2-Amino-5-cyanopyridine → (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-cyanopyridin-2-yl)propanamide

HRID 1098166Notes

Reaction equation

HRID 1098166 reaction equation
C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=3)[N:49]=[CH:50][C:43]=12)[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=3)[N:49]=[CH:50][C:43]=12)[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1

Participants

5

Reactant 3

HCID 8182602-Amino-5-cyanopyridineHCID 16682925TrimethylaluminumHCID 59279503(2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate

Product 1

HCID 57504516(2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-cyanopyridin-2-yl)propanamideYield 17.6%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M in hexane) (0.455 mL, 0.91 mmol) was added to 6-aminonicotinonitrile (104 mg, 0.87 mmol) in toluene (10 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AB2) (500 mg, 0.79 mmol) in toluene (2 mL) was added and the reaction was allowed to warm to room temperature. The temperature was increased to 60° C. and stirred for 4 hours, then heated at reflux for 24 hours. The reaction mixture was concentrated in vacuo and neutralised with citric acid (1M, aq) and then diluted with water (10 ml) and DCM (10 mL). The mixture was poured onto a phase separator and the organic layer was evaporated in vacuo. The crude product 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. Fractions containing the desired compound were neutralised with MP-carbonate and evaporated to dryness to afford the product (100 mg, 17.6%). m/z (ES+) (M+H)+=719.51; HPLC tR=3.58 min.

Workup

  1. temperatureto warm to room temperature
  2. temperatureThe temperature was increased to 60° C.
  3. stirringstirred for 4 hours
  4. temperatureheated
  5. temperatureat reflux for 24 hours
  6. concentrationThe reaction mixture was concentrated in vacuo
  7. additiondiluted with water (10 ml) and DCM (10 mL)
  8. additionThe mixture was poured onto a phase separator
  9. customthe organic layer was evaporated in vacuo
  10. customThe crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length)
  11. additionFractions containing the desired compound
  12. customevaporated to dryness

Sources & evidence

ORD record
ord-a3ed486ccbad40879d93ef0e83521b30
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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