CA1210014A - Diastereomers of 1-ethyl-2-aminomethyl pyrrolidine - Google Patents
Diastereomers of 1-ethyl-2-aminomethyl pyrrolidineInfo
- Publication number
- CA1210014A CA1210014A CA000436420A CA436420A CA1210014A CA 1210014 A CA1210014 A CA 1210014A CA 000436420 A CA000436420 A CA 000436420A CA 436420 A CA436420 A CA 436420A CA 1210014 A CA1210014 A CA 1210014A
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- Canada
- Prior art keywords
- ethyl
- toluoyl
- pyrrolidine
- aminomethyl
- tartrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
Abstract New diastereomers (+)-di-p-toluoyl-D-tartrate of levo l-ethyl-2-aminomethyl-pyrrolidine, (-)-di-p-toluoyl-L-tartrate of dextro l-ethyl-2-amino-methylpyrrolidine, (-)-di-p-toluoyl-L-tartrate of levo l-ethyl-2-aminomethyl-pyrrolidine or (+)-di-p-toluoyl-D-tartrate of dextro l-ethyl-2-amino-methylpyrrolidine, and process for their preparation.
Description
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 H NCH -CH CH
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 H NCH -CH CH
2 2 \ / 2 N
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.
- - .
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.
- - .
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a diastereomer selected from the group consisting of the (+)-di-p-toluoyl-D-tartrate of levo 1-ethyl-2-aminomethyl-pyrrolidine, the (-)-di-p-toluoyl-L-tartrate of dextro 1-ethyl-2-aminomethyl-pyrrolidine, the (-)-di-p-toluoyl-L-tartrate of levo 1-ethyl-2-aminomethyl-pyrrolidine, and the (+)-di-p-toluoyl-D-tartrate of dextro 1-ethyl-2-aminomethyl-pyrrolidine which process comprises (a) to obtain the (-)-di-p-toluoyl-L-tartrate of levo 1-ethyl-2-aminomethyl-pyrrolidine and the (-)-di-p-toluoyl-L-tartrate of dextro 1-ethyl-2-aminomethyl-pyrrolidine, reacting, in a first step, racemic 1-ethyl-2-aminoethyl-pyrrolidine with (-)-di-p-toluoyl-L-tartaric acid dissolved in methanol and, in a second step, the obtained solution with water whereby the (-)-di-p-toluoyl-L-tartrate of levo 1-ethyl-2-aminomethyl-pyrrolidine is crystallised and isolated, the (-)-di-p-toluoyl-L-tartrate of dextro 1-ethyl-2-aminomethyl-pyrrolidine remaining in the mother liquor, or (b) to obtain the (+)-di-p-toluoyl-D-tartrate of dextro 1-ethyl-2-aminomethyl-pyrrolidine and the (+)-di-p-toluoyl-D-tartrate of levo 1-ethyl-2-aminomethyl-pyrrolidine, reacting, in a first step, racemic 1-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-tartrate of dextro 1-ethyl-2-aminomethyl-pyrrolidine is crystallised and isolated, the (+)-di-p-toluoyl-D-tartrate of levo 1-ethyl-2-aminomethyl-pyrrolidine remaining in the mother liquor, or (c) to obtain the (-)-di-p-toluoyl-L-tartrate of dextro 1-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 crystallizing and isolating the (-)-di-p-toluoyl-L-tartrate of dextro 1-ethyl-2-aminomethyl-pyrrolidine, followed by addition of water to the mother liquor to crystallize the (-)-di-p-toluoyl-L-tartrate of levo l-ethyl-2-aminomethyl-pyrrolidine, (d) to obtain the (+)-di-p-toluoyl-D-tartrate of levo l-ethyl-2-aminomethyl-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 crystallizing 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.
2. The (+)-di-p-toluoyl-D-tartrate of levo l-ethyl-2-aminomethyl-pyrrolidine, the (-)-di-p-toluoyl-L-tartrate of dextro l-ethyl-2-amino-methyl-pyrrolidine, the (-)-di-p-toluoyl-L-tartrate of levo l-ethyl-2-aminomethyl-pyrrolidine or the (+)-di-p-toluoyl-D-tartrate of dextro l-ethyl-2-aminomethyl-pyrrolidine when made by a process according to claim 1 or an obvious chemical equivalent thereof.
3. A process according to claim 1 which comprises the further step of splitting the di-p-toluoyl-tartaric acid moiety from an obtained diastereomer to obtain a substantially pure optical isomer of l-ethyl-2-aminomethyl-pyrrolidine.
4. A process according to claim 3 wherein the di-p-toluoyl-tartaric acid moiety is split from the diastereomer by dissolving the diastereomer in water, rendering the water alkaline, extracting the amine and distilling.
5. A process for resolving racemic l-ethyl-2-aminomethyl-pyrrolidine into its two optical isomers which comprises converting the l-ethyl-2-aminomethyl-pyrrolidine into a diastereomer by a process according to claim 1, separating a diastereomer containing one of the optical isomers and splitting off the di-p-toluoyl-tartaric acid moiety from the diastereomer to obtain an optical isomer of l-ethyl-2-aminomethyl-pyrrolidine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8205568-2 | 1982-09-30 | ||
| SE8205568A SE447991B (en) | 1982-09-30 | 1982-09-30 | DIASTEREOMERS OF DI-P-TOLUOYL TARTRATE WITH 1-ETHYL-2-AMINOMETHYLPYRROLIDINE AND PROCEDURE FOR PREPARING THESE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1210014A true CA1210014A (en) | 1986-08-19 |
Family
ID=20348031
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000436420A Expired CA1210014A (en) | 1982-09-30 | 1983-09-09 | Diastereomers of 1-ethyl-2-aminomethyl pyrrolidine |
Country Status (10)
| Country | Link |
|---|---|
| AT (1) | AT377980B (en) |
| CA (1) | CA1210014A (en) |
| DD (1) | DD210261A5 (en) |
| DK (1) | DK435283A (en) |
| ES (1) | ES526077A0 (en) |
| FI (1) | FI833512A (en) |
| HU (1) | HU189751B (en) |
| NO (1) | NO833439L (en) |
| SE (1) | SE447991B (en) |
| SU (1) | SU1240353A3 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5227526A (en) * | 1992-06-16 | 1993-07-13 | Mallinckrodt Specialty Chemicals Company | Resolution of 3-dimethylamino-2-methylpropiophenone (3-DAMP) |
| GB0217447D0 (en) * | 2002-07-29 | 2002-09-04 | Betts John A | Personal deodorant |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1528014A (en) * | 1967-04-24 | 1968-06-07 | Ile De France | Process for the preparation of optical isomers of ethyl-1, aminomethyl-2-pyrrolidine |
-
1982
- 1982-09-30 SE SE8205568A patent/SE447991B/en not_active IP Right Cessation
-
1983
- 1983-09-09 CA CA000436420A patent/CA1210014A/en not_active Expired
- 1983-09-23 DK DK435283A patent/DK435283A/en not_active Application Discontinuation
- 1983-09-23 NO NO833439A patent/NO833439L/en unknown
- 1983-09-28 DD DD83255190A patent/DD210261A5/en unknown
- 1983-09-29 ES ES526077A patent/ES526077A0/en active Granted
- 1983-09-29 HU HU833404A patent/HU189751B/en unknown
- 1983-09-29 SU SU833646754A patent/SU1240353A3/en active
- 1983-09-29 FI FI833512A patent/FI833512A/en not_active Application Discontinuation
- 1983-09-30 AT AT0347583A patent/AT377980B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FI833512A (en) | 1984-03-31 |
| DD210261A5 (en) | 1984-06-06 |
| ES8405370A1 (en) | 1984-06-01 |
| DK435283D0 (en) | 1983-09-23 |
| DK435283A (en) | 1984-03-31 |
| NO833439L (en) | 1984-04-02 |
| ATA347583A (en) | 1984-10-15 |
| AT377980B (en) | 1985-05-28 |
| SE447991B (en) | 1987-01-12 |
| SU1240353A3 (en) | 1986-06-23 |
| SE8205568D0 (en) | 1982-09-30 |
| HU189751B (en) | 1986-07-28 |
| ES526077A0 (en) | 1984-06-01 |
| FI833512A0 (en) | 1983-09-29 |
| SE8205568L (en) | 1984-03-31 |
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