Potassium Sodium Tartrate → (2S)-3-[2-(tert-butyl-diphenylsilyl)oxyethoxy]-2-[1-(3-chloro-2-methylphenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5-cyanopyridin-2-yl)propanamide

HRID 1098177Notes

Reaction equation

HRID 1098177 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[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[C:52]=3[CH3:58])[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.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[C:43]2[CH:50]=[N:49][N:48]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[C:52]=3[CH3:58])[C:44]=2[N:45]=[CH:46][N:47]=1)[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

7

Reactant 4

HCID 9357Potassium Sodium TartrateHCID 8182602-Amino-5-cyanopyridineHCID 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 57504520(2S)-3-[2-(tert-butyl-diphenylsilyl)oxyethoxy]-2-[1-(3-chloro-2-methylphenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5-cyanopyridin-2-yl)propanamideYield 92.2%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent4×HCID 8857Ethyl AcetateSolvent

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 6-aminonicotinonitrile (0.426 g, 3.58 mmol) in toluene (15 mL) cooled to 0° C., over a period of 2 minutes under nitrogen and the resulting suspension stirred for 20 minutes at 0° C. 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. Cooled to ˜5° C. and a 10% solution of Rochelle's salt (25 mL) added followed by ethyl acetate (30 mL) and stirred at ambient temperature for 30 minutes. The organic phase was separated, washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated to a yellow gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (1.1 g, 92%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, s), 2.03 (3H, s), 3.71-3.78 (4H, m), 4.05-4.10 (1H, m), 4.14-4.19 (1H, m), 6.00-6.02 (1H, m), 7.34-7.45 (8H, m), 7.59-7.61 (4H, m), 7.67-7.69 (1H, m), 8.11-8.14 (1H, m), 8.20-8.23 (1H, m), 8.51 (1H, s), 8.84 (1H, s), 8.80-8.82 (1H, m), 11.55 (1H, s); m/z (ESI+) (M+H)+=732; HPLC tR=3.48 min.

Workup

  1. temperatureto warm to ambient temperature
  2. temperatureheated to 60° C. for 20hrs
  3. temperatureCooled to ˜5° C.
  4. stirringstirred at ambient temperature for 30 minutes
  5. customThe organic phase was separated
  6. washwashed with water (20 mL) and brine (20 mL)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. customevaporated to a yellow gum
  10. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane

Sources & evidence

ORD record
ord-c579b85a55b842d5b83082e5dffe6775
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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