(1S)-1-methyl-1,2,3,4-tetrahydroisoquinoline

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 73.45 g (240 mmole) of (S)-(−)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 12(1) above was suspended in 260 ml of decalin and the resulting suspension was heated to 150° C. 95.10 g (710 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 1600 g of ice-water with stirring. 70 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 700 ml of ethyl acetate, and then the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and then extracted three times, each time with 900 ml of ethyl acetate. The extracts were combined, washed with 200 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 27.6 g of the title compound. cooled to room temperature The supernatant was removed the lower layer was poured onto 1600 g of ice-water with stirring hydrochloric acid was added the mixture was stirred for 10 minutes This solution was washed three times each time with 700 ml of ethyl acetate, and then the aqueous layer was separated extracted three times washed with 200 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10.0 g (30.1 mmole) of (S)-(−)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 12(1) above was suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145° C. 13.47 g (96.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. 30 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.10 g of the title compound. cooled to room temperature with stirring the mixture was stirred for 10 minutes This solution was washed three times each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated extracted three times washed with 40 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.0 g (16.18 mmole) of (S)-(−)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example (2) above was suspended in 50 ml of decalin and then heated to 140° C. 6.47 g (48.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, and cooled to room temperature. The supernatant was removed and the lower layer was added to 70 g of ice-water with stirring. 20 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 100 ml of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 1.75 g of the title compound. cooled to room temperature The supernatant was removed the lower layer was added to 70 g of ice-water with stirring hydrochloric acid was added the mixture was stirred for 10 minutes This solution was washed three times each time with 100 ml of ethyl acetate, and the aqueous layer was separated extracted three times washed with 40 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.0 g (16.18 mmole) of (S)-(−)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example (2) above was suspended in 50 ml of decalin and then heated to 140° C. 6.47 g (48.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, and cooled to room temperature. The supernatant was removed and the lower layer was added to 70 g of ice-water with stirring. 20 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 100 ml of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 1.75 g of the title compound. cooled to room temperature The supernatant was removed the lower layer was added to 70 g of ice-water with stirring hydrochloric acid was added the mixture was stirred for 10 minutes This solution was washed three times each time with 100 ml of ethyl acetate, and the aqueous layer was separated extracted three times washed with 40 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

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

Procedure: In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(S)-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.

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

Procedure: In accordance with the same procedures as in Preparation 1-2, except that 25.6 ml of (S)-1-phenylethyl-amine(0.20M) and 34.8 g of α-chloro-α-(methylthio)-acetyl chloride(0.22M) were used as starting materials, 8.8 g of the title compound was obtained in oil form. In accordance with the same procedures as in Preparation 1-2

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 73.45 g(240 mmole) of (S)-(-)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 12(1) above was suspended in 260 ml of decalin and the resulting suspension was heated to 150° C. 95.10 g(710 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 1600 g of ice-water with stirring. 70 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 700 ml of ethyl acetate, and then the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and then extracted three times, each time with 900 ml of ethyl acetate. The extracts were combined, washed with 200 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 27.6 g of the title compound. cooled to room temperature The supernatant was removed the lower layer was poured onto 1600 g of ice-water with stirring hydrochloric acid was added the mixture was stirred for 10 minutes This solution was washed three times each time with 700 ml of ethyl acetate, and then the aqueous layer was separated extracted three times washed with 200 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10.0 g(30.1 mmole) of (S)-(-)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 12(1) above was suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145° C. 13.47 g(96.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. 30 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.10 g of the title compound. cooled to room temperature with stirring the mixture was stirred for 10 minutes This solution was washed three times each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated extracted three times washed with 40 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

Conditions: temp:51.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 176.20 g(1449 mmole) of (S)-(-)-α-methylbenzylamine was dissolved in 185 ml of dichloromethane and 218.04 g(1748 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 658 ml(5750 mmole) of 48% aqueous hydrobromic acid solution was added thereto and the solution thereby obtained was allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature to remove 580 ml of water as the by-product and aqueous hydrobromic acid solution. The residue was dissolved in 760 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 150 ml of ethyl acetate and then dried to obtain 306.5 g of the title compound. the reaction was added the solution thereby obtained to react at 126° C. for 30 minutes under refluxing The reaction solution was distilled for 2 hours under normal pressure at constant temperature to remove 580 ml of water as the by-product and aqueous hydrobromic acid solution The residue was dissolved in 760 ml of isopropyl alcohol with refluxing for 30 minutes this solution was cooled to 10° C. to stand for 3 hours The resulting solid product was filtered washed with 150 ml of ethyl acetate dried

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.0 g(16.18 mmole) of (S)-(-)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example (2) above was suspended in 50 ml of decalin and then heated to 140° C. 6.47 g(48.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, and cooled to room temperature. The supernatant was removed and the lower layer was added to 70 g of ice-water with stiring. 20 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 100 ml of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 1.75 g of the title compound. cooled to room temperature The supernatant was removed the lower layer was added to 70 g of ice-water with stiring hydrochloric acid was added the mixture was stirred for 10 minutes This solution was washed three times each time with 100 ml of ethyl acetate, and the aqueous layer was separated extracted three times washed with 40 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

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

Procedure: 22.1 g(133.16 mmole) of (S)-(-)-N-(2-hydroxyethyl)-α-methylbezylamine produced in Example 11(1) above was suspended in 105 ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126° C. for 30 minutes under refluxing. Then, the reaction solution was distilled for 2 hours under normal pressure at constant temperature and 95 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 112 ml of acetone, and 100 ml of ethyl acetate and 150 ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 70 ml of ethyl acetate and then dried to obtain 20 g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 130 ml of ethanol and then concentrated under reduced pressure. The residue was dissolved in 104 ml of acetone, diluted with 143 ml of ether, and then allowed to stand at 0° C. for 12 hours. The resulting solid product was filtered, collected and washed with 75 ml of ethyl acetate to obtain 6.7 g of the second crop of the title compound. the resulting suspension was reacted at 126° C. for 30 minutes under refluxing Then, the reaction solution was distilled for 2 hours under normal pressure at constant temperature and 95 ml of aqueous hydrobromic acid and water the reaction by-product, was removed The residue was dissolved in 112 ml of acetone 100 ml of ethyl acetate and 150 ml of ether were added to stand for 3 hours The resulting solid product was filtered washed with 70 ml of ethyl acetate dried

Conditions: temp:51.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 108.23 g(0.903 mmole) of (S)-(-)-α-methylbenzylamine was dissolved in 140 ml of dichloromethane and 144.0 g(1.071 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 52 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 117.4 g of the title compound, which had a pale yellow color. the reaction The reaction solution was concentrated under reduced pressure the residue was subjected to fractional distillation