2-Amino-5-fluoropyridine → HCID 57504539, compound

HRID 1098217Notes

Reaction equation

HRID 1098217 reaction equation
C[Al](C)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH2:21][C@H:22]([O:24][CH2:25][C@H:26]([O:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:27](OC)=[O:28])[CH3:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Si:13]([O:20][CH2:21][C@H:22]([O:24][CH2:25][C@H:26]([O:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:27]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=1)=[O:28])[CH3:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]

Participants

7

Reactant 4

HCID 27377012-Amino-5-fluoropyridineHCID 9855836Potassium sodium tartarateHCID 16682925TrimethylaluminumHCID 59279450HCID 59279450, compound

Product 1

HCID 57504539HCID 57504539, compoundYield 61.4%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M in hexane)(0.474 mL, 0.95 mmol) was added to 5-fluoropyridin-2-amine (102 mg, 0.91 mmol) in toluene (7 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-Methyl 3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AN2) (430 mg, 0.82 mmol) in toluene (7 mL) was added and the reaction was allowed to warm to room temperature and then heated to 100° C. for 5 hours in the microwave reactor. The reaction was allowed to cool to room temperature before adding EtOAc (30 mL) and 20% sodium potassium tartrate solution (30 mL), which was stirred vigorously for 16 hours. The phases were separated and the organic layer was washed with sat. brine (15 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to give (2S)-3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide (303 mg, 61.1%). 1H NMR (400 MHz, DMSO) δ-0.01 (d, 6H), 0.80 (s, 9H), 1.09 (d, 3H), 3.46-3.63 (m, 2H), 3.67-3.77 (m, 1H), 4.07-4.20 (m, 2H), 5.90-5.95 (m, 1H), 7.71-7.80 (m, 2H), 8.02-8.08 (m, 1H), 8.33-8.39 (m, 2H), 8.58 (s, 1H), 8.63 (s, 1H), 8.67-8.71 (m, 1H), 11.09 (s, 1H); m/z (ES+), (M+H)+=602.48; HPLC tR=3.33 min

Workup

  1. temperatureto warm to room temperature
  2. temperatureheated to 100° C. for 5 hours in the microwave reactor
  3. temperatureto cool to room temperature
  4. stirringwas stirred vigorously for 16 hours
  5. customThe phases were separated
  6. washthe organic layer was washed with sat. brine (15 mL)
  7. dry with materialdried (MgSO4)
  8. customevaporated
  9. customThe crude product was purified by flash silica chromatography
  10. washeluting with 30 to 50% EtOAc in isohexane

Sources & evidence

ORD record
ord-0bdd3a9cede94ee48b707fab5fbfb1e9
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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