methyl 5-chloro-4-hydroxy-2-methoxybenzoate

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

Procedure: In a 500 ml flask with a 40 cm Vigreux column, there are put 32 g (0.15 mole) of methyl 2-methoxy-4-hydroxy-5-chlorobenzoate, 120 ml of xylene and 23 g of levo 1-ethyl-2-aminomethylpyrrolidine. It is heated gently. A solution is obtained. The methyl alcohol formed in the form of a methanol-xylene azeotrope is distilled at 60°-62° C in about an hour. At the end of the reaction, 10 ml of xylene is distilled at 135° C. In the distillate, 5 ml of alcohol are recuperated for 6 ml theoretical. In a 500 ml flask with a 40 cm Vigreux column, there are put It is heated gently A solution is obtained

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

Procedure: In a 500 ml flask equipped with a 40 cm Vigreux column, there are put 40 g (0.184 mole) of methyl 2-methoxy-4-hydroxy-5-chlorobenzoate, 160 ml of xylene and 35.5 g of dextro 1-ethyl-2- aminomethylpyrrolidine. It is heated gently. There is complete dissolution when heating begins. The methyl alcohol formed as a methanol - xylene azeotrope is distilled at 61°-63° C. At the end of the reaction, a little xylene is distilled. In 90 minutes, 40 ml containing 7 ml of methyl alcohol are distilled. The excess xylene and amine are then distilled under vacuum. The residue is a solid. It is recovered with 300 ml of water, drained, washed until neutral as indicated by the phenol-phthalein and dried at 60° C. There are obtained 58 g (yield 100%) of N-(1-ethyl-2-pyrrolidylmethyl)-4-hydroxy-5-chlorobenzamide in base state which are transformed to the hydrochloride. This is done by dissolving the base in 200 ml of absolute alcohol and adding an alcohol solution of 14.5 ml of concentrated hydrochloric acid in 40 ml of alcohol. The hydrochloride crystallizes, is drained, washed with alcohol, and air-dried. It is a white solid (m.p. 228° C; [α]D = + 8° (5% water). In a 500 ml flask equipped with a 40 cm Vigreux column, there It is heated gently dissolution when heating

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

Procedure: In a 500 ml flask equipped with a 40 cm Vigreux column, there are put 40 g (0.184 mole) of methyl 2-methoxy-4-hydroxy-5-chlorobenzoate, 160 ml of xylene and 35.5 g of dextro 1-ethyl-2- aminomethylpyrrolidine. It is heated gently. There is complete dissolution when heating begins. The methyl alcohol formed as a methanol - xylene azeotrope is distilled at 61°-63° C. At the end of the reaction, a little xylene is distilled. In 90 minutes, 40 ml containing 7 ml of methyl alcohol are distilled. The excess xylene and amine are then distilled under vacuum. The residue is a solid. It is recovered with 300 ml of water, drained, washed until neutral as indicated by the phenol-phthalein and dried at 60° C. There are obtained 58 g (yield 100%) of N-(1-ethyl-2-pyrrolidylmethyl)-4-hydroxy-5-chlorobenzamide in base state which are transformed to the hydrochloride. This is done by dissolving the base in 200 ml of absolute alcohol and adding an alcohol solution of 14.5 ml of concentrated hydrochloric acid in 40 ml of alcohol. The hydrochloride crystallizes, is drained, washed with alcohol, and air-dried. It is a white solid (m.p. 228° C; [α]D = + 8° (5% water). In a 500 ml flask equipped with a 40 cm Vigreux column, there It is heated gently dissolution when heating

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

Procedure: A solution of methyl 5-chloro-4-hydroxy-2-methoxybenzoate (intermediate 53; 204 mg; 0.94 mmol) in 4.6 ml of anhydrous THF was stirred with external ice/water bath cooling. A solution of 1M LiAlH4 in THF was dropped in (1.9 ml; 1.9 mmol). After 5 minutes the external bath was removed and the stirring prosecuted for 3 additional hours. With external cooling 0.072 ml of water were added followed by 0.072 ml of 4N NaOH solution and 0.144 additional ml of water. After filtration the cake was thoroughly washed with THF and the filtrates were concentrated giving the title compound in 34% yield. cooling After 5 minutes the external bath was removed With external cooling 0.072 ml of water were added After filtration the cake was thoroughly washed with THF the filtrates were concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-chloro-4-hydroxy-2-methoxybenzoic acid (intermediate 52; 4.17 g; 13.69 mmol) in 123 ml of anhydrous methanol, 2.2 ml of acetyl chloride were added. The solution was stirred at 60° C. under nitrogen atmosphere for 18 hrs. The solution was evaporated under reduced pressure and the residue purified by preparative reversed-phase HPLC (Cl2CH2/EtOAc from 100/0 to 80/20), affording 2.2 g (75%) of a red solid. The solution was evaporated under reduced pressure the residue purified by preparative reversed-phase HPLC (Cl2CH2/EtOAc from 100/0 to 80/20)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-chloro-4-hydroxy-2-methoxybenzoic acid (intermediate 52; 4.17 g; 13.69 mmol) in 123 ml of anhydrous methanol, 2.2 ml of acetyl chloride were added. The solution was stirred at 60° C. under nitrogen atmosphere for 18 hrs. The solution was evaporated under reduced pressure and the residue purified by preparative reversed-phase HPLC (Cl2CH2/EtOAc from 100/0 to 80/20), affording 2.2 g (75%) of a red solid. The solution was evaporated under reduced pressure the residue purified by preparative reversed-phase HPLC (Cl2CH2/EtOAc from 100/0 to 80/20)

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

Procedure: In a 500 ml flask with a 40 cm Vigreux column, there are put 32 g (0.15 mole) of methyl 2-methoxy-4-hydroxy-5-chlorobenzoate, 120 ml of xylene and 23 g of levo 1-ethyl-2-aminomethylpyrrolidine. It is heated gently. A solution is obtained. The methyl alcohol formed in the form of a methanol-xylene azeotrope is distilled at 60°-62° C in about an hour. At the end of the reaction, 10 ml of xylene is distilled at 135° C. In the distillate, 5 ml of alcohol are recuperated for 6 ml theoretical. In a 500 ml flask with a 40 cm Vigreux column, there are put It is heated gently A solution is obtained

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

Procedure: In a 500 ml flask equipped with a 40 cm Vigreux column, there are put 40 g (0.184 mole) of methyl 2-methoxy-4-hydroxy-5-chlorobenzoate, 160 ml of xylene and 35.5 g of dextro 1-ethyl-2- aminomethylpyrrolidine. It is heated gently. There is complete dissolution when heating begins. The methyl alcohol formed as a methanol - xylene azeotrope is distilled at 61°-63° C. At the end of the reaction, a little xylene is distilled. In 90 minutes, 40 ml containing 7 ml of methyl alcohol are distilled. The excess xylene and amine are then distilled under vacuum. The residue is a solid. It is recovered with 300 ml of water, drained, washed until neutral as indicated by the phenol-phthalein and dried at 60° C. There are obtained 58 g (yield 100%) of N-(1-ethyl-2-pyrrolidylmethyl)-4-hydroxy-5-chlorobenzamide in base state which are transformed to the hydrochloride. This is done by dissolving the base in 200 ml of absolute alcohol and adding an alcohol solution of 14.5 ml of concentrated hydrochloric acid in 40 ml of alcohol. The hydrochloride crystallizes, is drained, washed with alcohol, and air-dried. It is a white solid (m.p. 228° C; [α]D = + 8° (5% water). In a 500 ml flask equipped with a 40 cm Vigreux column, there It is heated gently dissolution when heating

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

Procedure: A solution of methyl 5-chloro-4-hydroxy-2-methoxybenzoate (intermediate 53; 204 mg; 0.94 mmol) in 4.6 ml of anhydrous THF was stirred with external ice/water bath cooling. A solution of 1M LiAlH4 in THF was dropped in (1.9 ml; 1.9 mmol). After 5 minutes the external bath was removed and the stirring prosecuted for 3 additional hours. With external cooling 0.072 ml of water were added followed by 0.072 ml of 4N NaOH solution and 0.144 additional ml of water. After filtration the cake was thoroughly washed with THF and the filtrates were concentrated giving the title compound in 34% yield. cooling After 5 minutes the external bath was removed With external cooling 0.072 ml of water were added After filtration the cake was thoroughly washed with THF the filtrates were concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-chloro-4-hydroxy-2-methoxybenzoic acid (intermediate 52; 4.17 g; 13.69 mmol) in 123 ml of anhydrous methanol, 2.2 ml of acetyl chloride were added. The solution was stirred at 60° C. under nitrogen atmosphere for 18 hrs. The solution was evaporated under reduced pressure and the residue purified by preparative reversed-phase HPLC (Cl2CH2/EtOAc from 100/0 to 80/20), affording 2.2 g (75%) of a red solid. The solution was evaporated under reduced pressure the residue purified by preparative reversed-phase HPLC (Cl2CH2/EtOAc from 100/0 to 80/20)