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WO2025168523A1 - Procédé de résolution chirale d'acide trans-2,2-dichloro-3-(3,5-dichlorophényl)-cyclopropane-1-carboxylique par chromatographie chirale - Google Patents

Procédé de résolution chirale d'acide trans-2,2-dichloro-3-(3,5-dichlorophényl)-cyclopropane-1-carboxylique par chromatographie chirale

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Publication number
WO2025168523A1
WO2025168523A1 PCT/EP2025/052754 EP2025052754W WO2025168523A1 WO 2025168523 A1 WO2025168523 A1 WO 2025168523A1 EP 2025052754 W EP2025052754 W EP 2025052754W WO 2025168523 A1 WO2025168523 A1 WO 2025168523A1
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WO
WIPO (PCT)
Prior art keywords
chiral
eluent
amylose tris
stationary phase
vol
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.)
Pending
Application number
PCT/EP2025/052754
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English (en)
Inventor
Christophe Pierre Alain Chassaing
Raina SEUPEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Intervet International BV
Intervet Inc
Original Assignee
Intervet International BV
Intervet Inc
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Filing date
Publication date
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Publication of WO2025168523A1 publication Critical patent/WO2025168523A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to the field of enantiomer resolution and particularly to a process of chiral resolution of trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid by chiral chromatography.
  • Trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid has Formula I as shown below. It is one of the intermediates in the synthesis of compounds known from LIS2018/0098541 A1 and WO2016/168059 A1.
  • Formula I is one of the intermediates in the synthesis of compounds known from LIS2018/0098541 A1 and WO2016/168059 A1.
  • trans isomers namely the (R,R) and (S,S) enantiomers are considered: (1F?,3F?)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid (“the (R,R) enantiomer”) and (1 S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid (“the (S,S) enantiomer”).
  • the compound of Formula I is often obtained as a racemic mixture of the (R,R) and (S,S) enantiomers. For further use of one of the two enantiomers it is desired to perform chiral resolution of the racemate.
  • the process is suitable to be used in an industrial environment.
  • the process can be implemented as a continuous process.
  • the present invention provides a process of chiral resolution of a racemic compound of Formula I Formula I by comprising the following steps: a) absorbing the racemic compound onto a chiral stationary phase; b) passing an eluent through the chiral stationary phase in an amount sufficient to elute the enantiomers contained in the racemic mixture from the chiral stationary phase; c) isolating the enantiomers partially or completely separately from each other, wherein the eluent comprises a mixture of an apolar solvent and a polar co-solvent selected from aliphatic alcohols, ethyl acetate and acetonitrile, and wherein the chiral stationary phase selected from the list consisting of amylose tris (S)-a- methylbenzyl carbamate, amylose tris (3-chloro-4-methylphenylcarbamate), amylose tris (3,5- dimethylphenylcarbamate) and amylose tris (3-chloro-5-methyl
  • Racemate or “racemic compound”, or “racemic mixture” is a mixture that has equal amounts of left- and right-handed (R and S) enantiomers of a chiral molecule.
  • Chiral molecule means that the molecule is non-superimposable on its mirror image.
  • Enantiomer is each of the two non-superimposable images.
  • the Cahn-lngold-Prelog convention is one of the systems used to designate each enantiomer.
  • the chiral centers of the molecule are assigned a designation of R or S depending upon the configuration of the groups attached to the chiral center.
  • Each of the four groups attached to an asymmetric carbon (chiral center) is ranked based on its atomic number. When the molecule is oriented, so the lowest ranked group is facing away from the viewer, the remaining groups are counted in descending order. If the order proceeds clockwise, the chiral center is designated R. If the order proceeds counterclockwise, the chiral center is designated S.
  • Chiral chromatography is a method to separate enantiomers of chiral compounds in a liquid chromatography column. The process uses an eluent (mobile phase) and a chiral stationary phase.
  • chiral chromatography method comprises the following steps: a) absorbing a racemic mixture that is desired to separate onto a chiral stationary phase; b) passing an eluent through the chiral stationary phase in an amount sufficient to elute the enantiomers contained in the racemic mixture from the chiral stationary phase; c) isolating the enantiomers partially or completely separately from each other.
  • HPLC high performance liquid chromatography
  • amylose tris (S)-a-methylbenzyl carbamate amylose tris (3-chloro-4-methylphenylcarbamate), amylose tris (3,5-dimethylphenylcarbamate) and amylose tris (3-chloro-5-methylphenylcarbamate).
  • amylose tris (3,5-dimethylphenylcarbamate) or amylose tris (3-chloro-5-methylphenylcarbamate) is used.
  • amylose tris (3,5-dimethylphenylcarbamate) is used because it allowed to reach a higher optical purity at certain compound loadings.
  • Amylose tris (S)-a-methylbenzyl carbamate is for example available as Chiralpak® AS-V (from Daicel).
  • Amylose tris (3-chloro-4- methylphenylcarbamate) is for example available as Chiralpak® AZ (from Daicel).
  • Amylose tris (3,5- dimethylphenylcarbamate) is available as Lux Amylose 1 (from Phenomenex), Chiralpak® AD and Chiralpak® IA (both from Daicel).
  • Amylose tris (3-chloro-5-methylphenylcarbamate) is available as Chiralpak® IG (from Daicel).
  • a suitable solvent system to be used as an eluent needs to be found.
  • the solvent system should, on one hand, be able to sufficiently dissolve the racemic mixture, which can be a challenge for poorly soluble compounds.
  • the solvent system should be suitable for column chromatography, meaning that it for example should not lead to degradation of the stationary phase or interact with the chiral selector of the CSP too much.
  • Form I unlike other aliphatic carboxylic acids substituted with an aromatic lipophilic moiety, is well soluble in some organic solvents commonly used in column chromatography, particularly in some polar solvents such as short chain aliphatic alcohols, ethyl acetate and acetonitrile. This allowed to envisage their separation by chiral HPLC with sufficient productivity.
  • the solvent (eluent) preferably comprises a mixture of an apolar solvent and a polar co-solvent.
  • the apolar solvent is preferably selected from alkanes or aromatic hydrocarbons, such as heptane, n- hexane, iso-hexane, cyclohexane, isooctane, toluene, preferably from heptane and hexane.
  • the polar co-solvent is preferably selected from aliphatic alcohols, ethyl acetate and acetonitrile, preferably an aliphatic alcohol.
  • Preferred aliphatic alcohols are primary and secondary alcohols, more preferably a primary alcohol. In other embodiments, a secondary alcohol can be used.
  • the eluent comprises a mixture of heptane or hexane as the apolar solvent, and an alcohol as the polar co-solvent.
  • a mixture of heptane and an alcohol is used.
  • n-heptane is used.
  • hexane and an alcohol can be used.
  • Hexane can be n-hexane or iso-hexane. Suitable iso-hexanes are 2-methylpentane, 3-methylpentane or 2,3-dimethylbutane, preferably 2- methylpentane.
  • the eluent comprises a mixture of n-heptane and an alcohol selected from methanol, ethanol, 1-propanol and 2-propanol, preferably a mixture of n-heptane and ethanol. In other embodiments, the eluent comprises a mixture of n-heptane and methanol. In yet other embodiments, the eluent comprises a mixture of n-heptane and 1-propanol. In yet other embodiments, the eluent comprises a mixture of n-heptane and 2-propanol.
  • the eluent can comprise a mixture of n-hexane and an alcohol selected from methanol, ethanol, 1-propanol and 2-propanol, preferably a mixture of n-hexane and ethanol.
  • the eluent comprises a mixture of n-hexane and methanol.
  • the eluent comprises a mixture of n-hexane and 1-propanol.
  • the eluent comprises a mixture of n-hexane and 2-propanol.
  • the eluent can comprise a mixture of iso-hexane (2-methylpentane) and an alcohol selected from methanol, ethanol, 1-propanol and 2-propanol, preferably a mixture of isohexane and ethanol.
  • the eluent comprises a mixture of iso-hexane and methanol.
  • the eluent comprises a mixture of iso-hexane and 1-propanol.
  • the eluent comprises a mixture of iso-hexane and 2-propanol.
  • the alcohol is preferably present in the eluent in an amount of 0.1-15% (vol/vol), more preferably 1- 10% (vol/vol), yet more preferably 5-10% (vol/vol). It has been observed that the content of more than 10% (vol/vol) alcohol led to overlapping peaks and did not allow baseline separation. The content of 5-10% (vol/vol) has been found optimal to allow baseline separation.
  • the eluent further comprises an acid, for example a carboxylic acid.
  • suitable acids include acetic acid, trifluoroacetic acid (TFA) and formic acid.
  • TFA trifluoroacetic acid
  • the acid lowers the pH of the mixture, which prevents the racemate of Formula I from converting into a deprotonated form. Without the use of an acid, it was observed that the peaks were overlapping and tailing, which makes the separation difficult or impractical.
  • TFA is used as it leads to higher resolution results than other acids.
  • the acid can be present in the eluent in an amount of 0.01-5% (vol/vol), preferably 0.05-1 % (vol/vol).
  • the process according to the invention surprisingly allows to achieve both high selectivity and productivity, which make it well suitable for a large-scale preparative separation.
  • the process is implemented as a continuous process.
  • a continuous process operates on the bases of continuous flow, as opposed to batch, intermittent or sequence operations.
  • a skilled person is aware of continuous liquid chromatography processes.
  • Continuous processes for chiral chromatography can be implemented such as SMB (simulated moving bed) process, which is a multi-column continuous purification process, which consists of columns connected in series, with inlet/outlet lines connected between the columns.
  • SMB simulated moving bed
  • the SMB technique is based on a quasi counter-current contact between the stationary and mobile phases mimicking a true moving bed. Skilled person is aware of SMB systems and is able to determine how the process described above can be implemented in an SMB system.
  • Coated polysaccharide-based chiral stationary phases are phases in which the polysaccharide is not covalently bonded to the underlying silica.
  • Immobilized polysaccharide chiral stationary phases are those in which the polysaccharide is covalently linked to the underlying silica.
  • the efficiency of a chiral separation process can be judged by the degree of separation achieved between the enantiomers of a racemate and the productivity as measured in terms of the mass of racemate processed per the mass of the chiral stationary phase used per a period of time.
  • the productivity of the described process is preferably greater than 1.0 KKD of racemate (or crude material treated), more preferably greater than 1.5 KKD.
  • the productivity of the process can for example be in the range of 1.0 to 6.0 KKD of racemate.
  • Productivity (KKD) is defined as the kg amount of racemate (crude material treated) that can be separated per kg of chiral stationary phase (CSP) per day.
  • the selectivity (a) is the ratio of the retention factors of the two peaks of the two enantiomers as shown in Equation 1. It can be visualized as the distance between the apices of the two UV signals.
  • TE2 is the retention time of the second eluting enantiomer
  • TEI is the retention time of the first eluting enantiomer
  • TE2 is the retention time of the second eluting enantiomer and To the time taken by the mobile phase to pass through the column.
  • Retention factor is preferably low, e.g. less than 12, preferably in the range 2-11.
  • the compound with Formula I is surprisingly highly soluble in polar solvents such as specifically ethanol, methanol, 2-propanol, ethyl acetate and acetonitrile, which are also preferred solvents of choice for performing chromatographic separations.
  • polar solvents such as specifically ethanol, methanol, 2-propanol, ethyl acetate and acetonitrile, which are also preferred solvents of choice for performing chromatographic separations.
  • Addition of an acid such as TFA was also tested because it was observed that without the use of acids the peaks were often overlapping and tailing, which makes separation difficult or ineffective. However, it was observed that the addition of TFA negatively impact solubility in some solvents.
  • Example 2 Chiral stationary phases screening The ability of the following chiral stationary phases to separate a racemic mixture of Formula I was determined. Diluted racemate was injected on each stationary phase, and the product was eluted with binary mixtures of solvents (A for apolar solvent, B for polar co-solvent) as mobile phases.
  • the chiral stationary phases are recited in Table 2, the conditions are recited in Table 3, the combination of CSPs and mobile phases screened are in Table 4.
  • the first screening tests used neutral mobile phases without TFA. However, even if separations were observed, the peaks obtained were very broad and tailing (e.g. in #1 and #3). This would make separation of enantiomers very difficult or ineffective.
  • an acid such as trifluoroacetic acid (TFA) was added to the mobile phases.
  • combinations #2 and #4-8 used four CSPs which are preferred in this invention: amylose tris (S)-a-methyl benzyl carbamate, amylose tris (3-chloro-4-methylphenylcarbamate), amylose tris (3,5-dimethylphenylcarbamate) and amylose tris (3-chloro-5-methylphenylcarbamate).
  • a sample of a racemic mixture of Formula I was solubilized at 20 g/L in eluent consisting of a n-heptane/ethanol 95/5 (vol/vol) + 0.1 (vol%) TFA.
  • This solution was injected on an amylose tris (3,5- dimethylphenylcarbamate) coated on silica gel column (Chiralpak® AD).
  • the sample was eluted with the eluent at 25 °C. Both enantiomers were obtained using multi-column continuous process Varicol.
  • the productivity (KKD) was estimated to be 2.5 kg of racemate/kg of chiral stationary phase/day on a continuous process translating into 1 .3 kg of desired enantiomer/kg of chiral stationary phase/day.
  • a sample of a racemic mixture of Formula I was solubilized at 20 g/L in eluent consisting of a n-heptane/ethanol 95/5 (vol/vol) + 0.1 (vol%) TFA.
  • This solution was injected on an amylose tris (3,5- dimethylphenylcarbamate) coated on silica gel column (Chiralpak® AD).
  • the sample was eluted with the eluent at 30 °C. Both enantiomers were obtained using multi-column continuous process Varicol.
  • the productivity (KKD) was estimated to be 2.9 kg of racemate/kg of chiral stationary phase/day on a continuous process translating into 1.5 kg of desired enantiomer/kg of chiral stationary phase/day.
  • a sample of a racemic mixture of Formula I was solubilized at 20 g/L in eluent consisting of a n-heptane/ethanol 90/10 (vol/vol) + 0.1 (vol%) TFA.
  • This solution was injected on an amylose tris (3,5-dimethylphenylcarbamate) coated on silica gel column (Chiralpak® AD).
  • the sample was eluted with the eluent at 25 °C. Both enantiomers were obtained using multi-column continuous process Varicol.
  • the productivity (KKD) was estimated to be 2.1 kg of racemate/kg of chiral stationary phase/day on a continuous process translating into 1.1 kg of desired enantiomer/kg of chiral stationary phase/day.
  • optical purity was >99 area% (UV-HPLC at 280 nm) and the recovery >95%, translating into 47.5% yield with maximum achievable 50%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de résolution chirale d'acide trans-2,2-dichloro-3-(3,5-dichlorophényl)-cyclopropane-1-carboxylique par chromatographie chirale à l'aide d'un éluant comprenant un mélange d'un solvant apolaire et d'un co-solvant polaire choisi parmi les alcools aliphatiques, l'acétate d'éthyle et l'acétonitrile, et utilisant une phase stationnaire chirale choisie dans la liste constituée par le tris (S)-α-méthylbenzyl carbamate d'amylose, le tris (3-chloro-4-méthylphénylcarbamate) d'amylose, le tris (3,5-diméthylphénylcarbamate) d'amylose et le tris (3-chloro-5-méthylphénylcarbamate) d'amylose.
PCT/EP2025/052754 2024-02-05 2025-02-04 Procédé de résolution chirale d'acide trans-2,2-dichloro-3-(3,5-dichlorophényl)-cyclopropane-1-carboxylique par chromatographie chirale Pending WO2025168523A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP24155730 2024-02-05
EP24155730.5 2024-02-05

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016168059A1 (fr) 2015-04-17 2016-10-20 Dow Agrosciences Llc Molécules présentant une utilité en tant que pesticides, ainsi qu'intermédiaires, compositions, et procédés associés
US20180098541A1 (en) 2016-10-12 2018-04-12 Dow Agrosciences Llc Molecules haveing pesticidal utiliy and intermediates, compositions and processes related thereto

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016168059A1 (fr) 2015-04-17 2016-10-20 Dow Agrosciences Llc Molécules présentant une utilité en tant que pesticides, ainsi qu'intermédiaires, compositions, et procédés associés
US20180098541A1 (en) 2016-10-12 2018-04-12 Dow Agrosciences Llc Molecules haveing pesticidal utiliy and intermediates, compositions and processes related thereto

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