N,N-dibutylbutan-1-amine;hydrochloride

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

Procedure: 1.50 g (4.25 mmol) of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran (Ia) were dissolved in 4.71 g (21.2 mmol) of tri-n-butylamine-hydrochloride at 150° C. After 16 h LC-MS analysis indicated the complete consumption of the starting material and the reaction mixture was cooled to room temperature. After addition of 20 ml of water and 50 ml MTBE the phases were separated, the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water, dried over MgSO4 and evaporated. Flash chromatography gave the title compound which crystallized to yield 1.10 g (76%). the complete consumption of the starting material After addition of 20 ml of water and 50 ml MTBE the phases were separated the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water dried over MgSO4 evaporated

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

Procedure: 1.85 g (5.25 mmol) of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran (from example 3) were dissolved in 5.84 g (26.32 mmol) of tri-n-butylamine hydrochloride at 200° C. After 4 h LC-MS indicated the complete consumption of the starting material and the reaction mixture was cooled to room temperature. After addition of 20 ml of water and 50 ml MTBE the phases were separated, the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water, dried over MgSO4 and evaporated. Flash chromatography gave the title compound which crystallized to yield 1.50 g (83%). the complete consumption of the starting material After addition of 20 ml of water and 50 ml MTBE the phases were separated the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water dried over MgSO4 evaporated

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

Procedure: 1.85 g (5.25 mmol) of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran (from example 3) were dissolved in 5.84 g (26.32 mmol) of tri-n-butylamine hydrochloride at 200° C. After 4 h LC-MS indicated the complete consumption of the starting material and the reaction mixture was cooled to room temperature. After addition of 20 ml of water and 50 ml MTBE the phases were separated, the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water, dried over MgSO4 and evaporated. Flash chromatography gave the title compound which crystallized to yield 1.50 g (83%). the complete consumption of the starting material After addition of 20 ml of water and 50 ml MTBE the phases were separated the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water dried over MgSO4 evaporated

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: While stirring, 18.54 g (100 mmole) of tri-n-butylamine was added drop by drop to 7.50 g (50 mmole) of L-(+)-tartaric acid, which was dissolved in 50 ml of water, whereby the solution was heated to 30° C. Subsequently, 18.81 g (100 mmole) of 3-chloro-2-hydroxy-propyltrimethylammonium chloride, which was dissolved in 100 ml of water, was added to the solution. The resultant clear solution was extracted with 8 separate portions of 150 ml of methylene chloride. The extractions were evaporated under vacuum. 21.65 g (97.6 percent yield) of tributylamine hydrochloride was obtained. (Together, the two last extractions only still contained 0.14 g of material.) The aqueous layer was evaporated in a rotary evaporator until dry. 23.22 g of a very viscous oil (102.5 percent) resulted. This was dissolved hot in 30 ml of methanol. It was mixed slowly with 93 ml of acetone until it became cloudy. The latter was again made to disappear by the addition of a few drops of methanol. After 72 hours, the mother liquor was decanted. The crystal crust was washed with acetone/methanol (3:1) and was dried under vacuum. The yield was 7.20 g of crystals (31.8 percent or 63.6 percent of the theory). The crystals had a melting point of 147° to 170° C. The crude tartrate was dissolved in 10 g of hot methanol and gradually 45 ml of acetone were added, whereupon the crystallization immediately started. The crystallization vessel was kept overnight in the refrigerator. The mother liquor was decanted off; the crystal cake was washed with acetone and dried. 5.78 g of crystals, corresponding to 51 percent of the theory, were obtained. The crystals had a melting point of 150° to 152° C. and a [α]D24 of -7.5° (c=1.04 in water). The tributylamine was recovered from the methylene chloride residue (raw tributylamine hydrochloride) with a yield of 96 percent by placing the residue in a solution of methylene chloride, shaking the solution with 1N of caustic soda solution and removing the solvent under vacuum. was added to the solution The resultant clear solution was extracted with 8 separate portions of 150 ml of methylene chloride The extractions were evaporated under vacuum

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

Procedure: 1.50 g (4.25 mmol) of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran (Ia) were dissolved in 4.71 g (21.2 mmol) of tri-n-butylamine-hydrochloride at 150° C. After 16 h LC-MS analysis indicated the complete consumption of the starting material and the reaction mixture was cooled to room temperature. After addition of 20 ml of water and 50 ml MTBE the phases were separated, the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water, dried over MgSO4 and evaporated. Flash chromatography gave the title compound which crystallized to yield 1.10 g (76%). the complete consumption of the starting material After addition of 20 ml of water and 50 ml MTBE the phases were separated the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water dried over MgSO4 evaporated

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

Procedure: 1.85 g (5.25 mmol) of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran (from example 3) were dissolved in 5.84 g (26.32 mmol) of tri-n-butylamine hydrochloride at 200° C. After 4 h LC-MS indicated the complete consumption of the starting material and the reaction mixture was cooled to room temperature. After addition of 20 ml of water and 50 ml MTBE the phases were separated, the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water, dried over MgSO4 and evaporated. Flash chromatography gave the title compound which crystallized to yield 1.50 g (83%). the complete consumption of the starting material After addition of 20 ml of water and 50 ml MTBE the phases were separated the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water dried over MgSO4 evaporated

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

Procedure: The crude products of the foregoing examples containing minor amounts of acid-acceptor amine hydrochloride can be used without further purification in the reduction step to produce the corresponding phenylethanolamine compound. For example, a sample of 3,4-bis(p-toluyloxy)phenyl N-(tert-butyl)aminomethyl ketone hydrochloride containing about 6 percent of tributylamine hydrochloride was reduced with sodium borohydride to give 3,4-bis(p-toluyloxy)-α-[(tert-butylamino)methyl]benzyl alcohol (bitolterol) in greater than 90% yield.

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

Procedure: The crude products of the foregoing examples containing minor amounts of acid-acceptor amine hydrochloride can be used without further purification in the reduction step to produce the corresponding phenylethanolamine compound. For example, a sample of 3,4-bis(p-toluyloxy)phenyl N-(tert-butyl)aminomethyl ketone hydrochloride containing about 6 percent of tributylamine hydrochloride was reduced with sodium borohydride to give 3,4-bis(p-toluyloxy)-α-[(tert-butylamino)methyl]benzyl alcohol (bitolterol) in greater than 90% yield.

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

Procedure: To this end, thiophosphoryl chloride and a primary alkylamine, for example n-butylamine, are reacted in molar ratios of preferably 0.9 to 1.1 mol of amine per mole of thiophosphoryl chloride in an inert solvent, for example ethyl acetate. The auxiliary base used is a trialkylamine, for example tri-n-butylamine, which is reacted to give the tri-n-butylamine hydrochloride. In a second reaction step, the N-alkylthiophosphoryl dichloride which has been formed in the first reaction is reacted with ammonia at temperatures of between preferably −20° C. and 50° C. to give the desired product N-alkylthiophosphoric triamide. In parallel with, and independently of, the second reaction step, ammonia acts as base 2 and accepts the hydrogen chloride from the trialkylamine hydrochloride with formation of ammonium chloride.

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: While stirring, 18.54 g (100 mmole) of tri-n-butylamine was added drop by drop to 7.50 g (50 mmole) of L-(+)-tartaric acid, which was dissolved in 50 ml of water, whereby the solution was heated to 30° C. Subsequently, 18.81 g (100 mmole) of 3-chloro-2-hydroxy-propyltrimethylammonium chloride, which was dissolved in 100 ml of water, was added to the solution. The resultant clear solution was extracted with 8 separate portions of 150 ml of methylene chloride. The extractions were evaporated under vacuum. 21.65 g (97.6 percent yield) of tributylamine hydrochloride was obtained. (Together, the two last extractions only still contained 0.14 g of material.) The aqueous layer was evaporated in a rotary evaporator until dry. 23.22 g of a very viscous oil (102.5 percent) resulted. This was dissolved hot in 30 ml of methanol. It was mixed slowly with 93 ml of acetone until it became cloudy. The latter was again made to disappear by the addition of a few drops of methanol. After 72 hours, the mother liquor was decanted. The crystal crust was washed with acetone/methanol (3:1) and was dried under vacuum. The yield was 7.20 g of crystals (31.8 percent or 63.6 percent of the theory). The crystals had a melting point of 147° to 170° C. The crude tartrate was dissolved in 10 g of hot methanol and gradually 45 ml of acetone were added, whereupon the crystallization immediately started. The crystallization vessel was kept overnight in the refrigerator. The mother liquor was decanted off; the crystal cake was washed with acetone and dried. 5.78 g of crystals, corresponding to 51 percent of the theory, were obtained. The crystals had a melting point of 150° to 152° C. and a [α]D24 of -7.5° (c=1.04 in water). The tributylamine was recovered from the methylene chloride residue (raw tributylamine hydrochloride) with a yield of 96 percent by placing the residue in a solution of methylene chloride, shaking the solution with 1N of caustic soda solution and removing the solvent under vacuum. was added to the solution The resultant clear solution was extracted with 8 separate portions of 150 ml of methylene chloride The extractions were evaporated under vacuum

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

Procedure: 1.50 g (4.25 mmol) of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran (Ia) were dissolved in 4.71 g (21.2 mmol) of tri-n-butylamine-hydrochloride at 150° C. After 16 h LC-MS analysis indicated the complete consumption of the starting material and the reaction mixture was cooled to room temperature. After addition of 20 ml of water and 50 ml MTBE the phases were separated, the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water, dried over MgSO4 and evaporated. Flash chromatography gave the title compound which crystallized to yield 1.10 g (76%). the complete consumption of the starting material After addition of 20 ml of water and 50 ml MTBE the phases were separated the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water dried over MgSO4 evaporated

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

Procedure: 1.85 g (5.25 mmol) of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran (from example 3) were dissolved in 5.84 g (26.32 mmol) of tri-n-butylamine hydrochloride at 200° C. After 4 h LC-MS indicated the complete consumption of the starting material and the reaction mixture was cooled to room temperature. After addition of 20 ml of water and 50 ml MTBE the phases were separated, the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water, dried over MgSO4 and evaporated. Flash chromatography gave the title compound which crystallized to yield 1.50 g (83%). the complete consumption of the starting material After addition of 20 ml of water and 50 ml MTBE the phases were separated the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water dried over MgSO4 evaporated