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

HRID 2367478Notes

Reaction equation

HRID 2367478 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+].[C:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:37])(=[O:27])[CH3:26]>O1CCOCC1.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.CCOC(C)=O>[C:25]([C:28]1[CH:33]=[CH:32][C:31]([C:6]2[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([N:16]3[C@H:11]([CH3:10])[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15]3)[CH:7]=2)=[CH:30][C:29]=1[F:37])(=[O:27])[CH3:26]

Participants

9

Reactant 4

HCID 655222-Amino-4,6-dichloropyrimidine2×HCID 516892Sodium BicarbonateHCID 121330274-Acetyl-3-fluorophenylboronic acidHCID 58504783(3S,6R)-6-Methylpiperidine-3-carboxylic acid

Product 1

HCID 58504564(3S,6R)-1-[6-(4-Acetyl-3-fluorophenyl)-2-amino-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acidYield 48.7%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent3×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
117 °C

Procedure

A mixture of 4,6-dichloro-2-pyrimidinamine (1.69 g, 10.31 mmol), (3S,6R)-6-methyl-3-piperidinecarboxylic acid (2.037 g, 10.31 mmol) and NaHCO3 (3.90 g, 46.4 mmol) in 1,4-dioxane (100 mL) and water (50 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 (4-acetyl-3-fluorophenyl)boronic acid (2.81 g, 15.5 mmol) and Pd(Ph3P)4 (0.238 g, 0.206 mmol) were added, and the reaction mixture was stirred for 24 hours at 117° C. The mixture was poured into water (300 mL) and EtOAc (200 mL). At this moment the pH of the solution was 9. The compound stayed in the water layer. The water layer was separated from the organic layer. There was some black colored and yellow colored suspension in the warer layer, which was filtered out. (They were not product). To the aqueous layer, 6N HCl was added dropwise until the pH=4. A precipitate was formed. The precipitate was filtered, washed with water, and dried to afford the title compound (1.87 g) as a light yellow solid. LC-MS (ES) m/z=373 [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. customThe water layer was separated from the organic layer
  5. filtrationwas filtered out
  6. additionTo the aqueous layer, 6N HCl was added dropwise until the pH=4
  7. customA precipitate was formed
  8. filtrationThe precipitate was filtered
  9. washwashed with water
  10. customdried

Sources & evidence

ORD record
ord-d80d0d0ae3654546a619ff589573bb96
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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