2-Amino-5-methylpyridine → (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)-4-(methylsulfonamido)butanamide

HRID 1098022Notes

Reaction equation

HRID 1098022 reaction equation
C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24]2=[N:25][CH:26]=[N:27][C:28]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[C:31]3=[O:39])=[C:23]2[CH:22]=[N:21]1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24]2=[N:25][CH:26]=[N:27][C:28]([O:29][C@@H:30]([CH2:34][CH2:33][NH:32][S:35]([CH3:38])(=[O:37])=[O:36])[C:31]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=3)=[O:39])=[C:23]2[CH:22]=[N:21]1

Participants

5

Reactant 3

HCID 153482-Amino-5-methylpyridineHCID 16682925TrimethylaluminumHCID 57504518HCID 57504518, compound

Product 1

HCID 57504390(2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)-4-(methylsulfonamido)butanamideYield 36%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M in hexane) (0.164 mL, 0.33 mmol) was added to 5-methylpyridin-2-amine (33.8 mg, 0.31 mmol) in toluene (5 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (3S)-3-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-1-(methylsulfonyl)pyrrolidin-2-one (Intermediate AC1) (116 mg, 0.28 mmol) in toluene (1 mL) was added and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was then heated to reflux for 2.5 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid and sodium potassium tartrate solution (sat.) and stirred vigorously for 45 mins. The mixture was separated and the aqueous re-extracted with ethyl acetate, the organic layer was dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (52.0 mg, 35.4%). 1H NMR (400 MHz, CDCl3) δ 2.30 (3H, s), 2.37-2.55 (2H, m), 2.98 (3H, s), 3.35-3.55 (2H, m), 4.95-5.10 (1H, m), 6.04 (1H, t), 7.44-7.58 (4H, m), 7.60-7.65 (1H, m), 8.07-8.15 (2H, m), 8.44 (1H, s), 8.61 (1H, s), 8.69 (1H, s); m/z (ES+) (M+H)+=516.28; HPLC tR=1.84 min.

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour
  3. temperatureThe reaction was then heated
  4. temperatureto reflux for 2.5 hours
  5. temperatureto cool
  6. concentrationconcentrated in vacuo
  7. stirringstirred vigorously for 45 mins
  8. customThe mixture was separated
  9. extractionthe aqueous re-extracted with ethyl acetate
  10. dry with materialthe organic layer was dried (MgSO4)
  11. customevaporated
  12. customThe residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length)

Sources & evidence

ORD record
ord-f436f7e476184d2d96c482495dcf32b4
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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