Acetaldehyde → 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]tetrahydro-2H-pyran-4-carboxylic acid

HRID 1867692Notes

Reaction equation

HRID 1867692 reaction equation
Cl.[Cl:2][C:3]1[C:4]([F:33])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:31][CH3:32])=[C:17]([CH2:20][NH:21][C:22]4([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH:34](=O)[CH3:35].S([O-])([O-])(=O)=O.[Mg+2].C([BH3-])#N.[Na+]>C(OCC)C.CO>[Cl:2][C:3]1[C:4]([F:33])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:31][CH3:32])=[C:17]([CH2:20][N:21]([CH2:34][CH3:35])[C:22]4([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1

Participants

8

Reactant 5

HCID 177AcetaldehydeHCID 313Hydrochloric AcidHCID 24083Sulfuric acid magnesium salt (1:1)HCID 5003444Sodium cyanoborohydrideHCID 579798634-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]tetrahydro-2H-pyran-4-carboxylic acid

Product 1

HCID 579798524-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]tetrahydro-2H-pyran-4-carboxylic acidYield 63%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
40 °C

Procedure

1M HCl in diethyl ether (1.4 ml) was added to a stirred suspension of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]tetrahydro-2H-pyran-4-carboxylic acid (0.66 g, 1.43 mmol), acetaldehyde (1.6 ml, 28.6 mmol) and anhydrous magnesium sulfate (0.34 g, 2.83 mmol) in methanol (10 ml). Sodium cyanoborohydride (0.36 g, 5.71 mmol) was added and the resulting mixture heated at 40° C. for 4 hours. The reaction mixture was then filtered and evaporated. The residues were purified by column chromatography on silica, eluting with 7M ammonia in methanol/methylene chloride (16/84). Fractions containing the desired product were combined and evaporated. The resulting gum was triturated with diethyl ether to give 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]tetrahydro-2H-pyran-4-carboxylic acid as a white solid (440 mg, 63%); 1H NMR Spectrum: (DMSO-d6) δ 0.79 (t, 3H), 1.71-1.84 (m, 2H), 2.07-2.11 (d, 2H), 2.67-2.76 (q, 2H), 3.23-3.33 (t, 2H), 3.80-3.88 (m, 2H), 3.89-3.95 (m, 5H), 7.16 (s, 1H), 7.22-7.29 (m, 1H), 7.43-7.49 (m, 1H), 7.52-7.57 (dd, 1H), 8.38 (s, 1H), 8.41 (s, 1H); Mass Spectrum: (M+H)+ 489.

Workup

  1. filtrationThe reaction mixture was then filtered
  2. customevaporated
  3. customThe residues were purified by column chromatography on silica
  4. washeluting with 7M ammonia in methanol/methylene chloride (16/84)
  5. additionFractions containing the desired product
  6. customevaporated
  7. customThe resulting gum was triturated with diethyl ether

Sources & evidence

ORD record
ord-f414524e5ca64d4cb26d748f0ea137a1
Source dataset
uspto-grants-2009_12
Patent number
US07632840B2

Reaction notes

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