2,6-dimethoxybenzaldehyde

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: A mixture of 1.52 ml of diethyl malonate, 1.66 g of 2,6-dimethoxybenzaldehyde, 0.1 ml of piperidine, 0.11 ml of glacial acetic acid and 100 ml of toluene was boiled at 110° C. on a water separator for 3.5 hours. The solution was extracted with 10% NaHCO3 solution and back-washed with saturated NaCl solution. The organic phase was dried, filtered under suction and evaporated under reduced pressure. There were obtained 2.8 g of diethyl (2,6-dimethoxybenzylidene)malonate, as a dark yellow oil. for 3.5 hours The solution was extracted with 10% NaHCO3 solution back-washed with saturated NaCl solution The organic phase was dried filtered under suction evaporated under reduced pressure

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

Procedure: A mixture of 25.0 g (150 mmol) 2,6-dimethoxybenzaldehyde, 19.1 g (165 mmol) 3-amino-2,4-dimethylpentane and 0.500 g p-toluenesulfonic acid in 100 ml toluene was heated in a Dean-Stark apparatus to reflux for 2 hours. Then the cooled reaction mixture was washed with aqueous NaHCO3 solution, brine dried over Na2SO4, filtered and evaporated. The crude product was filtered through a silica pad with heptane/ethyl acetate 2:1 as eluent: 22.0 g [1-(2,6-dimethoxy-phenyl)-meth-(E)-ylidene]-(1-isopropyl-2-methyl-propyl)-amine as slightly yellow crystals: MS (EI): 264.3 ((M+H)+.), 262.3 ((M-H)+.), 248.3 ((M−CH3)+.), 220.2 ((M−(CH3)2CH)+.), 100%). was heated in a Dean-Stark apparatus to reflux for 2 hours Then the cooled reaction mixture was washed with aqueous NaHCO3 solution, brine dried over Na2SO4 filtered evaporated The crude product was filtered through a silica pad with heptane/ethyl acetate 2:1 as eluent

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

Procedure: A mixture of 25.0 g (150 mmol) 2,6-dimethoxybenzaldehyde, 19.1 g (165 mmol) 3-amino-2,4-dimethylpentane and 0.500 g p-toluenesulfonic acid in 100 ml toluene was heated in a Dean-Stark apparatus to reflux for 2 hours. Then the cooled reaction mixture was washed with aqueous NaHCO3 solution, brine dried over Na2SO4, filtered and evaporated. The crude product was filtered through a silica pad with heptane/ethyl acetate 2:1 as eluent: 22.0 g [1-(2,6-dimethoxy-phenyl)-meth-(E)-ylidene]-(1-isopropyl-2-methyl-propyl)-amine as slightly yellow crystals: MS (EI): 264.3 ((M+H)+.), 262.3 ((M-H)+.), 248.3 ((M−CH3)+.), 220.2 ((M−(CH3)2CH)+.), 100%). was heated in a Dean-Stark apparatus to reflux for 2 hours Then the cooled reaction mixture was washed with aqueous NaHCO3 solution, brine dried over Na2SO4 filtered evaporated The crude product was filtered through a silica pad with heptane/ethyl acetate 2:1 as eluent

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

Procedure: The starting material 2,6-dimethoxyphenethylamine was prepared from 2,6-dimethoxybenzaldehyde. Reaction with nitromethane according to the procedure described in Vogel, Textbook of Practical Organic Chemistry, p. 176 (Longman 1978, 4th Ed.) yielded 2,6-dimethoxy-β-nitrostyrene. This compound (1.1 g, 5.3 mmole) was dissolved in diethyl ether/tetrahydrofuran (2:1, 200 ml) and lithium aluminium hydride (0.5 g, 13 mmol) was added in small portions. The mixture was refluxed for 120 minutes and then treated with 0.6 ml H2O, 0.6 ml 15% NaOH (aq) and 1.8 ml H2O. The mixture was filtered and purified by acid-base partitioning (NH4OH (aq) HCl dil. (aq)) and evaporated. The crude product 2,6-dimethoxyphenethylamine was pure enough to be used directly in the following reaction where it was condensed with the product of Example 103, in a manner analogous to Example 105, to give the titled product.

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

Procedure: (39) To a solution of 2,6-dimethoxybenzaldehyde (250 mg, 1.50 mmol) and acetophenone (180 mg, 1.50 mmol) in 2.2 ml of methanol was added 1.0 ml of 40% sodium hydroxide in water at 10° C. After stirring overnight at room temperature, a solid precipitated. The precipitate was recrystallized from methanol to afford 350 mg (87.1%) of a white, flaky solid: mp 54.9-55.8° C. (lit. mp 54-55° C., Noyce and Jorgenson, J. Am. Chem. Soc., 1963, 85, 2420-2426). 1H NMR (250 MHz) δ 8.33-8.26 (d, 1 H), 8.05-7.97 (m, 3 H), 7.57-7.49 (m, 3 H), 7.30 (m, 1 H), 6.61-6.57 (d, 2 H), 3.92 (s, 6 H); 13C NMR (62.7 MHz) 192.3, 160.6, 139.2, 136.0, 132.4, 131.7, 128.6, 125.1, 113.1, 105.8, 103.9, 56.0 ppm. a solid precipitated The precipitate was recrystallized from methanol to afford 350 mg (87.1%) of a white, flaky solid

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

Procedure: Add, one after another, 1.13 g (14.7 mmol) of ammonium acetate, 40.4 mL (500 mmol) of pyridine and 31.2 g (367 mmol) of 2-cyanoacetic acid to a solution of 61 g (367 mmol) of 2,6-dimethoxybenzaldehyde in 360 mL of toluene. Reflux the reaction mixture for 15 h, distilling the toluene-water azeotrope in Dean-Stark apparatus. Take up the solution in 500 mL toluene and 40 mL pyridine and reflux again for 48 h in the Dean-Stark apparatus. After concentration under reduced pressure, take up the residue in 800 mL of dichloromethane (DCM) and wash successively with 1 L of 1N HCl aqueous solution, 500 mL of saturated aqueous solution of sodium carbonate (Na2CO3) and 1 L of water. After drying over sodium sulphate (Na2SO4) and concentration under reduced pressure, we obtain 62 g of (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile in the form of brown oil, which is used “as is” in the next stage. Add Reflux the reaction mixture for 15 h distilling the toluene-water azeotrope in Dean-Stark apparatus 40 mL pyridine and reflux again for 48 h in the Dean-Stark apparatus After concentration under reduced pressure wash successively with 1 L of 1N HCl aqueous solution, 500 mL of saturated aqueous solution of sodium carbonate (Na2CO3) and 1 L of water After drying over sodium sulphate (Na2SO4) and concentration under reduced pressure, we

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

Procedure: 1 g (4.48 mmol) of 5-amino-4-cyano-1-phenyl-3-pyrazoleacetonitrile is suspended in 15 mL of toluene, in a round-bottomed flask, under an argon atmosphere, surmonted by a Dean and Stark apparatus. 0.744 g (1 eq.) of 2,6-dimethoxybenzaldehyde and 0.030 mL of piperidine are added to the mixture. The reaction medium is refluxed overnight, and is then allowed to return to ambient temperature. A whitish precipitate forms and is filtered off and washed with toluene. The filtrate is concentrated to dryness and the residue is taken up in ethanol with agitation for 15 minutes. The suspension is filtered and the filtrate is concentrated to dryness. The residue is combined with the precipitate previously obtained, and purified on silica gel (eluent: 98/2 dichloromethane/methanol). 619 mg of product are thus obtained with a yield of 37%. The reaction medium is refluxed overnight to return to ambient temperature A whitish precipitate forms and is filtered off washed with toluene The filtrate is concentrated to dryness The suspension is filtered the filtrate is concentrated to dryness previously obtained purified on silica gel (eluent: 98/2 dichloromethane/methanol)

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

Procedure: 1 g (4.48 mmol) of 5-amino-4-cyano-1-phenyl-3-pyrazoleacetonitrile is suspended in 15 mL of toluene, in a round-bottomed flask, under an argon atmosphere, surmonted by a Dean and Stark apparatus. 0.744 g (1 eq.) of 2,6-dimethoxybenzaldehyde and 0.030 mL of piperidine are added to the mixture. The reaction medium is refluxed overnight, and is then allowed to return to ambient temperature. A whitish precipitate forms and is filtered off and washed with toluene. The filtrate is concentrated to dryness and the residue is taken up in ethanol with agitation for 15 minutes. The suspension is filtered and the filtrate is concentrated to dryness. The residue is combined with the precipitate previously obtained, and purified on silica gel (eluent: 98/2 dichloromethane/methanol). 619 mg of product are thus obtained with a yield of 37%. The reaction medium is refluxed overnight to return to ambient temperature A whitish precipitate forms and is filtered off washed with toluene The filtrate is concentrated to dryness The suspension is filtered the filtrate is concentrated to dryness previously obtained purified on silica gel (eluent: 98/2 dichloromethane/methanol)

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

Procedure: (39) To a solution of 2,6-dimethoxybenzaldehyde (250 mg, 1.50 mmol) and acetophenone (180 mg, 1.50 mmol) in 2.2 ml of methanol was added 1.0 ml of 40% sodium hydroxide in water at 10° C. After stirring overnight at room temperature, a solid precipitated. The precipitate was recrystallized from methanol to afford 350 mg (87.1%) of a white, flaky solid: mp 54.9-55.8° C. (lit. mp 54-55° C., Noyce and Jorgenson, J. Am. Chem. Soc., 1963, 85, 2420-2426). 1H NMR (250 MHz) δ 8.33-8.26 (d, 1H), 8.05-7.97 (m, 3H), 7.57-7.49 (m, 3H), 7.30 (m, 1H), 6.61-6.57 (d, 2H), 3.92 (s, 6H); 13C NMR 192.3, 160.6, 139.2, 136.0, 132.4, 131.7, 128.6, 125.1, 113.1, 105.8, 103.9, 56.0 ppm. a solid precipitated The precipitate was recrystallized from methanol to afford 350 mg (87.1%) of a white, flaky solid

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

Procedure: The starting material 2,6-dimethoxy-phenethylamine was prepared from 2,6-dimethoxy-benzaldehyde. Reaction with nitromethane according to the procedure described in Vogel, Textbook of Practical Organic Chemistry, p. 176 (Longman 1978, 4th Ed.) yielded 2,6-dimethoxy-β-nitrostyrene. This compound (1.1 g, 5.3 mmole) was dissolved in diethyl ether/tetrahydrofuran (2:1, 200 ml) and lithium aluminium hydride (0.5 g, 13 mmol) was added in small portions. The mixture was refluxed for 120 minutes and then treated with 0.6 ml H2O, 0.6 ml 15% NaOH (aq) and 1.8 ml H2O. The mixture was filtered and purified by acid-base partitioning (NH4OH (aq) HCl dil. (aq)) and evaporated. The crude product 2,6-dimethoxyphenethylamine was pure enough to be used directly in the following reaction where it was condensed with the product of Example 103, in a manner analogous to Example 105, to give the titled product.