MC1059A1 - NEW PROCESS FOR THE PREPARATION OF 2-AMINOMETHYL PYRROLIDINE - Google Patents

Description

IBilSM.

PATENT FOR INVENTION

Filed by the public limited company known as: SOCIETE D'ETUDES SCIENTIFIQUES ET INDUSTRIELLES

FROM ILE-DE-FRANCE

Subject: NEW PROCESS FOR PREPARING 2-AMINOMETHYL PYRROLIDINE

French application priority: No. 74/07342, filed on March 4, 1974

The present invention relates to a new process for preparing 2-aminomethyl pyrrolidine (V) and synthetic intermediates.

The process for preparing the invention consists of reacting 2-pyrrolidone (I) with a reactive benzyl compound, then reacting the N-benzyl 2-pyrrolidine (II) obtained with a lower alkyl sulfate, an alkali alkoxide, nitromethane, to form N-benzyl 2-nitromethylene pyrrolidin (III), which by reduction leads to N-benzyl 2-aminomethyl pyrrolidine (IV) and then to 2-aminomethyl pyrrolidine (V).

2

10

The process according to the invention can be illustrated by the following diagram:

N/

H

(I)

-0 + X-CH

/ \

N.

CH.

(II)

o

~SD

(I) S04 (RI)2

(2) R20M

(3) CH NO £5 5 2

N

CH2 - NH2

CH,

N,

CH,

. CHNO,

/ \

(III)

/

N

H

H2 / catalysis ch2 - NH2

(IV) (V)

35 where X is an atom or a reactive group such as a logogen atom or a tosyl group,

R-j- is a lower alkyl group comprising (l) carbon atoms,

R2 is an alkyl group,

30M is an alkali metal.

Examples of reactive benzyl compounds used in the first phase of the process include benzyl halides such as benzyl chloride, bromide, iodide, or benzyl p-toluene sulfonate. The reaction of these compounds with pyrrolidinone occurs in a solvent such as benzene, toluene, or xylene, or in a basic medium such as an alkali metal.

According to the process of the invention, a lower alkyl sulfate, an alkali alkoxide, nitromethane are reacted with N-benzyl 2-pyrrolidone (il) to obtain compound (III).

10. As an example of a lower alkyl sulfate, we can cite dimethyl, diethyl, dipropyl, and diisopropyl sulfate. Alkali metal alkoxide is obtained by the oxidation of an alcohol such as methanol, ethanol, propanol, isopropanol, butanol, etc., with an alkali metal such as sodium or potassium.

15 The product obtained from formula

20

R1 and R2, having the aforementioned meanings, can be isolated and purified. It can also be used for the following reaction 25 without being isolated.

The reduction of N-benzyl 2-nitromethylenepyrrolidine (III) leads to 2-aminomethylpyrrolidine (v) via N-benzyl 2-aminomethylpyrrolidine (IV) which can be isolated and purified.

50 In the latter case, the reduction of the compound (llï) into

(IV) can be obtained by chemical reduction using metals such as iron, zinc, in the presence of aides such as hydrochloric or acetic, or by reduction with hydrogen in the presence of catalysts such as Eaney nickel, palladium carbon, platinum black 55 etc... The hydrogenation pressure used varies from atmospheric pressure to 150 atmospheres.

It is also possible to reduce N-benzyl 2-nitromethylene pyrrolidine (III) to 2-aminomethyl pyrrolidine (V) without isolating the N-benzyl 2-aminomethyl pyrrolidine. The reduction is carried out in an acidic medium with hydrochloric acid.

gene in the presence of catalysts, as described above.

The 2-aminomethylpyrrolidine obtained can be transformed into salts by the addition of mineral acid such as hydrochloric, 5-hydrobromic, sulfuric, or an organic acid such as oxalic acid, tartaric acid, maleic acid, etc.

The process of the present invention has the advantage of producing 2-arainoraethylpyrrolidine from 2-pyrrolidone, a very common and inexpensive product, in a reduced number of steps (j5, or 4 if the intermediate (IV) is isolated) with a very good yield and very high purity.

Since 2-aminomethylpyrrolidine is used as an intermediate in the synthesis of substances with interesting pharmacodynamic properties, the purity criterion is essential here.

The following examples illustrate, but are not limited to, the present invention.

EXAMPLE"!

2-amlnomethyl pyrrolidine 20 a) N-benzyl 2-pyrrolidone

In a 6-liter flask containing 2100 mL of ethanol, 138 g of sodium were introduced. At the end of the reaction, the mixture was cooled to 15–20°C and 510 g of 2-pyrrolidone were added. After evaporation of the alcohol under reduced pressure, 2400 mL of xylene were added. A portion of the solvent was distilled to completely remove the alcohol.

With the mixture at reflux temperature, 759 g of benzyl chloride were added. After maintaining the reaction temperature at reflux for eight hours, the mixture was cooled and filtered. The solvent was distilled under vacuum, and after purification by distillation, 862 g of N-benzyl 2-pyrrolidone were obtained (yield 82 g; Eb/23 mm Hg = 148–1500 °C).

b) N-benzyl 2-nitromethylene pyrroididine -35 875 g of

N-benzyl 2-pyrrolidone and 630 g of dl-methyl sulfate. After heating this mixture for one and a half hours at 650°C, then cooling it to around 15°C, a solution of 115 g of sodium in 3500 ml of methanol was added. The reaction mixture was left under 40°C stirring for thirty minutes at room temperature, then 460 g of

nitromethane was added. After stirring was maintained for one hour, the solution was left to stand for approximately twelve hours, and then the solvent was evaporated under vacuum.

After adding 800 ml of water to the residue, crystallization, filtration of the crystals formed, washing with water and drying in an oven at 50°C, 764 g of N-benzyl 2-nitromethylene pyrrolidine were obtained, (yield 71; PF = 99°C).

c) 2-aminomethyl pyrrolidine

In a 1-liter autoclave, 61 g of 10N-benzyl-2-nitromethylenepyrrolidine, 3500 mL of ethanol, hydrochloric ethanol in sufficient quantity so that the number of moles of hydrochloric acid introduced was twice that of nitromethylenepyrrolidine, approximately 150 g of Raney nickel, and hydrogen were added until a pressure of 50 kg was reached. The autoclave was left under agitation for one hour, then hydrogen was added again until a pressure of 145 kg was reached. After heating the mixture for five hours at 100°C, cooling, and filtering out the nickel, the solvent was evaporated to dryness under reduced pressure. The residue was dissolved in 200 mL of methyl 20 chloride, then sodium hydroxide (40°F) and potassium hydroxide pellets were added.

After decantation, the organic phase was dried and filtered; the solvent was evaporated.

By distillation, 17 g of 2-aminomethyl pyrrolidine were obtained (Eb/32 mm Hg = 86 - 89° C; yield 60.7%).

EXAMPLE 2 2-amnomethyl pyrrolidine a) identical to example 1.

b) identical to example 1.

30 c) N-benzyl 2-amlnomethyl pyrrolidine

In a 5-liter autoclave, 218 g of N-benzyl 2-nitromethylene pyrrolidine, 900 ml of methanol, 120 g of Raney nickel, and hydrogen were introduced until a pressure of 40 kg was obtained. The autoclave was left under agitation for one hour and 35 ml; the mixture was then cooled; after filtration and washing of the nickel with methanol, evaporation of the solvent, and distillation of the residue, 179 g of N-benzyl 2-amnomethyl pyrrolidine were obtained (yield 94 g; Eb/7 mm Hg = 137-140°C).

d) 2-aminomethyl pyrrolidine

40. 190 g of

N-benzyl 2-aminomethyl pyrrolidine, a solution of 160 mL of hydrochloric acid (d = 1.18) in 140 mL of water, and approximately 75 g of Raney nickel, and hydrogen were added until a pressure of 1350 kg was reached. The autoclave was agitated and then heated to 100°C. Hydrogen was added again until a pressure of 100 kg was reached, and the autoclave was left agitated for one hour.

washed with water. The filtrate was evaporated to dryness under reduced pressure, then the residue was dissolved in 500 ml of ethanol and solution 10 was neutralized by a solution of 128 g of potassium hydroxide pellets in 600 ml of ethyl alcohol.

After solvent extraction under vacuum, the residue was dissolved in benzene. The benzene solution was dried and filtered, and the solvent was distilled under reduced pressure. Distillation of the residue yielded 78 g of 2-aminomethylpyrrolidine (yield 78 g; Eb. = 167 - 170°C; purity by vapor chromatography).

After the mixture cooled, the nickel was filtered out.

After filtration of the potassium chloride formed, distill-

£17.6).

Claims (1)

CLAIM NEW PREPARATION PROCESS PB 2-AMINOMETHYL PYRROLIDINE with the formula: I H ch2nh2 10 of its addition salts with mineral or organic acids, characterized in that 2-pyrrolidone is reacted with a reactive benzyl compound of formula X-CH in which X represents a reactive atom or group such as a halogen atom or a tosyl group, and in that the N-benzyl 2-pyrrolidone formed is treated with a lower alkyl sulfate, an alkali alkoxide, nitromethane, and in that the N-benzyl 2-nitromethylene pyrrolidine obtained is reduced to 2-aminomethyl pyrrolidine, either directly by catalytic reduction, or via N-benzyl 2-aminomethyl pyrrolidine by chemical or catalytic reduction, which may or may not be isolated and which is subsequently reduced to form N-benzyl 2-aminomethyl pyrrolidine. moH OuC, nor !?company defends Scieritifiqt o o çes\\jo\s ni y Scientists and Industrialists of Île-de-France The Representative J. EPUEOAN