2-Amino-5-fluoropyridine → (2S)-3-((S)-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

HRID 1098220Notes

Reaction equation

HRID 1098220 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 59279482(2S)-methyl 3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate

Product 1

HCID 57504540(2S)-3-((S)-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)propanamideYield 100%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M in hexanes)(0.608 mL, 1.22 mmol) was added to 5-fluoropyridin-2-amine (130 mg, 1.16 mmol) in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AO2) (552 mg, 1.06 mmol) in toluene (8 mL) was added and the reaction was 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 to afford the product (638 mg, 100%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 0.05 (d, 6H), 0.87 (s, 9H), 1.17 (d, 3H), 3.51-3.58 (m, 1H), 3.60-3.69 (m, 2H), 4.18-4.22 (m, 2H), 6.00 (t, 1H), 7.40-7.49 (m, 2H), 7.98-8.03 (m, 1H), 8.13 (d, 1H), 8.22-8.28 (m, 1H), 8.44 (s, 1H), 8.60-8.64 (m, 2H), 8.94 (s, 1H); m/z (ES+), (M+H)+=602.55; HPLC tR=3.35 min

Workup

  1. temperaturethe reaction was heated to 100° C. for 5 hours in the microwave reactor
  2. temperatureto cool to room temperature
  3. stirringwas stirred vigorously for 16 hours
  4. customThe phases were separated
  5. washthe organic layer was washed with sat. brine (15 mL)
  6. dry with materialdried (MgSO4)
  7. customevaporated

Sources & evidence

ORD record
ord-71859fd958cc4c4ca007743a6b62c0d1
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

Loading…