WO2009080708A1 - Use of enantiopure n-sulphonyl pyroglutamic acid as resolving agent - Google Patents

Use of enantiopure n-sulphonyl pyroglutamic acid as resolving agent Download PDF

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Publication number
WO2009080708A1
WO2009080708A1 PCT/EP2008/067910 EP2008067910W WO2009080708A1 WO 2009080708 A1 WO2009080708 A1 WO 2009080708A1 EP 2008067910 W EP2008067910 W EP 2008067910W WO 2009080708 A1 WO2009080708 A1 WO 2009080708A1
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WO
WIPO (PCT)
Prior art keywords
sulphonyl
enantiopure
pyroglutamic acid
use according
enantiomers
Prior art date
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PCT/EP2008/067910
Other languages
French (fr)
Inventor
Roland Callens
Ronan Gire
Cyrille Pousset
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Solvay (Société Anonyme)
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Publication of WO2009080708A1 publication Critical patent/WO2009080708A1/en

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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
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds

Definitions

  • the invention relates to use of an enantiopure compound and to a process for the manufacture of an enantiopure compound.
  • Drugs of the Future 2006 31(4) p. 314-319 describes optical resolution of 2-(aminomethyl)-3 ,4-dihydro-2H- 1 -benzopyrane with N-tosyl(L)-proline.
  • the present invention makes available a process which makes possible the manufacture of enantiopure compounds, in particular of enantiopure amino alcohols or ersters, in an economic way, in particular as regards the yields and optical purities of enantiopure compounds and the overall economics of the process.
  • the invention concerns in consequence the use of enantiopure N-sulphonyl pyroglutamic acid as resolving agent for the separation of enantiomers by crystallization or precipitation.
  • enantiopure is intended to denote a chiral compound essentially composed of one enantiomer.
  • Use is generally made of an enantiopure N-sulphonyl pyroglutamic acid having an enantiomeric excess of greater than or equal to 99 %. Preference is given to an enantiopure resolving agents having an enantiomeric excess of greater than or equal to 99.5 %.
  • the N-sulphonyl group is an alkylsulphonyl or arylsulphonyl group, preferably an arylsulphonyl group.
  • the p-toluenesulphonyl group is more particularly preferred.
  • the enantiopure N-sulphonyl pyroglutamic acid has (S)-conf ⁇ guration. In another embodiment, the enantiopure N-sulphonyl pyroglutamic acid has (R)-configuration.
  • the enantiopure N-sulphonyl pyroglutamic acid can be used for example for separation of enantiomers of a compound comprising a primary or secondary amino group. In one preferred embodiment, such compound is an aminoalcohol. In another preferred embodiment, such compound is an amino ester.
  • the enantiopure N-sulphonyl pyroglutamic acid is generally used for separation of enantiomers from a, for example racemic, mixture of enantiomers.
  • the quantity of enantiopure N-sulphonyl pyroglutamic acid used is generally from 1 to 3, preferably from 1 to 2 molar equivalents relative to the desired enantiomer. If appropriate, the enantiopure N-sulphonyl pyroglutamic acid can be partly replaced by a achiral carboxylic acid, e.g. formic acid. In that case, the quantity of enantiopure N-sulphonyl pyroglutamic acid used is at least 1 molar equivalents relative to the desired enantiomer.
  • the enantiopure N-sulphonyl pyroglutamic is generally dissolved in a polar organic solvent.
  • polar organic solvents include esters such as ethyl acetate, alcohols such as isopropanol and nitriles such as acetonitrile.
  • the N-sulphonyl pyroglutamic acid is manufactured by cyclization of N-sulphonyl glutamic acid in a reaction medium and is used as resolving agent without isolation from the reaction medium of the cyclization.
  • the invention also relates to a process for the manufacture of an enantiopure compound comprising the use according to the invention, in particular a process for the manufacture of an enantiopure compound capable of forming a diastereomeric salt or a diastereomeric complex with a N-sulphonyl pyroglutamic acid, starting from a mixture of enantiomers of the said compound, which comprises (a) providing a solution comprising an enantiopure N-sulphonyl pyroglutamic acid in accordance with the use according to the invention and the mixture of enantiomers of the said compound and (b) crystallizing or precipitating from said solution a diastereomeric salt or a diastereomeric complex of said compound with the N-sulphonyl pyroglutamic acid enriched in one of the enantiomers of said compound.
  • the process according to the invention makes it possible to obtain good results for the preparation of enantiomers of an enantiopure compound capable of forming a diastereomeric salt or a diastereomeric complex with a N-sulphonyl pyroglutamic acid.
  • the process according to the invention is particularly economical, as high crystallization/precipitation yields can be obtained.
  • initiation is carried out by cooling the solution.
  • initiation is carried out by introducing a seed material into the solution.
  • crystallization or precipitation is initiated by modifying the composition of the solution e.g. by adding a solvent.
  • the process according to the invention often further comprises recovering the crystallized or precipitated diastereomeric salt or diastereomeric complex and optionally recrystallizing it.
  • the enantiopure compound can be liberated from the crystallized or precipitated diastereomeric salt or diastereomeric complex by treatment with a strong acid such as a mineral acid e.g. aqueous HCl.
  • a strong acid such as a mineral acid e.g. aqueous HCl.
  • Diisopropyl urea DIU was then filtered and salts were washed with 6 eq. of acetonitrile.
  • the quantity of Pip-EtOH (Piperidine-2-ethanol) to introduce.
  • the salt's resolution was achieved with a ratio of 0.5 eq. pTos GIp-OH to 1 eq. of PipEtOH.
  • 1 eq of Piperidine-2-ethanol was dissolved in 25 eq of CH3CN and mixed with the pTos-Glu-OH solution at room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Use of enantiopure N-sulphonyl pyroglutamic acid as resolving agent for the separation of enantiomers by crystallization or precipitation.

Description

USE OF ENANTIOPURE N-SULPHONYL PYROGLUTAMIC ACID AS
RESOLVING AGENT
The invention relates to use of an enantiopure compound and to a process for the manufacture of an enantiopure compound.
The production of enantiopure compounds is a matter of great importance in the pharmaceutical, chemical and biotechnology industries. This is because the two enantiomers of a chemical substance with an identical constitution can have radically different biological activities.
WO-A-2005/023838 in the name of the applicants describes separation of enantiomers by derivatization with activated N-protected aminoacids. This process gives good results but requires a chemical reaction to liberate the separated enantiomer.
Drugs of the Future 2006 31(4) p. 314-319 describes optical resolution of 2-(aminomethyl)-3 ,4-dihydro-2H- 1 -benzopyrane with N-tosyl(L)-proline.
The present invention makes available a process which makes possible the manufacture of enantiopure compounds, in particular of enantiopure amino alcohols or ersters, in an economic way, in particular as regards the yields and optical purities of enantiopure compounds and the overall economics of the process.
The invention concerns in consequence the use of enantiopure N-sulphonyl pyroglutamic acid as resolving agent for the separation of enantiomers by crystallization or precipitation.
It has been found that enantiopure N-sulphonyl pyroglutamic acid can be used as efficient resolving agent
The term "enantiopure" is intended to denote a chiral compound essentially composed of one enantiomer. The enantiomeric excess (ee) is defined : ee (%) = 100(xi -X2V(Xi-X2) with xi>x2; X1 and x2 represent the content of enantiomer 1 or 2 respectively in the mixture.
Use is generally made of an enantiopure N-sulphonyl pyroglutamic acid having an enantiomeric excess of greater than or equal to 99 %. Preference is given to an enantiopure resolving agents having an enantiomeric excess of greater than or equal to 99.5 %.
In the use according to the invention the N-sulphonyl group, is an alkylsulphonyl or arylsulphonyl group, preferably an arylsulphonyl group. The p-toluenesulphonyl group is more particularly preferred.
In a preferred embodiment, the enantiopure N-sulphonyl pyroglutamic acid has (S)-confϊguration. In another embodiment, the enantiopure N-sulphonyl pyroglutamic acid has (R)-configuration. The enantiopure N-sulphonyl pyroglutamic acid can be used for example for separation of enantiomers of a compound comprising a primary or secondary amino group. In one preferred embodiment, such compound is an aminoalcohol. In another preferred embodiment, such compound is an amino ester.
Specific examples of compounds which have been separated involving the use according to the invention include enantiomers of Methyl 2-(piperidyl)- acetate, enantiomers of piperidine-2-ethanol, enantiomers of 3-amino-3- phenylpropan-1-ol and 2-amino-butane-l-ol.
In the use according to the invention the enantiopure N-sulphonyl pyroglutamic acid is generally used for separation of enantiomers from a, for example racemic, mixture of enantiomers.
The quantity of enantiopure N-sulphonyl pyroglutamic acid used is generally from 1 to 3, preferably from 1 to 2 molar equivalents relative to the desired enantiomer. If appropriate, the enantiopure N-sulphonyl pyroglutamic acid can be partly replaced by a achiral carboxylic acid, e.g. formic acid. In that case, the quantity of enantiopure N-sulphonyl pyroglutamic acid used is at least 1 molar equivalents relative to the desired enantiomer.
In the use according to anyone of claims, the enantiopure N-sulphonyl pyroglutamic is generally dissolved in a polar organic solvent. Examples of polar organic solvents include esters such as ethyl acetate, alcohols such as isopropanol and nitriles such as acetonitrile.
Particularly efficient examples of separation with N-p-toluenesulphonyl pyroglutamic acid are given hereafter (compound/solvent) : Methyl 2-(piperidyl)-acetate/isopropanol piperidine-2-ethanol/acetonitrile 3-amino-3-phenylpropan-l-ol/water saturated ethyl acetate+isopropanol.
In one particular embodiment, the N-sulphonyl pyroglutamic acid is manufactured by cyclization of N-sulphonyl glutamic acid in a reaction medium and is used as resolving agent without isolation from the reaction medium of the cyclization. The invention also relates to a process for the manufacture of an enantiopure compound comprising the use according to the invention, in particular a process for the manufacture of an enantiopure compound capable of forming a diastereomeric salt or a diastereomeric complex with a N-sulphonyl pyroglutamic acid, starting from a mixture of enantiomers of the said compound, which comprises (a) providing a solution comprising an enantiopure N-sulphonyl pyroglutamic acid in accordance with the use according to the invention and the mixture of enantiomers of the said compound and (b) crystallizing or precipitating from said solution a diastereomeric salt or a diastereomeric complex of said compound with the N-sulphonyl pyroglutamic acid enriched in one of the enantiomers of said compound.
It has been found, surprisingly, that the process according to the invention makes it possible to obtain good results for the preparation of enantiomers of an enantiopure compound capable of forming a diastereomeric salt or a diastereomeric complex with a N-sulphonyl pyroglutamic acid. The process according to the invention is particularly economical, as high crystallization/precipitation yields can be obtained.
In the process according to the invention, it is often desirable to initiate the crystallization or precipitation. In one embodiment, initiation is carried out by cooling the solution. In another embodiment, initiation is carried out by introducing a seed material into the solution. In still another embodiment, crystallization or precipitation is initiated by modifying the composition of the solution e.g. by adding a solvent.
The process according to the invention often further comprises recovering the crystallized or precipitated diastereomeric salt or diastereomeric complex and optionally recrystallizing it.
The enantiopure compound can be liberated from the crystallized or precipitated diastereomeric salt or diastereomeric complex by treatment with a strong acid such as a mineral acid e.g. aqueous HCl.
It is possible to recover enantiopure N-sulphonyl pyroglutamic acid after separation of the liberated enantiopure compound. This recovery can be carried out, for example, by extraction with an organic solvent which forms a biphasic system with water. Polar organic solvents such as for example ethyl acetate have given good results in the recovery. If appropriate, the solution of enantiopure N-sulphonyl pyroglutamic acid obtained from the recovery can be used as such for a subsequent separation.
The examples here after are intended to illustrate the invention without however limiting it.
Example 1
Enantiomerically pure pTosGlp-OH. Methyl 2-(piperidyl)-acetate salt.
Precipitation 0.5 equivalent of (L)-pTosGlp-OH (N-p-toluenesulphonyl pyroglutamic acid) was mixed with 1 equivalent of methyl 2-(piperidyl)-acetate in 43 equivalent of isopropanol at room temperature. Stirring at room temperature was maintained for about 3 h then the solution was first cooled down to room temperature and then put into the fridge (5°C). After few hours at 5°C, the powder was filtered and dried under vacuum. After drying, we obtained a white powder in 80 % yield with the following ratio 7.3:92.7 D :L.
1 equivalent of pTosGlp-OH. Methyl 2-(piperidyl)-acetate salt (in a ratio 7.3:92.7 according the derivatisation) was suspended in 80 equivalent isopropanol. By heating the suspension (800C), we obtained a solution. Stirring at 800C was maintained for about Vi h then the solution was first cooled down at room temperature and then put into the fridge (5°C). After few hours at 5°C, the crystals were filtered and dried under vacuum. After drying, we obtained crystals in 70 % yield with the following ratio 0.5:99.5 D:L. Example 2 Enantiomerically pure pTosGlp-OH. Piperidine-2-ethanol salt.
1 eq. of pTos-Glu-OH was suspended in 32 eq. of acetonitrile. Under nitrogen atmosphere, the solution was cooled at -5 ± 5°C, at this temperature DIC (diisopropylcarbodiimide) (1.25 eq.) was introduced.
Stirring at 0 ± 5°C was maintained for 30 minutes and then the solution was warmed to room temperature before starting the heating at 50 0C.
The mixture was cooled down to 5 ± 5°C, stirring at 5 ± 5°C was maintained for 60 minutes
Diisopropyl urea DIU was then filtered and salts were washed with 6 eq. of acetonitrile. In function of the quantity of pTosGlp-OH in solution, calculated by HPLC calibration, we determined the quantity of Pip-EtOH (Piperidine-2-ethanol) to introduce. The salt's resolution was achieved with a ratio of 0.5 eq. pTos GIp-OH to 1 eq. of PipEtOH. 1 eq of Piperidine-2-ethanol was dissolved in 25 eq of CH3CN and mixed with the pTos-Glu-OH solution at room temperature. When precipitation had started, the mixture was kept at RT for 2 h, then the solution was placed at 15°C for 12 h. The powder was filtered, twice washed with 20 eq of EtOAc and dried under vacuum. After drying, we obtained a white powder in 67 % yield with the following ratio 7:93 D:L.
Then this solid was dissolved at 75°C in a solution of 63 eq. of acetonitrile and 7 eq of water. Then the mixture was cooled to 5°C ± 5°C and kept at that temperature for 12h. The powder was filtered, washed with 5 eq of acetonitrile and dried under vacuum. After drying, we obtained a white powder in 75 % yield with the following ratio 1 :99 D:L.

Claims

C L A I M S
1 - Use of enantiopure N-sulphonyl pyroglutamic acid as resolving agent for the separation of enantiomers by crystallization or precipitation.
2 - Use according to Claim 1 in which the N-sulphonyl group, is an alkylsulphonyl or arylsulphonyl group, preferably an arylsulphonyl group.
3 - Use according to Claim 2 in which the N-sulphonyl group, is the p-toluenesulphonyl group.
4 - Use according to anyone of claims 1 to 3, wherein the enantiopure N-sulphonyl pyroglutamic acid has (S)-confϊguration.
5 - Use according to anyone of claims 1 to 3, wherein the enantiopure
N-sulphonyl pyroglutamic acid has (R)-confϊguration.
6 - Use according to anyone of claims 1 to 5, for separation of enantiomers of a compound comprising a primary or secondary amino group.
7 - Use according to claim 6, wherein the compound is an aminoalcohol.
8 - Use according to anyone of claims 1 to 6, wherein the enantiopure
N-sulphonyl pyroglutamic is dissolved in a polar organic solvent.
9 - Use according to claim 8, wherein the polar organic solvent is acetonitrile.
10 - Use according to anyone of claims 1 to 9, in which the N-sulphonyl pyroglutamic acid is manufactured by cyclization of N-sulphonyl glutamic acid in a reaction medium and is used as resolving agent without isolation from the reaction medium of the cyclization.
PCT/EP2008/067910 2007-12-21 2008-12-18 Use of enantiopure n-sulphonyl pyroglutamic acid as resolving agent WO2009080708A1 (en)

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EP07150334 2007-12-21
EP07150334.6 2007-12-21

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1183781A (en) * 1968-02-14 1970-03-11 Ici Ltd Resolution Process.
WO2005023838A1 (en) * 2003-09-09 2005-03-17 Solvay (Société Anonyme) Process for the manufacture of an enantiopure compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1183781A (en) * 1968-02-14 1970-03-11 Ici Ltd Resolution Process.
WO2005023838A1 (en) * 2003-09-09 2005-03-17 Solvay (Société Anonyme) Process for the manufacture of an enantiopure compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SWAN J M ET AL: "The synthesis of L-Glutaminyl-L-asparagine, L-GLUTAMINE AND L-ISOGLUTAMINE FROM P-TOLUENESULFONYL-L-GLUTAMIC ACID", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 76, 1 January 1954 (1954-01-01), pages 3110 - 3113, XP002269297, ISSN: 0002-7863 *

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