Method of preparation of 1-alkyl-2-aminométhylpyrrolidines.

AS AFRICAN INDUSTRIAL PROPERTY AND THE MALAGASY PATENT

In Yaounde (Cameroon) International Patent Classification: 07 № 03823 C.

0. Α·Μ) Ρ. 1. ■</ -. 16 To 20 hr 5 November 1971 request Mn to rO.A.M.P. 1. (G.P. no. 54,406) by the Company called VBE1> FRATMANN S. A. residing in Swiss.

DELIVERED THE

Published at № of official ballot

Priority: Patent application deposited under Swiss

the no. 16 628/70 10 November 1970 on behalf of the applicant.

The present invention relates to a novel process for the preparation of L-alkyl 2 a-aminométhylpyrrolidines and intermediates thereof.

This process is essentially characterized in that the 5 is reacted in a solvent medium an L-alkyl 2 pyrrolidone with phosgene to a temperature between + and - 5 °c lu °C, that added to the obtained product whose temperature has been lowered again between 0 °c - 20 °c and an alkali alcoholate, added nitromethane mixture returned to temperature

10 room, and is reduced in the group Nitromethylene obtained by grouping aminomethyl.

This enables the manufacture of a chemical element, used in particular as synthesis intermediate, avoiding using known methods elongate delicate starting from pyrrolidine as raw material.

The method object of the present invention is illustrated by the following of the following reactions:

-■*

(1) + C0C1₂

(2) + 2Meor₂

VBE1 (I-)

(3) HC +₃ N0₂

(1) (2)

(3)

wherein R and R ^₂ are alkyl groups.

The mth an alkali metal such as sodium, potassium hydroxide, andc.

According to the inventive method have reacted an L-alkyl 2 pyrrolidone (I-) with phosgene, an alkali alcoholate and nitromethane to give the compound (III).

Examples of alkyl group (the R ^) in the L-alkyl 2 a-phenyl include methyl, ethyl, propyl, isolpropyle, butyl, or ISO andc.

The reaction L-alkyl 2 pyrrolidone with phosgene can be conducted in a solvent such as benzene, toluene, xylene, and so the reaction is performed at low temperature between - 5 °c et + 10 °c for example. Has the following chemical structure:

wherein has the same meaning as indicated above. It can be isolated and purified. It can however be used for the following reaction with the alkali metal alcoholate and nitromethane without isolation and without purification. The solvent used in the previous step is commonly maintained. The treatment to the alkali metal alcoholate is to be conducted at low temperature, at temperatures ranging from 0 °c - 20 °c and are preferred. Reaction of the product obtained:

where Β and2 · have the same meanings as indicated above with nitromethane, occurs at ambient temperature.

The L-alkyl 2 - mitroraéthylènepyrrolidines (ll) may be isolated and purified, but can also be used as such, without isolation and without purification, for the following reaction: the reduction of the L-alkyl 2 a-nitrométhylènepyrrolidines (ll) is produced by the action of an acid on a metal or by hydrogen in the presence of a metallic hydrogenation catalyst. As metals, in the case of the reduction by chemical means, used mainly iron and zinc with hydrochloric or acetic acid. The reaction is conducted in wine solvent, the acid used serving as a solvent, and the operation is conducted with heating. In the case of the catalytic hydrogenation, hydrogenation catalyst used blacks of metal oxides, metals, colloidal metals, metals on suitable support. The catalysts are most frequently employed are: platinum black, the thodium on alumina, palladium on carbon and Raney nickel. The catalytic hydrogenation is conducted in a solvent such as water, the inéthanol, ethanol, isopropanol, butanol, tetrahydrofuran, dioxane or other inert solvents. These solvents can be used alone or in combination. The hydrogenation pressure may range from atmospheric pressure to high pressures. Typically used at pressures ranging from atmospheric pressure to a few atmospheres. It is preferable to stop the reaction when the calculated amount of hydrogen has been absorbed. (II) the reaction product is isolated after filtration of the catalyst, followed by evaporation of the solvent.

The 1-alkyl 2 a-aminométhylpyrrolidines (lll) thus obtained can be converted into salts, by addition of a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or an organic acid such as oxalic acid, tartaric acid, maleic acid and picric acid.

00' Following example is given to illustrate the invention, but this, without limiting in any way the latter.

a) preparation of L-ethyl-2 a-nitrométhylènepyrrolidine mainly in a balloon to two pipes provided with a mechanical stirrer, a bulb of bromine and a thermometer is 23 g of 1-ethylpyrrolidone dissolved in 100 ml of anhydrous toluene.

Cooled to 0 °c and introduced by maintaining the temperature between 0 and 5 °c 90 ml of a benzene solution to 217. of phosgene. With each drop poured, it precipitates white product are noted and a release of gas carbon dioxide. Duration of introduction is about one hour. Phosgene is introduced completed is kept stirring for 3 hours at 0 °c, then cooled to - 15 °c is introduced dropwise while maintaining the temperature between - 5 and - 15 °c a solution of 170 ml of absolute ethanol in which have been solubilized 9.5 g of sodium. The duration of introduction is about one hour, because the reaction is very exothermic. After ten minutes of introduction of sodium ethoxide sodium chloride begins to precipitate. After completion of the reaction, the mixture is allowed under stirring until it reaches room temperature. Is then introduced within ten minutes without cooling and 18 g of nitromèthane. Allowed to stir for two hours and then allowed to stand for 12 hours. Then the mixture is diluted with a liter of water.

The organic layer that is decanted is separated. The aqueous phase is extracted three times with 150 ml of chloroform each time. The organic phases are combined, dried over sodium sulfate, filter, vacuum evaporated to dry. The residue, well-crystallized is resumed by ordinary 100 ml ether. The product is dewatered and dried at 40 °c. Obtained 25 g of L-ethyl 2 a-nitrométhylènepyrrolidine (F. ii 131 °c - RT-: 78%).

Calculated: C.% 53.84% 7.69% 17.95 D of H

Found 9.ï C. 7 . 7.39% 18.04% 53.60 H-n-

b) preparation of L-ethyl-2 a-amlnométhvlpyrrolidine

To a solution of 25 g of L-ethyl 2 a-nitrométhylènepyrrolidine in 500 ml of methanol, there is added about 5g of Raney nickel and the reaction mixture is hydrogenated to both pressure and ambient temperature to 4 equivalents absorbing molecular hydrogen thereby requiring about 5 hours. Raney nickel is separated by filtration and the solvent is evaporated under reduced pressure. By distilling the residue, obtained 17g L-ethyl-2 a-aminométhylpyrrolidine, as oil (eb/20 mm: 60 - 61 °c), with efficiency of 65 percent.

The products prepared by the method of the invention provide an intermediate stage, for the manufacture of active ingredients usable, especially in the pharmaceutical industry and particularly in gastrointestinal gastroenterology, neurology and any other applications.