Diisopropylethylamine → 4-{5-[4-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3,3-difluoroazetidin-1-yl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acid

HRID 531310Notes

Reaction equation

HRID 531310 reaction equation
[F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:53][C:54]1([F:58])[CH2:57][NH:56][CH2:55]1.CCN(C(C)C)C(C)C>C1COCC1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22]([N:56]4[CH2:57][C:54]([F:58])([F:53])[CH2:55]4)[N:21]=3)[C@H:14]2[CH3:49])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:50])[CH:8]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 27582473,3-Difluoroazetidine hydrochlorideHCID 900093774-{5-[4-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acid2×

Product 1

HCID 721899784-{5-[4-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3,3-difluoroazetidin-1-yl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acidYield 88%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 52, 80 mg, 0.106 mmol) in THF (5 mL) was added 3,3-difluoroazetidine hydrochloride (41.1 mg, 0.317 mmol) and DIEA (0.092 mL, 0.529 mmol). The reaction mixture was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated, and the residue was purified on reverse phase HPLC, eluting with water and acetonitrile (10% to 100%), to give the title compound as a yellowish solid after lyophilization (72 mg, 88% yield). LCMS (M+H)+: 770.1. 1H NMR (CDCl3, 500 MHz): δ 8.35 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.87 (m, 1H), 7.79 (s, 2H), 5.82 (d, 9.0 Hz, 1H), 5.50 (m, 1H), 4.75 (m, 1H), 4.58-4.34 (m, 4H), 4.09 (m, 1H), 3.75 (s, 3H), 1.33 (s, 9H), 0.81 (d, 7.0 Hz, 3H). RTA IC50: 800 nM.

Workup

  1. customThe solvent was evaporated
  2. customthe residue was purified on reverse phase HPLC
  3. washeluting with water and acetonitrile (10% to 100%)

Sources & evidence

ORD record
ord-923c76f0cbb14afaae0f82d63f173847
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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