Lithium Hydroxide → HCID 86719442, compound

HRID 2278697Notes

Reaction equation

HRID 2278697 reaction equation
[Br:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=3)[CH2:11][C@H:10]2[CH3:24])[CH:5]=[CH:4][C:3]=1[N:25]1[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]1.[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=3)[CH2:11][C@H:10]2[CH3:24])[CH:5]=[CH:4][C:3]=1[N:25]1[C@@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:37])([F:39])[F:38])=[N:26]1

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 86719443HCID 86719443, compound

Product 1

HCID 86719442HCID 86719442, compoundYield 94.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of methyl 2-((4S,5S)-1-(2-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 (6.5 mg, 10.25 μmol) in THF (0.5 mL) and water (0.04 mL) at rt was added 1.0M aqueous lithium hydroxide (0.04 mL, 0.040 mmol). The mixture was stirred at rt for 13.5 h and then partially evaporated to remove most of the THF. The remaining solution was partitioned between water (40 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-(2-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 (6 mg, 89% yield) as a white solid: LC-MS [M+H] 619, 621. 1H NMR (400 MHz, CD2Cl2) δ 7.96 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.91 (dd, J=8.8, 2.8 Hz, 1H), 6.29 (s, 1H), 4.63 (m, 1H), 3.99 (dt, J=4.1, 8.8 Hz, 1H), 3.86 (s, 3H), 3.52 (m, 2H), 3.27 (m, 1H), 2.89 (m, 1H), 2.66 (dd, J=12.2, 9.3 Hz, 1H), 2.41 (m, 2H), 2.18 (m, 2H), 1.79 (m, 1H), 1.41 (d, J=7.1 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H). Analytical HPLC (Zorbax method, 0% Solvent B start): RT=8.69 min, HI: 97%. hGPR40 EC50=844 nM.

Workup

  1. custompartially evaporated
  2. customto remove most of the THF
  3. customThe remaining solution was partitioned between water (40 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-9ba6a41449dd4b42beb318d7b26b2caa
Source dataset
uspto-grants-2015_09
Patent number
US09133163B2

Reaction notes

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