dimethyl 3-oxopentanedioate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Starting from dimethyl acetonedicarboxylate, dimethyl tetra-C-methylacetonedicarboxylate was obtained by methylation, and this was converted into the dicarboxylic acid methyl ester chloride and then methylated with dimethylcadmium. The methyl 2,2,4,4-tetramethyl-3,5-dioxohexanecarboxylate obtained was cyclized in the presence of sodium methanolate. The total yield (based on dimethyl acetonedicarboxylate) is 0.01% (Chem. Ber. 92, 2033 (1959)). dimethyl tetra-C-methylacetonedicarboxylate was obtained by methylation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Accordingly, compounds of formula (Ca) are prepared, as set forth above in REACTION SCHEME 2B, by first combining a pentane-3-dioate, e.g. dimethyl 3-oxopentanedioate shown, with a 1,2-bismethyl aromatic having a suitable leaving group on each methyl group, e.g., 1,2-bis(bromomethyl)benzene, in a mixed protic/aprotic solvent medium, e.g., THF-MeOH, and a metal alkoxide, e.g., sodium methoxide. The metal alkoxide can be added as such or made in situ via careful addition (e.g., at low temperature) of the appropriate metal to at least the protic solvent, preferably prior to combination with the remaining reactants. The intermediate benzo[7]annulene product so formed can be optionally isolated and may contain one or two carboxy ester groups depending on the reaction conditions, e.g., methyl 7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6,8-dicarboxylate, as shown above. The intermediate, dimethyl 7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6,8-dicarboxylate, is subjected to basic hydrolysis (saponification) conditions followed by acidification to give compounds of formula (Ca). Accordingly, compounds of formula (Ca) are prepared as set forth above in REACTION SCHEME 2B made in situ via careful addition (e.g., at low temperature) of the appropriate metal to at least the protic solvent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of dimethyl 3-oxopentanedioate (3.48 g, 20 mmol) in ethanol (12 mL) and water (40 mL) at room temperature was added sodium acetate (12.0 g, 146 mmol), and was followed by addition of 4-(methylsulfonyl)benzenediazonium solution (20 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The product was collected by filtration, then washed with water (˜50 mL) and dried overnight under reduce pressure to yield 7.0 g (83%) of (E)-dimethyl 2-(2-(4-(methylsulfonyl)phenyl)hydrazono)-3-oxopentanedioate as a yellow solid. MS (ESI) 357 (M+H). The resulting reaction mixture The product was collected by filtration washed with water (˜50 mL) dried overnight

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of dimethyl 3-oxopentanedioate (3.48 g, 20 mmol) in ethanol (12 mL) and water (40 mL) at room temperature was added sodium acetate (12.0 g, 146 mmol), and was followed by the addition of 3,4-dichlorobenzenediazonium solution (20 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The product was collected by filtration, then washed with water (˜50 mL) and dried overnight under reduced pressure to yield 6.776 g (93%) of (E)-dimethyl 2-(2-(3,4-dichlorophenyl)hydrazono)-3-oxopentanedioate as a yellow solid. MS (ESI) 347 (M+H). The resulting reaction mixture The product was collected by filtration washed with water (˜50 mL) dried overnight under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl 3-ketoglutarate (13 g) in methanol (50 ml) was treated with ammonium formate (5 g) and NaCNBH3 (2 g). 10 ml of H2O was added and the excess solvent removed under reduced pressure. The semi-solid was dissolved in 5% aqueous HCl (250 ml), and washed with CH2Cl2 (2×50 ml). The aqueous layer was made basic (pH>9) with K2CO3 and the product was extracted using CH2Cl2 (2×75 ml). The organic layers were combined and dried with Na2SO4. The excess solvent was removed to give 2.5 g of the dimethyl (±)3-aminoglutarate. This was dissolved in methanol (50 ml) and treated with 4N HCl/Dioxane (10 ml). The excess solvent was removed under reduced pressure to give a 2.7 g of dimethyl (±)3-aminoglutarate hydrochloride. MS and 1H-NMR were consistent with the desired product. the excess solvent removed under reduced pressure The semi-solid was dissolved in 5% aqueous HCl (250 ml) washed with CH2Cl2 (2×50 ml) the product was extracted dried with Na2SO4 The excess solvent was removed

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of t-butyl 3-amino-2-butenoate (3.911 g, 24.8 mmol), 2,6-dichlorobenzaldehyde (4.354 g, 24.8 mmol), and dimethyl acetonedicarboxylate (3.657 ml, 24.8 mmol) in methanol (50 ml) was refluxed for 45 h. The solvent was evaporated and the residue was chromatographed on 800 g silica gel (dichloromethane/ethyl acetate: 23/2 as eluent) to give 1.18 g of product. On silica GF plates, the product was blue fluorescent at Rf=0.3. was refluxed for 45 h The solvent was evaporated the residue was chromatographed on 800 g silica gel (dichloromethane/ethyl acetate: 23/2 as eluent)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of dimethyl acetonedicarboxylate (44.1 ml, 0.3 mole) and p-toluene-sulfonic acid (0.19 g, 1 mmol) in benzene (50 ml) was bubbled NH3 gas for 30 min. The mixture was refluxed with azeotropic removal of water using Dean-Stark trap. The bubbling of NH3 gas and azeotropic removal of water was repeated three times to give a total 5 ml of water. The reaction mixture was diluted with benzene and filtered through celite. The filtrate was concentrated to give an amber oil, 50.75 g. An equal volume of ether was added to this oil and hexane added until cloudy, and stirred slowly overnight to afford a crystalline product. This crystalline was collected by filtration and washed once with 1/1 of ether/hexane to give 44.55 g (85.75%) of crystalline, mp 47°-50° C. The bubbling of NH3 gas and azeotropic removal of water to give a total 5 ml of water filtered through celite The filtrate was concentrated to give an amber oil, 50.75 g added until cloudy to afford a crystalline product This crystalline was collected by filtration washed once with 1/1 of ether/hexane to give 44.55 g (85.75%) of crystalline, mp 47°-50° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100.0 g of dimethyl 1,3-acetonedicarboxylate was dissolved in 2,800 ml of dioxane, and added thereto were 52.5 g of 2,5-dihydroxy-1,4-dithiane and 5.0 g of lithium bromide. The resulting mixture was refluxed for 15 hours, cooled to room temperature, and concentrated by evaporation. To the residue, 1,000 ml of n-hexane was added, stirred, and the hexane layer was separated. This extraction procedure was repeated twice using 500 ml portions of n-hexane. The separated n-hexane layers were combined and concentrated under reduced pressure to obtain 60.9 g (yield of 49%) of the title compound as an oil, which was directly used in the next step without any purification. An analytical sample of the title compound could be obtained by vacuum distillation. added The resulting mixture was refluxed for 15 hours concentrated by evaporation To the residue, 1,000 ml of n-hexane was added the hexane layer was separated This extraction procedure concentrated under reduced pressure