2-(dimethylamino)benzaldehyde

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

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

Procedure: To a solution of 2.8 g (0.07 mol) of 60% sodium hydride dispersion, 7.46 g (0.05 mole) N,N-dimethylaminobenzaldehyde, and 100 mL of dry, freshly distilled 1,2-dimethoxyethane (DME) under nitrogen, at room temperature, was added 15.3 g (0.05 mole) diethyl 4-methylsulfonylbenzylphosphonate with vigorous stirring. The mixture immediately turned bright yellow. The mixture was heated at reflux for 2 hours. After cooling the very bright yellow solution was poured over 300 g of crushed ice under nitrogen blanket. The bright yellow solid was collected by filtration, washed with water, and air dried. Recrystallization from a 1:1 mixture of absolute ethanol and dry pyridine yielded 9.97 g (66%) of bright yellow crystals mp 242°-243° C. The mixture was heated at reflux for 2 hours After cooling the very bright yellow solution The bright yellow solid was collected by filtration washed with water, and air dried Recrystallization from a 1:1 mixture of absolute ethanol and dry pyridine

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

Procedure: This example demonstrates that the reaction of N,N-dimethylaniline with hexamethylenetetramine can be carried out with the addition of toluene to the reaction medium to give dimethylaminobenzaldehyde directly in high yield in one step. There is no need for an additional hydrolysis step since the initially formed Schiff's base is converted to the desired product, p-dimethylaminobenzaldehyde (DMAB) under the reaction conditions. In addition, there is substantial reduction in the amounts of hexamethylenetetramine (0.5 compared to 1.5 mol) and acetic acid (2-3 compared to 7 mol) required to obtain comparable yields of dimethylaminobenzaldehyde when toluene is added compared to its absence. The inventive process gives very high selectivity (>90%) to the desired product, which affords efficient utilization of starting materials. to obtain comparable

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

Procedure: The title compound was prepared according to the procedure of Example 70, with the modification that trimethylacetaldehyde was used in step a instead of 2-dimethylamino-benzaldehyde and 5-amino-2-methyl-benzoic acid benzyl ester replaced 3-amino-benzoic acid benzyl ester in step c. 1H NMR (300 MHz, d6-DMSO) 12.75 (1H, br s), 11.85 (1H, br s), 9.38 (1H, s), 8.25 (1H, s), 7.76 (1H, d), 7.21 (1H, d), 2.88 (2H, m), 2.45 (3H, s), 1.94 (3H, br s), 1.70-1.59 (6H, m), 1.510 (6H, br s), 1.34 (11H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 61.52; H, 8.39; N, 7.91%. C35H54N4O8.1.5 H2O requires: C, 61.29; H, 8.38; N, 8.17%.

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

Procedure: The title compound was prepared according to the procedure of Example 70, with the modification that trimethylacetaldehyde was used in step a instead of 2-dimethylamino-benzaldehyde and 5-amino-2-methyl-benzoic acid benzyl ester replaced 3-amino-benzoic acid benzyl ester in step c. 1H NMR (300 MHz, d6-DMSO) 12.75 (1H, br s), 11.85 (1H, br s), 9.38 (1H, s), 8.25 (1H, s), 7.76 (1H, d), 7.21 (1H, d), 2.88 (2H, m), 2.45 (3H, s), 1.94 (3H, br s), 1.70-1.59 (6H, m), 1.510 (6H, br s), 1.34 (11H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 61.52; H, 8.39; N, 7.91%. C35H54N4O8.1.5 H2O requires: C, 61.29; H, 8.38; N, 8.17%.

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

Procedure: 5-(2-Adamantan-1-yl-ethyl)-2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)-1H-imidazole-4-carboxylic acid benzyl ester was prepared according to the procedure of Example 70, step a, with the modification that (1R)-(−)-myrtenal was used in instead of 2-dimethylamino-benzaldehyde. The benzyl ester was hydrolysed according to the procedure of Example 20, step c and the resulting 5-(2-adamantan-1-yl-ethyl)-2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)-1H-imidazole-4-carboxylic acid was reacted with 3-amino-benzoic acid methyl ester hydrochloride using essentially the same procedure as in Example 52, step a. Deprotection was carried out following essentially the procedure of Example 36, step d to afford the title compound. 1H NMR (300 MHz, d4-MeOH) 8.36 (1H, t), 7.90 (1H, ddd), 7.75 (1H, dt), 7.42 (1H, t), 6.30 (1H, m), 3.02 (1H, dt), 2.99 (2H, m), 2.57 (1H, m), 2.49 (2H, dd), 2.19 (1H, m), 1.95 (3H, s), 1.71 (6H, m), 1.60 (6H, d), 1.42 (2H, m), 1.40 (3H, s), 1.26 (1H, d), 0.90 (3H, s) was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 62.39; H, 7.98; N, 7.58%. C39H56N4O8.2.2 H2O requires: C, 62.55; H, 8.14; N, 7.48%.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydroxide (0.5 ml of 2N) was added to a mixture of trimethoxyacetophenone (2.1 g, 0.01 mole), dimethylaminobenzaldehyde (1.49 g, 0.01 mole), and ethanol (50 ml). The reaction mixture was allowed to stir at room temperature until a thin layer chromatography (50% ethyl acetate in hexane) indicated that the reaction was complete. After cooling to about 0° C., the mixture was filtered, the solid residue washed with water, then with methanol. Recrystallization from methanol gave the title compound, m.p. 145°-146° C. Elemental analysis for C20H23NO4 : Calcd: C, 70.36; H, 6.79; N, 4.10%. Found: C, 70.21; H, 6.98; N, 3.83%. Also prepared by substantially the same procedure as in example 2 were: the mixture was filtered the solid residue washed with water Recrystallization from methanol

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

Procedure: To a solution of 2.8 g (0.07 mol) of 60% sodium hydride dispersion, 7.46 g (0.05 mole) N,N-dimethylaminobenzaldehyde, and 100 mL of dry, freshly distilled 1,2-dimethoxyethane (DME) under nitrogen, at room temperature, was added 15.3 g (0.05 mole) diethyl 4-methylsulfonylbenzylphosphonate with vigorous stirring. The mixture immediately turned bright yellow. The mixture was heated at reflux for 2 hours. After cooling the very bright yellow solution was poured over 300 g of crushed ice under nitrogen blanket. The bright yellow solid was collected by filtration, washed with water, and air dried. Recrystallization from a 1:1 mixture of absolute ethanol and dry pyridine yielded 9.97 g (66%) of bright yellow crystals mp 242°-243° C. The mixture was heated at reflux for 2 hours After cooling the very bright yellow solution The bright yellow solid was collected by filtration washed with water, and air dried Recrystallization from a 1:1 mixture of absolute ethanol and dry pyridine

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

Procedure: This example demonstrates that the reaction of N,N-dimethylaniline with hexamethylenetetramine can be carried out with the addition of toluene to the reaction medium to give dimethylaminobenzaldehyde directly in high yield in one step. There is no need for an additional hydrolysis step since the initially formed Schiff's base is converted to the desired product, p-dimethylaminobenzaldehyde (DMAB) under the reaction conditions. In addition, there is substantial reduction in the amounts of hexamethylenetetramine (0.5 compared to 1.5 mol) and acetic acid (2-3 compared to 7 mol) required to obtain comparable yields of dimethylaminobenzaldehyde when toluene is added compared to its absence. The inventive process gives very high selectivity (>90%) to the desired product, which affords efficient utilization of starting materials. to obtain comparable

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydroxide (0.5 ml of 2N) was added to a mixture of trimethoxyacetophenone (2.1 g, 0.01 mole), dimethylaminobenzaldehyde (1.49 g, 0.01 mole), and ethanol (50 ml). The reaction mixture was allowed to stir at room temperature until a thin layer chromatography (50% ethyl acetate in hexane) indicated that the reaction was complete. After cooling to about 0° C., the mixture was filtered, the solid residue washed with water, then with methanol. Recrystallization from methanol gave the title compound, m.p. 145°-146° C. Elemetal analysis for C20H23NO4 : Calcd: C, 70.36; H, 6.79; N, 4.10%. Found: C, 70.21; H, 6.98; N, 3.83%. Also prepared by substantially the same procedure as in example 2 were: the mixture was filtered the solid residue washed with water Recrystallization from methanol

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

Procedure: To a suspension of methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylate dihydrochloride (240 mg) in CH2Cl2 (2.4 mL) was added DIEA (260 uL), 2-(dimethylamino) benzaldehyde (122.6 mg), and sodium triacetoxyborohydride (317 mg), which was stirred at room temperature for 15 hours. To the resultant was added saturated NaHCO3 aq., which was stirred for 20 min. The mixture was extracted with CH2Cl2. The organic phase was washed with brine and dried over Na2SO4, filtered, and evaporated in vacuo. The residue was washed with hexane to give methyl (2E)-3-[5-({(3R)-1-[2-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylate as a beige powder. was stirred for 20 min The mixture was extracted with CH2Cl2 The organic phase was washed with brine dried over Na2SO4 filtered evaporated in vacuo The residue was washed with hexane

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

Procedure: A solution of 2-(dimethylamino)benzaldehyde (0.50 g, 3.35 mmol) and ethanolamine (0.409 g, 6.7 mmol) in anhydrous EtOH (13 mL) was stirred at it for 17 hours before sodium triacetoxyborohydride (1.42 g, 6.7 mmol) was added. The reaction mixture was stirred for 4.5 hours, added water, and the pH1 was adjusted to 12 with 5 M NaOH. The mixture was extracted with EtOAc, and the organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of DCM:MeOH 9:1 to 1:1, to provide the desired product 2-(4-(dimethylamino)benzylamino)ethanol (51A). was added The mixture was extracted with EtOAc the organic phases were dried over MgSO4 filtered concentrated under reduced pressure The crude material was purified by column chromatography on silica gel eluting with a gradient of DCM:MeOH 9:1 to 1:1