Note: Descriptions are shown in the official language in which they were submitted.
S 707-l 1 83-D6-0
Diastereomers
Description
Field of the invention
__ _________ ______
The present invention relates to new diastereomers and
to a new process to prepare them.
The diastereomers are useful as intermediates for the pre-
paration of pharmaceutically active compounds.
Prior Art
_ _ _ _ _ _ _ _ _
From UK Patent Specification No. 1 Z07 752 it is known
that l-ethyl-2-aminomethyl-pyrrolidine
CH2 -- CH2
H NCH -CH CH
2 2 \ / 2
N
C2H5
can be resolved in its two optical isomers with the aid of
optically active tartaric acid. D~-)-tartaric acid forms
a crystalline tartrate with the levorotatory amine while
L(~)-tartaric forms a crystalline tartrate with the dextro-
rotatory amine. The free amine is then obtained by dis-
solving the tartrate in water, rendering the medium
alkaline, extracting the amine and distilling it. The
method has poor reproducability when precipitating the
crude tartrate and results in low yields ~below 4D %).
Due to the fact that no recrystallization is made, but
instead a series o-F leachings, unsatisfactory purity in
the crude precipitate causes very time-consuming and
__; .
doub-tEul purification processes. The structure of the crystals in the crude
precipitate is of a kind that makes the reaction mixture very viscid and
difficult to filtrate.
Disclosure of the invention
The object of the present invention is to provide a method of re-
solving l-ethyl-2-aminomethylpyrrolidine without the inherent drawbacks of
the method at which tartaric acid is used, that is poor yield and optical
purity, poor reproducability3 lack of recryst~ tion and 1mg~n~y crystals.
The method according to the present invention involves resolution
of the optical isomers of 1-ethyl-2-aminomethylpyrrolidine by forming salts
with (-)-di-p-toluoyl-L-tartaric acid or with (~)-di p-toluoyl-D-tartaric
acid.
COOH
HC-O-CO ~ CH3 di-p-toluoyl-
HT-O-CO ~ CH3 tartaric acid
COOH
Thus, in one aspect the invention provides a process for the pre-
paration of a diastereomer selected from the group consisting of
the (~)-di-p-toluoyl-D-tartrate of levo l-ethyl-2-aminomethyl-
pyrrolidine,
the (-)-di--p-toluoyl-L-tartrate of dextro l-ethyl-2-aminomethyl-
pyrrolidine,
the (-)-di-p-toluoyl-L-tartrate of levo l-ethyl-2-aminomethyl-
pyrrolidine, and
the (~)-di-p-toluoyl-D-tàrtrate of dextro l-ethyl-2-aminomethyl-
pyrrolidine
which process comprises
(a) to obtain the (-)-di-p-toluoyl-L-tartrate of levo l-ethyl-2-
aminomethyl-pyrrolidine and the (-)-di-p-toluoyl-L-tartrate of dextro 1-
~I
\\
- 2a -
ethyl-2-aminomethyl-pyrrolidine, reacting, in a first step, racemic l-ethyl-
2-aminomethyl-pyrrolidine with (-)-di-p-to~uoyl-L-tart~ric dissolved ln
methanol and, in a second step, the obtained solution with water whereby
the (-)-di-p-toluoyl-L-tartrate of levo l-ethyl-2-aminomethyl-pyrrolidine
is crystallised and isolated, the (-)-di-p-toluoyl-L-tartrate of dextro
l-ethyl-2-aminomethyl-pyrrolidine rP~;n;ng in the mother liquor, or
(b) to obtain the (+)-di-p-toluoyl-D-tartrate of dextro l-ethyl-
2-~m;n: thyl-pyrrolidine and the (+)-di-p-toluoyl-D-tartrate of levo 1-
ethyl-2-aminomethyl-pyrrolidine, reacting, in a first step, racemir l-ethyl-
2-aminomethyl-pyrrolidine with (+)-di-p-toluoyl-D-tartaric acid dissolved
in methanol and, in a second step, the obtained solution with water whereby
the (+)-di-p-toluoyl D-tartra~e of dextro l-ethyl-2-aminomethyl-pyrrolidine
is crystallised and isolated, the (+)-di-p-toluoyl-D-tartrate of levo 1-
ethyl-2-aminomethyl-pyrrolidine rr~;n;nE in the mother liquor, or
(c) to obtain the (-)-di-p-toluoyl-L-tartrate of dextro l-ethyl-
2-aminomethyl-pyrrolidine and the (-)-di-p-toluoyl-L-tartrate of levo 1-
ethyl-2-aminomethyl-pyrrolidine, reacting racemic 1-ethyl-2-aminomethyl-
pyrrolidine with (-)-di-p-toluoyl-L-tartaric acid in pure methanol and
cryst~ll;z;ng and isolating the (-)-di-p-toluoyl-L-tartrate o dextro 1-
ethyl-2-aminomethyl-pyrrolidine, ollowed by addition of water to the mother
liquor to crystallize the (-)-di-p-toluoyl-L-tartrate of levo l-ethyl-2-
aminomethyl-pyrrolidine 9
(d) to obtain the (+)-di-p-toluoyl-D-tartrate of levo l-ethyl-2-
~m;n~ thyl-pyrrolidine and the (+)-di-p-toluoyl-D-tartrate of dextro
l-ethyl-2-aminomethyl-pyrrolidine, reacting racemic 1-ethyl-2 aminomethyl-
pyrrolidine with (+)-di-p-toluoyl-D-tartaric acid in pure methanol and
cryst~ll;z;ng and isolating the (+)-di-p-toluoyl-D-tartrate of levo l-ethyl-
2-aminomethyl-pyrrolidine, followed by addition of water to the mother liquor
to crystallize the (+)-di-p-toluoyl-D-tartrate of dextro l-ethyl-2-amino-
methyl-pyrrolidine.
~, O`;
- 2b -
Four different dias-tereomers are obtained according to the method
of the present invention. They are not previously disclosed in the
literature:
(+)-di-p-toluoyl-D-tartrate of levo l-ethyl-2-aminomethylpyrro-
lidine,
(-)-di-p-toluoyl-L-tartrate of dextro l-ethyl-2-aminomethyl-
pyrrolidine,
(-)-di-p-toluoyl-L-tartrate of levo l-ethyl-2-am-in~methyl-
pyrrolidine and,
~2~
(+)-di-p-toluoyl-D-tartrate of dextro l-ethyl-2-arninomethyl-
pyrrolidine.
The diastereomers can be prepared by direct precipitation
or by a two-step process.
A. Direct precipitation means that one diastereomer is
isolated as a crystalline salt while the other dia-
- stereomer remains dissolved in the mother liquor. The
~ 10 levorotatory amine is precipitated with levorotatory
di-p-toluoyl-L-tartaric acid in a solution of water/
methanol (preferable ratio l-1.2 v/v) and is isolated
while the dextrorotatory amine ~with (-)-di-p-toluoyl-
~; L-tartaric acid) remains in the mother liquor.
Correspondingly, dextrorotatory amine is precipitated
with dextrorotatory ~+)-di-p-toluoyl-D-tartaric acid
- and isolated while the levorotatory amine (with (~)-di-
-p-toluoyl-D-tartaric acid) remains in the mother
liquor.
B. In the two-step prooess the two diastereomers are
-~ isolated individually. nextrorotatory amine is preci-
pitated with levorotatory (-)-di-p-toluoyl-L-tartaric
acid in a solution of pure methanol and is then isolated.
By addition of water ~ratio water/methanol 1.~-1.5 (v/v)]
; to the methanol mother liquor a crystalline salt of
levorotatory amine and levorototory acid is obtained.
Correspondingly, levorotatory amine is precipitated
with dextrorotatory (~)-di-p-toluoyl-D-tartaric acid in
a solution o~ pure methanol and by treating the methanol
mother liquor with water a crystalline salt of dextro-
rotatory amine and dextrorotatory acid is obtained.
In Drder to obtain the optically active l-ethyl-2-
aminomethylpyrrolidine the corresponding diastereomer
is treated by conventional technique, that i5, the dia-
stereomer is dissolved in water, the medium is rendered
alkaline, the amine is extracted and distilled.
By using the method of the invention, the amine (-)-1-
ethyl-2-aminomethylpyrrolidine has been prepared to a
- purity of 96 ~ and in a yield of 85 % with (-)-di-p-
'~ 10 toluoyl-L-tartaric acid (monohydrate) in a two-step
process. Correspondingly (l)-l-ethyl-2-aminomethyl-
pyrrolidine has been prepared to a purity of 90 % and
in a yield of 85 %.
Optically purifications can be made by recrystallization
from pure methanol or from a mixture of methanol and water.
Best mode_of_carrying_out the _nvention
The following illustrates the principles and the adaptation
of the invention, however, without limiting it thereto.
Example 1. Preparation of ~-)-di-p-toluoyl-L-tartrate of
levorotatory l-ethyl-2-aminomethylpyrrolidine
(direct`method)
.;
( 60 g of (-)-di-p-toluoyl-L-tartaric acid ~monohydrate) is
dissolved in 300 ml of methanol in a 1 litre three-necked
oalloon flask provided with a mechanical agitator, a
thermometer and a-dropping funnel. lB.4 g of racemic
l-ethyl-2-aminomethylpyrrolidine is introduced during
15 minutes through the dropping funnel without the
temperature exceeding 30C. The transparent solution
is kept at 25C in 15 minutes, whereafter about 300 ml
of water is added during ca 30 minutes. Addition of seed
crystals at 20-25C initiates crystallization which con-
tinues at room temperature during 1 hour. Before filtra-
tion the suspension is cooled to 10C and the filtrate
~z~
is washed with 50 ml of ice-cooled water. Yield: 65 %.
Purity = 91,_%,,,(-)-amine.
Preparation of the salt of the dextrorotatory 1-ethyl-2-
aminomethyl is made in the same way as described above
by exchanging the levorotatory acid for the dextrorotatory
acid. Corresponding yield and purity is obtained.
, ~, Example 2. Preparation of ~-)-di-p-toluoyl-L-tartrate of
dextrorotatory and levorotatory 1-ethyl-2-
-aminomethylpyrrolidine (two-step process)
. 40 g of (-)-di-p-toluoyl-L-tartaric acid ~monohydrate~
is dissolved in 12û ml of methanol in a 250 ml three-
necked balloon flask provided with a mechanical agitator,
. a thermometer and a dropping funnel. 12.7 g of racemic
;! l-ethyl-2-aminomethylpyrrolidine is introduced with agita-
tion during 15 minutes through the dropping funnel without
,' the temperature exceeding 2DC. After addition of seed
crystals and cooling to 5-15~C salt of the dextrorotatory
amine precipitates. After crystallization for 2 hours 24 g
of ~-)-di-p-toluoyl-L-tartrate of dextrorotatory l-ethyl-
2-aminomethylFyrrolidine is obtained and washed with 10 ml
' ~ of ice-cooled methanol. Yield: 90 %. Purity = 90 % ~+)-
amine.
100 ml of water is added during 15 minutes to the mDther
liquor which is at room temperature. After addition of
j seed crystals at room temperature the salt of the levo-
rotatory amine precipitates. After crystallization for 2
hours ~1 hour at 20C and 1 hour at lDC) 21,9 g of ~-)-
-di-p-toluoyl-L-tartrate of levorotatory l-ethyl-2-
aminomethylpyrrolidine is obtained and washed with 10 ml
of ice-cooled water. Yield: 86 %. Purity = 96 % [-)-amine.
If [+)-di-p-toluoyl-D-tartaric acid [monohydrate) i5 used
the procedure is the same but the first salt isolated is
[+)-di-p-toluoyl-D-tartrate of levorotatory l-ethyl-2-
`; -aminomethylpyrrolidine and the second is (~)-di-p-
-toluoyl-D-tartrate of dextrorotatory l-ethyl-2-amino-
methylpyrrolidine.
Example 3. Recrystallization of (-)-di-p-toluoyl-L-
tartrate of levorotatory l-ethyl-2-aminomethyl-
pyrrolidine from methanol-water
,~ 15.7 g of the title compound (purity = 74 % ~-)-amine) is
; ` 10 dissolved with heating in 30 ml of methanol. At room
temperature 30 ml of water is then added to the three-
necked balloon flask through the dropping funnel. After
addition of seed crystals the title compound precipitate
and is filtered off at 10C after 2 hours and washed with
5 ml of water. Yield: 8~ %. Purity = 91 % (-~-amine.
., .
- (-)-di-p-toluoyl-L-tartrate of dextrorotatory l-ethyl-2-` -aminomethylpyrrolidine is recrystallized in the same
manner.
Example 4. Recrystallization of (+)-di-p-toluoyl-D-
; - -tartrate of levorotatory l-ethyl-2-amino-
methylpyrrolidine from methanol
15 g of the title compound (purity = o5 % (-)-amine) is
dissolved with heating in 35 ml of methanol. After addition
of seed crystals at 45-5nc the title compound precipitates
again and after a crystallization time of 1 hour it can be
filtered off at 10C and washed with 10 ml of ice-cooled
methanol. Yield: ao%. Purity = 96 % (-)-amine.
(-)-di-p-toluoyl-D-tartrate of dextrorotatory l-ethyl-2-
aminomethylpyrrolidine is recrystallized in the same manner.
- - .
