Tetrahydrofuran → 3-Fluoro-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid

HRID 1948538Notes

Reaction equation

HRID 1948538 reaction equation
[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[OH:34][CH:35]([C:50]1[CH:55]=[CH:54][C:53](/[C:56](=[N:58]/O)/[NH2:57])=[CH:52][CH:51]=1)[C:36]([N:39]1[CH2:44][CH2:43][CH2:42][C@H:41]([C:45]([O:47]CC)=[O:46])[CH2:40]1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-:77].C1COCC1>C(Cl)Cl.CN(C=O)C>[F:77][C:41]1([C:45]([OH:47])=[O:46])[CH2:42][CH2:43][CH2:44][N:39]([CH2:36][CH:35]([OH:34])[C:50]2[CH:55]=[CH:54][C:53]([C:56]3[N:58]=[C:16]([C:10]4[O:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:11]=4[C:12]([F:13])([F:14])[F:15])[O:18][N:57]=3)=[CH:52][CH:51]=2)[CH2:40]1

Participants

9

Reactant 6

HCID 8028TetrahydrofuranHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 2724141Tetrabutylammonium FluorideHCID 583740941236188-80-9HCID 58374179HCID 58374179, compound

Product 1

HCID 583741183-Fluoro-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent

Procedure

To a mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (70.8 mg, 0.275 mmol) and oxalyl chloride (0.048 mL, 0.550 mmol) in DCM (5 mL) was added DMF (3 drops) at 25° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and dried. The residue was dissolved in acetonitrile (5.00 mL). Next, DIEA (0.048 mL, 0.275 mmol) and (3S)-ethyl 1-(1-hydroxy-1-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)-2-methylpropan-2-yl)piperidine-3-carboxylate (100 mg, 0.275 mmol) were added. The reaction mixture was stirred at 25° C. After stirring overnight, the reaction mixture showed a significant amount of coupled but uncyclized material. Next, 1M TBAF in THF (0.275 mL, 0.275 mmol) was added and reaction mixture was stirred for another 48 hrs. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Fractions with correct mass were isolated and concentrated in vacuo. The residue was treated with 6N HCl/dioxane (1:1) at 50° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass and freeze-dried overnight. Recovered 32 mg of (3S)-1-(1-hydroxy-2-methyl-1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propan-2-yl)piperidine-3-carboxylic acid, TFA. MS (m+1)=547. HPLC Peak RT=1.90 minutes (Analytical Method B). Purity=92%.

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. customdried
  3. dissolutionThe residue was dissolved in acetonitrile (5.00 mL)
  4. stirringThe reaction mixture was stirred at 25° C
  5. stirringAfter stirring overnight
  6. customreaction mixture
  7. stirringwas stirred for another 48 hrs
  8. filtrationThe reaction mixture was filtered
  9. custompurified by HPLC
  10. custom25 minute
  11. customFractions with correct mass were isolated
  12. concentrationconcentrated in vacuo
  13. additionThe residue was treated with 6N HCl/dioxane (1:1) at 50° C. overnight
  14. filtrationThe reaction mixture was filtered
  15. custompurified by HPLC
  16. custom25 minute
  17. customIsolated fractions with correct mass and freeze-dried overnight
  18. customRecovered 32 mg of (3S)-1-(1-hydroxy-2-methyl-1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propan-2-yl)piperidine-3-carboxylic acid, TFA

Sources & evidence

ORD record
ord-14e4cfa528ab45f0882851b0f75903cb
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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