2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile

Abstract

2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile.

Claims

1. A compound of 2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile.

Description

PREPARATION EXAMPLES

[0054] The Examples which follow serve to illustrate the present invention.

[0055] Compounds of Formula (I) are prepared using malononitrile (N≡C—CH.sub.2—C≡N), which is commercially available. Other reagents used in accordance with the preparation examples are also commercially available. 2-Bromo-5-chloro-1,3-dimethyl-benzene and 2-iodo-5-chloro-1,3-dimethyl-benzene may be prepared according to literature methods as described in, eg, WO 2006/084663.

Example 1

Preparation of 2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile

[0056] ##STR00019##

[0057] To a 400 mL vessel equipped with a mechanical stirrer, thermometer, distillation head and dropping funnel, solid sodium hydroxide (10.9 g, 0.27 mol, microprills with 0.5-1 mm diameter) is charged under an inert atmosphere.

[0058] 1-Methyl-2-pyrrolidone (NMP, 137 g) is added to the vessel in one portion through the dropping funnel and the reaction mixture cooled to 10-15° C. while stirring. A solution of malononitrile (N≡C—CH.sub.2—C≡N) (6.6 g, 0.10 mol) in NMP (8.9 g) is added through the dropping funnel over 10-15 minutes maintaining the temperature at 10-15° C. The reaction mixture is then heated to 100° C. and a vacuum (30 mbar) applied, upon which solvent (40 g) is distilled off.

[0059] 2-Bromo-5-chloro-1,3-dimethyl-benzene (20 g, 0.089 mol) is then added through the dropping funnel over 5-10 minutes, whilst maintaining the temperature at 100-110° C. A mixture containing palladium (II) chloride (0.19 g, solution in conc. hydrochloric acid, assay 20% Pd, 0.36 mmol), triphenylphosphine (0.45 g, 1.6 mmol) and NMP (18 g) is then added through the dropping funnel over a 5-10 minute period. The temperature is allowed to rise to 124° C. and the reaction mixture stirred at this temperature for 2-3 hours. Conversion is monitored by pulling samples and subsequent HPLC analysis.

[0060] When conversion is complete, a vacuum (20-40 mbar) is applied and solvent (90 g) is distilled off. The resulting residue is cooled below 100° C. and water (95 g) is added. After cooling to room temperature, the resulting mixture is filtered through hyflo (Hyflo® SuperGel® diatomaceous earth, ca. 10 g) and the filter cake washed with water (20 g). To the combined filtrates, hydrochloric acid (20.6 g, assay 32%, 0.18 mol) is added to adjust the pH from 13.3 to 2.7.

[0061] The resulting mixture is extracted with tert-butyl-methyl ether (2×110 g). The organic phases are washed with water (2×50 g) and the combined organic phases evaporated to dryness. The resulting solid residue is recrystallized from iso-propanol (63 g) and the resulting crystals filtered, washed with cold iso-propanol (5 g) and dried under vacuum to yield 2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile (melting point (m.p.) 145-147° C.).

[0062] .sup.1H-NMR (CDCl.sub.3) δ(ppm): 2.6 (5), 6H; 5.3 (s), 1H; 7.2 (s), 2H.

Example 2

Preparation of 2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile

[0063] To a 1 litre vessel equipped with mechanical stirrer, thermometer, distillation head, joints for dosing liquids by pump, and gas inlet tube (below surface) solid sodium hydroxide (87.1 g, 2.18 mol, microprills with 0.5-1 mm diameter) is charged under an inert atmosphere.

[0064] 1-Methyl-2-pyrrolidone (NMP, 682 g) is added in one portion while stirring and the resulting mixture cooled to 10-14° C. A solution of malononitrile (49.2 g, 0.736 mol) in NMP (65 g) is added via a pump over 15-20 minutes while maintaining the temperature at 10-14° C. A vacuum (30 mbar) is applied and the resulting mixture is heated to 100-110° C. until solvent (198 g) is distilled off. The mixture is then heated to 130° C. and a stream of nitrogen (4.5 litres/hour) is passed through.

[0065] A mixture containing palladium (II) chloride (1.15 g, solution in conc. hydrochloric acid; assay 20% Pd, 2.17 mmol), triphenylphosphine (1.50 g; 5.72 mmol) and NMP (147 g) is dosed in via a pump within a 70 minute period. After 20 minutes feeding the aforementioned mixture, 2-bromo-5-chloro-1,3-dimethyl-benzene (160 g, 0.715 mol) is also dosed in in parallel via a pump within 50 minutes.

[0066] After both additions have been completed, the reaction mixture is maintained at 130° C. for a further 3 hours. A vacuum (20-30 mbar) is applied and solvent (603 g) is distilled off. The resulting residue is cooled below 100° C. and water (450 g) is added. The resulting mixture is cooled to 40° C. Hydrochloric acid (180 g, assay 32%, 1.58 mol) is added in order to reduce the pH from 13.1 to 2.0. Toluene (535 g) is added for extraction of the product.

[0067] The two phase mixture is filtered through hyflo (ca. 15 g) and the filter-cake washed with toluene (45 g). The combined filtrates are transferred to a separation funnel, the aqueous phase separated and the organic phase washed with water (400 g). All aqueous phases are re-extracted with toluene (360 g) and all organic phases combined and evaporated to dryness. The solid residue is recrystallized with iso-propanol (650 g). The resulting crystals are filtered and washed with iso-propanol (55 g) and dried under vacuum to yield 2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile (m.p. 145-147° C.).

Example 3

Preparation of 2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile

[0068] To a 250 mL vessel equipped with a mechanical stirrer, thermometer, distillation head and dropping funnel, solid sodium hydroxide (3.9 g, 0.10 mol, microprills with 0.5-1 mm diameter) is charged under an inert atmosphere.

[0069] 1-Methyl-2-pyrrolidone (NMP, 68 g) is added to the vessel in one portion through the dropping funnel and the reaction mixture cooled to 10-15° C. while stirring. A solution of malononitrile (N≡C—CH.sub.2—C≡N) (2.27 g, 0.034 mol) in NMP (2.7 g) is added through the dropping funnel over 5 minutes maintaining the temperature at 10-15° C. The reaction mixture is then heated to 100° C. and a vacuum (30 mbar) applied, upon which solvent (32 g) is distilled off. The mixture is then heated to 130° C. and a stream of nitrogen is passed through.

[0070] 2-Iodo-5-chloro-1,3-dimethyl-benzene (9.0 g, 95% purity, 0.032 mol) is then added through the dropping funnel over 5 minutes at 130° C. A mixture containing palladium (II) chloride (0,150 g, solution in conc, hydrochloric acid, assay 20% Pd, 0.281 mmol), triphenylphosphine (0.186 g, 0.709 mmol) and NMP (13.7 g) is then added through the dropping funnel over a 2-minute period. The temperature is allowed to rise to 130° C. and the reaction mixture stirred at this temperature for 80 min. Conversion is monitored by pulling samples and subsequent HPLC analysis. A second portion of a mixture containing palladium (II) chloride (0.103 g, solution in conc. hydrochloric acid, assay 20% Pd, 0.194 mmol), triphenylphosphine (0.132 g, 0.504 mmol) and NMP (9.76 g) is then added through the dropping funnel over a 2-minute period and the reaction mixture stirred at 130° C. for 40 min.

[0071] When conversion is complete, a vacuum (20-40 mbar) is applied and solvent (38 g) is distilled off. The resulting residue is cooled to 80° C. and water (30 g) is added. After cooling to room temperature, the resulting mixture is filtered through a filter paper and the filter cake washed with water (10 g). To the combined filtrates, hydrochloric acid (9.6 g, assay 32%, 0.084 mol) is added to adjust the pH from 13.3 to 1.3.

[0072] The resulting mixture is extracted with toluene (50 g). The organic phase is washed with water (2×20 g) and evaporated to dryness. The resulting solid residue is recrystallized from 1-pentanol (17 g) and the resulting crystals filtered, washed with 1-pentanol (4 g) and dried under vacuum to yield 2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile (melting point (m.p.) 145-147° C.).

Example 4

Preparation of 2-(4-chloro-2,6-dimethyl-phenyl)acetic acid

[0073] ##STR00020##

[0074] To a 500 mL reaction vessel equipped with thermometer, mechanical stirrer, distillation head with water trap and dropping funnel is added water (100 g) and concentrated sulphuric acid (assay 98%, 179 g, 1.79 mol).

[0075] The mixture is stirred and heated to 120-130° C., and a solution of 2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile (assay 92.8%, 91.5 g, 0.415 mol) in toluene (1070 g) dosed in over 2 hours. The solvent (toluene/water azeotrope) is distilled off, and the water separated in the water trap is transferred back to the reaction mixture. After all of the organic solvent has been distilled off, the resulting reaction mass is heated to 140° C. for an additional 4 hours. Conversion is monitored by sampling and HPLC-analysis.

[0076] After complete conversion, the reaction mass is cooled to 60° C. and introduced into well-agitated water (900 g). The resulting mixture, a suspension, is cooled to 25° C. and filtered. The filter-cake, the desired product, is washed with water (2×220 g) and dried under vacuum. Crude 2-(4-chloro-2,6-dimethyl-phenyl)acetic acid is obtained, which is recrystallized from toluene (608 g) affording pure 2-(4-chloro-2,6-dimethyl-phenyl)acetic acid (m.p. 187-189° C.).

[0077] .sup.1H-NMR (CDCl.sub.3) δ(ppm); 2.2 (s), 6H; 3.6 (s), 2H; 7.0 (s), 2H.

Example 5

Preparation of 2-(4-chloro-2,6-dimethyl-phenyl)acetic acid

[0078] To a 300 mL reaction vessel equipped with thermometer, mechanical stirrer and reflux condenser is added water (41 g) and concentrated sulphuric acid (assay 98%, 72 g, 0.72 mol). The mixture is stirred and heated to 140° C.

[0079] Solid 2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile (assay 98.4%, 50 g, 0.24 mol) is added over a 70 minute period in 10 equal portions while maintaining the temperature at 140° C. The reaction mixture is stirred at 140° C. for another 2-3 hours and conversion is controlled by sampling and HPLC-analysis. When conversion is complete, the resulting mixture, a suspension, is cooled to room temperature. Water (100 g) is added and the suspension is filtered. The filter-cake, the desired product, is washed with water (2×50 g) and dried under vacuum. Crude 2-(4-chloro-2,6-dimethyl-phenyl)acetic acid is obtained.