Lithium Hydroxide → HCID 86719444, compound

HRID 2278698Notes

Reaction equation

HRID 2278698 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([N:25]2[C@@H:29]([CH2:30][C:31]([O:33]C)=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:39])([F:38])[F:37])=[N:26]2)[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:11][C@H:10]1[CH3:24].[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([N:25]2[C@@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:37])([F:38])[F:39])=[N:26]2)[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:11][C@H:10]1[CH3:24]

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 86719445HCID 86719445, compound

Product 1

HCID 86719444HCID 86719444, compoundYield 100.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of methyl 2-((4S,5S)-1-(3-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (44 mg, 0.069 mmol) in THF (2.0 mL) and water (0.2 mL) at rt was added 1.0M aqueous lithium hydroxide (0.2 mL, 0.200 mmol). After stirring at rt for 4.5 h, the reaction mixture was partially evaporated to remove most of the THF. The remaining solution was partitioned between water (50 mL) and Hex (15 mL). The aqueous layer was acidified to pH 2 by dropwise addition of 1M HCl, and then extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was dried under vacuum to afford 2-((4S,5S)-1-(3-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (43 mg, 100% yield) as a white solid: LC-MS [M+H] 619, 621. 1H NMR (500 MHz, CD2Cl2) δ 7.97 (s, 1H), 7.36 (d, J=2.8 Hz, 1H), 7.02 (dd, J=9.0, 2.8 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 6.30 (s, 1H), 4.41 (m, 1H), 4.02 (dt, J=3.9, 8.3 Hz, 1H), 3.86 (s, 3H), 3.54 (m, 2H), 3.28 (m, 1H), 2.90 (m, 1H), 2.84 (dd, J=16.5, 3.1 Hz, 1H), 2.18 (m, 2H), 1.86 (m, 2H), 1.35 (d, J=7.1 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H). Analytical HPLC (Zorbax method, 50% Solvent B start): RT=8.55 min, HI: 100%. hGPR40 EC50=45 nM.

Workup

  1. customthe reaction mixture was partially evaporated
  2. customto remove most of the THF
  3. customThe remaining solution was partitioned between water (50 mL) and Hex (15 mL)
  4. additionThe aqueous layer was acidified to pH 2 by dropwise addition of 1M HCl
  5. extractionextracted with CH2Cl2 (3×30 mL)
  6. dry with materialThe combined organic extracts were dried (Na2SO4)
  7. concentrationconcentrated
  8. customThe residue was dried under vacuum

Sources & evidence

ORD record
ord-b2e0e0e62a084cdcbf3cc77fe82922d1
Source dataset
uspto-grants-2015_09
Patent number
US09133163B2

Reaction notes

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