Hydrochloric Acid → (2S)-Methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate

HRID 1098131Notes

Reaction equation

HRID 1098131 reaction equation
[H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:22]=[CH:23][C:16]=12.Cl>C1COCC1>[Cl:30][C:29]1[C:24]([N:21]2[C:17]3=[N:18][CH:19]=[N:20][C:15]([O:3][C@@H:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6])=[C:16]3[CH:23]=[N:22]2)=[N:25][CH:26]=[CH:27][CH:28]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 575044824-Chloro-1-(3-chloropyridin-2-YL)-1H-pyrazolo[3,4-D]pyrimidine2×HCID 59279510(S)-methyl 2-hydroxy-3-isopropoxypropanoate

Product 1

HCID 59279531(2S)-Methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoateYield 64.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Sodium hydride (1.84 g, 45.9 mmol) was added to a stirred solution of (S)-methyl 2-hydroxy-3-isopropoxypropanoate (Intermediate C7a) (6.0 g, 30.6 mmol) in anhydrous THF (200 mL) at 0° C., under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then a solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (8.14 g, 30.59 mmol) in dry THF (50 mL) was added dropwise, maintaining the temperature below 5° C. The reaction mixture was stirred at 0° C. for 10 minutes. Then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M HCl. The majority of the THF was evaporated in vacuo and then EtOAc (100 mL) was added. The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 70% EtOAc in isohexane to afford (2S)-methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate (7.76 g, 64.8%), ee 53%. A sample of this (1.48 g) was purified by preparative chiral-HPLC on a 50 mm 20um chiralcel OJ column, eluting with 30% isopropanol in isohexane (modified with 0.1% TEA), to give (2S)-methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate (1.03 g, 99% ee). 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.14 (6H, m), 3.68-3.75 (4H, m), 3.98-4.00 (2H, m), 5.80-5.82 (1H, m), 7.74-7.77 (1H, m), 8.33-8.35 (1H, d), 8.59 (1H, s), 8.64 (1H, s), 8.67-8.68 (1H, m); m/z (ESI+) (M+H)+=392; HPLC tR=2.13 min.

Workup

  1. temperaturemaintaining the temperature below 5° C
  2. stirringThe reaction mixture was stirred at 0° C. for 10 minutes
  3. temperatureto warm to ambient temperature
  4. stirringstirred for 1 hour
  5. customThe majority of the THF was evaporated in vacuo
  6. additionEtOAc (100 mL) was added
  7. customThe organic layer was separated
  8. extractionthe aqueous layer re-extracted with EtOAc (2×100 mL)
  9. washThe combined organics were washed with saturated brine (75 mL)
  10. dry with materialdried (MgSO4)
  11. customevaporated
  12. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 70% EtOAc in isohexane

Sources & evidence

ORD record
ord-00ee551815d346b7b714f50889b5faa3
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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