Dimethylformamide → ethyl 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetate

HRID 1948534Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1948534
[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[OH:30][CH:31]([C:45]1[CH:50]=[CH:49][C:48](/[C:51](=[N:53]/O)/[NH2:52])=[CH:47][CH:46]=1)[CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:34]1>ClCCl>[OH:30][CH:31]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[N:53]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:11]=3[C:12]([F:13])([F:14])[F:15])[O:18][N:52]=2)=[CH:47][CH:46]=1)[CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:34]1

Komponenten

6

Edukt 4

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 583741783-(Pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acidHCID 87214058HCID 87214058, Verbindung

Produkt 1

HCID 66955359ethyl 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetate

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel2×

Versuchsvorschrift

Under an argon atmosphere, 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid, Int-IV (40 mg, 0.155 mmol) was suspended in dichloromethane (1.5 mL) with sonication and DMF (5 μl, 0.065 mmol) was added. Oxalyl chloride (54.3 μl, 0.620 mmol) was added dropwise over 1-2 minutes. The reaction vial was flushed with argon and sealed. After 3 h, the contents were concentrated in vacuo. The material was re-constituted in dichloromethane and a solution of ethyl 2-((3R)-1-(2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (54.1 mg, 0.155 mmol) in DCM (1-2 mL) was added. The reaction mixture was stirred for 3 days at room temperature and then purified by Prep HPLC to afford ethyl 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetate which was suspended in dioxane (2-3 mL) and 3N aq HCl (1 mL) was added. The mixture was placed in a sand bath heated to 50° C. overnight. The solution was evaporated, re-evaporated from chloroform-d and then placed under high vacuum to give 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid as a clear colorless film. 1H NMR (500 MHz, MeOD) δ ppm 8.69 (1 H, d, J=4.72 Hz), 8.14 (2H, d, J=8.32 Hz), 7.95 (1H, td, J=7.70, 1.80 Hz), 7.86 (1H, d, J=7.77 Hz), 7.61 (2H, d, J=8.32 Hz), 7.49-7.56 (1H, m), 5.17 (1H, dd, J=9.71, 4.16 Hz), 3.80 (1H, br. s.), 3.52-3.67 (4H, m), 2.89 (1H, br. s.), 2.73 (1H, t, J=11.93 Hz), 2.18-2.39 (3H, m), 1.79-1.94 (3H, m). HPLC RT=0.77 min, MH+=544. Waters Masslynx instrument equipped with a BEH 2.1×50 mm 17 uM C18 column and a method of 2-98% B solvent over 1.6 min at a flow rate of 0.8 mL/min. Solvent A is water; solvent B is acetonitrile and both contain 0.5% TFA.

Aufarbeitung

  1. additionwas added
  2. customThe reaction
  3. customvial was flushed with argon
  4. customsealed
  5. concentrationthe contents were concentrated in vacuo
  6. custompurified by Prep HPLC

Quellen und Nachweise

ORD-Eintrag
ord-807197b16ae740ebb978af2cbf7cb395
Quelldatensatz
uspto-grants-2013_03
Patentnummer
US08399451B2

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