2-methylpentanedioic acid

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

Procedure: The cleavage in stage (c) is advantageously carried out in the presence of molecular oxygen or a gas which contains molecular oxygen and an inert gas, such as nitrogen, carbon dioxide, argon or steam. A molar ratio of formylvaleric esters to molecular oxygen of from 1:0.05 to 1:3, in particular from 1:0.2 to 1:1.5, e.g., from 1:0.25 to 1:1.25, is advantageously used. This increases the catalyst life and in particular the yield of pentenoic esters. The presence of molecular oxygen was not indicated since methyl 5-formylvalerate is oxidized to monomethyl adipate in a yield of 96% by molecular oxygen at as low as 50° C., as disclosed in European Patent 131,860, and it was therefore to be expected that 4- and 3-formylvaleric esters would be oxidized in a similar manner to give 2-methylglutaric acid and 3-ethylsuccinic esters. This increases the catalyst life

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 100 mL graduated cylinder was placed 54.4 mL of an aqueous reaction mixture containing 1.84M 4-cyanopentanoic acid ammonium salt (0.1 mole 4-cyanopentanoic acid ammonium salt, produced by the enzymatic hydrolysis of 2-methylglutaronitrile; Example 9, filtered product mixture from reaction #5), then 25.8 ml of 40 wt. % methylamine (9.31 g methylamine, 0.3 mole) was added and the final volume adjusted to 100 mL with distilled water. The final concentrations of 4-cyanopentanoic acid ammonium salt and methylamine were 1.0M and 3.0M, respectively. To the resulting solution was added 0.636 g (5 wt. %/wt. of 4-cyanopentanoic acid) of 5% Pd on carbon powder, and the resulting mixture charged to a 300-mL 314 SS Autoclave Engineers EZE-Seal stirred autoclave equipped with a Dispersimax® turbine-type impeller. After flushing the reactor with nitrogen, the contents of the reactor were stirred at 1000 rpm and heated at 160° C. under 500 psig of hydrogen gas for 4 h. Samples (ca. 1.5 mL) were removed via a sampling tube over the course of the reaction for analysis. After cooling to room temperature, analysis of the final reaction mixture by gas chromatography indicated a 72.8% yield of 1,5-dimethyl-2-piperidone, 3.5% 5-methyl-2-piperidone, 19.9% 2-methylglutaric acid, and no 4-cyanopentanoic acid ammonium salt remaining. Example 9, filtered product mixture was added equipped with a Dispersimax® turbine-type impeller After flushing the reactor with nitrogen the contents of the reactor were stirred at 1000 rpm Samples (ca. 1.5 mL) were removed via a sampling tube over the course of the reaction for analysis After cooling to room temperature analysis of the final reaction mixture by gas chromatography

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

Procedure: 2-Methylglutaric acid (14.6 g.) and acetyl chloride (26 ml.) are heated in the steam bath for one hour. The mixture is concentrated to dryness in vacuo and the residue evaporated twice from toluene. The residue is dissolved in methanol (4.7 ml.), heated on the steam bath for one hour and concentrated to dryness. The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.). The crystalline salt is filtered, stirred and treated with boiling ethyl acetate (75 ml.). The insoluble material is filtered off, and the filtrate is concentrated to one-third volume and chilled. The crystals are filtered and dried to yield 11.3 g. of 4-methoxycarbonyl-2-methyl butanoic acid dicyclohexylamine salt, m.p. 97°-99°. The salt is converted to the free acid by treatment with Dowex 50. The mixture is concentrated to dryness in vacuo the residue evaporated twice from toluene The residue is dissolved in methanol (4.7 ml.) heated on the steam bath for one hour concentrated to dryness The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.) The crystalline salt is filtered treated with boiling ethyl acetate (75 ml.) The insoluble material is filtered off the filtrate is concentrated to one-third volume chilled The crystals are filtered dried to yield 11.3 g

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

Procedure: 2-Methylglutaric acid (14.6 g.) and acetyl chloride (26 ml.) are heated in the steam bath for one hour. The mixture is concentrated to dryness in vacuo and the residue evaporated twice from toluene. The residue is dissolved in methanol (4.7 ml.), heated on the steam bath for one hour and concentrated to dryness. The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.). The crystalline salt is filtered, stirred and treated with boiling ethyl acetate (75 ml.). The insoluble material is filtered off, and the filtrate is concentrated to one-third volume and chilled. The crystals are filtered and dried to yield 11.3 g. of 4-methoxycarbonyl-2-methyl butanoic acid dicyclohexylamine salt, m.p. 97°-99°. The salt is converted to the free acid by treatment with Dowex 50. The mixture is concentrated to dryness in vacuo the residue evaporated twice from toluene The residue is dissolved in methanol (4.7 ml.) heated on the steam bath for one hour concentrated to dryness The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.) The crystalline salt is filtered treated with boiling ethyl acetate (75 ml.) The insoluble material is filtered off the filtrate is concentrated to one-third volume chilled The crystals are filtered dried to yield 11.3 g

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

Procedure: 2-Methylglutaric acid (14.6 g.) and acetyl chloride (26 ml.) are heated in the steam bath for one hour. The mixture is concentrated to dryness in vacuo and the residue is evaporated twice from toluene. The residue is dissolved in methanol (4.7 ml.) and heated on the steam bath for one hour and concentrated to dryness. The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.). The crystalline salt is filtered off and the filtrate is concentrated to one third volume and chilled. The crystals are filtered and dried to yield 11.3 g. of 4-methoxycarbonyl-2-methyl butanoic acid dicyclohexylamine salt, m.p. 97°-99°. The salt is converted to the free acid by distribution between ethyl acetate and aqueous acid. The mixture is concentrated to dryness in vacuo the residue is evaporated twice from toluene The residue is dissolved in methanol (4.7 ml.) heated on the steam bath for one hour concentrated to dryness The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.) The crystalline salt is filtered off the filtrate is concentrated to one third volume chilled The crystals are filtered dried to yield 11.3 g

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

Procedure: 2-Methylglutaric acid (14.6 g.) and acetyl chloride (26 ml.) are heated in the steam bath for one hour. The mixture is concentrated to dryness in vacuo and the residue is evaporated twice from toluene. The residue is dissolved in methanol (4.7 ml.) and heated on the steam bath for one hour and concentrated to dryness. The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.). The crystalline salt is filtered off and the filtrate is concentrated to one third volume and chilled. The crystals are filtered and dried to yield 11.3 g. of 4-methoxycarbonyl-2-methyl butanoic acid dicyclohexylamine salt, m.p. 97°-99°. The salt is converted to the free acid by distribution between ethyl acetate and aqueous acid. The mixture is concentrated to dryness in vacuo the residue is evaporated twice from toluene The residue is dissolved in methanol (4.7 ml.) heated on the steam bath for one hour concentrated to dryness The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.) The crystalline salt is filtered off the filtrate is concentrated to one third volume chilled The crystals are filtered dried to yield 11.3 g

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 100 mL graduated cylinder was placed 54.4 mL of an aqueous reaction mixture containing 1.84 M 4-cyanopentanoic acid ammonium salt (0.1 mole 4-cyanopentanoic acid ammonium salt, produced by the enzymatic hydrolysis of 2-methylglutaronitrile; Example 9, filtered product mixture from reaction #5), then 25.8 ml of 40 wt. % methylamine (9.31 g methylamine, 0.3 mole) was added and the final volume adjusted to 100 mL with distilled water. The final concentrations of 4-cyanopentanoic acid ammonium salt and methylamine were 1.0 M and 3.0 M, respectively. To the resulting solution was added 0.636 g (5 wt. %/wt. of 4-cyanopentanoic acid) of 5% Pd on carbon powder, and the resulting mixture charged to a 300-mL 314 SS Autoclave Engineers EZE-Seal stirred autoclave equipped with a Dispersimax® turbine-type impeller. After flushing the reactor with nitrogen, the contents of the reactor were stirred at 1000 rpm and heated at 160° C. under 500 psig of hydrogen gas for 4 h. Samples (ca. 1.5 mL) were removed via a sampling tube over the course of the reaction for analysis. After cooling to room temperature, analysis of the final reaction mixture by gas chromatography indicated a 72.8% yield of 1,5-dimethyl-2-piperidone, 3.5% 5-methyl-2-piperidone, 19.9% 2-methylglutaric acid, and no 4-cyanopentanoic acid ammonium salt remaining. Example 9, filtered product mixture was added equipped with a Dispersimax® turbine-type impeller After flushing the reactor with nitrogen the contents of the reactor were stirred at 1000 rpm Samples (ca. 1.5 mL) were removed via a sampling tube over the course of the reaction for analysis After cooling to room temperature analysis of the final reaction mixture by gas chromatography

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

Procedure: 2-Methylglutaric acid (14.6 g.) and acetyl chloride (26 ml.) are heated in the steam bath for 1 hour. The mixture is concentrated to dryness in vacuo and the residue evaporated twice from toluene. The residue is dissolved in methanol (4.7 ml.), heated on the steam bath for 1 hour and concentrated to dryness. The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.). The crystalline salt is filtered, stirred and treated with boiling ethyl acetate (75 ml.). The insoluble material is filtered off, and the filtrate is concentrated to one-third volume and chilled. The crystals are filtered and dried to yield 11.3 g. of 4-methoxycarbonyl-2-methyl butanoic acid dicyclohexylamine salt, m.p. 97°-99°. The salt is converted to the free acid by treatment with Dowex 50. The mixture is concentrated to dryness in vacuo the residue evaporated twice from toluene The residue is dissolved in methanol (4.7 ml.) heated on the steam bath for 1 hour concentrated to dryness The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.) The crystalline salt is filtered treated with boiling ethyl acetate (75 ml.) The insoluble material is filtered off the filtrate is concentrated to one-third volume chilled The crystals are filtered dried to yield 11.3 g

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

Procedure: 2-Methylglutaric acid (14.6 g.) and acetyl chloride (26 ml.) are heated in the steam bath for one hour. The mixture is concentrated to dryness in vacuo and the residue is evaporated twice from toluene. The residue is dissolved in methanol (4.7 ml.) and heated on the steam bath for one hour and concentrated to dryness. The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.). The crystalline salt is filtered off and the filtrate is concentrated to one third volume and chilled. The crystals are filtered and dried to yield 11.3 g. of 4-methoxycarbonyl-2-methyl butanoic acid dicyclohexylamine salt, m.p. 97°-99°. The salt is converted to the free acid by distribution between ethyl acetate and aqueous acid. (b) 4-methoxycarbonyl-2-methylbutanoic acid (3.1 g.), L-alanine benzyl ester (3.58 g.) and hydroxybenzotriazole (2.7 g.) are dissolved in dichloromethane. The solution is chilled in the ice bath and dicyclohexylcarbodiimide (4.12 g.) is added. After stirring 15 minutes in the ice bath and 18 hours at room temperature the precipitate is filtered off and the filtrate is concentrated to dryness. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness to yield N-(4-methoxycarbonyl-2-methylbutanoyl)-L-alanine benzyl ester. The mixture is concentrated to dryness in vacuo the residue is evaporated twice from toluene The residue is dissolved in methanol (4.7 ml.) heated on the steam bath for one hour concentrated to dryness The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.) The crystalline salt is filtered off the filtrate is concentrated to one third volume chilled The crystals are filtered dried to yield 11.3 g is added is filtered off the filtrate is concentrated to dryness The residue is dissolved in ethyl acetate washed neutral The organic phase is dried over magnesium sulfate concentrated to dryness

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

Procedure: 2-Methylglutaric acid (14.6 g.) and acetyl chloride (26 ml.) are heated in the steam bath for one hour. The mixture is concentrated to dryness in vacuo and the residue is evaporated twice from toluene. The residue is dissolved in methanol (4.7 ml.) and heated on the steam bath for one hour and concentrated to dryness. The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.). The crystalline salt is filtered off and the filtrate is concentrate to one third volume and chilled. The crystals are filtered and dried to yield 11.3 g. of 4-methoxycarbonyl-2-methyl butanoic acid dicyclohexylamine salt, m.p. 97°-99°. The salt is converted to the free acid by distribution between ethyl acetate and aqueous acid. The mixture is concentrated to dryness in vacuo the residue is evaporated twice from toluene The residue is dissolved in methanol (4.7 ml.) heated on the steam bath for one hour concentrated to dryness The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.) The crystalline salt is filtered off the filtrate is concentrate to one third volume chilled The crystals are filtered dried to yield 11.3 g

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

Procedure: 2-Methylglutaric acid (14.6 g.) and acetyl chloride (26 ml.) are heated in the steam bath for one hour. The mixture is concentrated to dryness in vacuo and the residue is evaporated twice from toluene. The residue is dissolved in methanol (4.7 ml.) and heated on the steam bath for one hour and concentrated to dryness. The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.). The crystalline salt is filtered off and the filtrate is concentrated to one third volume and chilled. The crystals are filtered and dried to yield 11.3 g. of 4-methoxycarbonyl-2-methyl butanoic acid dicyclohexylamine salt, m.p. 97°-99°. The salt is converted to the free acid by distribution between ethyl acetate and aqueous acid. The mixture is concentrated to dryness in vacuo the residue is evaporated twice from toluene The residue is dissolved in methanol (4.7 ml.) heated on the steam bath for one hour concentrated to dryness The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.) The crystalline salt is filtered off the filtrate is concentrated to one third volume chilled The crystals are filtered dried to yield 11.3 g

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

Procedure: 2-Methylglutaric acid (14.6 g.) and acetyl chloride (26 ml.) are heated in the steam bath for one hour. The mixture is concentrated to dryness in vacuo and the residue is evaporated twice from toluene. The residue is dissolved in methanol (4.7 ml.) and heated on the steam bath for one hour and concentrated to dryness. The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.). The crystalline salt is filtered off and the filtrate is concentrated to one third volume and chilled. The crystals are filtered and dried to yield 11.3 g. of 4-methoxycarbonyl-2-methyl butanoic acid dicyclohexylamine salt, m.p. 97°-99°. The salt is converted to the free acid by distribution between ethyl acetate and aqueous acid. The mixture is concentrated to dryness in vacuo the residue is evaporated twice from toluene The residue is dissolved in methanol (4.7 ml.) heated on the steam bath for one hour concentrated to dryness The residue is dissolved in a mixture of ether (17 ml.), dicyclohexylamine (16.7 ml.) and hexane (83 ml.) The crystalline salt is filtered off the filtrate is concentrated to one third volume chilled The crystals are filtered dried to yield 11.3 g