Thionyl Chloride → N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)cyclobutanecarboxamide

HRID 1365529Notes

Reaction equation

HRID 1365529 reaction equation
FC(F)(F)[C:3]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4]1.O=S(Cl)Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C@:23]([C:32]2[CH:37]=[C:36]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=2)([NH2:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21][CH:22]=1>ClCCCl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:31][C:7]([CH:3]2[CH2:4][CH2:5][CH2:6]2)=[O:9])([C:32]2[CH:37]=[C:36]([O:38][C:39]([F:43])([F:44])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21][CH:22]=1

Participants

5

Reactant 3

HCID 24386Thionyl ChlorideHCID 27828381-(Trifluoromethyl)cyclobutanecarboxylic acidHCID 59134703(S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine

Product 1

HCID 72463508N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)cyclobutanecarboxamideYield 22%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a solution of 1-trifluoromethylcyclobutyl carboxylic acid (22.7 mg, 0.135 mmol) in DCE (1 mL) was added SOCl2 (16 mg, 0.135 mmol) and the resulting mixture was heated at reflux for 2 h. The reaction mixture was allowed to cool down to room temperature and TEA was added (31 μL, 0.23 mmol), followed by the addition of (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (20 mg, 0.045 mmol). The reaction was stirred at room temperature for 18 h, concentrated and the residue purified by preparative HPLC Shimadzu-AXIA column, 30×100 mm eluting with 30-100% MeOH (90% in H2O, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm to give N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)cyclobutanecarboxamide (5.2 mg, 22% yield). LCMS: RT=2.14 min [M+H] 525.2 (LCMS Method 2.); NMR: 400 MHz 1H (CDCl3) 8.29 ppm, 1H, s; 8.13 ppm, 1H, s; 7.68 ppm, 1H, m; 7.11 ppm, 6H, m; 6.87 ppm, 1H, m; 6.57 ppm, 2H, m; 5.87 ppm, 1H, t, J=53 Hz; 4.45 ppm, 1H, dd, J=12.8, 3.6 Hz; 3.51 ppm, 1H, dd, J=12.8, 3.6 Hz; 3.09 ppm, 1H, m; 2.20 ppm, 4H, m; 1.94 ppm, 2H, m.

Workup

  1. temperaturethe resulting mixture was heated
  2. temperatureat reflux for 2 h
  3. additionTEA was added (31 μL, 0.23 mmol)
  4. concentrationconcentrated
  5. customthe residue purified by preparative HPLC Shimadzu-AXIA column, 30×100 mm
  6. washeluting with 30-100% MeOH (90% in H2O, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm

Sources & evidence

ORD record
ord-9a2aab28914e48cf94a6792b57ea2a2d
Source dataset
uspto-grants-2011_02
Patent number
US07888376B2

Reaction notes

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