Tetrahydrofuran → 2-(2-(3-(4-((S)-2,3-dihydroxypropoxy)-3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2-(4-fluorophenyl)cyclohexanone

HRID 71232Notes

Reaction equation

HRID 71232 reaction equation
[C:1]1([C:7]2(CCC(O)=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=C[CH:4]=[CH:3][CH:2]=1.CC1(C)[O:23][C@H:22]([CH2:24][O:25][C:26]2[C:35]([CH3:36])=[CH:34][C:29]([C:30](=[NH:33])[NH:31][OH:32])=[CH:28][C:27]=2[CH3:37])[CH2:21][O:20]1.C(N=C=NC(C)C)(C)C.[F-:48].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:66]1[CH2:70][O:69][CH2:68][CH2:67]1>ClCCl>[OH:23][C@@H:22]([CH2:21][OH:20])[CH2:24][O:25][C:26]1[C:27]([CH3:37])=[CH:28][C:29]([C:30]2[N:33]=[C:4]([CH2:3][CH2:2][C:1]3([C:7]4[CH:12]=[CH:11][C:10]([F:48])=[CH:9][CH:8]=4)[CH2:6][CH2:68][CH2:67][CH2:66][C:70]3=[O:69])[O:32][N:31]=2)=[CH:34][C:35]=1[CH3:36]

Participants

7

Reactant 5

HCID 8028TetrahydrofuranHCID 12734DiisopropylcarbodiimideHCID 3439853-(1-Phenylcyclohexyl)propanoic acidHCID 2724141Tetrabutylammonium FluorideHCID 178426656HCID 178426656, compound

Product 1

HCID 566439532-(2-(3-(4-((S)-2,3-dihydroxypropoxy)-3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2-(4-fluorophenyl)cyclohexanoneYield 28%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of 3-(1-(4-fluorophenyl)cyclohexyl)propanoic acid (20 mg, 0.08 mmol, Preparation 1C) and (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-hydroxy-3,5-dimethylbenzimidamide (23.5 mg, 0.08 mmol) in dichloromethane (1.5 mL) was treated with N,N′-diisopropylcarbodiimide (15 μL, 0.096 mmol). The reaction mixture was stirred at room temperature for 2 h and then treated with a solution of 1N tetra-n-butylammonium fluoride in THF (40 μL, 0.04 mmol). After 3.5 h, the reaction mixture was concentrated and the residue was cooled to 0° C. and treated with TFA (1 mL). After 1 min, the ice bath was removed and stirring was continued for additional 1 h. The reaction mixture was concentrated and the residue was purified by reversed-phase autoprep HPLC (Phenomenex S10 30×100 mm, 40 min gradient time, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.1% TFA; Final solvent: 90% aq. MeOH—0.1% TFA) to obtain 2-(2-(3-(4-((S)-2,3-dihydroxypropoxy)-3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2-(4-fluorophenyl)cyclohexanone (37.4 mg, 28% yield) as a colorless viscous oil. LC/MS: m/e 469.20 (M+H)+. 1H NMR (400 MHz, CD3OD): δ ppm 7.64 (s, 2H), 7.33-7.51 (m, 2H), 6.92-7.15 (m, 2H), 3.96-4.04 (m, 1H), 3.87-3.94 (m, 1H), 3.79-3.86 (m, 1H), 3.64-3.77 (m, 2H), 2.47-2.68 (m, 2H), 2.34 (s, 6H), 2.03-2.18 (m, 4H), 1.55-1.81 (m, 4H), 1.31-1.56 (m, 4H).

Workup

  1. waitAfter 3.5 h
  2. concentrationthe reaction mixture was concentrated
  3. temperaturethe residue was cooled to 0° C.
  4. additiontreated with TFA (1 mL)
  5. waitAfter 1 min
  6. customthe ice bath was removed
  7. stirringstirring
  8. waitwas continued for additional 1 h
  9. concentrationThe reaction mixture was concentrated
  10. customthe residue was purified by reversed-phase autoprep HPLC (Phenomenex S10 30×100 mm, 40 min gradient time, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.1% TFA; Final solvent: 90% aq. MeOH—0.1% TFA)

Sources & evidence

ORD record
ord-0f5b3ee13ee54b019af8065cbe73d852
Source dataset
uspto-grants-2014_09
Patent number
US08822510B2

Reaction notes

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