How is cyclopentamine synthesized?

Answer 1

"Cyclopentadrine" N-α-dimethylcyclopentaneethaneamine hydrochloride CAS No.: 102-45-4 (base)

cyclopentanone

cyanoacetic acid

ammonium acetate

hydrogen

magnesium

methyl iodide

methylamine

hydrogen chloride

A mixture of 126g (1.5 mols) of cyclopentanone, 128g (1.5 mols) cyanoacetic acid, 31g (0.5 mol) of ammonium acetate and 200cc of dry benzene is heated under a refluxing condenser and a water trap. The mixture is refluxed for about 12 hours after which time no more water collects in the trap, and the formation of cyclopentylideneacetonitrile is complete. The reaction mixture comprising a mixture of cyclopentylideneacetonitrile and cyclopentylideneacetic acid is washed with about one liter of 2% hydrochloric acid and the benzene layer is separated and the mixture is distilled to cause decarboxylation of the cyclopentylideneacetic acid present. The distillate comprising cyclopentylideneacetonitrile which boils at 172º to 175ºC is purified by distillation. A mixture of 53.5g (0.5 mol) of cyclopentylideneacetonitrile dissolved in 50cc of absolute ethanol and 0.5g of a palladium-carbon catalyst is hydrogenated with hydrogen at a pressure of about 40lb for about 3 hours. An additional amount of 0.8g of palladium-carbon catalyst is then added and the hydrogenation continued for about 4 hours during which time the reduction is substantially completed and the cyclopentylideneacetonitrile is converted to cyclopentylacetonitrile. The reaction mixture is filtered to remove the catalyst and the alcohol is evaporated in vacuo. The residue comprising chiefly cyclopentylacetonitrile is washed with dilute hydrochloric acid to remove any amine which may have been formed during the hydrogenation process, and the organic residue comprising cyclopentylacetonitrile is dissolved in ether, the ether solution dried over anhydrous magnesium sulfate and distilled. The cyclopentylacetonitrile boils at 185º to 187º C and has a refractive index of nD25 = 1.4456. To an ethereal solution of methyl magnesium iodide prepared from 26.7g (1.1 mols) of magnesium and 160g (1.13 mols) of methyl iodide in 200cc of dry ether, is added a solution of 79g (0.72 mol) of cyclopentylacetonitrile in 100cc of dry ether. The reaction mixture is refluxed for 4 hours. The reaction mixture is then decomposed with ice in the usual way, and the ether layer containing the cyclopentylacetone is separated, is dried over anhydrous magnesium sulfate and the ether removed by evaporation. The residue comprising cyclopentylacetone is purified by distillation in vacuo. The cyclopentylacetone boils at 82º to 84ºC at about 32mm pressure. A mixture of 75g (0.6 mol) of cyclopentylacetone, 75g (2.4 mols) of methylamine, and 10g of Raney nickel catalyst is placed in a high pressure bomb previously cooled to a temperature below -6ºC, and hydrogen is admitted under an initial pressure of about 2000 psi. The bomb is then heated to about 135º to 150ºC for about 2 hours, during which time reductive amination takes place and 1-cyclopentyl-2-methylaminopropane is produced. During the period of heating the reaction mixture is agitated by rocking the bomb. The bomb is then cooled and opened thus permitting the escape of hydrogen and most of the excess methylamine. The reaction mixture is filtered to remove the nickel catalyst and the filtrate comprising 1-cyclopentyl-2-methylaminopropane is purified by distillation under reduced pressure. 1-Cyclopentyl-2-methylaminopropane boils at 83º to 86ºC at about 30mm pressure. 1-Cyclopentyl-2-methylaminopropane thus produced is a colorless liquid of slightly ammoniacal odor. It has a refractive of nD25 = 1.4500. Analysis showed the presence of 9.79% N as compared with a calculated value of 9.99% N. 141g (1 mol) of 1-cyclopentyl-2-methylaminopropane are dissolved in 500cc of dry ether, and dry hydrogen chloride is passed into the solution until the weight of the mixture and container has increased by 36g. During the addition of the hydrogen chloride, the hydrochloric acid addition salt of 1-cyclopentyl-2-methylaminopropane precipitates as a white powder. The salt is filtered off and washed with dry ether. 1-Cyclopentyl-2-methylaminopropane hydrochloride thus prepared melts at about 113º to 115ºC. The yield is practically quantitative.

Merck Index 2733

Kleeman & Engel p.268

I.N. p.277

Rohrmann, E.; U.S. Patent 2,520,015; August 22, 1950; assigned to Ell Lilly and Company