Oxalyl chloride → 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid

HRID 1948545Notes

Reaction equation

HRID 1948545 reaction equation
[C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[Si]([O:41][C@@H:42]([C:56]1[CH:61]=[CH:60][C:59](/[C:62](=[N:64]/O)/[NH2:63])=[CH:58][CH:57]=1)[CH2:43][N:44]1[CH2:49][CH2:48][CH2:47][C@H:46]([CH2:50][C:51]([O:53]CC)=[O:52])[CH2:45]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.C1COCC1.CN(C=O)C>[OH:41][C@@H:42]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[N:64]=[C:16]([C:9]3[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[O:18][N:63]=2)=[CH:58][CH:57]=1)[CH2:43][N:44]1[CH2:49][CH2:48][CH2:47][C@H:46]([CH2:50][C:51]([OH:53])=[O:52])[CH2:45]1

Participants

9

Reactant 5

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 2724141Tetrabutylammonium FluorideHCID 27833724-Phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acidHCID 58374199ethyl 2-[(3R)-1-[(2S)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]ethyl]piperidin-3-yl]acetate

Product 1

HCID 509231312-((R)-1-((S)-2-hydroxy-2-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acidYield 98%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of commercially available 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid (44.0 mg, 0.162 mmol) in DCM (4 mL) was added oxalyl chloride (45 μL, 0.514 mmol) followed by a drop of DMF. The solution bubbled. After 1 h, diisopropylethylamine (45 μL, 0.258 mmol) was added followed by ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (50.0 mg, 0.108 mmol) in THF (2 mL). The reaction mixture was stirred overnight and the next day LCMS showed the product had formed so the reaction was treated with TBAF (216 μL, 0.216 mmol) and then heated to 60° C. overnight. The next day, the reaction was extracted from 1 M HCl using EtOAc×3 and the organics layers were combined and concentrated in vacuo. This residue was taken up in a 1:1 mixture of THF and 6 M HCl and heated for 2 h. LCMS after this time showed the desired product so the reaction was concentrated and then purified by HPLC to give 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (42 mg, 98% yield). MS (M+1)=558.3; HPLC RT=2.11 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (1H, br. s.), 9.72 (1H, br. s.), 8.14-8.26 (1H, m), 8.05 (2H, m, J=8.36 Hz), 7.61 (2H, m, J=8.14 Hz), 7.41-7.53 (5H, m), 6.35 (1H, br. s.), 5.18 (1H, br. s.), 3.42-3.71 (2H, m), 3.10-3.21 (1H, m), 2.63-2.94 (2H, m), 2.08-2.31 (3H, m), 1.66-1.91 (3H, m), 0.99-1.24 (1H, m).

Workup

  1. customThe solution bubbled
  2. customhad formed so the reaction
  3. extractionThe next day, the reaction was extracted from 1 M HCl
  4. concentrationconcentrated in vacuo
  5. additionThis residue was taken up in a 1:1 mixture of THF and 6 M HCl
  6. temperatureheated for 2 h
  7. concentrationwas concentrated
  8. custompurified by HPLC

Sources & evidence

ORD record
ord-422614e5622b42148659deb068a6c40f
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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