Note: Descriptions are shown in the official language in which they were submitted.
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The present invention concerns a novel process for
the preparation of 2-aminomethyl-pyrrolidine (V) and the :.
synthesis intermediates.
The process of the invention comprises reacting 2-
pyrrolidone (I) with a reactive benzylated compound, then
reacting the resulting N-benzyl-2-pyrrolidone (II~ with a
lower alkyl sulphate, an alkaline alcoholate, and nitromethane, ~ -
to form N-benzyl-2-nitromethylene-pyrrolidine (III), which by
reduction results in N-benzyl-2-aminomethyl-pyrrolidine (IV),
then 2-aminomethyl-pyrrolidine (V).
The process of the invention can be illustrated by
the following diagram:
= 1- X-CH2~
(I) (II) :
(1) S04(Rl)2 ¦ ¦ ;
~, ~ ~=CHN02 ~ : :
(2) R20M CH2 ~ H2/catalyst
(3) CH3N02 (III) \=/
CH2 - NH21 ~ CH2 - NH2
CH2 ~ H
(IV) ~==~J , (V)
in which X is a reactive group or atom such as a halogen atom
or a tosyl group,
Rl is a lower alkyl group containing from 1 to 3
carbon atoms,
R2 iS an alkyl group,
M is an alkali metal.
~. ~
The following can be mentioned as examples of the
reactive benzylated compound used in the first stage of the
process: benzyl halides such as chloride, bromide or iodide,
or benzyl p-toluene sulphonate. The action oF these compounds
on pyrrolidone occurs in a solvent such as benzene, toluene or
xylene, in a basic medium such as an alkaline alcoholate.
In accordance with the process oF the invention, a
lower alkyl sulphate, an alkaline alcoholate and nitromethane
are reacted on N-benzyl-2-pyrrolidone (II) to produce compound
10 (III). The following can be mentioned as examples oF a lower
alkyl sulphate: dimethyl, diethyl, dipropyl or diisopropyl
sulphates. The alkali metal alcoholate is produced by the
action of an alcohol such as methanol, ethanol, propanol,
isopropanol, butanol, etc., on an alkali metal such as sodium
or potassium. ~
The product produced, having the formula: ~ .
l ;~`
O R 2
IH2~
Rl and R2 being as defined above, can be isolated and purified.
It can also be used for the following reaction, without being
isolated.
Reduction of N-benzyl-2-nitromethylene-pyrrolidine
(III) results in 2-aminomethyl-pyrrolidine (V) through the
intermediary of N-benzyl-2-aminomethyl-pyrrolidine (IV) which
can be isolated and purified.
In this latter case, reduction of the compound (III)
to the compound (IV) can be effected by chemical reduction by
means of metals such as iron or zinc, in the presence of acids
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such as hydrochloric or acetic acid, or by reduction by means
of hydrogen in the presence of catalysts such as Raney nickel,
palladium-bearing carbon, platinum black, etc. The hydrogen-
ation pressure used varies from atmospheric pressure to 150
atmospheres.
It is also possible to effect the reduction of N-
benzyl-2-nitromethylene-pyrrolidine (III) to 2-aminomethyl-
pyrrolidine (V) without isolating N-benzyl-2-aminomethyl-
pyrrolidine (IV).
Reduction is effected in an acid medium by hydrogen
in the presence of catalysts, as described above.
The 2-aminomethyl-pyrrolidine produced can be con-
verted into salts by the addition of a mineral acid such as
hydrochloric, hydrobromic or sulphuric acid, or an organic
acid such as oxalic acid, tartric acid, maleic acid, etc.
The process of the present invention has the
advantage of producing 2-aminomethyl-pyrrolidine from 2-
pyrrolidone, a widely available product at moderate cost, in `~
a reduced number of stages (three stages, or four stages if
the intermediate (IV) is isolated), in a very good yield andin a very high state of purity.
As 2-aminomethyl-pyrrolidine is used as an inter-
mediate in the synthesis of substances having attractive
pharmacodynamic properties, the purity criterion is here
essential.
The following examples illustrate the present
invention but without limiting it.
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EXAMPLE 1
2-aminomethyl-pyrrolidine
a) N-benzyl-2-pyrrolidone
138 g of sodium are introduced into a 6 litre
balloon flask containing 2,100 ml of ethanol. At the end of
the reaction, the mixture is cooled to from 15 to 20C and
510 9 of 2-pyrrolidone is introduced. After evaporation of
the alcohol under reduced pressure, 2,400 ml of xylene is
added. A part of the solvent is distilled in order completely
to remove the alcohol.
With the mixture at reflux temperature, 759 g of
benzyl chloride is introduced. After the reaction temperature
has been maintained for 8 hours at the reflux temperature, the ~ -
mixture is cooled and filtered. The solvent is distilled
under vacuum and after purification by distillation, 862 g of
N-benzyl-2-pyrrolidone is produced (yield: 82%; boiling point/
23 mm Hg: 148 to 150C).
b) N-benzyl-2-nitromethylene-pyrrolidine
875 g of N-benzyl-2-pyrrolidone and 630 9 of
dimethyl sulphate are introduced into a 6 litre balloon flask.
After this mixture has been heated for 1 1/2 hours at 65C,
followed by cooling to about 15C, the solution of 115 9 of
sodium in 3500 ml of methanol is introduced. The reaction
mixture is left with agitation for 30 minutes at ambient
temperature and then 460 g of nitromethane is added. Agitation
is maintained for 1 hour, then the solution is left at rest
for about 12 hours. The solvent is then evaporated under
vacuum.
After the addition of 800 ml of water to the residue,
crystallization, filtration of the crystals formed, washing
with water and drying in a drying oven at 50C, 764 9 of N-
~L~4~V~ :
benzyl-2-nitramethylene-pyrrolidine is produced (yield: 71%i
melting point: 99C).
c) 2-aminomethyl-pyrrolidine
Introduced into a 1 litre autoclave are 61 g of N- -
benzyl-2-nitromethylene-pyrrolidine, 300 ml of ethanol, hydro-
chloric ethanol in an amount sufficient for the number of
hydrochloric acid mols introduced to be double the number of ~ ;
nitromethylene-pyrrolidine, approximately 150 9 Raney nickel,
and hydrogen, until a pressure of 50 kg ;s produced. The
autoclave is left under agitation for 1 hour, then further
hydrogen is introduced until the pressure reaches 145 kg.
After the mixture has been heated for 5 hours at 100C,
followed by cooling and filtration of the nickel, the solvent
is evaporated to dryness at reduced pressure. The residue is
dissolved in 200 ml of methylene chloride, then 40% sodium
hydroxide and potassium hydroxide in pellet form are added.
After decantation, the organic phase is dried and .
filtered, and the solvent is evaporated.
Distillation is effected to produce 17 9 of 2-
aminomethyl-pyrrolidine (boiling point/32 mm Hg: 86 to 89C;
yield: 60.7%).
EXAMPLE 2
2-aminomethyl-pyrrolid1ne
.
a) identical to Example 1
b) identical to Example 1
c) N-benzyl-2-aminomethyl-pyrrolidine
Introduced into a 5 litre autoclave are 218 9 of N-
benzyl-2-nitromethylene-pyrrolidine, 900 ml of methanol, 120 9
of Raney nickel, and hydrogen, until the pressure reaches 40
kg. The autoclave is left under agitation for 1 1/2 hours.
The mixture is then cooled. After filtration, and washing of
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. .
,
. . . .
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the nickel with methanol, evaporation of the solvent and
distillation of the residue, 179 9 of N-benzyl-2-aminomethyl-
pyrrolidine is produced (yield: 94%; boiling point/7 mm Hg:
137 to 140C~.
d) 2-aminomethyl-pyrrolidine
Introduced into a 1 litre autoclave is 190 9 of N-
benzyl-2-aminomethyl-pyrrolidine, a solution of 160 ml of
hydrochloric acid (d = 1.18) in 140 ml of water and approxi- ;
mately 75 9 of Raney nickel, and hydrogen until a pressure of
10 130 kg is reached. The autoclave is agitated and then heated ;~ ~ -
to 100C. Further hydrogen is introduced until the pressure
reaches 100 kg, and the autoclave is left under agitation for
1 hour.
After cooling of the mixture, the nickel is filtered
and washed with water. The filtrate is evaporated to dryness
under reduced pressure, then the residue is dissolved in 500
ml of ethanol and the solution is neutralized by means of a
solution of 128 g of potassium hydroxide in pellet form, in
600 ml of ethyl alcohol.
AftPr filtration of the potassium chloride formed
and distillation of the solvent under vacuum, the residue is
dissolved in benzene. The benzene solution is dried and
filtered and the solvent is distilled under reduced pressure.
Distillation of the residue provides 78 9 of 2-aminomethyl-
pyrrolidine (yield: 78%i boiling point: 167 to 170C; purity
by gas chromatography: 97.6%).
