(2S)-2-(Trifluoromethyl)oxirane → (R)-3-((S)-1-(5-chloropyridin-2-yl)-1-(3fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylamino)-1,1,1-trifluoropropan-2-ol

HRID 1365499Notes

Reaction equation

HRID 1365499 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[F:28][C:29]([F:34])([F:33])[C@@H:30]1[CH2:32][O:31]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:16][CH2:32][C@@H:30]([OH:31])[C:29]([F:34])([F:33])[F:28])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1

Participants

4

Reactant 2

HCID 7171781(2S)-2-(Trifluoromethyl)oxiraneHCID 59134582(S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine

Product 1

HCID 58920359(R)-3-((S)-1-(5-chloropyridin-2-yl)-1-(3fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylamino)-1,1,1-trifluoropropan-2-olYield 64%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
140 °C

Procedure

(S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl ethanamine (0.148 g, 0.376 mmol, prepared as described in Procedures 5, 6 and 7) was dissolved in anhydrous acetonitrile (1 mL). (S)-2-(trifluoromethyl)oxirane (approximate 85:15 ratio of R to S) (0.20 mL, excess) was added to the solution in a microwave vial followed by Yb(OSO2CF3)3 (0.020 g, mmol). The sealed vial was heated to 140° C. for 20 mins in the microwave. The reaction mixture was taken from the reaction vial via syringe and injected directly onto a silica gel ISCO cartridge column (40 g). The product eluted at 8 minutes with a gradient of 0-50% EtOAc in hexanes over 18 minutes and flow rate of 40 mL/min, (0.122 mg, 64% yield). The crude NMR of this material showed an 85:15 ratio of R to S at the hydroxy centre. The material was further purified on a Chiral cell AD column with 5% IPA in hexane as the mobile phase yielding 0.068 g of (R)-3-((S)-1-(5-chloropyridin-2-yl)-1-(3fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylamino)-1,1,1-trifluoropropan-2-ol as a colorless oil and a further 0.044 g of mixed fractions. LCMS: 2.06 min [M+1] 507.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 7.88 min (8 min gradient, MeOH/H2O 0.2% PPA Purity 100%; NMR: 400 MHz 1H (CDCl3) 8.42 ppm, 1H, d, J=2.2 Hz; 7.55 ppm, 1H, dd, J=8.36 and J=2.64 Hz; 7.30 ppm, 1H, s; 7.13 ppm, 3H, m; 7.08 ppm, 2H, m; 6.57 ppm, 2H, d, J=7.04 Hz; 3.85 ppm, IH, m; 3.76 ppm, 1H, d, J=12.2 Hz; 3.50 ppm, 1H, d, J=12.2 Hz; 2.78 ppm, 1H, dd, J=6.12 and 12.0 Hz; 2.64 ppm, 1H, dd, J=3.96 and J=12.2 Hz.

Workup

  1. customThe reaction mixture was taken from the reaction vial via syringe
  2. washThe product eluted at 8 minutes with a gradient of 0-50% EtOAc in hexanes over 18 minutes
  3. customThe material was further purified on a Chiral cell AD column with 5% IPA in hexane as the mobile phase

Sources & evidence

ORD record
ord-b99037fbe6054da7a9eab73f14418471
Source dataset
uspto-grants-2011_02
Patent number
US07888376B2

Reaction notes

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