Acetaldehyde → N-(3,4-dichlorophenyl)-7-{[(5-ethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride

HRID 244580Notes

Reaction equation

HRID 244580 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]4[S:25][C:26]5[CH2:27][NH:28][CH2:29][CH2:30][C:31]=5[N:32]=4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:33](=O)[CH3:34].[BH3-]C#N.[Na+].CO.C(OCC)(=O)C>C1COCC1.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]4[S:25][C:26]5[CH2:27][N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][C:31]=5[N:32]=4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]

Participants

6

Reactant 4

HCID 177Acetaldehyde3×HCID 5003444Sodium cyanoborohydride3×HCID 21584119Ethylacetate methanolHCID 53630967N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine

Product 1

HCID 66838644N-(3,4-dichlorophenyl)-7-{[(5-ethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochlorideYield 25.5%

Reagents, catalysts & solvents 1

HCID 21899815MeOH tetrahydrofuranSolvent

Procedure

N-(3,4-Dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine (0.249 g, 0.510 mmol) was taken up in 50% THF/MeOH (10 mL) and the solution was cooled with an ice bath. Acetaldehyde (0.057 mL, 1.0 mmol), followed by NaCNBH3 (0.038 g, 0.61 mmol) were added. The solution was allowed to warm to room temperature. After 4 h, additional acetaldehyde (0.050 mL, 0.89 mmol) and NaCNBH3 (0.040 g, 0.64 mmol) were added and the solution was stirred for 12 h. An additional 0.050 mL (0.89 mmol) of acetaldehyde and NaCNBH3 (0.020 g, 0.32 mmol) were added. The solution was poured into 10% MeOH/ethyl acetate (100 mL) and washed once with H2O (100 mL). The organic layer was dried (Na2SO4); filtered and the solvent was removed in vacuo. The crude product was purified via preparative HPLC (reverse phase, CH3CN/H2O/NH4OAc/AcOH). The solvents were removed, the product was taken up in MeOH and treated with 4.0M HCl/dioxane (0.025 mL), and lyophilized to provide 0.036 g (12%) of N-(3,4-dichlorophenyl)-7-{[(5-ethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride as a yellow solid.

Workup

  1. temperaturethe solution was cooled with an ice bath
  2. additionwere added
  3. washwashed once with H2O (100 mL)
  4. dry with materialThe organic layer was dried (Na2SO4)
  5. filtrationfiltered
  6. customthe solvent was removed in vacuo
  7. customThe crude product was purified via preparative HPLC (reverse phase, CH3CN/H2O/NH4OAc/AcOH)
  8. customThe solvents were removed
  9. additiontreated with 4.0M HCl/dioxane (0.025 mL)

Sources & evidence

ORD record
ord-6b09aecb7e69470387c9156c3e704ac2
Source dataset
uspto-grants-2014_02
Patent number
US08658654B2

Reaction notes

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