylamine 1% methanol)
  13. customto afford pure material, which

Sources & evidence

ORD record
ord-f2530feaaf7c417681871719fc35138c
Source dataset
uspto-grants-2014_08
Patent number
US08809538B2

Reaction notes

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