2-Amino-5-methylpyridine → HCID 57504320, compound

HRID 1097986Notes

Reaction equation

HRID 1097986 reaction equation
F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2=[N:37][CH:38]=[N:39][C:40]([O:41][C@@H:42]([CH2:46][O:47][CH:48]([CH3:50])[CH3:49])[C:43]([OH:45])=O)=[C:35]2[CH:34]=[N:33]1.[CH3:51][C:52]1[CH:53]=[CH:54][C:55]([NH2:58])=[N:56][CH:57]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2=[N:37][CH:38]=[N:39][C:40]([O:41][C@@H:42]([CH2:46][O:47][CH:48]([CH3:50])[CH3:49])[C:43]([NH:58][C:55]3[CH:54]=[CH:53][C:52]([CH3:51])=[CH:57][N:56]=3)=[O:45])=[C:35]2[CH:34]=[N:33]1

Participants

6

Reactant 4

HCID 153482-Amino-5-methylpyridineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57504479HCID 57504479, compound

Product 1

HCID 57504320HCID 57504320, compoundYield 47.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (333 mg, 0.88 mmol) was added to (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoic acid D2 (300 mg, 0.80 mmol), 5-methylpyridin-2-amine (95 mg, 0.88 mmol) and N-ethyldiisopropylamine (0.153 mL, 0.88 mmol) in DCM (15 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM (25 mL) and washed with saturated brine (20 mL). The aqueous layer was re-extracted with DCM (30 mL). The combined organics were evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (175 mg, 47.1%), 10% ee. 143 mg of this material was further purified by chiral preparative HPLC on Chiralcel OJ (50 mm×20 μm), eluent isohexane/EtOH/MeOH 70/15/15 to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (56 mg, >99% ee which eluted after the R enantiomer).

Workup

  1. washwashed with saturated brine (20 mL)
  2. extractionThe aqueous layer was re-extracted with DCM (30 mL)
  3. customThe combined organics were evaporated
  4. customto afford crude product
  5. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane
  6. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-a7c94cc864b94133856bc9c876956ffa
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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