Acetic Acid → 2-(4-Chloro-phenyl)-5-[4-(1-cyclopropyl-azetidin-3-yloxy)-3-methoxy-phenyl]-5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt

HRID 554846Notes

Reaction equation

HRID 554846 reaction equation
[NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:17]=[CH:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.C(O[C:34]1(O[Si](C)(C)C)[CH2:36][CH2:35]1)C.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[ClH:27].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([CH:34]6[CH2:36][CH2:35]6)[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH:17]=[CH:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 14798Sodium HydroxideHCID 2734686(1-Ethoxycyclopropoxy)trimethylsilaneHCID 5003444Sodium cyanoborohydrideHCID 249907925-(4-(azetidin-3-yloxy)-3-methoxyphenyl)-2-(4-chlorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one

Product 1

HCID 1317292492-(4-Chloro-phenyl)-5-[4-(1-cyclopropyl-azetidin-3-yloxy)-3-methoxy-phenyl]-5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride saltYield 69.6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Mix molecular sieves (100 mg, type 3A), 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (1.00 g, 2.27 mmol), and [(1-ethoxycyclopropyl)oxy]trimethylsilane (688.3 μL, 3.41 mmol), and acetic acid (651.3 μL, 11.37 mmoles) in dry methanol (11 mL) and reflux the mixture for 3 h. Cool the reaction to room temperature, then add sodium cyanoborohydride (376 mg, 5.68 mmoles) and slowly warm to 40° C. for one hour. Cool the mixture and add 1 N NaOH solution, then extract the aqueous layer with CHCl3 (3×25 mL). Dry the organic layer with Na2SO4, filter, and concentrate. Purify the crude material on silica gel chromatography using a gradient of 0-10% 2 N NH3/MeOH in CHCl3. Collect the desired fractions and remove the solvent via reduced pressure. Re-dissolve the resulting material in CHCl3 and add 1 N HCl/Et2O solution (2.27 mL). Remove the solvent and dry under vacuum to give 408 mg (35%) of the title compound. ES/MS m/z (35Cl) 480.0 [M+1]+.

Workup

  1. temperaturereflux the mixture for 3 h
  2. temperatureCool
  3. customthe reaction to room temperature
  4. temperatureCool the mixture
  5. extractionextract the aqueous layer with CHCl3 (3×25 mL)
  6. dry with materialDry the organic layer with Na2SO4
  7. filtrationfilter
  8. concentrationconcentrate
  9. customPurify the crude material on silica gel chromatography
  10. customCollect the desired fractions
  11. customremove the solvent via reduced pressure
  12. additionadd 1 N HCl/Et2O solution (2.27 mL)
  13. customRemove the solvent
  14. customdry under vacuum

Sources & evidence

ORD record
ord-4eb8ba24310a491298b239e21cc45f6f
Source dataset
uspto-grants-2011_11
Patent number
US08049013B2

Reaction notes

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