Sulfuric Acid → HCID 58930409, compound

HRID 908915Notes

Reaction equation

HRID 908915 reaction equation
C[N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]CCOC2C=C(C=CC=2)C=O)[CH2:4][CH2:3]1.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=2)[C:36]#[N:37])[CH2:24][CH2:23]1.[CH3:41]C(C[AlH]CC(C)C)C.OS(O)(=O)=O.[OH-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].[CH2:69]([Cl:71])Cl>C1(C)C=CC=CC=1.CO>[Cl:71][C:69]1[CH:3]=[CH:4][C:5]([C:6]2[N:37]=[C:36]([C:35]3[CH:34]=[C:33]([CH:40]=[CH:39][CH:38]=3)[O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:25]3[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]3)[NH:2][C:7]=2[CH3:41])=[CH:8][CH:9]=1

Participants

10

Reactant 7

HCID 1118Sulfuric AcidHCID 6344DichloromethaneHCID 14487Diisobutylaluminum hydrideHCID 14798Sodium HydroxideHCID 9855836Potassium sodium tartarateHCID 57434763HCID 57434763, compoundHCID 57434764HCID 57434764, compound

Product 1

HCID 58930409HCID 58930409, compoundYield 66%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 1140TolueneSolvent2×

Procedure

3-[4-(1-Methyl-piperidin-4-yl)-butoxy]-benzonitrile. To a 0° C. solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (0.74 g, 4.37 mmol), 3-hydroxy-benzonitrile (0.52 g, 4.37 mmol), and 3 mmol/g polymer supported PPh3 (2.30 g, 8.73 mmol) in THF (40 mL) was added diisopropyl azodicarboxylate (1.72 mL, 8.73 mmol) dropwise. After 6 h the mixture was filtered and concentrated. Purification by Method 1 afforded 840 mg (71%) of a yellow oil. MS (ESI): mass calcd for C17H24N2O, 272.19. m/z found, 273.4 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.38-7.33 (m, 1H), 7.24-7.20 (m, 1H), 7.14-7.09 (m, 2H), 3.96 (t, J=6.4, 2H), 2.88-2.80 (m, 2H), 2.26 (s, 3H), 1.94-1.84 (m, 2H), 1.82-1.73 (m, 2H), 1.72-1.64 (m, 2H), 1.52-1.42 (m, 2H), 1.34-1.17 (m, 5H). B. 3-[4-(1-Methyl-piperidin-4-yl)-butoxy]-benzaldehyde. To a stirred solution of 3-[4-(1-methyl-piperidin-4-yl)butoxy]-benzonitrile (0.84 g, 3.09 mmol) in toluene (5 mL) at 0° C. was added 1.5 M DIBAL-H in toluene (4.63 mL, 4.63 mmol). After 3 h, methanol (9 mL) and 1.0 M H2SO4 (10 mL) were added dropwise. After stirring for 30 min, the solution was neutralized with 1.0 M sodium hydroxide (10 mL) followed by addition of satd. aq. sodium potassium tartrate (40 mL) and CH2Cl2 (100 mL). After stirring for 30 min the solution was extracted with CHCl3 (3×50 mL), washed with brine and dried over Na2SO4. Purification by Method 1 afforded 0.56 g (66%) of the title compound. 1H NMR (400 MHz, CDCl3): 9.97 (s, 1H), 7.46-7.43 (m, 2H), 7.39-7.37 (m, 1H), 7.19-7.15 (m, 1H), 4.02 (t, J=6.6, 2H), 2.86-2.80 (m, 2H), 2.25 (s, 3H), 1.92-1.83 (m, 2H), 1.83-1.75 (m, 2H), 1.73-1.63 (m, 2H), 1.54-1.44 (m, 2H), 1.34-1.18 (m, 5H). C. 4-(4-{3-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-butyl)-1-methyl-piperidine. Preparation using the method described in General Procedure 3 afforded 49 mg (28%) of the title compound. MS (ESI): mass calcd for C26H32ClN3O, 437.22. m/z found, 438.4 [M+H]+. 1H NMR (400 MHz, CDCl3): 10.2 (br s, 1H), 7.64 (br s, 1H), 7.48-7.44 (m, 1H), 7.41-7.26 (m, 4H), 7.31-7.27 (m, 1H), 6.88-6.84 (m, 1H), 3.95-3.85 (m, 2H), 2.85-2.77 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H), 1.93-1.82 (m, 2H), 1.76-1.60 (m, 4H), 1.45-1.35 (m, 2H), 1.30-1.15 (m, 5H).

Workup

  1. additionfollowed by addition of satd
  2. stirringAfter stirring for 30 min the solution
  3. extractionwas extracted with CHCl3 (3×50 mL)
  4. washwashed with brine
  5. dry with materialdried over Na2SO4
  6. customPurification by Method 1

Sources & evidence

ORD record
ord-59651dc142364b288eeb846d172af161
Source dataset
uspto-grants-2011_09
Patent number
US08017639B2

Reaction notes

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