2-chloropropanal

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

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-1,1-bis(methyloxy)propane (31 ml), 1,4-dioxan (20 ml), water (20 ml) and concentrated hydrochloric acid (7.2 ml) was heated under reflux for 30 minutes. After cooling in an ice bath, sodium bicarbonate (7.2 g) was added portionwise. The mixture which contained 2-chloropropionaldehyde was stirred for stirred for a further thirty minutes. In the meantime methylamine (40% in water, 110 ml) and water (20 ml) were cooled in an ice bath and 1,3-acetonedicarboxylic acid (20 g) was added portionwise whilst keeping the temperature below 20° C. After cooling to 110° C., the solution containing the 2-chloropropionaldehyde was added slowly whilst keeping the temperature below 15° C. The reaction mixture was stirred at 15° C. for one hour, then at room temperature for sixteen hours. The reaction mixture was cooled, acidified to pH 1 by the addition of 5N hydrochloric acid, and the resulting solid collected by filtration. The solid was washed with cold water, then diethyl ether. After drying, the solid washed with diethyl ether, and then dried, to afford the title compound as a buff solid 11.85 g. was heated under reflux for 30 minutes After cooling in an ice bath for stirred for a further thirty minutes the temperature below 20° C was added slowly the temperature below 15° C The reaction mixture was stirred at 15° C. for one hour at room temperature for sixteen hours The reaction mixture was cooled the resulting solid collected by filtration The solid was washed with cold water After drying the solid washed with diethyl ether dried

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

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

Procedure: To 68 ml. of 1.6M butyllithium in hexane at -50°C. is added dropwise, with stirring, 7.4 g. of 1-pentyne. The resulting white sludge is diluted with 20 ml. of hexane, brought to 10°C. and treated with 11 g. of freshly prepared β -chloropropionaldehyde (Org. Syn., Coll. Vol. I, p. 166) at such a rate that the temperature is maintained at 10°-15°C. The solution is allowed to stir at ambient temperature for 18 hours then treated with saturated ammonium chloride solution. The organic phase is separated, washed with dilute hydrochloric solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation gives 5.1 g. of product b.p. 65°-66°C. at 0.3 nm.; λ max. 2.95 (--OH) and 4.55 μ (-C≡C-); vapor phase chromatography shows one peak. The resulting white sludge is diluted with 20 ml brought to 10°C. treated with 11 g is maintained at 10°-15°C to stir at ambient temperature for 18 hours The organic phase is separated washed with dilute hydrochloric solution dried with anhydrous magnesium sulfate Distillation gives 5.1 g

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

Procedure: The second step in the synthesis of AV1013 involves reacting the intermediate (IPPP), with 2-chloro-propan-1-one under Friedel-Craft conditions to synthesize the corresponding chloroketone. Thus, reaction of isopropylpyrazolo[1,5-a]pyridine (IPPP) with 2-chloropropionyl chloride in the presence of aluminum chloride (Example 1, Step 2), gave 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (i.e., 2-chloro-desmethylibudilast). In an alternate strategy as described in Example 8, IPPP is allowed to react with propanoyl chloride under Friedel-Crafts acylation conditions to give desmethylibudilast. It should be noted that the terms desmethylibudilast and Nor-methyl ibudilast are used interchangeably throughout the specification. The obtained Nor-methyl ibudilast is then converted to the corresponding alpha-chloroketone (2-chloro-desmethylibudilast), by techniques known in the chemical art, for example, via chlorination.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-1,1-bis(methyloxy)propane (31 ml), 1,4-dioxan (20 ml), water (20 ml) and concentrated hydrochloric acid (7.2 ml) was heated under reflux for 30 minutes. After cooling in an ice bath, sodium bicarbonate (7.2 g) was added portionwise. The mixture which contained 2-chloropropionaldehyde was stirred for stirred for a further thirty minutes. In the meantime methylamine (40% in water, 110 ml) and water (20 ml) were cooled in an ice bath and 1,3-acetonedicarboxylic acid (20 g) was added portionwise whilst keeping the temperature below 20° C. After cooling to 110° C., the solution containing the 2-chloropropionaldehyde was added slowly whilst keeping the temperature below 15° C. The reaction mixture was stirred at 15° C. for one hour, then at room temperature for sixteen hours. The reaction mixture was cooled, acidified to pH 1 by the addition of 5N hydrochloric acid, and the resulting solid collected by filtration. The solid was washed with cold water, then diethyl ether. After drying, the solid washed with diethyl ether, and then dried, to afford the title compound as a buff solid 11.85 g. was heated under reflux for 30 minutes After cooling in an ice bath for stirred for a further thirty minutes the temperature below 20° C was added slowly the temperature below 15° C The reaction mixture was stirred at 15° C. for one hour at room temperature for sixteen hours The reaction mixture was cooled the resulting solid collected by filtration The solid was washed with cold water After drying the solid washed with diethyl ether dried