IE43228B1

IE43228B1 - Heterocyclic aminoalcohols

Info

Publication number: IE43228B1
Application number: IE1165/76A
Authority: IE
Original assignee: Ile De France
Priority date: 1975-06-09
Filing date: 1976-06-01
Publication date: 1981-01-14
Also published as: BG24800A3; JPS6059227B2; RO69253A; FR2314177A1; IN141747B; SE410852B; DD125072A5; IE43228L; GB1499708A; CH614939A5; DK251876A; ZM6476A1; CA1077949A; GB1499707A; DE2623000A1; PH15172A; YU131076A; ATA399876A; MC1104A1; AU504920B2

Abstract

1499707 Aminoalcohols SOC D'ETUDES SCIENTIFIQUES ET INDUSTRIELLES DE L'ILE-DE-FRANCE 8 June 1976 [9 June 1975] 23694/76 Heading C2C Compounds of the general formula (R 1 = C 1-5 hydroxyalkyl; R 2 = H, C 1-3 alkyl; m = 1-3) and their acid addition and quaternary ammonium salts and N-oxides are prepared by reacting the corresponding 2-one (in which the hydroxy group may be acylated) with a dialkyl sulphate, alkali metal alkoxide and primary C 1-4 nitroalkane and reducing the resulting N - hydroxyalkyl - 2 - nitromethylene derivative, optionally followed by salt formation and/or resolution.

Description

The present invention provides substituted heterocyclic N-alkanolamines of general formula R NH -CH (IV) in which R^ is a . hydroxyalkyl group, Rj is a hydrogen atom or a straight or branched alkyl group with 1 to 3 carbon atoms, (i.e. methyl, ethyl, propyl or isopropyl), and m is 1, 2 or 3, their addition salts with pharmacologic ally acceptable acids, their quaternary ammonium salts and their N-oxides, including the dextrorotatory and laevorotatory isomers of such compounds.

In accordance with the present invention, these amines are prepared by reacting a compound of formula; ί ί in which m is 1, 2 or 3 and Rg is hydroxyalkyl or acyloxyilkyl, in the reaction scheme below with a C-|__5 alkyl sulphate, an alkali metal alcoholate and a primary u'.troalkane to give a heterocyclic 2-nitromethylene Nilkanolamine (III), and reducing the latter. Compounds 432 28 of formula (III) are claimed, in Patent Specification No. 43229 The reaction scheme of course shows specific reagents, to the use of which the invention is not limited: i 1 K (Cil3}2S04 I C=0 2. CH-CH--ONa 3 2 CH -CH2-OH OCH N ' OC_H_ ι 2 5 CH2-CH2-OH Ch2-nh2 CH2-CH2-OH (IX) (IV) Dimethyl sulphate, diethyl sulphate, dipropyl sulphate and diisopropyl sulphate may be mentioned as examples of alkyl sulphates used to obtain the compound II.

The alkali metal alcoholate is formed in known manner by reacting an alcohol such as methanol, ethanol, propanol, isopropanol or butanol with an alkali metal such as sodium or potassium.

The final reduction step may be carried out by means of a metal such as iron or zinc, in the presence of an acid such as hydrochloric or acetic acid, or by reduction by hydrogen in the presence of a catalyst such as Raney nickel, palladium on charcoal, or platinum black. The hydrogenation pressure varies from atmospheric to 150 atmospheres.

In the example shown above intermediate product (II) may be isolated and purified. It may also be used for the 20 subsequent reaction without being isolated. - 3 3 2 28 The compounds of the invention may be reacted with pharmacologically acceptable mineral or organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, oxalic acid, acetic acid, tartaric acid, citric acid, or methanesulphonic acid, in order to give acid-addition, salts.

They may also be reacted with alkyl halides or sulphates to give quaternary ammonium salts.

The compounds may be resolved into their d and 1. isomers by formation of salts with optically active acids and selective crystallisation in known manner.

The compounds of the invention are intermediate compounds in the synthesis of substances possessing valuable therapeutic properties.

The following Examples are presented in order to illustrate the technical characteristics of the present invention.

Example 1 3-(2-hydroxyethyl)-2-aminomethyl-pyrrolidine Stage 1: N-(2-hydroxyethyl)-2-nitromethylene-pyrrolidine 264 g of N-(2-acetoxyethyl)-2-pyrrolidinone was placed Ln a 3-litre flask and 194 g of dimethyl sulphate added drop iy drop. The solution obtained was heated at 6O-63°C for .¾ hours. The solution was cooled and a solution of sodium ;thoxide (formed from 35.5 g of sodium) in absolute ethyl ilcohol (1080 ml) was added at a temperature of 15°C. The lixture was itirred for 1 hour and 141 g of nitromethane :hen added. The reaction mixture was then heated for 5 tours at the reflux temperature.

The sodium methyl sulphate was filtered off and the alcohol and ethyl acetate were then evaporated off.

The precipitate formed hy adding- chloroform was filtered off; after evaporation of the solvent an oil was obtained. This was dissolved in 450 ml of dioxane. The crystals obtained were filtered, washed and dried. 132.6 g of N-(2-hydroxyethyl)-2-nitromethylene-pyrrolidine was obtained (melting point 123-124°c)Stage 2: N-(2-hydroxyethyl)-2-aminomethyl-pyrrolidine 146 g of H-(2-hydroxyethyl)-2-nitromethylene-pyrrolidine, 350 ml of methyl alcohol and 45 g of Raney nickel were placed in a 1-litre autoclave. Reduction was carried out under 50 kg of hydrogen pressure. Absorption began in the cold and was complete after 15 minutes (final temperature 5O-6O°C). After cooling, the nickel was suction filtered and washed with alcohol. The solvent was evaporated and the residue was distilled in vacuo. g of N-(2-hydroxyethyl)-2-aminomethyl-pyrrolidine was obtained.

(Yield 73%, b.p. 10 mm/Hg = 134°C; n^0 = 1.4975).

Example 2 N - (3-hydroxypropyl)-2-aminome Lhyl-pyrrolidine Stage 1: N-(3-hydroxypropyl)-2-nitromethylene-pyrrolidine, 289 g of N-(3-acetoxypropyl)-2-pyrrolidinone was placed in a 2-litre cask and 185.6 g of dimethyl sulphate added drop by drop. The mixture was heated for 3¾ hours at 6O-65°C. After cooling, a solution of sodium propoxide formed from 35.7 g of sodium in propyl alcohol (850 ml) was added at a temperature of 12°C and the mixture was stirred 228 for 1 hour. After addition of 141.3 g of nitromethane and heating for 4 hours at 5O-55°C, the resulting precipitate of sodium me thylsulphate was filtered off and the solvents (propyl alee hoi and propyl acetate) were evaporated off. 1700 n1 of chloroform was added and the mixture was filtered. The oil obtained after evaporation of the chloroform was dissolved in 500 ml of methyl isobutyl ketone.

After crystallisation, the precipitate was filtered, washed with methyl isobutyl ketone, and dried. 147 g of N-(3-hydroxypropyl)-2-nitromethylene-pyrrolidine was obtained (m.p. 63°C).

Stage 2: N-(3-hydroxypropyl)-2-aminomethyl-pyrrolidine The N-(3-hydroxypropyl)-2-nitromethylene-pyrrolidine, 350 ml of methanol and 45 g of Raney nickel were placed in a 5-litre autoclave. The autoclave was flushed out 4 times with nitrogen and reduction was then carried out under a hydrogen pressure of 50 kg at 55°C. After 4 hours, fresh lydrogen was added to bring the pressure to 50 kg, and lydrogenation was continued for a further 4 hours.

After filtration of the mixture, the alcohol was evaporated off and the product obtained was distilled in racuo. 94 g of N-(3-hydroxypropyl)-2-aminomethyl-pyrrolidine zns obtained (Yield 79. i%? b.p. 14 mm/Hg = 146-15O°C; ij = 1.4915). Purit- by quantitative determination in ι non-aqueous medium with HClO^j 89.9%.

The N-(3-acetoxypr:>pyl)-2-pyrrolidinone, which serves ,s starting material, was prepared as follows: 208 g of N-(3-hydroxypropyl)-2-pyrrolidinone and 22 g of acetic anhydride were placed in a 1-litre flask. 3 228 The tempera!are of the medium was raised to 30°C. 0.5 ml of 95% concentrated sulphuric acid was added and the mixture was carefully heated c>n a water bath and then at 150°C for two hours. After cooling, 1.6 g of sodium acetate was added and 259.5 g of N-(3-acetoxypropyl)-2-pyrrolidinone Obtained by distillation in vacuo (Yield 96.4%, b.p. 12 mm/Hg = 165-170°C).

Claims

1. CLAIMS:1. Compounds of the general formula: (CH ) , 2 m H 2 N-CH 'N' l R. in which R^ is a C^ hydroxyalkyl group, R 2 is a hydrogen atom or a straight or branched alkyl group with 1 to 3 carbon atoms, and mis i, 2 or 3; their addition salts with pharmacologically acceptable acids, their quaternary ammonium salts ahd their N-oxides, including the dextrorotatory and laevoratatory isomers of such compounds.

2. N- (2-hydroxyethyl)-2-aminomethyl-pyrrolidine *

3. N-(3-hydroxypropyl)-2-aminomethyl-pyrrolidine.

4. A method of preparing a compound as claimed in Claim 1, that comprises reducing a compound of formula: (CH ) 2 m o 2 n-c. Ln which R^, R 2 and m are as defined in Claim 1.

5. A method of preparing the compound claimed in Haim 2, that comprises reducing N-(2-hydroxyethyl)-2litromethylene-pyrrolidine.

6. A method of preparing the compound claimed in :laim 3, that comprises reducing N-(3-hydroxypropyl)-2litromethylene-pyrrolidine.

7. A method as claimed in Claim 4, including the itep of preparing the starting material by a method as - 8 4 3 2 2 8 claimed in Claim 4 of Patent Specification No. 43229.

8. A method as claimed in Claim 5, including the step of preparing the starting material by a method as claimed in Claim 5 of Patent Specification No. 43229. 5

9. A method as claimed in Claim 6, including the step of preparing the starting material by a method as claimed in Claim 6 of Patent Specification No. 43229.

10. A method as claimed in Claim 7, substantially as hereinbefore described in Example 1 or 2. 10

11. A method as claimed in Claim 4, substantially as hereinbefore described in Example 1 or 2.

12. A compound as claimed in Claim 1 when prepared by a method as claimed in any one of Claims 7 to 11.