Hydrochloric Acid → (3S)-1-(2-hydroxy-2-(4-(5-(3-(6-methylpyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid

HRID 1948530Notes

Reaction equation

HRID 1948530 reaction equation
[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([OH:19])=O)[O:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[OH:44][CH:45]([C:58]1[CH:63]=[CH:62][C:61](/[C:64](=[N:66]/O)/[NH2:65])=[CH:60][CH:59]=1)[CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][C@H:49]([C:53]([O:55]CC)=[O:54])[CH2:48]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.Cl>CN(C=O)C.C(OCC)(=O)C.CC#N>[OH:44][CH:45]([C:58]1[CH:59]=[CH:60][C:61]([C:64]2[N:66]=[C:17]([C:11]3[O:10][N:9]=[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[C:12]=3[C:13]([F:14])([F:15])[F:16])[O:19][N:65]=2)=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][C@H:49]([C:53]([OH:55])=[O:54])[CH2:48]1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 152842Bis(2-oxo-3-oxazolidinyl)phosphinic chlorideHCID 11078149TBAF tetrahydrofuranHCID 583741633-(6-Methylpyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acidHCID 86656389(3S)-ethyl 1-(2-hydroxy-2-(4-(N'-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate

Product 1

HCID 58374130(3S)-1-(2-hydroxy-2-(4-(5-(3-(6-methylpyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of 3-(6-methylpyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid (100 mg, 0.367 mmol) and DIEA (0.128 mL, 0.735 mmol) in DMF (3 mL) was added BOP—Cl (103 mg, 0.404 mmol). After 15 minutes, (3S)-ethyl 1-(2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate, (refer to Preparation 14B) (136 mg, 0.404 mmol) was added. The reaction mixture was stirred at room temperature. After 1 hour, 1M TBAF/THF (0.367 mL, 0.367 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried with MgSO4, filtered, and concentrated. The resulting material was purified by on a silica gel cartridge using an EtOAc/hexanes gradient. The peak with the desired mass was isolated by LCMS. This residue was dissolved in MeCN and treated with 6N HCl 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 were freeze-dried overnight to yield 6 mg of (3S)-1-(2-hydroxy-2-(4-(5-(3-(6-methylpyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.14 (2H, d, J=8.35 Hz), 7.81 (1H, t, J=7.69 Hz), 7.63 (3H, t, J=7.25 Hz), 7.39 (1H, d, J=7.91 Hz), 5.12-5.24 (1H, m), 3.93 (1H, d, J=12.74 Hz), 3.70-3.86 (1H, m), 3.57 (1H, d, J=11.86 Hz), 3.32-3.44 (1H, m), 3.24-3.32 (2H, m), 2.73-3.12 (2H, m), 2.48-2.56 (3H, m), 1.74-2.32 (2H, m), 1.41-1.65 (1H, m). MS (m+1)=544. HPLC Peak RT=2.96 minutes (Analytical Method A). Purity=90%.

Workup

  1. additionwas added
  2. waitAfter 1 hour
  3. stirringthe reaction mixture was stirred overnight
  4. washwashed with saturated NaCl
  5. dry with materialThe organic layer was dried with MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting material was purified by on a silica gel cartridge
  9. customThe peak with the desired mass was isolated by LCMS
  10. filtrationThe reaction mixture was filtered
  11. custompurified by HPLC
  12. custom25 minute
  13. customIsolated fractions with correct mass were freeze-dried overnight

Sources & evidence

ORD record
ord-c2bfb970b5294868a0575f293aef4df6
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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