(3aα,4α.7α,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-lH-isoindole- l,3(2H)-dione (27D)

 


Example 27 (3aα,4α.7α,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-lH-isoindole- l,3(2H)-dione (27D)

A. (endo, endo)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (27A)

Compounds 27A, 27B and 27C were synthesized in accordance with the approaches described in Sprague et al, J. Med. Chem. 28, 1580-1590 (1985). A mixture of furan (100 mL, 1.38 mol, 1 eq) and maleic acid (159.6 g, 1.38 mol, 1 eq) in H₂O (340 mL) was stiπed at room temperature for 5 days. The mixture was placed in a separatory funnel and the aqueous layer was separated from the layer containing the unreacted furan. The aqueous layer was treated with charcoal, filtered tlirough celite and placed in the refrigerator. The desired product crystallized from solution upon seeding, was filtered, washed with cold water and dried over P₂O₅ to give 70 g (0.38 mol, 28%) of compound 27A as a white solid. B. (endo, endo)-7-Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid (27B)

To a solution of compound 27A (69 g, 0.375 mol, 1 eq) in EtOH (700 mL) was added 10% Pd/C (4.5 g, cat.) and the mixture was shaken under a hydrogen atmosphere at 55 psi until gas uptake ceased. The mixture was filtered through celite and concentrated in vacuo to give 66 g (0.355 mol, 95%) of compound 27B as a white solid.
C. (3aα,4α,7α,7aα)-Hexahydro-4,7-epoxyisobenzofuran-l,3-dione (27C)

A solution of compound 27B (66 g, 355 mol) in acetyl chloride (300 mL) was refluxed for 1 h. The reaction solution was concentrated in vacuo and the resulting residue was recrystallized from benzene to give 49.2 g (0.292 mol, 82%o) of compound 27C as a white solid (>99% endo by 'H NMR). D. (3aα,4α,7α,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-lH-isoindole- l,3(2H)-dione (27D)
Compound 27C (45 mg, 0.30 mmol, 1 eq) was combined with 2- naphthalenamine (47 mg, 0.33 mmol, 1.1 eq) in acetic acid (1 mL) and heated at 115°C overnight. After the reaction was cooled to rt, a drop of water was added, and the resulting precipitate was filtered. The material was washed with methanol and dried to provide 65.7 mg (74.5%) of compound 27D as a white crystalline solid. HPLC: 99% at 2.68 min (retention time) (YMC S5 ODS column 4.6 x 50 mm, 10- 90% aqueous methanol over 4 minutes containing 0.2%> phosphoric acid, 4 mL/min, monitoring at 220 nm), MS (ESI): m/z 294.0 [M+H]⁺.








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(3aα,4β,7β,7aα)-2-[3.5-Bis(trifluoromethyl)phenyl]hexahydro-4.7-epoxy-lH- isoindole-l,3(2H)-dione

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Example 8 (3aα,4β,7β,7aα)-2-[3.5-Bis(trifluoromethyl)phenyl]hexahydro-4.7-epoxy-lH- isoindole-l,3(2H)-dione (8)

3,5-Bis-(trifluoromethyl)-aniline (0.017 g, 0.0075 mmol) was dissolved in acetic acid (0.300 mL) and transfeπed to a 1.5 mL conical vial with a septa cap. Stock solutions of an additional 95 amines were prepared as described above. To each of the above vials was added 0.4 mL (0.12 mmol) of a stock solution of exo-7- oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride in acetic acid. The vials were then sealed and heated at 110°C for 11 h. Upon cooling to 25°C, the caps were removed from the vials and the acetic acid was removed in vacuo. To each vial was added 1 mL of 2:1 acetone/methylene chloride and the vials were heated at 40°C for 1 h. Once all products were in solution, they were transfeπed via robot to filter tubes with coarse frits pre- wetted with 0.2 mL of water. Nitrogen was blown through each tube until the volatile organics were removed. 1.5 mL of 10% aq K₂CO₃ was then added to each tube followed by vigorous shaking at 25°C for 15 min. The tubes were then drained, resealed and 1.0 mL of water was added to each tube followed by shaking. The tubes were drained again and washed with water a second time. The resulting residues in each tube was then dried in vacuo for 48 h. After drying, 1.0 mL of 20% TFA in methylene chloride was added to each tube and the racks were shaken for 30 min. The tubes were then drained into a 96-well plate with pre-tared custom micro-tubes present. Each tube was assayed for product purity (analytical LC) and identity (LC-MS). The tubes were then concentrated in vacuo and weighed for yields. The tube containing the reaction of 3,5-bistrifluoromethylaniline and exo-7- oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride, yielded 0.022 g of compound 8 as a white solid. HPLC: 94% at 4.03 min (retention time) (YMC S5 ODS column 4.6 x 50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS (ES): m/z 434.2 [M+Na+MeOH]⁺\ Of the remaining 95 additional reactions run, a total of 80 final compounds were obtained in >70% purity and >5 mg yield. Several samples needed further purification which was performed by short SiO₂ column eluting with methylene chloride/acetone. See Table 2 below.










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