2-Amino-4,6-dichloropyrimidine → (3S,6R)-1-[2-amino-6-(1H-indazol-6-yl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid

HRID 2367481Notes

Reaction equation

HRID 2367481 reaction equation
Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C@H:11]1[NH:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH:27]=[N:26]1>O1CCOCC1.O.CCOC(C)=O.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.C(O)(C)C>[NH2:9][C:4]1[N:5]=[C:6]([N:16]2[C@H:11]([CH3:10])[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15]2)[CH:7]=[C:2]([C:31]2[CH:32]=[C:33]3[C:28]([CH:27]=[N:26][NH:25]3)=[CH:29][CH:30]=2)[N:3]=1

Participants

10

Reactant 4

HCID 655222-Amino-4,6-dichloropyrimidine2×HCID 516892Sodium BicarbonateHCID 441192506-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazoleHCID 58504783(3S,6R)-6-Methylpiperidine-3-carboxylic acid

Product 1

HCID 58504583(3S,6R)-1-[2-amino-6-(1H-indazol-6-yl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acidYield 22.1%

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
117 °C

Procedure

A mixture of 4,6-dichloro-2-pyrimidinamine (0.2 g, 1.22 mmol), (3S,6R)-6-methyl-3-piperidinecarboxylic acid (0.265 g, 1.342 mmol) and NaHCO3 (V, 6.10 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was stirred overnight at 117° C. into a sealed tube. The reaction was allowed to cool to room temperature. LCMS showed that most of the starting material 4,6-dichloro-2-pyrimidinamine had been consumed. Then 1H-indazole-6-boronic acid pinacol ester (0.327 g, 1.342 mmol) and Pd(Ph3P)4 (0.028 g, 0.024 mmol) were added, and the reaction mixture was stirred for 24 hours at 117° C. The mixture was poured into water (200 mL). The formed solid was filtered. To the aqueous layer, 6N HCl was added dropwise until the pH=4. A precipitate was formed and the solution looked cloudy. A solution of 10% isopropanol in EtOAc (200 mL) was used to extract the compound, but most of the compound stayed in water. This organic layer was discarded. Then a solution of 10% isopropanol in CH2Cl2 (100 mL) was used for the extraction. The mixture turned cloudy after sitting for 30 minutes, and a significant amount of solid was formed. The white solid was filtered, washed with water, and dried to afford the title compound (95 mg) as a white solid. LC-MS (ES) m/z=353 [M+H]+.

Workup

  1. temperatureto cool to room temperature
  2. customhad been consumed
  3. stirringthe reaction mixture was stirred for 24 hours at 117° C
  4. filtrationThe formed solid was filtered
  5. additionTo the aqueous layer, 6N HCl was added dropwise until the pH=4
  6. customA precipitate was formed
  7. extractionto extract the compound
  8. extractionThen a solution of 10% isopropanol in CH2Cl2 (100 mL) was used for the extraction
  9. waitafter sitting for 30 minutes
  10. customa significant amount of solid was formed
  11. filtrationThe white solid was filtered
  12. washwashed with water
  13. customdried

Sources & evidence

ORD record
ord-f30b7515904a49de82e01c4cb4b21995
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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