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 1948534Notes

Reaction equation

HRID 1948534 reaction equation
[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

Participants

6

Reactant 4

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

Product 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

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-807197b16ae740ebb978af2cbf7cb395
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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