| 93% |
With trifluoroacetic acid; In chloroform; at 20℃; for 6h;Inert atmosphere; Cooling with ice; |
Compound 2 was prepared according to a modified method of Veale et al. (E. B. Veale, J. E. O'Brien, T. McCabe and T. Gunnlaugsson, Tetrahedron, 2008, 64, 6794-6800). In an ice/water bath, under a nitrogen atmosphere, to a solution of phthalimido-acetaldehydediethylacetal (13 g, 49 mmol) in CHCl3 (150 mL), TFA (100 mL) was added. The resulting solution was stirred for 1 h. Then the ice bath was removed and the reaction mixture was stirred at r.t. for a further 5 h. The solvent was removed in vacuo and co-evaporated with CH2Cl2 several times to remove the remaining traces of TFA. This yielded the product (Compound 2) as an off-white solid (9 g, 93%). No purification was necessary. 1H NMR (CDCl3, 400 MHz) delta 9.68 (s, 1H, CHO), 7.91 (m, 2H), 7.78 (m, 2H), 4.59 (s, 2H); 13C NMR (CDCl3, 100 MHz): delta (100 MHz, CDCl3) 193.6, 167.6, 134.4, 131.9, 123.7, 47.4. |
| 88% |
With hydrogenchloride; water; for 0.0833333h;Heating / reflux; |
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 hours, which afforded 63.3 g (88 %) of phthalimido-acetaldehyde as a solid. 1H-NMR (300 MHz, CDCl3) delta 4.58 (s, 2H), 7.76 - 7.78(m, 2H), 7.90 - 7.92 (m, 2H), 9.67 (s, 1H). |
| 88% |
With hydrogenchloride; for 0.0833333h;Heating / reflux; |
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 hours, which afforded 63.3 g (88%) of phthalimido-acetaldehyde as a solid. 1H-NMR (300 MHz, CDCl3) delta 4.58 (s, 2H), 7.76-7.78 (m, 2H), 7.90-7.92 (m, 2H), 9.67 (s, 1H). |
| 88% |
With hydrogenchloride; water; for 0.0833333h;Heating / reflux; |
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) delta 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 trans-1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (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) delta 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) delta 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) delta1.50 (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) delta 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 filtere... |
| 84% |
With trifluoroacetic acid; In dichloromethane; at 20 - 25℃; for 24h; |
Step 1. Preparation of C95. A solution of C94 (50.0 g, 189.9 mmol) indichloromethane (100 mL) was treated with trifluoroacetic acid (50.0 mL, 661.3 mmol). The reaction mixture was stirred at room temperature for 24 hours. The dichloromethane and trifluoroacetic acid was displaced with toluene (4 x 150 mL) using vacuum, to a final volume of 120 mL. The solution was added to heptane (250 mL) and the solid was collected by filtration. The solid was washed with a mixture of toluene and heptane (1 : 3, 60 mL), followed by heptane (2 x 80 mL) and dried under vacuum at 50 C for 19 hours to afford C95 as a solid. Yield: 30.0 g, 158 mmol, 84%. 1H NMR (400 MHz, CDCI3) delta 9.66 (s, 1 H), 7.86 - 7.93 (m, 2H), 7.73 - 7.80 (m, 2H), 4.57 (s, 2H). HPLC retention time 5.1 minutes; column: Agilent Extended C-18 column (75 mm x 3 mm, 3.5 muetaeta); column temperature 45 C; flow rate 1.0 mL / minute; detection UV 230 nm; mobile phase: solvent A = acetonitrile (100%), solvent B = acetonitrile (5%) in 10 mM ammonium acetate; gradient elusion: 0-1.5 minutes solvent B (100%), 1.5-10.0 minutes solvent B (5%), 10.0-13.0 minutes solvent B (100%); total run time 13.0 minutes. |
| 80% |
With hydrogenchloride; water; at 100℃; for 0.5h; |
The foregoing compound (3 g) and hydrochloric acid (15mL) were heated at 100 C for 30minutes with stirring. The product crystallised on cooling. It was collected and purified from diethyl ether. Yield 80%;Elemental analysis calculated for C10H7NO3 (189.17): C 63.4,H 3.7, N 7.4; found: C 62.4, H 3.4, N 7.5. 1H NMR (300MHz, CDCl3): delta9.62 (s, 1H), 7.85-7.65 (m, 4H), 4.45 (s, 2H). ES-MS:m/z 190. IR: nu(C=O) 1721 cm-1. |
| 56% |
|
A.7.1 Synthesis of (1,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-acetaldehydeTo a solution of phthalimideacetaldehyde diethylacetal (10 g) in dry THF (57 mL), was added aq 6N HCI (207 mL) and the mixture was stirred at rt for 20 h. The reaction mixture was concentrated in vacuo, treated carefully with sat. NaHCOs solution and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to yield the title compound as a white solid (4.53 g, 56%). |
| 56% |
With hydrogenchloride; In tetrahydrofuran; at 20℃; for 20h; |
To a solution of phthalimideacetaldehyde diethylacetal (10 g) in dry THF (57 mL), was added aq 6N HCl (207 mL) and the mixture was stirred at rt for 20 h. The reaction mixture was concentrated in vacuo, treated carefully with sat. NaHCO3 solution and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to yield the title compound as a white solid (4.53 g, 56%).1H-NMR (CDCl3): delta=4.55 (s, 2H); 7.75 (dd, 2H); 7.91 (dd, 2H); 9.6 (s, 1H). |
| 55% |
With sulfuric acid; for 2h;Reflux; |
Compound 3 was prepared by the condensation of commercially available aminoacetaldehyde diethyl acetal with the phthalic anhydride (1:1 mol ratio), using toluene under reflux, in the presence of a catalytic amount of DMAP (yield 52%) for 2 h. In the next step, <strong>[78902-09-7]2-(2,2-diethoxyethyl)isoindoline-1,3-dione</strong> (3) underwent acid hydrolysis (sulphuric acid at 70%) in reflux for 2 h. After the reaction was completed, it was allowed to reach at room temperature and was then cooled to induce precipitation. The formed precipitate was filtered on a sintered funnel with distilled water, yielding 55% of the pure product. For the synthesis of 5a and 5b, 2-(1,3-dioxoisoindol-2-yl) acetaldehyde (4) reacted with thiosemicarbazide (in the ratio 1:1) (for 5a) or 4-phenyl-3-thiosemicarbazide (for 5b), in ethanol, under reflux with catalytic amount of HCl (4 drops) for 4 h. The reactions were followed by thin layer chromatographic plate analysis. The formed precipitate was filtered on a sintered funnel with ethanol to yield the pure product (yield 76% for 5a and 70% for 5b). |
| 63.3 g (88%) |
With hydrogenchloride; |
Example 1 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 hours, which afforded 63.3 g (88%) of phthalimido-acetaldehyde as a solid. 1H-NMR (300 MHz, CDCl3): delta4.58 (s, 2H), 7.76-7.78(m, 2H), 7.90-7.92 (m, 2H), 9.67 (s, 1H). |
|
With hydrogenchloride; In tetrahydrofuran; water; at 75℃; for 5h; |
A solution of <strong>[78902-09-7]phthalimidoacetaldehyde diethyl acetal</strong> (39.6 g, 150.4 mmol) in a mixture of THF (80 mL) and aqueous HCl (50 mL, 10%) was heated at 75 C. for 5 hours, cooled to 25 C. and partitioned between ethyl acetate and half-saturated NaHCO3. The organic phase phase was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (36.81 g), which was used without further purification. |
|
With hydrogenchloride; In tetrahydrofuran; water; at 75℃; for 5h; |
To a solution of phthalimide diethylacetal (15 g) in tetrahydrofuran (THF) (30 mL) was added 10% aqueous HCl (18 mL). After heating at 75 C. for 5 hrs, the solution was allowed to cool to RT, and ethyl acetate (100 mL) was added. The solution was extracted with saturated sodium carbonate solution (100 mL), brine (100 mL), and the organic layer was separated and dried over magnesium sulfate (MgSO4). The solution was filtered and evaporated to provide 11.2 g of the titled compound. |
|
With hydrogenchloride; In tetrahydrofuran; water; at 75℃; for 5h; |
EXAMPLE 3E (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde A solution of <strong>[78902-09-7]phthalimidoacetaldehyde diethyl acetal</strong> (39.6 g, 150.4 mmol) in a mixture of THF (80 mL) and aqueous HCl (50 mL, 10%) was heated at 75 C. for 5 hours, cooled to 25 C. and partitioned between ethyl acetate and half-saturated NaHCO3. The organicphase was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (36.81 g), which was used without further purification. |
|
With hydrogenchloride; water; In tetrahydrofuran; at 75℃; for 5h; |
Example 28; (2S, 35)-3-methyl-2-{3-[(6-methyl-2-pyridinyl) methyl]-2-oXo-l-imidazolidinyl} pentanoic acid ;Example 28A; (1, 3-oxo-1, 3-dihydro-2H-isoindol-2-yl) acetaldehyde; To a solution of phthalimide diethylacetal (15 g) in tetrahydrofuran (THF) (30 mL) was added 10% aqueous HC1 (18 mL). After heating at 75C for 5 hrs, the solution was allowed to cool to room temperature, and ethyl acetate was separated and dried over magnesium sulfate (MgS04). The solution was filtered and evaporated to provide 11.2 g of the titled compound |
|
With hydrogenchloride; In tetrahydrofuran; water; at 75℃; for 5h; |
EXAMPLE 28A (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde To a solution of phthalimide diethylacetal (15 g) in tetrahydrofuran (THF) (30 mL) was added 10% aqueous HCl (18 mL). After heating at 75 C. for 5 hrs, the solution was allowed to cool to room temperature, and ethyl acetate was separated and dried over magnesium sulfate (MgSO4). The solution was filtered and evaporated to provide 11.2 g of the titled compound. |
|
With hydrogenchloride; In tetrahydrofuran; |
Step 1: Synthesis of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde A solution of <strong>[78902-09-7]2-[2,2-bis(ethyloxy)ethyl]-1H-isoindole-1,3(2H)-dione</strong> (24.60 g, 93 mmol) in THF (150 mL) under nitrogen was treated with 1N HCl (aq) (75 mL, 75 mmol) and brought to reflux After stirring for 20 h, the reaction was evaporated in vacuo and the residue was triturated with 1N HCl (100 mL). The resulting solid was collected by filtration, washed with 1N HCl, water, and Et2O and dried under high vacuum to provide the desired product as a white solid: 1H NMR (d6-DMSO, 300 MHz) delta 9.60 (1H, s), 7.87-7.95 (4H, m), 4.6 (2H, s). |
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