Dichloromethane → (+/-)-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexy]phenylacetamide Hydrochloride

HRID 1600017Notes

Reaction equation

HRID 1600017 reaction equation
[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[N:37]1([C@@H:42]2[CH2:47][CH2:46][CH2:45][CH2:44][C@H:43]2[NH:48][CH3:49])[CH2:41][CH2:40][CH2:39][CH2:38]1.C(Cl)[Cl:51]>>[ClH:51].[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:48]([CH3:49])[C@@H:43]2[CH2:44][CH2:45][CH2:46][CH2:47][C@H:42]2[N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:12])=[CH:7][CH:8]=1

Participants

6

Reactant 5

HCID 6344Dichloromethane2×HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 118342(alpha,alpha,alpha-Trifluoro-4-tolyl)acetic acidHCID 27960291-Hydroxybenzotriazole hydrateHCID 13377463Cyclohexanamine, N-methyl-2-(1-pyrrolidinyl)-, trans-

Product 1

HCID 9887513(+/-)-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexy]phenylacetamide Hydrochloride

Conditions

Temperature
5 °C

Procedure

To a solution of 4-trifluoromethylphenyl acetic acid (1.45 g, 7.08 mmol) in10 mL of dry CH2Cl2 under a nitrogen atmosphere was added 1-hydroxybenzotriazole hydrate (HOBT) (0.95 g, 7.08 mmol) and stirred. Thereaction mixture was cooled to 0°→5° C. and added solid EDCI ([1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl])(1.35 g, 7.08 mmol) and stirred this temperature for 30 min. A solution (±) 3 (1.0 g, 5.48 mmol) in 10 mL of dry CH2Cl2 was added followed byN,N-diisopropylethylamine (Hunig's Base) (0.915 g, 7.08 mmol). The reactionmixture was stirred for 24 h while warming to the room temperature. The reaction mixture was then poured on to excess of ice-cold saturated aqueous NaHCO3 solution and stirred for 30 min. After dilution with CH2Cl2, the organic was separated, washed with saturated salt solution, and dried over anhydrous Na2SO4. Removal of solvent gave a brown oil which was chromatographed on a silica gel column [solventsystem: CH2Cl2 : CH3OH: 28% NH4OH (99:1:2)] to give the desired product as free base. The hydrochloride salt was prepared from1M etherial HCl and recrystallized from CH2Cl2 :Et2O (1:1)to give (±) 5g HCl as a cream colored solid, 0.68 g (30%); 213°-215° C.; 1H NMR (200 MHz, CDCl3) δ1.02-1.47 (m, 4H), 1.52-2.22 (m, 8H), 2.75-2.90 (m, 2H), 2.94 (s, 3H), 3.07 (m, 1H), 3.37 (m, 1H), 3.62 (d, J=15.0 Hz, 1H), 3.77 (m, 1H), 4.17 (d, J=15.0 Hz, 1H), 4.57 (m, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H). Anal Calcd for C20H27F3N2 O.HCl.0.25H2O: C, 58.68; H, 7.02; N, 6.84. Found: C, 58.68; H, 6.84;N, 6.69.

Workup

  1. stirringstirred this temperature for 30 min
  2. stirringThe reactionmixture was stirred for 24 h
  3. temperaturewhile warming to the room temperature
  4. additionThe reaction mixture was then poured on to excess of ice-cold saturated aqueous NaHCO3 solution
  5. stirringstirred for 30 min
  6. customAfter dilution with CH2Cl2, the organic was separated
  7. washwashed with saturated salt solution
  8. dry with materialdried over anhydrous Na2SO4
  9. customRemoval of solvent
  10. customgave a brown oil which
  11. customwas chromatographed on a silica gel column [solventsystem: CH2Cl2 : CH3OH: 28% NH4OH (99:1:2)]

Sources & evidence

ORD record
ord-49306d08a05b4517869e03e3617d8830
Source dataset
uspto-grants-1998_04
Patent number
US05744458

Reaction notes

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