Lithium Hydroxide → HCID 90151173, compound

HRID 2278685Notes

Reaction equation

HRID 2278685 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([O:31]C)=[O:30])[C@H:26]([CH3:33])[C:25]([C:34]([F:37])([F:36])[F:35])=[N:24]4)=[CH:19][CH:18]=3)[C@H:12]([CH3:38])[CH2:11]2)[CH:9]=1)[CH3:2].[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([OH:31])=[O:30])[C@H:26]([CH3:33])[C:25]([C:34]([F:36])([F:37])[F:35])=[N:24]4)=[CH:19][CH:18]=3)[C@H:12]([CH3:38])[CH2:11]2)[CH:9]=1)[CH3:2]

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 90151183HCID 90151183, compound

Product 1

HCID 90151173HCID 90151173, compoundYield 99%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (2.57 g, 4.66 mmol) in THF (85 mL) and water (8.5 mL) was added a 1 M aqueous solution of LiOH (58.2 mL, 23.3 mmol) and the reaction mixture was stirred at rt until complete for 1 h. The reaction mixture was concentrated to remove the THF and hexanes were added. An emulsion formed. The layers were separated as much as possible. Brine was added to the emulsion and the layers separated completely. The combined aqueous layer and brine aqueous layer was acidified to pH 2 with 1 M aqueous HCl. The product was extracted with CH2Cl2 (3×) and the combined organic layers were dried (MgSO4) and concentrated to provide 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (2.4720 g, 4.60 mmol, 99% yield) as a white foam. To a solution of 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (7.72 g, 14.4 mmol) in acetonitrile (50 mL) was added 3 N aqueous HCl (9.57 mL, 28.7 mmol). The solution was concentrated. 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid, HCl (8.08 g, 14.0 mmol, 97% yield) was isolated as an off-white solid. LC-MS Anal. Calc'd for C27H31F4N3O4: 537.55. found [M+H] 538.3. 1H NMR (400 MHz, CD3CN) δ 7.99 (br. s., 1H), 7.24 (ddd, J=12.0, 9.3, 1.2 Hz, 1H), 7.12-7.04 (m, 2H), 7.02-6.93 (m, 3H), 4.47-4.38 (m, 1H), 4.18 (td, J=10.0, 4.1 Hz, 1H), 4.04 (q, J=6.9 Hz, 2H), 3.78-3.65 (m, 2H), 3.62 (dd, J=12.4, 4.1 Hz, 1H), 3.42 (td, J=11.8, 4.4 Hz, 1H), 3.37-3.27 (m, 1H), 2.83 (br. s., 1H), 2.73 (dd, J=16.5, 3.0 Hz, 1H), 2.54-2.38 (m, 2H), 2.36-2.28 (m, 1H), 1.37 (t, J=7.0 Hz, 3H), 1.30 (d, J=7.2 Hz, 3H), 1.11 (d, J=6.9 Hz, 3H). Analytical HPLC (Orthogonal method) RT=13.3 min, HI: 97%. hGPR40 EC50=154 nM. hGPR40 IP1 EC50=11 nM. Acute oral glucose tolerance: −52% @ 0.3 mg/kg (average of two experiments).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customto remove the THF and hexanes
  3. additionwere added
  4. customAn emulsion formed
  5. customThe layers were separated as much as possible
  6. additionBrine was added to the emulsion
  7. customthe layers separated completely
  8. extractionThe product was extracted with CH2Cl2 (3×)
  9. dry with materialthe combined organic layers were dried (MgSO4)
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-da30e077fd2a4168b6d44a8b5705ab99
Source dataset
uspto-grants-2015_09
Patent number
US09133163B2

Reaction notes

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