Citric Acid → (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)-N-(5-methylpyridin-2-yl)propanamide

HRID 1098224Notes

Reaction equation

HRID 1098224 reaction equation
[H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[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:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:40]=2[N:41]=[CH:42][N:43]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:40]=2[N:41]=[CH:42][N:43]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1

Participants

6

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 57438615HCID 57438615, compoundHCID 57504665(S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide

Product 1

HCID 57504424(2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)-N-(5-methylpyridin-2-yl)propanamideYield 91%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (50.1 mg, 1.25 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AU2) (250 mg, 0.52 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 7-chloro-3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (Intermediate AP2) (278 mg, 1.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (15 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane to give (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)-N-(5-methylpyridin-2-yl)propanamide (335 mg, 91%). 1H NMR (400 MHz, CDCl3) δ0.97 (s, 9H), 2.28 (s, 3H), 3.67-3.84 (m, 4H), 4.26 (d, 2H), 6.15 (t, 1H), 7.30-7.41 (m, 5H), 7.48-7.71 (m, 10H), 8.06-8.14 (m, 2H), 8.68 (s, 1H), 8.76 (s, 1H); m/z (ES+), (M+H)+=708.65; HPLC tR=3.84 min

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour
  3. customthe majority of the THF removed in vacuo
  4. additionThe reaction mixture was diluted with water (20 mL) and EtOAc (50 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with EtOAc (2×50 mL)
  7. washThe combined organics were washed with saturated brine (15 mL)
  8. dry with materialdried (MgSO4)
  9. customevaporated
  10. customThe crude product was purified by flash silica chromatography
  11. washeluting with 0 to 50% EtOAc in isohexane

Sources & evidence

ORD record
ord-e3397b39012e4640955ed656d08ba079
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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