Tetrahydrofuran → HCID 56644366, compound

HRID 71272Notes

Reaction equation

HRID 71272 reaction equation
C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[OH:16][CH:17]([C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:38][OH:39])[NH2:37])=[CH:32][CH:31]=1)[CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]([O:27]CC)=[O:26])[CH2:20]1.[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2([CH2:54][CH2:55][C:56](O)=O)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:44]=[C:45]([Cl:47])[CH:46]=1.C(N(C(C)C)CC)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2([CH2:54][CH2:55][C:56]3[O:39][N:38]=[C:36]([C:33]4[CH:32]=[CH:31][C:30]([CH:17]([OH:16])[CH2:18][N:19]5[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]([OH:27])=[O:26])[CH2:20]5)=[CH:35][CH:34]=4)[N:37]=3)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:44]=[C:45]([Cl:47])[CH:46]=1

Participants

9

Reactant 6

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 152842Bis(2-oxo-3-oxazolidinyl)phosphinic chlorideHCID 2724141Tetrabutylammonium FluorideHCID 66686108HCID 66686108, compoundHCID 123273571HCID 123273571, compound2×

Product 1

HCID 56644366HCID 56644366, compoundYield 76.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

BOP-Cl (33.4 mg, 0.131 mmol) was added to a mixture of (3S)-ethyl 1-(2-hydroxy-2-(4-(N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (Intermediate 3, 40 mg, 0.119 mmol), 3-(1-(3,5-dichlorophenyl)cyclohexyl)propanoic acid (35.9 mg, 0.119 mmol), and diisopropylethyl amine (0.042 mL, 0.239 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 2 h, and a 1M solution of tetra-n-butylammonium fluoride in THF (0.119 mL, 0.119 mmol) was added. The mixture was heated to 80° C. overnight, diluted with ethyl acetate, and washed with saturated aqueous NaCl solution. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was dissolved in acetonitrile (3 mL), treated with 6 N aq. HCl solution and heated to 50° C. overnight. The mixture was filtered, and purified by HPLC (HPLC conditions: Phenomenex Luna C18 5 micron column (250×30 mm); 25-100% AcCN/water (0.1% TFA); 25 minute gradient; 30 mL/min). Isolated fractions with the correct mass were collected and freeze-dried overnight to obtain (3S)-1-(2-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)-3-piperidinecarboxylic acid (52 mg, 63% yield) as a white solid. HPLC retention time=3.75 minutes (Waters Sunfire C18 4.6×50 mm) eluting with 10-90% aqueous methanol with 0.1% TFA over a 4 minute gradient. LC/MS: m/e 572.16, 574.10 (M+H)+.

Workup

  1. temperatureThe mixture was heated to 80° C. overnight
  2. washwashed with saturated aqueous NaCl solution
  3. dry with materialThe organic layer was dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe crude product was dissolved in acetonitrile (3 mL)
  7. additiontreated with 6 N aq. HCl solution
  8. temperatureheated to 50° C. overnight
  9. filtrationThe mixture was filtered
  10. custompurified by HPLC (HPLC conditions: Phenomenex Luna C18 5 micron column (250×30 mm); 25-100% AcCN/water (0.1% TFA); 25 minute gradient; 30 mL/min)
  11. customIsolated fractions with the correct mass were collected
  12. customfreeze-dried overnight

Sources & evidence

ORD record
ord-4a95e073fe7d415cb8993774ba292c23
Source dataset
uspto-grants-2014_09
Patent number
US08822510B2

Reaction notes

Loading…