Trifluoroacetic acid → 3-(3-(4-(5-(2-(1-(3,5-Dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxy-1-azetidinyl)propanoic acid

HRID 71274Notes

Reaction equation

HRID 71274 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([OH:39])[CH2:31][N:30]([C:32](OC(C)(C)C)=O)[CH2:29]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:40]([OH:46])([C:42](F)(F)F)=[O:41].C(OC(C)(C)C)(=O)C=C.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([OH:39])[CH2:29][N:30]([CH2:32][CH2:42][C:40]([OH:46])=[O:41])[CH2:31]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 15458tert-Butyl acrylateHCID 81531DiisopropylethylamineHCID 66692429Tert-butyl 3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate

Product 1

HCID 566443673-(3-(4-(5-(2-(1-(3,5-Dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxy-1-azetidinyl)propanoic acidYield 56%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

tert-Butyl 3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate (56 mg, 0.098 mmol, HPLC purity: 80%) was treated with TFA in dichloromethane for 1 h and concentrated. The residue was dissolved in 2-propanol (3 mL). tert-Butyl acrylate (0.143 mL, 0.978 mmol) and diisopropylethyl amine (0.034 mL, 0.196 mmol) were added and the mixture was heated to 80° C. overnight. The reaction mixture was concentrated and then treated with TFA in dichloromethane for 3 h. The mixture was concentrated and a DMF solution of the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain 3-(3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxy-1-azetidinyl)propanoic acid (30 mg, 56% yield). HPLC retention time=3.75 minutes (Waters XBridge C18 4.6×50 mm) eluting with 5-95% aqueous AcCN with 0.05% TFA over a 5.3 minute gradient. LC/MS: m/e 544.07, 545.97 (M+H)+.

Workup

  1. concentrationconcentrated
  2. dissolutionThe residue was dissolved in 2-propanol (3 mL)
  3. concentrationThe reaction mixture was concentrated
  4. additiontreated with TFA in dichloromethane for 3 h
  5. concentrationThe mixture was concentrated
  6. customa DMF solution of the crude material was purified via preparative LC/MS with the following conditions
  7. customa 5-minute hold
  8. additionFractions containing the desired product
  9. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-9102edf285d14f59a4f7015984251f6e
Source dataset
uspto-grants-2014_09
Patent number
US08822510B2

Reaction notes

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