| 86% |
With zinc chloride diethyl ether; In dichloromethane; benzene; at 0 - 20℃; |
To a mixture of phthalimidoacetaldehyde (64 g, 0.34 mol) and <strong>[54125-02-9]trans-1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene</strong> (81.5 g, 0.38 mol) in benzene (600 ml) stirred for 15 min. under nitrogen was added dropwise a 45 % solution of zinc chloride diethyl ether complex in dichloromethane (55.5 ml, 0.17 mol) at 0 C. The reaction was allowed warm up to room temperature overnight. To the reaction mixture was added water (500 ml) and the resulting mixture was extracted with ethyl acetate (200 ml). The organic extract was washed successively with 1.0 N hydrochloric acid (2 x 200 ml) and brine (200 ml). The organic phase was dried (Na2SO4), filtered and the solvent evaporated invacuo which afforded a slowly crystallising oil (98 g). To the solid was added a mixture of ethyl acetate and diethyl ether (400 ml, 1:1) and the resulting precipitate was filtered off, washed with a small portion of diethyl ether and dried at 50 C for 1 hour affording 59.8 g (69 %) of 2-(4-oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindote-1,3-dione as a solid. The filtrate was evaporated invacuo and the residue purified by column chromatography on silica gel (1 L) using a mixture of ethyl acetate and heptane (1:2) as eluent. Pure fractions were collected and the solvent evaporated invacuo to almost dryness, the solid was filtered off and dried invacuo at 50 C for 16 h affording an additional 15 g (17 %) of 2-(4-oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid.1H-NMR (300 MHz, CDCl3) δ 2.61 (d, 2H), 3.85 (dd, 1H), 4.18 (dd, 1H), 4.76 (m, 1H), 5.43 (d, 1H), 7.28 (d, 1H), 7.69 - 7.77 (m, 2H), 7.84 - 7.88 (m, 2H). |
| 86% |
With ZnCl2*Et2O; In benzene; at 0 - 20℃; |
Example 28 7-(((Benzo[1,3]dioxole-5-carbonyl)-amino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid; Phthalimidoacetaldehyde diethyl acetal (100 g, 0.38 mol) and 1 N hydrochloric acid (600 ml) was mixture was stirred at reflux temperature for 5 min. or until a homogeneous solution is obtained. The reaction mixture was cooled and the precipitate was filtered off and dried in vacuo at 50 C. for 16 h which afforded 63.3 g (88%) of phthalimidoacetaldehyde as a solid.1H NMR (300 MHz, CDCl3) δ 4.58 (s, 2H), 7.76-7.78 (m, 2H), 7.90-7.92 (m, 2H), 9.67 (s, 1H).To a mixture of phthalimidoacetaldehyde (64 g, 0.34 mol) and <strong>[54125-02-9]trans-1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene</strong> (81.5 g, 0.38 mol) in benzene (600 ml) stirred for 15 min. under nitrogen was added dropwise a 45% solution of zinc chloride diethyl ether complex in dichloromethane (55.5 ml, 0.17 mol) at 0 C. The reaction was allowed warm up to room temperature overnight. To the reaction mixture was added water (500 ml) and the resulting mixture was extracted with ethyl acetate (200 ml). The organic extract was washed successively with 1.0 N hydrochloric acid (2×200 ml) and brine (200 ml). The organic phase was dried (Na2SO4), filtered and the solvent evaporated in vacuo which afforded a slowly crystallising oil (98 g). To the solid was added a mixture of ethyl acetate and diethyl ether (400 ml, 1:1) and the resulting precipitate was filtered off, washed with a small portion of diethyl ether and dried at 50 C. for 1 h affording 59.8 g (69% of 2-(4-oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid. The filtrate was evaporated in vacuo and the residue purified by column chromatography on silica gel (1 L) using a mixture of ethyl acetate and heptane (1:2) as eluant. Pure fractions were collected and the solvent evaporated in vacuo to almost dryness, the solid was filtered off and dried in vacuo at 50 C. for 16 h affording an additional 15 g (17%) of 2-(4-oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid.1H NMR (300 MHz, CDCl3) δ 2.61 (d, 2H), 3.85 (dd, 1H), 4.18 (dd, 1H), 4.76 (m, 1H), 5.43 (d, 1H), 7.28 (d, 1H), 7.69-7.77 (m, 2H), 7.84-7.88 (m, 2H).2-(4-Oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione (13 g, 0.051 mol) was dissolved in ethyl acetate (250 ml) and placed in a Parr bottle. 10% Pd/C (1.5 g) was carefully added and the mixture was shaken under a pressure of 30 psi of hydrogen for 6.5 h (Parr apparatus). Filtration followed by evaporation of the ethyl acetate in vacuo afforded a crude 11.5 g of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione pure enough for the next step. Analytical pure compound could be obtained by purification of a small sample (250 mg) by column chromatography on silica gel, utilising a mixture of hexane/ethyl acetate as a gradient (from 100/0 to 50/50). Pure fractions were collected and the solvent evaporated in vacuo affording 142 mg (55%) of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid.1H NMR (400 MHz, CDCl3) δ 2.30-2.68 (m, 4H), 3.62 (m, 1H), 3.74 (m, 1H), 4.00 (m, 2H), 7.75 (m, 2H), 7.88 (m, 2H).To a mixture of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione (11.5 g, 44 mmol), tert-butyl cyanoacetate (6.9 g, 49 mmol) and elemental sulfur (1.6 g, 49 mmol) in ethanol (250 ml) was added morpholin (15 ml) and the resulting mixture was stirred at 50 C. for 16 h. The cooled reaction mixture was filtered and the precipitate filtered off and washed with diethyl ether and dried in vacuo affording 6.5 g (35%) of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.The filtrate was evaporated in vacuo and the residue was dissolved in ethyl acetate (200 ml) washed with water (2×100 ml), brine (100 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo affording 6.0 g (33%) of almost regioisomer pure 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.2-amino-5-(1,3-dioxo-1,3'-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester1H NMR (300 MHz, CDCl3) δ1.50 (s, 9H), 2.54-2.63 (m, 1H), 2.84-2.90 (m, 1H), 3.79 (q, 1H), 3.96-4.04 (m, 2H), 4.48-4.62 (m, 2H), 5.91 (bs, 2H, NH2), 7.70 (m, 2H), 7.84 (m, 2H).2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester1H NMR (300 MHz, CDCl3) δ 1.50 (s, 9H), 2.71-2.90 (m, 2H), 3.67-3.77, (m, 2H), 4.02-4.15 (m, 2H), 4.90 (m, 1H), 6.04 (bs, 2H, NH2), 7.70 (m, 2H), 7.84 (m, 2H).To a solution of 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (6.0 g, 0.014 mol) in ethanol (100 ml) was added hydrazine-hydrate (1.4 ml, 0.029 mol). The mixture was stirred at reflux temperature for 1 h. The cooled reaction mixture was filtered and the solvent ev... |
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