Lithium Hydroxide → (+/-)-10,11-Dihydro-3-[2-[2-(ethylamino)thiazol-4-yl]-1-ethoxy]-5h-dibenzo[a,d]cycloheptene-10-acetic acid

HRID 1369239Notes

Reaction equation

HRID 1369239 reaction equation
[Li+].[OH-].[CH2:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:23][CH:22]([CH2:24][C:25]([O:27]CC)=[O:26])[C:21]4[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=4[CH2:19][C:18]=3[CH:34]=2)[N:10]=1)[CH3:4].C(O)(C(F)(F)F)=O.CC#N.O>C1COCC1.O>[CH2:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:23][CH:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21]4[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=4[CH2:19][C:18]=3[CH:34]=2)[N:10]=1)[CH3:4]

Participants

8

Reactant 4

HCID 3939Lithium HydroxideHCID 6422Trifluoroacetic acidHCID 12071470Ethyl (+/-)-10,11-dihydro-3-[2-[2-(ethylamino)thiazol-4-yl]-1-ethoxy]-5 H-dibenzo[a,d]cycloheptene-10-acetateHCID 18373917Acetonitrile--water (1/1)2×

Product 1

HCID 12071471(+/-)-10,11-Dihydro-3-[2-[2-(ethylamino)thiazol-4-yl]-1-ethoxy]-5h-dibenzo[a,d]cycloheptene-10-acetic acid

Reagents, catalysts & solvents 3

HCID 962WaterCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

1.0 N LiOH (0.32 mL, 0.32 mmole) was added dropwise to a solution of ethyl (±)-10,11-dihydro-3-[2-[2-(ethylamino)thiazol-4-yl]-1-ethoxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (145.0 mg, 0.32 mmole) in THF (2.4 mL) and H2O (0.48 mL) at 0° C. The resulting pinkish-orange two-phase mixture was stirred at 0° C. for 10 min, during which time the color faded to orangish-yellow, then was warmed to RT. After 1.5 hr, a little more H2O (5 drops) was added, and the reaction was stirred for 42 hr, then was cooled to 0° C. and neutralized with TFA (0.025 mL). The THF was removed on the rotavap, and the resulting oily residue was diluted with 0.1% TFA/CH3CN to give a homogeneous solution. ODS chromatography (gradient: 40% CH3CN/H2O containing 0.1% TFA, then 45% CH3CN/H2O containing 0.1% TFA) gave fractions containing the title compound. These were pooled, and the CH3CN was removed on the rotavap. The resulting aqueous mixture was made basic at 0° C. to afford a homogeneous solution. Careful acidification to pH 4-5 with 1.0 N HCl gave a solid precipitate, which was collected, washed with plenty of H2O, and dried to afford the title compound (80.9 mg, 51%) as an off-white solid: HPLC (Hamilton PRP-1®, 45% CH3CN/H2O containing 0.1% TFA) k′=0.89; 1H NMR (400 MHz, CD3OD) δ7.02-7.18 (m, 4 H), 7.00 (d, J=8.3 Hz, 1 H), 6.79 (d, J=2.6 Hz, 1 H), 6.68 (dd, J=8.3, 2.6 Hz, 1 H), 6.45 (s, 1 H), 4.26 (d, J=14.9 Hz, 1 H), 4.20 (t, J=6.4 Hz, 2 H), 3.87 (d, J=14.9 Hz, 1 H), 3.68-3.80 (m, 1 H), 3.34 (q, J=7.3 Hz, 2 H, partially obscured by residual solvent signal), 3.30 (dd, 1 H, obscured by residual solvent signal), 2.99 (t, J=6.4 Hz, 2 H), 2.92 (dd, J=15.0, 9.4 Hz, 1 H), 2.62 (dd, J=15.9, 5.0 Hz, 1 H), 2.47 (dd, J=15.9, 9.3 Hz, 1 H), 1.27 (t, J=7.3 Hz, 3 H); MS (ES) m/e 423 (M+H)+. Anal. Calcd for C24H26N2O3S.0.67 CF3CO2H: C, 61.03; H, 5.39; N, 5.62. Found: C, 61.21; H, 5.36; N, 5.60.

Workup

  1. temperaturethen was warmed to RT
  2. waitAfter 1.5 hr
  3. stirringthe reaction was stirred for 42 hr
  4. customThe THF was removed on the rotavap
  5. additionthe resulting oily residue was diluted with 0.1% TFA/CH3CN
  6. customto give a homogeneous solution

Sources & evidence

ORD record
ord-808fcec2e46e4f7d9489c2e1e9b35aee
Source dataset
uspto-grants-2003_06
Patent number
US06576643B2

Reaction notes

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