Ethyl Acetate → (2S)-3-[2-(tert-butyl-dimethylsilyl)oxyethoxy]-2-[1-(3-chloro-2-methylphenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5-methylpyridin-2-yl)propanamide

HRID 1098179Notes

Reaction equation

HRID 1098179 reaction equation
C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1C=CC=CC=1)[C:14]1C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[C:42]2[CH:49]=[N:48][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[CH3:57])[C:43]=2[N:44]=[CH:45][N:46]=1)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:20])[CH3:14]

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 153482-Amino-5-methylpyridineHCID 16682925TrimethylaluminumHCID 59279525(2S)-Methyl 3-[2-(tert-butyl-diphenylsilyl)oxyethoxy]-2-[1-(3-chloro-2-methylphenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanoate

Product 1

HCID 57504652(2S)-3-[2-(tert-butyl-dimethylsilyl)oxyethoxy]-2-[1-(3-chloro-2-methylphenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5-methylpyridin-2-yl)propanamideYield 113%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent4×

Conditions

Temperature
0 °C

Procedure

A solution of 2M trimethyl aluminium in toluene (1.790 mL, 3.58 mmol) in toluene (15 mL) was added dropwise to a stirred suspension of 5-methylpyridin-2-amine (0.387 g, 3.58 mmol) in toluene (15 mL) cooled to 0° C., over a period of 2 minutes under nitrogen and the resulting suspension was stirred at 0° C. for 20 minutes. A solution of (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AE2) (1.05 g, 1.63 mmol) in toluene (10 mL) was added dropwise over 2 minutes, the mixture allowed to warm to ambient temperature and then heated to 60° C. for 20hrs. The reaction was cooled to ˜5° C. and a 10% solution of Rochelles salt (25 mL) added followed by ethyl acetate (30 mL). The organic phase was separated, washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in iso-hexane to afford the product (1.1 g, 94%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, s), 2.03 (3H, s), 2.24 (3H, s), 3.70-3.79 (4H, m), 4.03-4.07 (1H, m), 4.12-4.16 (1H, m), 5.99-6.00 (1H, m), 7.33-7.47 (8H, m), 7.55-7.62 (5H, m), 7.67-7.69 (1H, m), 7.86-7.89 (1H, m), 8.17-8.18 (1H, m), 8.50 (1H, s), 8.53 (1H, s), 10.87 (1H, s); m/z (ESI+) (M+H)+=721; HPLC tR=3.63 min.

Workup

  1. temperatureto warm to ambient temperature
  2. temperatureheated to 60° C. for 20hrs
  3. temperatureThe reaction was cooled to ˜5° C.
  4. customThe organic phase was separated
  5. washwashed with water (20 mL) and brine (20 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in iso-hexane

Sources & evidence

ORD record
ord-9b72f3b2900a485a87f0d75106c90fb2
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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