Hydrochloric Acid → 1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)-piperidinyl-1-ethyl)-4-(RS)-(3-thienyl)pyrrolidine

HRID 380485Notes

Reaction equation

HRID 380485 reaction equation
[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:15]([CH:23]=O)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.Cl.[CH3:39][Mg]Br>C1C=CC=CC=1.C1COCC1.CCOCC.O>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:15]([CH2:23][CH2:39][N:35]3[CH2:34][CH2:33][CH:32]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)[CH2:37][CH2:36]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 27591364-(4-Fluorophenyl)piperidineHCID 206943831-(1-Naphthoyl)-3-(SR)-formyl-4-(RS)-thiophen-3-ylpyrrolidineHCID 178418573HCID 178418573, compound

Product 1

HCID 702132571-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)-piperidinyl-1-ethyl)-4-(RS)-(3-thienyl)pyrrolidine

Reagents, catalysts & solvents 4

HCID 241BenzeneSolventHCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of 0.16 g (0.47 mmol) of 1-(1-naphthoyl)-3-(SR)-formyl-4-(RS)-(3-thienyl)pyrrolidine (Example 88), and 0.085 g (0.47 mmol) of 4-(4-fluorophenyl)-piperidine in 10 mL of benzene was heated to reflux in a flask fitted with a Dean-Stark trap to azeotrope off the water. After 2 h, the benzene was removed by freeze-drying to give a white powder. The residue was redissolved in 6 mL of THF and the solution was cooled to −78° C. To this solution was added 0.56 mL (0.56 mmol) of a 1N solution of HCl in ether. The mixture was warmed to rt and stirred 30 min at rt. The mixture was then cooled to 0° C. and to it was added 1 mL (1.41 mmol) of methyl magnesium bromide (1N in THF). The reaction mixture was warmed to rt and stirred for 3 h at which time it was quenched with water. The reaction mixture was filtered though a thin layer of silica and concentrated. The residue was purified by chomatography (HPLC, Waters RCM 25×100, silica, hexanes: 0.1% iPr2NH in t-butylmethylether, 8:2.25) to give the two isomers of the title compound.

Workup

  1. temperatureto reflux in a flask
  2. customfitted with a Dean-Stark trap
  3. customthe benzene was removed
  4. customby freeze-drying
  5. customto give a white powder
  6. temperatureThe mixture was warmed to rt
  7. temperatureThe mixture was then cooled to 0° C. and to it
  8. temperatureThe reaction mixture was warmed to rt
  9. stirringstirred for 3 h at which time it
  10. customwas quenched with water
  11. filtrationThe reaction mixture was filtered though a thin layer of silica
  12. concentrationconcentrated
  13. customThe residue was purified by chomatography (HPLC, Waters RCM 25×100, silica, hexanes: 0.1% iPr2NH in t-butylmethylether, 8:2.25)

Sources & evidence

ORD record
ord-4bee9b133bf34b028ac7e82715289050
Source dataset
uspto-grants-2001_10
Patent number
US06303593B1

Reaction notes

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