2-Phenyl-3-isopropyl-5-hydroxymethyloxazolidine

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

Procedure: Isopropyl or sec. butyl amino analogues of the compounds of the above examples are prepared by substituting suitable oxazolidines e.g. 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine, (S)-2-methyl-3-sec. butyl-5-hydroxymethyloxazolidine, 3-isopropyl-5-hydroxymethyloxazolidine for the (S)-2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine reactant.

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

Procedure: Analogously to the description in Example 11, 8.2 g (0.05 mol) of 2,3-dichloro-5-methyl-pyrazine, 11 g (0.05 mol) of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine and 3.4 g of a 50% strength suspension of sodium hydride in paraffin oil give 2-chloro-3-(3'-isopropylamino-2'-hydroxy-propoxy)-5-methyl-pyrazine, melting point 109°-110° C. when crystallised from benzene. The fumarate prepared therefrom by means of fumaric acid crystallises from methanol-ether, melting point 164°-165° C.

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.8 g of sodium hydride dispersion (55% strength) are cautiously added in portions to a solution of 27.5 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine in 100 ml of dimethylformamide at 20°-40° C. and after foaming has ceased the mixture is stirred for a further 1-2 hours at 40° C. 12.7 g of 2-chloro-4-methyl-pyridine are then added and the reaction mixture is stirred for 2 hours at 80° C. After evaporating off the solvent in vacuo, the evaporation residue is taken up in ether and the ether solution is washed with water, dried over magnesium sulphate and evaporated in vacuo. Crude 2-[3'-isopropyl]-2'-phenyl-oxazolidinyl-(5')]-methoxy-4-methyl-pyridine is thus obtained. the reaction mixture is stirred for 2 hours at 80° C After evaporating off the solvent in vacuo the ether solution is washed with water dried over magnesium sulphate evaporated in vacuo

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.8 g of sodium hydride dispersion (55% strength) are cautiously added in portions to a solution of 27.5 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine in 100 ml of dimethylformamide at 20°-40° C. and after foaming has ceased the mixture is stirred for a further 1-2 hours at 40° C. 12.7 g of 2-chloro-4-methyl-pyridine are then added and the reaction mixture is stirred for 2 hours at 80° C. After evaporating off the solvent in vacuo, the evaporation residue is taken up in ether and the ether solution is washed with water, dried over magnesium sulphate and evaporated in vacuo. Crude 2-[3'-isopropyl]-2'-phenyl-oxazolidinyl-(5')]-methoxy-4-methyl-pyridine is thus obtained. the reaction mixture is stirred for 2 hours at 80° C After evaporating off the solvent in vacuo the ether solution is washed with water dried over magnesium sulphate evaporated in vacuo

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

Procedure: 12 g of sodium hydride dispersion (55% strength) are added in portions to 44 g of 5-(2'-aminoethyl)-2,3-dichloro-pyridine and 55 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine, dissolved in 500 ml of 1,2-dimethoxyethane, whilst cooling with ice at 0°-10° C. The reaction mixture is then stirred for 2 hours at room temperature and 16 hours under reflux. Working up gives crude 5-(2'-aminoethyl)-3-chloro-2-[3'-isopropyl-2'-phenyloxazolidinyl-(5')]-methoxy-pyridine, which is hydrolysed without further purification, analogously to Example (37), to give 5-(2'-aminoethyl)-3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine (boiling point 165°-185° C./0.06 mm Hg). whilst cooling with ice at 0°-10° C under reflux Working up gives crude 5-(2'-aminoethyl)-3-chloro-2-[3'-isopropyl-2'-phenyloxazolidinyl-(5')]-methoxy-pyridine, which is hydrolysed without further purification, analogously to Example (37)

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

Procedure: 10.7 g of 2-chloro-3-morpholinyl-5-methyl-pyrazine and 16.6 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine are dissolved in 130 ml of hexamethylphosphoric acid triamide. 3.6 g of a 50% strength suspension of sodium hydride in paraffin oil are introduced into this solution over the course of 30 minutes at 0°-5° C., whilst stirring. The mixture is then stirred for 1 hour at 0°-5° C. and 24 hours at room temperature. The reaction mixture is then poured onto 500 ml of ice water and extracted by shaking with ether. The ether extracts are washed with water and evaporated in a waterpump vacuum. The residue is taken up in 200 ml of 1 N sulphuric acid and the reaction mixture is stirred for 15 hours at room temperature and then extracted by shaking with ether. The acid aqueous phase is rendered alkaline with concentrated sodium hydroxide solution and is then extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue crystallises from ether-pentane. 2-(3'-Isopropylamino-2'-hydroxy-propoxy)-3-morpholinyl-5-methyl-pyrazine, melting point 77°-78° C., is thus obtained. are introduced into this solution over the course of 30 minutes at 0°-5° C. The mixture is then stirred for 1 hour at 0°-5° C. and 24 hours at room temperature extracted by shaking with ether The ether extracts are washed with water evaporated in a waterpump vacuum the reaction mixture is stirred for 15 hours at room temperature extracted by shaking with ether is then extracted by shaking with ether The ether extracts are washed with water dried over sodium sulphate evaporated in a waterpump vacuum The residue crystallises from ether-pentane

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

Procedure: 0.3 g of potassium are dissolved in 15 cc of absolute tert.butanol, and 1.5 g of 1-chloro-7-methoxyisoquinoline and 1.7 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine are added. The solution is heated to 50° for 1 hour, whereupon it is evaporated to dryness. The product is digested with water, extracted with ether, the ether phase is dried and the ether is distilled off. 1-(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)-7-methoxyisoquinoline is obtained as an oil. The solution is heated to 50° for 1 hour, whereupon it is evaporated to dryness extracted with ether the ether phase is dried the ether is distilled off

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

Procedure: 0.3 g of potassium are dissolved in 15 cc of absolute tert.butanol, and 1.5 g of 1-chloro-7-methoxyisoquinoline and 1.7 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine are added. The solution is heated to 50° for 1 hour, whereupon it is evaporated to dryness. The product is digested with water, extracted with ether, the ether phase is dried and the ether is distilled off. 1-(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)-7-methoxyisoquinoline is obtained as an oil. The solution is heated to 50° for 1 hour, whereupon it is evaporated to dryness extracted with ether the ether phase is dried the ether is distilled off

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

Procedure: 22.2 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine was dissolved in 130 ml of anhydrous dimethyl formamide, and with stirring, 50% sodium hydride was added. To the resulting solution was added a solution of 22.75 g of 2-chloro-6-(tetrahydro-2-pyranyloxy)methylpyridine in 250 ml of anhydrous dimethyl formamide. The mixture was stirred at 80° C. for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and 500 ml of 10% hydrochloric acid was added. The mixture was stirred at 80° C. for 20 minutes. The reaction solution was evaporated to dryness under reduced pressure to afford 10 g (yield 41.6%) of 1-isopropylamino-3-(6-hydroxymethyl-2-pyridyloxy)-2-propanol. The mixture was stirred at 80° C. for 1 hour After the reaction the solvent was distilled off under reduced pressure, and 500 ml of 10% hydrochloric acid was added The mixture was stirred at 80° C. for 20 minutes The reaction solution was evaporated to dryness under reduced pressure

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

Procedure: Analogously to the description in Example 11, 8.2 g (0.05 mol) of 2,3-dichloro-5-methyl-pyrazine, 11 g (0.05 mol) of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine and 3.4 g of a 50% strength suspension of sodium hydride in paraffin oil give 2-chloro-3-(3'-isopropylamino-2'-hydroxy-propoxy)-5-methyl-pyrazine, melting point 109°-110° C. when crystallised from benzene. The fumarate prepared therefrom by means of fumaric acid crystallises from methanol-ether, melting point 164°-165° C.

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

Procedure: 12 g of sodium hydride dispersion (55% strength) are added in portions to 44 g of 5-(2'-aminoethyl)-2,3-dichloro-pyridine and 55 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine, dissolved in 500 ml of 1,2-dimethoxyethane, whilst cooling with ice at 0°-10° C. The reaction mixture is then stirred for 2 hours at room temperature and 16 hours under reflux. Working up gives crude 5-(2'-aminoethyl)-3-chloro-2-[3'-isopropyl-2'-phenyl-oxazolidinyl-(5')]-methoxy-pyridine, which is hydrolysed without further purification, analogously to Example 37), to give 5-(2'-aminoethyl)-3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine (boiling point 165°-185° C./0.06 mm Hg). whilst cooling with ice at 0°-10° C under reflux Working up gives crude 5-(2'-aminoethyl)-3-chloro-2-[3'-isopropyl-2'-phenyl-oxazolidinyl-(5')]-methoxy-pyridine, which is hydrolysed without further purification, analogously to Example 37),

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

Procedure: 10.7 g of 2-chloro-3-morpholinyl-5-methyl-pyrazine and 16.6 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine are dissolved in 130 ml of hexamethylphosphoric acid triamide. 3.6 g of a 50% strength suspension of sodium hydride in paraffin oil are introduced into this solution over the course of 30 minutes at 0°-5° C., whilst stirring. The mixture is then stirred for 1 hour at 0°-5° C. and 24 hours at room temperature. The reaction mixture is then poured onto 500 ml of ice water and extracted by shaking with ether. The ether extracts are washed with water and evaporated in a waterpump vacuum. The residue is taken up in 200 ml of 1 N sulphuric acid and the reaction mixture is stirred for 15 hours at room temperature and then extracted by shaking with ether. The acid aqueous phase is rendered alkaline with concentrated sodium hydroxide solution and is then extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue crystallises from etherpentane. 2-(3'-Isopropylamino-2'-hydroxy-propoxy)-3-morpholinyl-5-methyl-pyrazine, melting point 77°-78° C., is thus obtained. are introduced into this solution over the course of 30 minutes at 0°-5° C. The mixture is then stirred for 1 hour at 0°-5° C. and 24 hours at room temperature extracted by shaking with ether The ether extracts are washed with water evaporated in a waterpump vacuum the reaction mixture is stirred for 15 hours at room temperature extracted by shaking with ether is then extracted by shaking with ether The ether extracts are washed with water dried over sodium sulphate evaporated in a waterpump vacuum The residue crystallises from etherpentane