methyl pentanimidate;hydrochloride

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 22 L, three-necked round bottom flask equipped with an air-powered mechanical stirrer was placed under a nitrogen atmosphere. The vessel was charged with methyl valerimidate hydrochloride (2.5 kg, 16 mol) and dimethylformamide (9.2 L). A thermometer was attached and the suspension cooled to 0°-15° C. with a cooling bath. Triethylamine (2.3 L) was added to the reaction at such a rate so that the internal temperature did not exceed 25° C. The cooling was stopped and the reaction was allowed to stir 1 hour. The reaction mixture was vacuum filtered using a Buchner funnel and a carboy (20 L). The filter cake was washed with additional dimethylformamide (1.0 L) and force-air dried for 15 min. The combined filtrates were saved. Another clean 22 L, three-necked round bottom flask equipped as above was placed under nitrogen. The vessel was charged with the combined filtrates from above followed by triethylamine (1.6 L) and 4-(aminomethyl)benzoic acid (1.7 kg, 11.5 mol). The thermometer was attached and the suspension was heated to an internal temperature of 65° C. with a heating mantle and a temperature controller. The heating was continued for 20 hours. The reaction was cooled to ambient temperature and filtered to yield 2.5 kg of product; 92% uncorrected yield. A 22 L, three-necked round bottom flask equipped with an air-powered mechanical stirrer the suspension cooled to 0°-15° C. with a cooling bath did not exceed 25° C filtered The filter cake was washed with additional dimethylformamide (1.0 L) force-air dried for 15 min Another clean 22 L, three-necked round bottom flask equipped The vessel was charged with the combined filtrates The heating was continued for 20 hours The reaction was cooled to ambient temperature filtered

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 10 gallon, glass-lined fixed reactor was charged with 7.0 kg (84.6 mol) of valeronitrile and 2.96 kg (92.2 mol, 1.1 eq) of methanol. The solution was stirred with cooling to about 5° C. under an atmosphere of nitrogen. A flow of hydrogen chloride gas from a gas cylinder was bubbled into the solution below the surface of the mixture at a rate such that the reaction temperature did not exceed 15° C. After about one hour, 3.67 kg (101 tool, 1.19 eq) of hydrogen chloride had been disbursed from the gas cylinder and addition was stopped. Stirring was continued for an additional 18 h at 0° C. Tert-butyl methyl ether (9.7 kg) was added to the suspension and stirring was continued for 3 h at 0° C. The slurry was then centrifuged under an atmosphere of nitrogen. After drying overnight under nitrogen and for several hours under reduced pressure at ambient temperature the product weighed 9.66 kg (76% yield uncorrected for purity) and had amp of 91°-92° C. The crude product was hygroscopic and was stored in sealed bottles under nitrogen at -5° C. A flow of hydrogen chloride gas from a gas cylinder was bubbled into the solution below the surface of the mixture at a rate such that the reaction temperature did not exceed 15° C Stirring was continued for an additional 18 h at 0° C stirring was continued for 3 h at 0° C After drying overnight under nitrogen and for several hours under reduced pressure at ambient temperature the product amp of 91°-92° C was stored in sealed bottles under nitrogen at -5° C.

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 10 gallon, glass-lined fixed reactor was charged with 7.0 kg (84.6 mol) of valeronitrile and 2.96 kg (92.2 mol, 1.1 eq) of methanol. The solution was stirred with cooling to about 5° C. under an atmosphere of nitrogen. A flow of hydrogen chloride gas from a gas cylinder was bubbled into the solution below the surface of the mixture at a rate such that the reaction temperature did not exceed 15° C. After about one hour, 3.67 kg (101 tool, 1.19 eq) of hydrogen chloride had been disbursed from the gas cylinder and addition was stopped. Stirring was continued for an additional 18 h at 0° C. Tert-butyl methyl ether (9.7 kg) was added to the suspension and stirring was continued for 3 h at 0° C. The slurry was then centrifuged under an atmosphere of nitrogen. After drying overnight under nitrogen and for several hours under reduced pressure at ambient temperature the product weighed 9.66 kg (76% yield uncorrected for purity) and had amp of 91°-92° C. The crude product was hygroscopic and was stored in sealed bottles under nitrogen at -5° C. A flow of hydrogen chloride gas from a gas cylinder was bubbled into the solution below the surface of the mixture at a rate such that the reaction temperature did not exceed 15° C Stirring was continued for an additional 18 h at 0° C stirring was continued for 3 h at 0° C After drying overnight under nitrogen and for several hours under reduced pressure at ambient temperature the product amp of 91°-92° C was stored in sealed bottles under nitrogen at -5° C.

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

Procedure: The title compound is prepared by stirring one equivalent of methyl valerimidate hydrochloride, one equivalent of 4-aminomethyl-2'-cyanobiphenyl, and one equivalent of sodium methoxide in methanol. The reaction mixture may then be stripped of solvent and the amidine and residual sodium chloride is used directly in the next reaction.

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

Procedure: The title compound is prepared by stirring one equivalent of methyl valerimidate hydrochloride, one equivalent of 4-aminomethyl-2'-cyanobiphenyl, and one equivalent of sodium methoxide in methanol. The reaction mixture may then be stripped of solvent and the amidine and residual sodium chloride is used directly in the next reaction.

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 22 L, three-necked round bottom flask equipped with an air-powered mechanical stirrer was placed under a nitrogen atmosphere. The vessel was charged with methyl valerimidate hydrochloride (2.5 kg, 16 mol) and dimethylformamide (9.2 L). A thermometer was attached and the suspension cooled to 0°-15° C. with a cooling bath. Triethylamine (2.3 L) was added to the reaction at such a rate so that the internal temperature did not exceed 25° C. The cooling was stopped and the reaction was allowed to stir 1 hour. The reaction mixture was vacuum filtered using a Buchner funnel and a carboy (20 L). The filter cake was washed with additional dimethylformamide (1.0 L) and force-air dried for 15 min. The combined filtrates were saved. Another clean 22 L, three-necked round bottom flask equipped as above was placed under nitrogen. The vessel was charged with the combined filtrates from above followed by triethylamine (1.6 L) and 4-(aminomethyl)benzoic acid (1.7 kg, 11.5 mol). The thermometer was attached and the suspension was heated to an internal temperature of 65° C. with a heating mantle and a temperature controller. The heating was continued for 20 hours. The reaction was cooled to ambient temperature and filtered to yield 2.5 kg of product; 92% uncorrected yield. A 22 L, three-necked round bottom flask equipped with an air-powered mechanical stirrer the suspension cooled to 0°-15° C. with a cooling bath did not exceed 25° C filtered The filter cake was washed with additional dimethylformamide (1.0 L) force-air dried for 15 min Another clean 22 L, three-necked round bottom flask equipped The vessel was charged with the combined filtrates The heating was continued for 20 hours The reaction was cooled to ambient temperature filtered

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 10 gallon, glass-lined fixed reactor was charged with 7.0 kg (84.6 mol) of valeronitrile and 2.96 kg (92.2 mol, 1.1 eq) of methanol. The solution was stirred with cooling to about 5° C. under an atmosphere of nitrogen. A flow of hydrogen chloride gas from a gas cylinder was bubbled into the solution below the surface of the mixture at a rate such that the reaction temperature did not exceed 15° C. After about one hour, 3.67 kg (101 tool, 1.19 eq) of hydrogen chloride had been disbursed from the gas cylinder and addition was stopped. Stirring was continued for an additional 18 h at 0° C. Tert-butyl methyl ether (9.7 kg) was added to the suspension and stirring was continued for 3 h at 0° C. The slurry was then centrifuged under an atmosphere of nitrogen. After drying overnight under nitrogen and for several hours under reduced pressure at ambient temperature the product weighed 9.66 kg (76% yield uncorrected for purity) and had amp of 91°-92° C. The crude product was hygroscopic and was stored in sealed bottles under nitrogen at -5° C. A flow of hydrogen chloride gas from a gas cylinder was bubbled into the solution below the surface of the mixture at a rate such that the reaction temperature did not exceed 15° C Stirring was continued for an additional 18 h at 0° C stirring was continued for 3 h at 0° C After drying overnight under nitrogen and for several hours under reduced pressure at ambient temperature the product amp of 91°-92° C was stored in sealed bottles under nitrogen at -5° C.