Ammonia → 1-Methyl-4-(4-phenylthiazol-2-yl)piperidine-4-carbonitrile

HRID 1397226Notes

Reaction equation

HRID 1397226 reaction equation
[NH2-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([CH2:14][C:15]#[N:16])[S:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:19][CH2:20][N:21]([CH2:23][CH2:24]Cl)[CH3:22].N>C1(C)C=CC=CC=1.O>[CH3:22][N:21]1[CH2:23][CH2:24][C:14]([C:11]2[S:12][CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:10]=2)([C:15]#[N:16])[CH2:19][CH2:20]1

Participants

7

Reactant 4

HCID 222AmmoniaHCID 5935Nitrogen mustard hydrochlorideHCID 24533Sodium amideHCID 704539(4-Phenyl-1,3-thiazol-2-yl)acetonitrile

Product 1

HCID 673253391-Methyl-4-(4-phenylthiazol-2-yl)piperidine-4-carbonitrileYield 17%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
0 °C

Procedure

Sodium amide (878 mg, 22.4 mmol) was suspended in toluene (15 mL) and cooled to 0° C. To this suspension was added dropwise a solution of (4-phenyl-thiazol-2-yl)-acetonitrile (1.5 g, 7.4 mmol) in toluene (10 mL) while maintaining the temperature at 0° C. The reaction mixture was stirred for 20 min. Separately the bis-(2-chloroethyl)methylamine hydrochloride (1.45 g, 7.4 mmol) was taken in water (8 mL), cooled to 0° C., and basified with aqueous ammonia solution (adjusted to pH of the solution to ˜8). The oily layer was separated out from the aqueous layer and the organic product was extracted with toluene. The toluene layer was dried over sodium hydroxide pellets. The dry toluene solution of bis-(2-chloroethyl)methylamine was added to the reaction mixture at 0° C. The reaction mixture was allowed to warm up to room temperature and further heated to 110° C. for 3 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% MeOH in CH2Cl2) to afford 1-methyl-4-(4-phenylthiazol-2-yl)piperidine-4-carbonitrile (350 mg, yield 17%). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.99-7.97 (m, 2H), 7.49-7.44 (m, 2H), 7.40-7.36 (m, 1H), 2.92-2.90 (m, 2H), 2.40-2.37 (m, 2H), 2.31-2.16 (m, 7H). MS (ESI) m/z: Calculated for C16H17N3S: 283.11. found: 284.2 (M+H)+.

Workup

  1. temperaturewhile maintaining the temperature at 0° C
  2. temperaturecooled to 0° C.
  3. customThe oily layer was separated out from the aqueous layer
  4. extractionthe organic product was extracted with toluene
  5. dry with materialThe toluene layer was dried over sodium hydroxide pellets
  6. additionThe dry toluene solution of bis-(2-chloroethyl)methylamine was added to the reaction mixture at 0° C
  7. temperatureto warm up to room temperature
  8. temperaturefurther heated to 110° C. for 3 h
  9. temperatureThe reaction mixture was then cooled to room temperature
  10. additiondiluted with EtOAc
  11. extractionextracted with EtOAc
  12. washThe combined extracts were washed with water and brine
  13. dry with materialdried over anhydrous sodium sulfate
  14. concentrationconcentrated under reduced pressure
  15. customThe crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-68d3adc57a39432f8eb0469c7f1a6753
Source dataset
uspto-grants-2014_12
Patent number
US08901156B2

Reaction notes

Loading…