Triphosgene → Phenylmethyl [(2R,4S)-1-{[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4-(2-propen-1-yl)-4-piperidinyl]carbamate

HRID 384022Notes

Reaction equation

HRID 384022 reaction equation
ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]1([CH2:19][O:20][C:21](=[O:40])[NH:22][C@@:23]2([CH2:37][CH:38]=[CH2:39])[CH2:28][CH2:27][NH:26][C@@H:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[CH2:24]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:44]=[C:45]([CH2:53][NH:54][CH3:55])[CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:13]1([CH2:19][O:20][C:21](=[O:40])[NH:22][C@@:23]2([CH2:37][CH:38]=[CH2:39])[CH2:28][CH2:27][N:26]([C:5]([N:54]([CH2:53][C:45]3[CH:46]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:48]=[C:43]([C:42]([F:41])([F:56])[F:57])[CH:44]=3)[CH3:55])=[O:11])[C@@H:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[CH2:24]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1

Participants

6

Reactant 4

HCID 94429TriphosgeneHCID 516892Sodium BicarbonateHCID 10956204{[3,5-Bis(trifluoromethyl)phenyl]methyl}(methyl)amineHCID 58169883Phenylmethyl [(2R,4S)-2-(4-fluoro-2-methylphenyl)-4-(2-propen-1-yl)-4-piperidinyl]carbamate2×

Product 1

HCID 58169864Phenylmethyl [(2R,4S)-1-{[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4-(2-propen-1-yl)-4-piperidinyl]carbamateYield 46%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent4×

Procedure

To a solution of triphosgene (0.714 g, 2.405 mmol) at 0° C. in dry ethyl acetate (5.5 ml) was slowly added a solution of phenylmethyl[(2R,4S)-2-(4-fluoro-2-methylphenyl)-4-(2-propen-1-yl)-4-piperidinyl]carbamate (Intermediate 18, 2 g, 5.23 mmol) and TEA (1.8 ml) in dry ethyl Acetate (10 ml) and the mixture was stirred for 5 minutes at the same temperature. Then a solution of {[3,5-bis(trifluoromethyl)phenyl]methyl}methylamine (WO 2007107818, 27 Sep. 2007) (1.479 g, 5.75 mmol) and TEA (1.63 ml) in dry Ethyl acetate (10 ml) was added in minutes at 0° C. The resulting suspension was refluxed for 5 hours. After cooling, NaHCO3 sat. aq. solution and ethyl acetate were added to the reaction mixture and two phases were separated. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by flash chromatography with Biotage SP1 (from 1:0 to 7:3 Cyclohexane/EtOAc; 40 M) to give two batches of the title compound: 1st batch (1.6 g, 2.40 mmol, 46.0% yield); 1H NMR (500 MHz, DMSO-d6) δ ppm 7.94 (s, 1H) 7.61 (s, 2H) 7.27-7.38 (m, 5H) 7.24 (dd, 1H) 7.18 (br. s., 1H) 6.91 (dd, 1H) 6.76-6.83 (m, 1H) 5.68-5.81 (m, 1H) 5.06-5.18 (m, 2H) 4.88-5.00 (m, 2H) 4.60 (d, 1H) 4.36-4.44 (m, 1H) 4.36 (d, 1H) 3.36-3.47 (m, 1H) 2.94-3.06 (m, 1H) 2.88 (s, 3H) 2.63-2.72 (m, 2H) 2.31 (s, 3H) 1.84-2.05 (m, 3H) 1.64 (t, 1H); UPLC: Rt=1.02 mins; m/z=666 [MH]+. The 2nd batch was purified again by flash chromatography via Biotage SP1 (from 1:0 to 7:3 Cyclohexane/EtOAc; 40 M) to give further two batches of the title compound (0.8 g and 0.15 g).

Workup

  1. temperatureThe resulting suspension was refluxed for 5 hours
  2. temperatureAfter cooling
  3. customwere separated
  4. extractionThe aqueous phase was extracted with ethyl acetate (3×)
  5. dry with materialthe combined organic phases were dried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated to dryness
  8. customThe residue was purified by flash chromatography with Biotage SP1 (from 1:0 to 7:3 Cyclohexane/EtOAc; 40 M)

Sources & evidence

ORD record
ord-1b83be6eb6f34ba9a6b4b19d0b383584
Source dataset
uspto-grants-2013_02
Patent number
US08367692B2

Reaction notes

Loading…