CS217999B2 - Method of making the 1-alkyl-2-aminomethylpyrrolidine - Google Patents

Abstract

It is an object of the invention to provide a alkyl-2-aminomethylpyrrolidines with alkyl a carbon atom of 1 to 5 carbon atoms the corresponding 1-alkyl-2-pyrrolidinone in the reaction with a lower trialkyloxonium fluoroborate and the 1-alkyl-2-nitromethylenepyrrolidine thus obtained reduced by catalytic hydration.

Description

The invention relates to a process for the preparation of 1-alkyl-2-aminomethylpyrrolidines.

Hitherto, 1-ethyl-2-amino-ethylpyrrolidine has been prepared by heating 1-ethyl-3-chloropiperidine in the form of hydrochloride with ammonia (see (U.S. Pat. No. 3,031,452). However, according to a known method, 1-ethyl-3- hydroxypiperidine, which is very difficult to isolate from the main product, is therefore not suitable for the production of intermediate products for the pharmaceutical industry where high purity compounds are required.

According to the invention, 1-alkyl-2-aminomethylpyrrolidines with high purity and good yield can be prepared without by-products, the starting material being very inexpensive.

The present invention provides a process for the preparation of 1-alkyl-1-aminomethyl-pyrrolidines of the general formula III wherein

Ri is the same as above with the lower straight chain trialkyloxonium fluoroborate of the formula

BFiO (R3) 3 where ·

R3 is straight chain alkyl of 1 to 5 carbon atoms, alkali metal alcoholate of 1 to 5 carbon atoms and nitrometharo, whereupon the resulting 1-alkyl-2-nitromethylene pyrrolidine of formula II is reduced

Wherein R 1 is the same as above, by catalytic hydrogenation.

where ¹

R 1 is an alkyl of 1 to 5 carbon atoms, characterized in that 1-alkyl-2-pyrrolidinone of the formula I is reacted

([}

The method according to the invention can be illustrated by the following scheme:

(1) BF ₄ O (R 3) 13 (2)! MORí

->

(ii) (ii) (iv) (tl)

Hz / catalysed hydrogenation of the catalyst

(3) CH 3 NO 2 kdei

R1 is an alkyl group having 1 to 5 carbon atoms,

R3 is a straight chain alkyl group of 1 to 5 carbon atoms,

R4 is an alkyl group having 1 to 5 carbon atoms,

M is an alkali metal atom.

In particular, the novel derivatives can be used for the synthesis of beosamides having antlemetic and central nervous system effects as described in U.S. Patent No. 3,342,826.

The 1-methyl-2-pyrrolidinone used as the starting material in the process of the invention may be prepared, for example, by the method disclosed in Chemical Abstracts, Vol. 54, p15510b (1960). 1-ethyl-2-pyrrolidinoin can be prepared as described in Chemical Abstracts, Vol. 53, p. 523f (1959), other starting materials can be produced in the same manner.

1-ethyl-2-pyrrolidinome can also be prepared by hydrogenation of 1-yl-2-pyrrolidinoin in the presence of a metal catalyst supporting catalytic catalyst by hydrogenation. The 1-vinyl-2-pyridinedinoin which is used as starting material in this reduction process can be prepared, for example, by the method disclosed in Chemical Abstracts, Vol. 56, 143015b (1960). This reduction process is carried out by hydrogenating 1-vinyl-2-pyrrolidime in the presence of a metal catalyst that promotes catalytic hydrogenation. Examples of metal catalysts supporting catalytic hydrogenation in the reduction of 1-vinyl-2-pyrrolidinone include powdered metal oxides, colloidal metals, supported metals and metals such as crystalline catalysts, where the metals are usually precious metals, transition metals and the like. A very frequently used catalyst is platinum black, rhodium on alumina, palladium on carbon and Raney nickel. The catalytic hydrogenation of 1-vimyl-2-pyrrolidinone is usually carried out in a solvent. Examples of suitable solvents include water, methanol, ethanol, isopropanol, butanol, tetrahydrofuran, dioxane, and other solvents inert to the reaction. These solvents may be used singly or in admixture. The initial hydrogen pressure of the reaction can be varied over a wide range from atmospheric pressure to high pressures, but generally, pressures from atmospheric pressure to several atmospheres are quite sufficient for a good reduction process. Preferably, the reaction is stopped when the theoretical amount of hydrogen is absorbed by suitably selecting the type and amount of catalyst, the initial hydrogen pressure, the reaction temperature, the duration of the reaction, and the like. The reaction product N-ethyl-2-pyrrolidinone may be isolated by removing the catalyst by filtration followed by evaporation of the solvent and, if desired, can be further purified. However, the reaction product can usually be used for the next reaction without purification.

The process according to the invention consists in reacting 1-alkyl-2-pyrrolidinone of the formula I with a lower-chain straight-chain trialkyl oxonium fluoroforonate, an alkali metal alkoxide and nitromethane to give a compound of the formula II. An example of an alkyl group in 1-alkyl-2-pyrrolidinone is methyl ethyl, propyl, isopropyl, butyl and the like.

The reaction of 1-alkyl-2-pyrrolidinome with a lower straight-chain trialkyl oxonium fluoroborate may be carried out in the presence or absence of a solvent. When the solvent is used, it is selected from the group of ethers, benzene, and the like. The reaction temperature may vary within wide limits, but is usually carried out at room temperature or at elevated temperature. The product so produced is likely to have the following structure:

(V) kdel / R1 and R3 are the same as above. The lower straight chain trialkyl Oxoniumfluorociboiride.n has the formula given in (ii) wherein R 3 is C 1 -C 5 alkyl with a straight chain such as methyl or ethyl.

The lower straight chain trialkyloxoniumfluorobciritan is usually prepared in situ. For example, it can be prepared by dropwise adding 1,2-epoxy-3-chloropropane to a solution of boron trifluoride in an ether of formula BFaO (R 3) 2, wherein R 3 is the same as above, at room temperature with stirring, then the resulting mixture is gently refluxed and then the ether is removed by alloying · which, when the lower straight chain tralkyloxonium fluoroboiritane already forms a wound precipitate, which is then washed with anhydrous ether. The reaction can be illustrated by the following equation:

And "CH _Z CH-CH _z + BF 4 ^ O (R _{3) 2} + 2 (R _{3) 2} O

- ₊ °

Bfy ORI ₃ J ₃

Cl ch ₂ ch-o r ₃ o-ch ₂ wherein R 3 is the same as above.

Usually, the above reaction is carried out in a solvent. Anhydrous ether, which can be used in a mixture of ¹ ' with other solvents such as anhydrous benzene, anhydrous dioxane and anhydrous dichlorethylene, is generally used as the reagent and also as the solvent.

As follows: the product compound of formula V is then reacted with an alkali metal ^1. By alkali metal alkoxide is meant a compound which is obtained by substituting an alkali metal such as sodium or potassium for a hydroxyl group in an alcohol such as methanol, ethanol, propanol, isopropanol or butainoh. The reaction is conveniently carried out in a solvent. A frequently used solvent is alcohol, but other solvents which are inert to the reaction components may also be used. The reaction temperature can be varied within a wide range, but the reaction is usually carried out under cooling, but not at elevated temperature at room temperature. The product thus obtained is likely to have the following structure:

where

R 1, R 3 and R 4 are the same as above.

(The compound of formula (VI) thus obtained can be isolated and purified, but can be used for the next reaction without isolation and purification.

The reaction of said compound with nitromethane is carried out in the presence or absence of a solvent. If a solvent is used, it is usually the solvent used in the previous step. The reaction temperature can be varied within wide limits, but usually the reaction mixture is cooled or operated at room temperature or heated.

The thus obtained 1-alkyl-2-nitromethylenopyrrolidolidine (II) can be isolated and purified, but can be subjected to reduction without isolation and without purification.

The reduction of the 1-alkyl-2-nitromethylenopyrrolidine of the formula II is carried out by treatment with hydrogen in the presence of a metal catalyst which promotes catalytic hydrogenation. Examples of metal catalysts that can be used to promote catalytic hydrogenation include powdered metal oxides, colloidal metals, supported metals, and metal catalysts in crystalline form, the metal usually being a precious metal, a transition metal, and the like.

Frequently used catalysts are, for example, platinum black, rhodium on alumina, palladium on carbon, and Raney nickel. The catalytic hydrogenation is usually carried out in a solvent. Examples of this solvent are water, methanol, ethanol, isopropanol, butanol, tetrahydrofuran, dioxane and other solvents which are inert to the reactants. These solvents may be used singly or in admixture. The initial hydrogen pressure used for the reaction can be varied over a wide range, from atmospheric pressure to high pressures, but atmospheric pressure or a few atmospheres pressure is usually sufficient for a good reduction process. It is preferred to stop the reaction when the theoretical amount of hydrogen has been absorbed by selecting the type and amount of catalyst, the initial hydrogen pressure, the reaction temperature, the duration of the reaction and the like. The reaction product of formula III can be isolated by removing the catalyst by filtration followed by evaporation of the solvent.

The thus obtained 1-alkyl-2-aminomethylpyrrolidine of formula III can be converted into salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and organic acids such as oxalic acid, tartaric acid, maleic acid or picric acid by conventional methods.

The following examples are provided to illustrate but not to limit the invention.

Example 1

a) Preparation of 1-ethyl-2-nitromethylenepyrrolidine (To a solution of 46.5 g of boron trifluoride compound and ether in 150 ml of anhydrous e217999 thera) was added dropwise 22.2 g of 1,2-epoxy-3-chloropropane at room temperature with stirring, and the resulting mixture was stirred at room temperature for 2 hours.

The ether was removed by decantation and the residue was washed several times with anhydrous ether. 2.2.6 g of 1-ethyl-2-pyrrolidinone was added dropwise to the triethyloxonium fluoroforonate thus obtained under ice-cooling. The resulting mixture was stirred at room temperature for 30 minutes and allowed to stand for 2 hours. The ether formed during the reaction is removed by decantation and the residue is added dropwise to a solution of 5.0 sodium in 100 ml of anhydrous ethanol under cooling. The resulting solution was stirred at the same temperature for 30 minutes and then treated with 18.0 g of nitromethane under ice-cooling. The resulting mixture was stirred at room temperature for 3 hours then allowed to stand overnight. Ethanol was removed by evaporation under reduced pressure and the residue was treated with water and then extracted with chloroform. The chloroform layer was dehydrated and evaporated under reduced pressure. The residue was washed with ether to yield

27.2 g l-ethyl-2-pyrrolidine ^and nitromethylenpyrro as crystals, mp 125-127 ° C.

Λmax EtOH λ 349 nm, (2-8.3 °).

For C7H12N2O2 calculated:

% H, 7.74;% N, 17.91;

found:

H, 7.85; N, 17.98.

bj Preparation of 1-ethyl-2-aminomethylpyrrolidine

To a solution of 23.4 g of 1-ethyl-2-nitromethylene pyrrolidine in 500 ml of methanol was added about 5 g of Raney nickel and the resulting mixture was hydrogenated at atmospheric pressure and at room temperature for 5 hours to absorb 4 molar equivalents of hydrogen. The reaction mixture was filtered to remove Raney nickel and the solvent was evaporated under reduced pressure. The residue was distilled to give 15.7 g of 1-ethyl-2-aminomethylpyrrolidine as an oil, bp 58-60 ° C at 20 mm Hg.

A single peak was detected by gas-liquid chromatography of this material and the infrared spectrum of this compound was identical to that of an authentic sample prepared by the method of US Patent No. 3031,452.

Example 2

a) Preparation of 1-methyl-2-nitromethylenepyrrolidine

To a solution of 91 g of the boron trifluoride compound and ether in 300 ml of anhydrous ether was added dropwise 44.5 g of 1,2-epoxy-3-chloropropane at room temperature with stirring, and the resulting mixture was stirred at room temperature for 2 hours. The ether was removed by decantation and the residue was washed several times with anhydrous ether. To the trietbyloixeinium trifluoroborate thus obtained was added dropwise 39.6 g of 1-methyl-2-pyrrolidinone under ice-cooling. The resulting mixture was stirred at room temperature for 30 minutes, then allowed to stand for 2 hours. The ether formed during the reaction is removed by decantation and the residue is added dropwise to a solution of 10 g of sodium in 200 ml of anhydrous ethanol under cooling.

The resulting solution was stirred at the same temperature for 30 minutes and then treated with 36.0 g of nitromethane under ice-cooling. The mixture was stirred at room temperature for 3 hours and allowed to stand overnight. Ethanol was evaporated under reduced pressure, the residue was mixed with water, and extracted with chloroform. The chloroform layer was dehydrated and evaporated under reduced pressure. The residue was washed with ether to give 44 g of 1-methyl-2-nitro-methylene-pyrrolidine as crystals, m.p. 154 ° C.

b) Preparation of 1-methyl-2-aminomethyl-pyrrolidine 1-methyl-1-nitromethylene-pyrrolidine in methanol was treated as described in Example 1b) to give 1-methyl-2-amino-methyl-pyrrolidine as an oil at 56 ° C under pressure 2397 Pa,

Claims (1)

A process for producing a l-alkyl-2-aminomethyl pyrrolidine of the formula III _-CH2-second where R 1 is C 1 -C 5 alkyl, characterized in that in the reaction of the -alkyl-2-pyrrolidinone of the formula I, a straight-chain alkyloxonium fluoroboiritane of the formula I is used. BF4O (R3) 3, wherein R3 is straight chain alkyl of 1 to 5 carbon atoms with an alkali metal alkoxide of 1 to 5 carbon atoms and mitromethane, whereupon the resulting 1-alkyl-2-nitromethylene pyrrolidine of formula II is reduced CHNO _of (II) fy (1) wherein R 1 is the same as above, catalytic hydrogenation. where Ri means the same as above with a lower tri-