Citric Acid → (2S)-Methyl 3-[2-(tert-butyl-diphenylsilyl)oxyethoxy]-2-[1-(3-chloro-2-methylphenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanoate

HRID 1098178Notes

Reaction equation

HRID 1098178 reaction equation
[H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[C:33]2[CH:40]=[N:39][N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=3[CH3:48])[C:34]=2[N:35]=[CH:36][N:37]=1)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 57438658HCID 57438658, compoundHCID 59279512(S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate

Product 1

HCID 59279525(2S)-Methyl 3-[2-(tert-butyl-diphenylsilyl)oxyethoxy]-2-[1-(3-chloro-2-methylphenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanoateYield 82%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% in mineral oil) (0.191 g, 4.77 mmol) was added in one portion to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (1.6 g, 3.97 mmol) in THF (15 mL) cooled to 0° C. under nitrogen. Slow gas evolution. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AE5) (1.109 g, 3.97 mmol) in THF (10 mL) was added dropwise over 2 minutes. The resulting suspension was stirred at 0° C. for 10 minutes, allowed to warm to ambient temperature and stirred for 72 hours to give an orange solution. Cooled to ˜5° C., 1M citric acid (30 mL) added, the mixture stirred for 10 minutes, diluted with EtOAc (50 mL), the organic phase separated and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (2.1 g, 82%). 1H NMR (400 MHz, DMSO) δ 0.95 (9H, s), 2.03 (3H, s), 3.68 (3H, s), 3.67-3.74 (2H, m), 3.78-3.82 (2H, m), 4.04-4.07 (1H, m), 5.87-5.91 (1H, m), 7.37-7.45 (8H, m), 7.61-7.65 (4H, m), 7.67-7.69 (1H, m), 8.48 (1H, s), 8.57 (1H, s); m/z (ESI+) (M+H)+=645; HPLC tR=3.65 min.

Workup

  1. stirringThe resulting suspension was stirred at 0° C. for 10 minutes
  2. temperatureto warm to ambient temperature
  3. stirringstirred for 72 hours
  4. customto give an orange solution
  5. temperatureCooled to ˜5° C.
  6. stirringthe mixture stirred for 10 minutes
  7. customthe organic phase separated
  8. washwashed sequentially with water (25 mL) and saturated brine (25 mL)
  9. dry with materialThe organic layer was dried (MgSO4)
  10. filtrationfiltered
  11. customevaporated in vacuo
  12. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane

Sources & evidence

ORD record
ord-b4a2641a7d0e4b9ab04b02497b2cc377
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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