WO2026013665A1 - Purification d'acides cis-2-alcénoïques - Google Patents

Purification d'acides cis-2-alcénoïques

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Publication number
WO2026013665A1
WO2026013665A1 PCT/IL2025/050574 IL2025050574W WO2026013665A1 WO 2026013665 A1 WO2026013665 A1 WO 2026013665A1 IL 2025050574 W IL2025050574 W IL 2025050574W WO 2026013665 A1 WO2026013665 A1 WO 2026013665A1
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Prior art keywords
cis
acid
crude
cda
salt
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English (en)
Inventor
Ari Ayalon
Ronit YAHALOMI SEGUI
Batya KAUFMAN
Michal RODENSKY
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Bromine Compounds Ltd
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Bromine Compounds Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/35—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing only non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/03—Monocarboxylic acids
    • 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
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • CDA cis-2- decenoic acid
  • CDA can act as an effective adjunctive to bromine-containing biocides in the treatment of biofilm and planktonic bacteria in water systems and on surfaces in contact with the water, to achieve significant enhancement in the killing of bacteria in both pure and mixed cultures typically found in industrial and natural waters, relative to treatment with the brominated biocides alone.
  • Cis-2-alkenoic acids can be prepared by a two-step process consisting of brominating 2-alkanone to give 1 , 3-dibromo-2- alkanone as the main product, followed by rearrangement of the 1 , 3-dibromo-2-alkanone to the cis-2-alkenoic acids: where R’ is alkyl, e.g., C2H5, C 3 H 7 , C 4 H 9 , CsHn and C 6 HI 3 .
  • R’ is alkyl, e.g., C2H5, C 3 H 7 , C 4 H 9 , CsHn and C 6 HI 3 .
  • the abovementioned two-step synthesis was first described by Rappe et al. [Acta Chemica Scandinavica (1965) , Vol. 19, p. 383- 389] .
  • the two-step synthesis shown above was further modified in a coassigned WO 2022/118309 by the addition of a catalytically effective amount of an alkali salt of ODA at the beginning of the rearrangement reaction, to advance the rearrangement reaction of the 1 , 3-dibromo-2-alkanone in an effective and manageable manner.
  • ODA is an oily substance with a high boiling point: Cahiez et al. ("Stereospecific syntheses of alkenyl lithium reagents from alkenyl iodides", Synthesis, 1976, 4, 245-8) reported a boiling point of 102-103°C/0.5 torr.
  • the crude ODA obtained through the synthetic pathway discussed above or by other methods usually has an assay of ⁇ 60-70% measured by high- performance liquid chromatography (HPLC) as absolute quantification based on calibration with a commercially available external standard (>97%) .
  • the range of impurities accompanying crude CDA is determined by the synthetic pathway, but it appears that the presence of organic acid impurities is unavoidable, e.g., trans-2-decenoic acid and in the case of the synthetic pathway involving the rearrangement of the 1 , 3-dibromo-2-decanone to CDA, also 2- bromomethylidene nonanoic acid (BMNA) .
  • BMNA 2- bromomethylidene nonanoic acid
  • the amount of BMNA formed as a by-product is not insignificant (WO 2022/118309) .
  • the tetrabutylammonium salt of CDA was characterized as a hydrate with a low melting point.
  • 2-decenoic acid with a few amine bases (butylamine, hexylamine, 2-ethylhexylamine, n-octylamine and dihexylamine) .
  • purification of cis-2-alkenoic acids can be achieved by selective precipitation/crystallization of organic ammonium salts of the cis-2-alkenoic acid whilst leaving acidic impurities in the solution.
  • selective precipitation/crystallization of an ammonium salt of cis-2-alkenoic acid it is meant an enrichment of the cis-2-alkenoic acid content in the isolated salt, compared to the crude acid before neutralization with the amine base, indicated by a > 5%, > 10%, > 15% increase in the HPLC assay of the salt compared to the HPLC assay of the crude cis-2-alkenoic acid (e.g., from 50-70% to 80-95%) .
  • Purification of cis-2-alkenoic acids by crystallization in the form of ammonium salts is amenable to large scale production. For example, it is cheaper than chromatography and thermal separation methods and it usually requires less sophisticated equipment leading to reduction of costs.
  • the invention is primarily directed to a method comprising reacting crude cis-2-alkenoic acid with an amine base and isolating the resultant ammonium salt of cis-2-alkenoic acid in a solid form, from an organic solvent or a mixture of organic solvents .
  • Suitable amine bases include cyclic amines and medium-chain acyclic amines.
  • the resultant ammonium salt of the cis-2- alkenoic acid is a useful intermediate that enables the purification of the crude acid to a high degree of purity on a large scale.
  • Some ammonium salts for example, salts which can be obtained by neutralization of CDA with cyclohexylamine in a range of solvents, form another aspect of the invention.
  • the cyclohexylammonium salt of CDA was examined under polarized light microscopy and analyzed by X-ray powder diffraction and was found to be crystalline.
  • the X-ray powder diffraction pattern of the cyclohexylammonium salt of CDA exhibits major diffraction peaks (3 or more) at positions 5.6, 11.3, 14.6, 17.2, 19.7, 23.0 and 28.9 20 ( ⁇ 0.1 20) [5.6, 11.3, 14.6, 17.2, 17.7, 18.2, 19.7, 23.0, 26.8 and 28.9 20 ( ⁇ 0.1 20) ] .
  • the cyclohexylammonium salt of CDA has single crystal parameters as tabulated in Table 5 below .
  • the method of the invention further comprises the steps of acidifying the ammonium salt of the cis-2-alkenoic acid to liberate the free acid and recovering the free acid.
  • Crude cis-2-alkenoic acid obtained by various synthetic pathways can be purified by the method of the invention, e.g, grades with HPLC assay in the range from 50% to 75-85%, e.g., 55 to 75%. Crude cis-2-alkenoic acid is characterized by an impurity profile consisting of >3%, e.g.
  • the 1 , 3-dibromo-2-alkanone undergoing the rearrangement reaction is most conveniently prepared by brominating the corresponding 2-alkanone [R-CH2-C (0) -CH3] (e.g., 2-heptanone, 2-octanone, 2- nonanone, 2-decanone or 2-undecanone) in concentrated hydrobromic acid (e.g., from 30% to 48% by weight HBr solution) , by the slow addition of elemental bromine (stoichiometry dictates a ⁇ 2 : 1 molar ratio of Br2: 2-alkanone) .
  • the bromination of the 2-alkanone may take place in an organic solvent such as halogenated hydrocarbon (CH2CI2 or CH2Br2) with the aid of acceptable bromination reagents.
  • the weight ratio of the 2-alkanone starting material to the aqueous HBr is from 1:1 to 1:2.
  • the reaction medium is chilled to a temperature in the range from 5 to 20°C, e.g., around 5 to 10°C. Under these conditions, elemental bromine adds smoothly to the 2-alkanone. After the addition of the elemental bromine has been completed, the reaction mixture is held at room temperature (15- 25°C) , optionally under stirring, for some time (“hold time”) . Hold time may last between 6 and 24 hours, e.g., between 6 and 12 hours.
  • the desired isomer, 1 , 3-dibromo-2-alkanone progressively becomes the predominant product with the passage of time, i.e., an extended hold time enables a significant interconversion of the 3 , 3-dibromo-2-alkanone isomer to the desired isomer 1 , 3-dibromo-2-alkanone .
  • the reaction mixture is worked-up by the addition of water, followed by separation into an aqueous phase (consisting of ⁇ 48% w/w hydrobromic acid) and an organic phase, consisting of the crude product .
  • 1 , 3-dibromo-2-alkanone used in the rearrangement reaction is a crude 1 , 3-dibromo-2-alkanone obtained by the steps of : brominating the corresponding 2-alkanone in concentrated hydrobromic acid by the addition of elemental bromine, whereby 1 , 3-dibromo-2-alkanone is formed in the reaction mixture alongside 3, 3-dibromo-2-alkanone; maintaining the reaction mixture over a hold time adjusted to maximize the interconversion of 3 , 3-dibromo-2-alkanone to 1,3- dibromo-2-alkanone (e.g., to reach >65%, >67%, >69% (GC, area%) of 1 , 3-dibromo-2-alkanone ) ; and collecting the crude 1,3- dibromo-2-alkanone .
  • brominating the corresponding 2-alkanone in concentrated hydrobromic acid by the addition of elemental bromine whereby 1 , 3-dibromo-2-alkanone is
  • a convenient way to carry out the rearrangement reaction comprises gradually adding 1 , 3-dibromo-2-alkanone to a reaction vessel that was previously charged with an alkaline aqueous solution (e.g., consisting of 10 to 30% w/w Na2COs, K2CO3 or a mixture thereof dissolved in water, or carbonate/bicarbonate mixtures) and preferably also a catalytically effective amount of an alkali metal salt of cis-2-alkenoic acid, at an elevated temperature, e.g., h35°C, for example, >40°C.
  • an alkaline aqueous solution e.g., consisting of 10 to 30% w/w Na2COs, K2CO3 or a mixture thereof dissolved in water, or carbonate/bicarbonate mixtures
  • an alkali metal salt of cis-2-alkenoic acid e.g., h35°C, for example, >40°C.
  • the gradual addition of the 1 , 3-dibromo-2-alkanone takes place when the reaction mixture is held at a temperature in the range of 40°C to 60°C.
  • the molar ratio of 1 , 3-dibromo-2-alkanone to the carbonate salt is from 1:2 to 1:4, e.g., around 1:3-1: 3.5.
  • the catalytically effective amount of the alkali metal salt of the cis-2-alkenoic acid added to the alkaline solution before the rearrangement reaction starts is preferably from 1 to 5-10 molar percent relative to the 1 , 3-dibromo-2-alkanone .
  • the reaction takes place during the addition of the 1,3-dibromo- 2-alkanone to the alkaline reaction mixture.
  • the occurrence of the reaction is marked by pH drop (i.e., the initial, strongly alkaline pH of 12-14 drops by at least 2 pH units, e.g., 2-4 pH units, during the addition of the 1 , 3-dibromo-2-alkanone ) , and by temperature rise (i.e., AT reactor) of ⁇ 5 to 10°C.
  • pH drop i.e., the initial, strongly alkaline pH of 12-14 drops by at least 2 pH units, e.g., 2-4 pH units, during the addition of the 1 , 3-dibromo-2-alkanone
  • temperature rise i.e., AT reactor
  • a pH drop of ⁇ 0.5-1.5 units is observed during the cooking period.
  • the progress of the reaction can be monitored by pH measurement (a constant pH indicates the end of the reaction) and/or GC analysis of the organic phase (to determine the disappearance of the 1 , 3-dibromo-2-alkanone, i.e., down to dl%, areal) .
  • AP-RM indicates the catalytically effective amount of the alkali metal salt of cis-2-alkenoic acid, added in advance to start up the rearrangement reaction.
  • the reaction mixture On completion of the rearrangement reaction, the reaction mixture is cooled to room temperature and separated into aqueous (heavy) and organic (light) phases. The organic phase can be discarded.
  • the aqueous phase which contains the cis-2-alkenoic acid in the form of its alkali metal salt (namely, sodium or potassium salts, determined by the base selected) is worked-up to isolate the product.
  • the catalytically effective amount of the alkali metal salt of the cis-2-alkenoic acid can be supplied to the reaction in an aqueous form by removing a minor portion of the aqueous phase, which was collected after the phase separation, and keeping this minor portion for addition in the next run of the process.
  • the purified aqueous solution is acidified, e.g., with the aid of concentrated hydrochloric acid (for example, commercially available 32% HC1 solution) , which is slowly added to the aqueous solution to reach a strongly acidic pH (e.g., from 1 to 2) .
  • concentrated hydrochloric acid for example, commercially available 32% HC1 solution
  • the acidified reaction mixture is separated into aqueous (heavy) and organic (light) phases.
  • the former contains bromide and chloride salts; the latter consists of the crude cis-2-decenoic acid, and possibly some residual organic solvent (e.g., DCM) which served in the washing stage, and water, which can be removed, e.g., by evaporation under vacuum, whereby the crude cis-2-alkenoic acid is obtained.
  • DCM residual organic solvent
  • the acidification reaction resulting in crude CDA is shown below:
  • the process of preparing crude cis-2-alkenoic acid further comprises acidification of the purified aqueous phase (i.e., recovered after the extraction with DCM) , to obtain a biphasic medium comprised of a heavy, salt-containing aqueous phase, and a light organic phase consisting essentially of a crude cis-2-alkenoic acid (as the free acid) , separating the crude cis-2-alkenoic acid and optionally removing residual organic solvents (e.g., DCM) from the crude cis-2-alkenoic acid by evaporation.
  • aqueous phase i.e., recovered after the extraction with DCM
  • a biphasic medium comprised of a heavy, salt-containing aqueous phase, and a light organic phase consisting essentially of a crude cis-2-alkenoic acid (as the free acid)
  • crude cis-2-alkenoic acid includes an as-synthesized cis-2- alkenoic acid (i.e., the direct product of chemical synthesis, as shown above) and any cis-2-alkenoic acid with insufficient purity level (i.e., material that was already treated to remove impurities by other methods) .
  • the as-synthesized cis-2-alkenoic acid may be supplied to the purification stage in an isolated form free of residual organic solvents (e.g., after evaporation of residual extraction solvents, e.g., DCM, used in a work-up stage) .
  • residual organic solvents e.g., DCM, used in a work-up stage
  • the as- synthesized cis-2-alkenoic acid can enter the purification step while it still contains residual extraction solvents.
  • a suitable extraction solvent can serve, at least in part, as the solvent for the neutralization reaction, from which the ammonium salt is crystallized.
  • the purification method of the invention can be used as a final clean-up step, after the application of other purification methods to an as-synthesized impure product, to raise the purity of the cis-2-alkenoic acid to >85%, >90% (by HPLC assay against an external standard) . That is, any cis-2-alkenoic acid with insufficient purity level ( ⁇ 85%; e.g., ⁇ 80%; ⁇ 70%, e.g., 50-75% HPLC assay) could benefit from the method of the invention to remove impurities, especially acidic impurities, e.g., the trans isomer and brominated acids such BMNA.
  • impurities especially acidic impurities, e.g., the trans isomer and brominated acids such BMNA.
  • the method comprises a reaction of crude cis-2-alkenoic acid with an amine base to form the corresponding ammonium salt in a solid (e.g., crystalline) form, separation of the ammonium salt from the mother liquor by filtration (or any other solid/liquid separation technique) , and acidification of the ammonium salt in an aqueous solution with the aid of a strong mineral acid, to recover the free acid.
  • a solid e.g., crystalline
  • the method comprises dissolving crude cis-2-alkenoic acid in an organic solvent or a mixture of organic solvents, adding the amine base to precipitate/crystallize the ammonium salt of cis-2-alkenoic acid, and separating the solid ammonium salt from the liquid phase.
  • the amine bases used in the invention are usually liquid at room temperature, showing good miscibility in a range of organic solvents. In addition, their HC1 salts dissolve well in water.
  • Suitable amine bases for use in the invention are selected from the group consisting of cyclic amines and medium-chain (straight or branched) acyclic aliphatic amines. C6-C10 primary amines with pKb ⁇ 4 (25°C) are also useful.
  • the cyclic amines include cyclic aliphatic amines, e.g., cyclic aliphatic primary amines of the formula C n H2n-i-NH2, with n ranging from 3 to 10, such as cyclopropylamine (C3H5-NH2) , cyclobutylamine (C4H7-NH2) , cyclopentylamine (C5H9-NH2) , cyclohexylamine (CeHn- NH2) and cycloheptylamine (C7H13-NH2) , and the corresponding secondary (Cnfbn-i-NHR 1 ) and tertiary (C n H2n-i-NR 1 R 2 ) amines, where R 1 and R 2 are independently lower alkyl groups, e.g., methyl, such as N, N-dimethylcyclohexylamine (CeHn-N (CH3) 2) .
  • Heterocyclic secondary amines e.g., with molecular formula (CH2) P NH, i.e., the nitrogen atom is a ring atom with p ranging from 4 to 9, such as pyrrolidine and piperidine can also be used.
  • cyclic aliphatic amine is also meant to include hydrocarbon rings where the -NH2, -NHR 1 or NR 2 R 2 group is not attached directly to a carbon ring atom, but rather through a short chain, such as 1-cyclohexyl-ethylamine (CeHn-CH (CH3) NH2) and 2-cyclohexyl-ethylamine (C6H11-CH2-CHNH2) .
  • the amine bases are usually monoamines.
  • Aromatic amines e.g., pyridine
  • the rings may be optionally substituted.
  • Medium-chain (straight or branched) acyclic aliphatic amines have a carbon skeleton consisting of six to 10 carbon atoms.
  • Preferred are normal primary aliphatic amines of the formula CH3 (CH2) m NH2, where m is 6, 7 or 8, e.g., n-octylamine .
  • the concentration of the cis-2-alkenoic acid in the organic solution is from 5 to 50% by weight, e.g., from 10 to 30% by weight.
  • an amine base is added to the organic solution.
  • Amine bases that are mentioned above are liquid at room temperature and they usually show good miscibility with a range of organic solvents, namely, the saturated hydrocarbons, halogenated hydrocarbons and ethers mentioned above.
  • an equimolar amount of the amine base is supplied to the neutralization reaction of the cis-2- alkenoic acid (the amount of the amine base is calculated as if the whole amount of crude material subjected to purification consists of the target cis-2-alkenoic acid) .
  • the addition of the amine base to a reaction vessel that was previously charged with the organic solvent (s) and the cis-2- alkenoic acid is preferably carried out in a gradual manner at ambient temperature under stirring.
  • the neutralization reaction of the acid by the base takes place with the evolution of heat. Usually, a temperature rise of ⁇ 1 to 10°C is observed. Most of the reaction occurs during the addition of the base.
  • the reaction mixture is allowed to cool down, either by leaving the solution to come to room temperature, or by placing the reaction vessel inside a cooling bath on a lab scale, or by using a conventional coolant system coupled to chemical reactors. Selective precipitation/crystallization occurs at a moderately low temperature, with crystals starting to separate out from the solution at ⁇ 20 °C. No significant cooling is needed to induce crystallization of the salt; cooling the reaction down to about 10-20°C, e.g., 15-20°C is sufficient to recover a major portion of the solute in the amine salt form.
  • another aspect of the invention is a method comprising dissolving the crude cis-2-alkenoic (e.g., cis-2- decenoic acid) in an organic solvent or in a mixture of organic solvents, gradually adding the amine base (e.g. cyclohexylamine) , e.g., at room temperature under stirring, allowing the reaction mixture to cool to crystallize the ammonium salt of cis-2-alkenoic acid, and separating the solid ammonium salt from the liquid phase, e.g., by filtration.
  • the crude cis-2-alkenoic e.g., cis-2- decenoic acid
  • the amine base e.g. cyclohexylamine
  • the purification method of the invention offers an efficient utilization of process solvents, i.e., 1) solvents used during the production of the crude cis-2-alkenoic acid, and 2) solvents used for the salt formation reaction between the amine and the crude cis-2-alkenoic acid.
  • the solvents used during production of the crude cis-2-alkenoic acid can act as solvents for the neutralization of the acid by an amine base and crystallization of the ammonium salt product. It is recalled that the synthesis of crude cis-2-alkenoic acid takes place in an alkaline aqueous solution. Upon completion of the synthesis, the reaction mixture is separated into aqueous and organic phases, and the aqueous phase, which contains the cis-2-alkenoic acid in the form of its alkali metal salt, is acidified to isolate the free acid.
  • the aqueous phase is washed with a water-immiscible organic solvent - e.g., dichloromethane - to extract and remove organic impurities.
  • a water-immiscible organic solvent e.g., dichloromethane - to extract and remove organic impurities.
  • the crude free acid that is ultimately liberated as an oil is accompanied by a residual amount of dichloromethane, e.g., the ratio DCM:CDA is from 1:10 to 1:3, e.g., 1 : 5 to 1 : 3.
  • the corresponding ammonium salt e.g., the cyclohexylamine salt of CDA
  • a solid e.g., crystalline form
  • HPLC assay HPLC assay
  • the crude cis-2-alkenoic acid purified by the method of the invention is obtained by: rearranging 1 , 3-dibromo-2-alkanone in a reaction vessel which was previously charged with an alkaline aqueous solution, separating the reaction mixture into aqueous and organic phases, and working-up the aqueous phase, which contains the cis-2- alkenoic acid in the form of its alkali metal salt, to isolate the free acid, wherein the work-up comprises: washing the aqueous phase with a water-immiscible organic solvent (e.g., DCM) to extract and remove organic impurities ;
  • a water-immiscible organic solvent e.g., DCM
  • Experimental work conducted in support of this invention also shows the recyclability of the filtrate streams produced by the separation of the solid ammonium salt from its mother liquor.
  • the recycled mother liquor can be used as a solvent in successive reactions, i.e., on addition of crude cis-2-alkenoic acid and amine base to the recycled solvent, to precipitate/crystallize a salt product, without employing fresh solvent, or using smaller amounts of the fresh solvent.
  • another aspect of the invention is a method comprising separation of the ammonium salt from the liquid phase, recycling and using the liquid phase (i.e., filtrate, supernatant) as a solvent in a subsequent run, wherein a crude cis-2-alkenoic acid and an amine base is added to the recycled solvent to recover additional crop of an ammonium salt.
  • the liquid phase i.e., filtrate, supernatant
  • the amine salt that was separated from the organic solvent is optionally dried or proceeds without removing the solvent to the acidification step.
  • the acidification reaction comprises adding the isolated ammonium salt into water, adding a strong mineral acid, e.g., hydrochloric acid (e.g., from 8 to 12% by weight HC1 solution) , thereby reducing the pH to below ⁇ 3, e.g., l ⁇ pH ⁇ 3, whereby the free acid is liberated from the amine salt, forming a light oily phase recoverable by phase separation. Owing to the miscibility of the amine HC1 salt in water, it remains in the aqueous phase. GC/ 1 H-NMR analysis of the purified free acid did not detect the amine base as an impurity.
  • hydrochloric acid e.g., from 8 to 12% by weight HC1 solution
  • Figure 1 relates to the crude CDA from preparation 1 (A) 1 H-NMR spectrum, (B) GC chromatogram and (C) HPLC chromatogram.
  • Figure 2 is a flowchart corresponding to the experiment described in Example 19, which involves the precipitation of CDA-CHA salt from t-BME, and filtrate recycling for 3 successive runs.
  • Figure 3 is a flowchart showing the recovery by acidification of free CDA from the CDA-CHA of Example 19.
  • Figure 4 is a HPLC chromatogram of the crude CDA (red, CDA assay 67%) used in Example 19, and the purified free CDA obtained (blue, CDA assay 88%) .
  • Figure 5 is a 1 H-NMR spectrum of the purified CDA (the free acid) obtained in Example 19.
  • Figures 6A-6C show GC chromatograms of cyclohexylamine (A, top) , CDA-cyclohexylamine salt (B, middle) and purified free CDA (C, bottom) .
  • Figure 7 shows X-ray powder diffraction patterns of cyclohexylammonium salt of cis-2-decenoic acid prepared with different starting materials.
  • Figure 8 shows configuration of the crystalline cyclohexylammonium salt of cis-2-decenoic acid.
  • CDA Method
  • HPLC analysis was performed by an Agilent 1200 LC system equipped with a quaternary pump, autosampler and diode array detector. CDA assay was determined against an external standard. Column: Kromasil C18 5p 250x4.6 mm i.d.
  • the assay of CDA was determined using an external standard calibration curve.
  • Step 1
  • the reaction was exothermic and accompanied by the emission of HBr gas, just before the end of the addition of the bromine, which was absorbed in a scrubber.
  • Step 2
  • aqueous solution of K2CO3, in a concentration of 25% w/w was prepared in a IL stirred reactor by the batchwise addition of K2CO3 (200 g) to water (600 g) .
  • the reaction was exothermic.
  • a part of the aqueous phase (which contained CDA-K) of the reaction mixture (50 g) remaining from a previous run (named AP-RM) .
  • the clear solution obtained was heated to 40°C and crude DBD of step 1 (200 g) was added to it dropwise over 60 min.
  • the progress of the reaction was monitored by GC and by the change of the pH.
  • the reaction was completed by cooking at 50°C for 3.0 h, with mechanical stirring.
  • the end of the reaction was determined by the pH (drop in the pH from 13.3 to 9.3) and by GC analysis of the reaction mixture (disappearance of 1,3-DBD to ⁇ 1% , area%) .
  • an organic phase appeared above the aqueous phase which contained unreacted 3-bromo-2-decanone (3-BD) and 3,3-DBD, and byproducts formed by a condensation reaction of crude DBD.
  • the phases were separated.
  • the organic phase (39 g) was organic waste. 50 g of the aqueous phase was taken for use in the next run .
  • the remainder of the aqueous phase (950 g) was washed three times with dichloromethane (DCM, 3 x 250 g) .
  • DCM dichloromethane
  • an aqueous phase was obtained containing cis-2-decenoic acid potassium salt (CDA-K) and organic by-products, KBr and KHCO3.
  • CDA-K cis-2-decenoic acid potassium salt
  • the purity of the crude CDA obtained was 88.2% (by GC area%) .
  • the main impurity in the crude product was 2-bromomethylidene nonanoic acid (BMNA) : 8.8% (by GC, area%) .
  • HPLC assay determined against an external standard was 69% assay.
  • CDA (assay 92%) was obtained from CV-Chem and was used as is for assessment of precipitation by various amine bases.
  • the potassium salt was prepared by the addition of 10g CDA to an equimolar amount of KOH aqueous solution (0.06M) in a 250 mL vessel. The resultant solution was evaporated, to give a slurry/paste like product. Samples of the product (0.1-0.6 g) were added to, and triturated in, different organic solvents (1-3 ml acetonitrile, THF, water or acetone) , but none of the treatments resulted in the formation of a workable, filtrable, powdery precipitate.
  • organic solvents 1-3 ml acetonitrile, THF, water or acetone
  • an antisolvent was added up to 2.5 ml (the organic solvents tested were acetonitrile, THF, acetone and IDA) .
  • the solution was left at 2-8°C for 48 hours, but no precipitate was observed.
  • a typical procedure consists of two steps.
  • a solventless salt formation was carried out, by adding an equimolar amount of the amine base to the neat crude CDA (1-3 g CDA of Preparation 1; as if all the crude material consists of CDA) .
  • the resultant material ⁇ 5g
  • the salt formation reaction took place in a round bottom flask equipped with a magnetic bar and thermometer .
  • a typical procedure consisted of dissolution of the crude CDA ( Preparation 1 ) in the organic solvent (usually in 1 : 8 w/v ratio ) , followed by gradual addition of an equivalent amount of the cyclohexylamine ( calculated as i f all crude CDA consisted of 100% CDA) .
  • the addition of base to the solution was exothermic .
  • the solution was cooled to 15-20 ° C, at which temperature precipitation started .
  • the suspension was stirred at 15-20 ° C for about an hour or two and then the solid was collected by vacuum filtration and washed with cold fresh solvent ( re-suspended on a filter ) .
  • the salt was dried under reduced pressure at 35 °C and analyzed by HPLC . The experimental conditions and results are tabulated below .
  • Table 2 yield was calculated for CDA content not product weight The results indicate that crude CDA could be purified owing to the selective crystallization of CDA-CHA from different solvents at moderate temperature, with increased content of CDA in the salt, as compared to the crude CDA.
  • CDA-CHA of Example 6A was acidified by suspending the salt (2 g) in water (lOmL) and the addition of 10% HC1 solution (2.2 g) to a pH ⁇ l-2.
  • the free acid (oil, 1.27 g) was quantitatively recovered and collected by phase separation. HPLC analysis indicated an assay of 83% and a total purification yield of 62%.
  • Salt formation reaction the reaction took place in a round bottom flask equipped with a magnetic bar and thermometer.
  • a typical procedure consisted of dissolving the crude CDA from preparations 1, 2 or 3 in DCM, with optional addition of MTBE to the stirred solution.
  • the amine base triethylamine (TEA) , tetradecylamine (TDA) , n-octylamine (NOA) and cyclohexylamine (CHA)
  • TDA tetradecylamine
  • NOA n-octylamine
  • CHA cyclohexylamine
  • the salt formation reaction was exothermic, marked by a temperature rise up to 30 °C.
  • the flask was placed in a water bath and the reaction mixture was allowed to cool down. The temperature at which precipitation/crystallization started is indicated in the table below.
  • the reaction mixture was further cooled down to 13-17 °C, as appropriate, and was held at this temperature for about 2h
  • the solid was filtered (A41 filter paper) under reduced pressure, and the filter cake was washed twice with 50 ml (10-15% of total solvent volume) of cold MTBE (vacuum was stopped before each solvent addition and resumed immediately after addition) .
  • the cake was dried under reduced pressure (at 36 °C) to yield the corresponding ammonium salt.
  • the filtrate was recycled as a solvent in three consecutive salt formation reactions.
  • the amount of crude CDA dissolved in the recycled solvent was equal to the equivalent amount of CDA isolated as the CHA salt in the previous run.
  • an equimolar amount of cyclohexylamine salt was gradually added, with evolution of heat.
  • the reaction mixture was cooled down to 14-17°C, to induce crystallization.
  • a crop of CDA cyclohexylamine salt was collected by filtration, washed as above, with the filtrate moving to the next run.
  • the conditions of the four successive precipitation reactions and the results are shown in Figure 2 and Table 4.
  • Table 4 The assay and yield of the CDA in the precipitated CDA-CHA salt was carried out by HPLC : a sample was acidified in the sample medium (ACN/HsPCh/water) , so the actual analyte was the free CDA.
  • the expected CDA assay was predicted assuming that all CDA in the precipitate is CDA-CHA, this value allows the evaluation of the selectivity of the precipitation (i.e., no selectivity will result in a predicted assay of ⁇ 65% as in the starting crude CDA, maximum selectivity - only CDA-CHA salt is precipitated - will give a predicted assay of 100%) .
  • the theoretical yield of the cycle is the ratio between the content of CDA in the crude CDA added in the cycle and the content of CDA in the precipitation.
  • the total amount of CDA cyclohexylamine salt collected after the four successive runs was 13.4g.
  • the assay of the free CDA was 88%.
  • the acidification is shown in the flowchart appended as Figure 3.
  • the total yield of CDA from the crude product was 63% of the CDA content in the crude.
  • Figure 4 is an HPLC chromatogram of the crude CDA (red, CDA assay 67%) and purified free CDA (blue, CDA assay 88%) .
  • the characteristic CDA peaks at 13.4' have the same height in both chromatograms, but minor peaks assigned to the impurities are significantly smaller in the chromatogram of the purified CDA (blue) .
  • Figure 5 is a 1 H-NMR spectrum of the purified free CDA and is devoid of peaks assigned to the cyclohexylamine base. Examples 20A-20B Reaction of CDA with cyclohexylamine in DCM/t-BME and characterization of the CDA-CHA salt
  • Figure 6 shows GC chromatograms of commercial cyclohexylamine (top) , a CDA-cyclohexylamine salt corresponding to the procedure of Example 20A (middle) and the purified free CDA resulting from Example 20A (bottom) .
  • a suitable crystal obtained using the procedures of the previous Example was selected and the data was collected on a diffractometer (wavelength: 1.54184 A) .
  • the crystal was kept at 100.15K during data collection.
  • 01ex2 the structure was solved with the olex2. solve structure solution program using Charge Flipping and refined with the SHELXL refinement package using Least Squares minimization. Details of the crystal are tabulated in Table 5.

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

Abstract

L'invention concerne un procédé consistant à faire réagir un acide cis-2-alcénoïque brut avec une base amine et à isoler le sel d'ammonium résultant de l'acide cis-2-alcénoïque sous une forme solide, à partir d'un solvant organique ou d'un mélange de solvants organiques. Le procédé peut être utilisé pour purifier l'acide cis-2-décénoïque brut. Le sel de cyclohexylammonium cristallin d'acide cis-2-décénoïque constitue un autre aspect de l'invention.
PCT/IL2025/050574 2024-07-07 2025-07-06 Purification d'acides cis-2-alcénoïques Pending WO2026013665A1 (fr)

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US8748486B2 (en) 2003-10-10 2014-06-10 Agency For Science, Technology And Research Inhibitors of yeast filamentous growth and method of their manufacture
WO2008143889A1 (fr) 2007-05-14 2008-11-27 Research Foundation Of State University Of New York Induction d'une réponse de dispersion physiologique dans des cellules bactériennes présentes dans un biofilm
WO2020240559A1 (fr) 2019-05-28 2020-12-03 Bromine Compounds Ltd. Procédé et composition de traitement de l'eau
JP2020199606A (ja) 2019-06-11 2020-12-17 株式会社マキタ 打撃工具
WO2022118309A1 (fr) 2020-12-01 2022-06-09 Bromine Compounds Ltd. Préparation d'acides cis-2-alcénoïques
WO2023238135A1 (fr) 2022-06-08 2023-12-14 Bromine Compounds Ltd. Préparation et purification d'acides cis-2-alcénoïques

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