Citric Acid → HCID 72192441, compound

HRID 531276Notes

Reaction equation

HRID 531276 reaction equation
C(N(CC)CC)C.[F:8][C:9]([F:54])([F:53])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[C:34]([O:46][CH3:47])=[N:35][CH:36]=[C:37]([C:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41])[CH:38]=4)=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=3)[C@H:21]2[CH3:52])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.Cl.[F:56][CH:57]1[CH2:60][NH:59][CH2:58]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C1COCC1>[F:8][C:9]([F:54])([F:53])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[C:34]([O:46][CH3:47])=[N:35][CH:36]=[C:37]([C:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41])[CH:38]=4)=[CH:31][N:30]=[C:29]([N:59]4[CH2:60][CH:57]([F:56])[CH2:58]4)[N:28]=3)[C@H:21]2[CH3:52])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 8471TriethylamineHCID 101250543-fluoroazetidine HydrochlorideHCID 118021407HCID 118021407, compound

Product 1

HCID 72192441HCID 72192441, compound

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

Triethylamine (0.218 mL, 1.566 mmol) was added to a mixture of THF (2 mL), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-{2-methoxy-5-[(2RS)-1,1,1-trifluoro-2-hydroxypropan-2-yl]pyridin-3-yl}-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Step B, 220 mg, 0.313 mmol) and 3-fluoroazetidine hydrochloride (105 mg, 0.939 mmol). The reaction was placed under nitrogen and heated to 60° C. for 45 minutes; LCMS showed complete conversion to product. The reaction was diluted with 20 mL ethyl acetate and poured into 20 mL 10% citric acid, The organic layer was washed with 30 mL brine, then dried over sodium sulfate and concentrated. Purification on an X-Bridge 21.2×150 mm RP column with sample loaded using 7:3:1 CH3CN/water/DMSO (3 mL) employed a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient at 15 mL/minutes over 20 minutes. The product of interest eluted in 70% portion of the above gradient. Rich cut of pure product peak was lyophilized to give product as a white solid. LCMS (M+H)+: 698.5. 1H NMR (500 MHz, CDCl3): 1:1 diasteromeric mixture: δ 8.38 (m, 1H), 8.26 (s, 0.5H), 8.24 (s, 0.5H), 7.91 (bs, 1H), 7.82 (m, 0.5H), 7.79 (d, J=2.2 Hz, 0.5H), 7.74 (s, 1H), 7.71 (s, 1H), 5.62 (d, J=8.4 Hz, 0.5H), 5.55 (m, 0.5H), 5.44 (m, 0.5H), 4.86 (m, 0.5H), 4.72 (d, J=16.5 Hz, 0.5H), 4.52 (m, 2.5H), 4.33 (m, 3H), 4.00 (s, 1.5H), 3.42 (bs, 0.5H), 3.28 (s, 0.5H), 3.99 (s, 1.5H), 1.85 (s, 3H), 0.77 (d, J=6.6 Hz, 1.5H), 0.73 (d, J=6.6 Hz, 1.5H). RTA IC50: 14 Nm.

Workup

  1. washThe organic layer was washed with 30 mL brine
  2. dry with materialdried over sodium sulfate
  3. concentrationconcentrated
  4. customPurification on an X-Bridge 21.2×150 mm RP column with sample
  5. customover 20 minutes
  6. washThe product of interest eluted in 70% portion of the above gradient
  7. customto give product as a white solid

Sources & evidence

ORD record
ord-ff341de6e3c74fa5899721c78a618f7b
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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