Preparation and purification of cis-2-enoic acids

Abstract

A process for purifying a crude cis-2-olefine acid by thermal separation, the process comprising subjecting the crude cis-2-olefine acid to wiped-film evaporation or vacuum distillation under a temperature-reduced pressure curve, thereby minimizing the isomerization of the cis-2-olefine acid to trans-2-olefine acid.

Description

[0001] The present invention relates to the synthesis and purification of long-chain cis-α,β-unsaturated acids (i.e., cis-2-enoic acids) having the formula R-CH=CH-COOH, wherein R represents an alkyl residue (linear or branched) containing, for example, not less than 4 carbon atoms.

[0002] Long-chain cis-2-enoic acids are reported to act as biodispersants. For example, WO 2008 / 143889 and Journal of Bacteriology 191: 1393-1403 (2009) show that cis-2-decenoic acid produced by the bacterium Pseudomonas aeruginosa can induce a physiologically mediated dispersion reaction of Pseudomonas aeruginosa and other Gram-negative and Gram-positive bacteria and fungi, leading to the disaggregation of surface-associated microbial populations and communities (called biofilms).

[0003] In the co-assigned WO 2020 / 240559, it was demonstrated that cis-2-decenoic acid can be used as an effective adjuvant for bromine-containing fungicides for treating biofilms and planktonic bacteria in water systems and on surfaces in contact with water, achieving significantly enhanced killing of bacteria in both pure and mixed cultures commonly found in industrial and natural waters compared to treatment with bromine-containing fungicides alone. Notably, it was shown in WO 2020 / 240559 that satisfactory enhancement of bromine-based water treatment can be achieved with moderately pure cis-2-decenoic acid (e.g., 80-95%) (by gas chromatography, GC area %).

[0004] WO 2020 / 240559 (Preparation 3) shows the purification of cis-2-decenoic acid by liquid-solid column chromatography. The experimental results reported below show that very high purity levels are achieved by liquid-solid column chromatography, but the yields are often unsatisfactory. For example, using silica gel as an adsorbent, using saturated hydrocarbons (heptane or hexane) and esters (ethyl acetate) as solvents, similar to Preparation 3 of WO 2020 / 240559, purity levels of up to 99% HPLC area% are achieved, but the yield of the final product is quite low (~25%-40% yield).

[0006] Cahiez et al. (“Stereospecific syntheses of alkenyllithium reagents from alkenyl iodides”, Synthesis, 1976, 4, 245-8) reported the synthesis of cis-2-decenoic acid and its purification by distillation, indicating a boiling point of 102-103° / 0.5 torr.

[0007] We have found that purification of cis-2-enoic acid (e.g., cis-2-decenoic acid) by thermal separation methods can result in isomerization of cis-isomers to trans-isomers. If the thermal separation by evaporation / distillation is improperly controlled, the amount of trans-isomers can exceed 1.0% (HPLC area). However, although cis-2-enoic acid has thermal instability, process variables (e.g., reduced pressure, temperature, and time) can be adjusted to suppress the formation of undesirable impurities driven by high temperatures. The experimental results shown below show that high assay values ​​(≥90%) and excellent purification yields (70%-90%) can be achieved, particularly with wiped film evaporation.

[0008] Thus, the present invention is generally directed to a process for purifying crude cis-2-enoic acid by thermal separation, the process comprising subjecting the crude cis-2-enoic acid to wiped-film evaporation or vacuum distillation at a temperature-reduced pressure curve to minimize isomerization of cis-2-enoic acid to trans-2-enoic acid.

[0009] The cis-2-enoic acid is preferably cis-2-decenoic acid and is purified by wiped film evaporation at a temperature of not less than 150° C. (e.g., 150° C. to 180° C.) and a reduced pressure of <5 mbar (e.g., 1 mbar-5 mbar, or 2 mbar-5 mbar, such as 2 mbar-4 mbar) to inhibit isomerization of the cis isomer to the trans isomer, such that the level of the trans isomer is less than 1.0% by HPLC area. The wiped film evaporation may include the step of collecting the condensate and returning it to the feed stream (to achieve the target assay value).

[0010] Crude cis-2-enoic acid obtained by various synthetic routes can be purified by the thermal separation method of the present invention (e.g., wiped film evaporation). However, crude cis-2-enoic acid prepared by a two-step process (including bromination of 2-alkanone to obtain 1,3-dibromo-2-alkanone; and rearrangement of 1,3-dibromo-2-alkanone to cis-2-enoic acid) can particularly benefit from purification by wiped film evaporation. This synthetic route is now described in detail, with reference to our previous patent application PCT / IL2021 / 051423 (≡WO 2022 / 118309).

[0011] The synthesis is based on a two-step process involving the bromination of the corresponding 2-alkanone to give crude 1,3-dibromo-2-alkanone as the major product accompanied by other isomers, followed by the rearrangement of the 1,3-dibromo-2-alkanone to the unsaturated acid, as shown in the following scheme: [wherein R' is an alkyl group, such as C2H5, C3H7, C4H9, C5H 11 and C6H 13The above two-step synthesis was first described by Rappe et al. in [Acta Chemica Scandinavica (1965), Vol. 19, p. 383-389]. The rearrangement occurs in an alkaline environment, using alkali metal carbonates or alkali metal bicarbonates as bases. The same research group reported a similar approach in Organic Syntheses (1973), Vol. 53, p. 123-127.

[0012] An attempt to modify this two-step synthetic pathway is found in US 8,748,486, where it is explained that alkali metal bicarbonates are only effective in promoting the preparation of short-chain cis-α,β-unsaturated acids. The authors report that the rearrangement reaction of long-chain bromoketones (e.g., 1,3-dibromo-2-decanone) in the presence of alkali metal bicarbonates is very slow and fails to give the desired fatty acids even after extended reaction times. The authors instead use alkali metal hydroxides to promote the preparation of long-chain cis-α,β-unsaturated acids (the terms "cis-α,β-unsaturated acids" and "cis-2-enoic acids" are used interchangeably).

[0013] Regarding this synthetic route, the experimental results reported below are consistent with the observations made in US 8,748,486: at alkaline pH, even at high reaction temperatures, the rearrangement reaction of long-chain 1,3-dibromo-2-alkanones hardly progresses and is prone to thermal runaway (a sudden and rapid rise in reaction temperature). Such a reaction profile is unacceptable for a process run on an industrial scale.

[0014] However, it was found that a quantitative amount of the target cis-2-enoic acid alkali metal salt should be provided in the reaction mixture to promote the rearrangement reaction of 1,3-dibromo-2-alkanone in an efficient and easily controlled manner to obtain cis-2-enoic acid. As shown below, the added cis-2-enoic acid alkali metal salt can be supplied to the rearrangement reaction from the previous round of experiments. With the help of a small amount of cis-2-enoic acid or its salt added at the beginning of the rearrangement reaction, an easily controlled process is provided.

[0015] Thus, the synthesis is based on a process for preparing a cis-2-enoic acid [R-CH=CH-COOH] or an alkali metal salt thereof [R-CH=CH-COOM, wherein M is an alkali metal], the synthesis comprising rearranging 1,3-dibromo-2-alkanone [R-CHBr-C(O)-CH2Br] in an alkaline environment (e.g., an alkaline environment generated from an alkali metal carbonate, or an alkali metal carbonate / bicarbonate mixture) in the presence of a catalytically effective amount of an alkali metal salt of a cis-2-enoic acid, and isolating the cis-2-enoic acid from the reaction mixture, the cis-2-enoic acid being in the form of a free acid or in the form of an alkali metal salt (e.g., by separating the reaction mixture into an aqueous phase and an organic phase, and treating the aqueous phase to recover the cis-2-enoic acid therefrom, the cis-2-enoic acid being in the form of a free acid or in the form of an alkali metal salt).

[0016] R is an alkyl group containing not less than four carbon atoms, for example, not less than five carbon atoms, for example, R is a C4-C11 alkyl group. For example, cis-2-decenoic acid (R is C7H 15 ) is collected as an oil. When the cis-2-decenoic acid thus formed is reacted with an alkali metal hydroxide (eg KOH), the corresponding potassium salt is obtained as a pasty solid.

[0017] The cis-2-enoic acid R-CH=CH-COOH prepared by the above synthetic route and purified by the present invention is preferably straight chain. That is, R is usually a straight chain alkyl CH3-(CH2) n -(3≤n, for example, 3≤n≤10, 3≤n≤6). For example, the preparation of cis-2-enoic acid by rearrangement of the corresponding 1,3-dibromo-2-alkanone as described below was studied (but it should be noted that R is not limited to a straight chain and can be a branched alkyl group, such as an isoalkyl group): 1,3-Dibromo-2-heptanone 1,3-Dibromo-2-octanone 1,3-Dibromo-2-nonanone 1,3-Dibromo-2-decanone 1,3-Dibromo-2-undecanone

[0018] And it is found that all of them benefit from the addition of a catalytically effective amount of the target cis-2-enoic acid or its alkali metal salt to the alkaline reaction mixture. The so-called "catalytically effective amount" means an addition amount of up to 15 mol%, for example, up to 10 mol%, such as 1 mol% to 5 mol%, based on 1,3-dibromo-2-alkanone.

[0019] The 1,3-dibromo-2-alkanones that undergo the rearrangement reaction are most conveniently prepared by brominating the corresponding 2-alkanone [R-CH2-C(O)-CH3] (e.g., 2-heptanone, 2-octanone, 2-nonanone, 2-decanone, or 2-undecanone) by slow addition of elemental bromine (stoichiometry dictates a molar ratio of Br2:2-alkanone of ~2:1) in concentrated hydrobromic acid (e.g., 30 wt% to 48 wt% HBr solution).

[0020] The weight ratio of the 2-alkanone starting material to the aqueous HBr solution is 1:1 to 1:2. The reaction medium is cooled to a temperature in the range of 5°C to 20°C, for example, about 5°C to 10°C. Under these conditions, elemental bromine is smoothly added to the 2-alkanone, with the majority of the reaction occurring during the addition of bromine; no accumulation of bromine is observed (marked by a characteristic yellow coloration of the reaction mixture).

[0021] On a laboratory scale, the addition time of bromine is typically 1 hour to 5 hours. After the addition of elemental bromine is complete, the reaction mixture is held at room temperature (15°C-25°C) for a period of time ("holding time"), optionally with stirring. The holding time may last from 6 hours to 24 hours, for example, from 6 hours to 12 hours. Longer holding times appear to be advantageous because the bromination reaction of 2-alkanone produces some isomeric by-products, primarily 3,3-dibromo-2-alkanone. GC analysis of the reaction mixture shows that the desired isomer 1,3-dibromo-2-alkanone gradually becomes the major product over time, i.e., an extended holding time enables a significant conversion of 3,3-dibromo-ketone to 1,3-dibromoketone.

[0022] In order to illustrate the importance of extended retention time in altering the distribution of an isomeric mixture comprising 1,3-dibromo-2-alkanone and 3,3-dibromo-2-alkanone in favor of the former and to the detriment of the latter, experimental data (reported in the following working examples) for bromination procedures based on 2-nonanone, 2-decanone or 2-undecanone are listed in Table A.

[0023] Table A

[0024] * In T R Time after bromine addition is completed at about 20°C

[0025] **Other impurities (including isomers of 3-bromo-2-alkanone and tribromo-2-alkanone) are also present

[0026] It can be seen that the product mixtures obtained by brominating different 2-alkanones in hydrobromic acid exhibit similar behavior after long holding times. Initially, the mixture contains 1,3-dibromo-2-alkanone and 3,3-dibromo-2-alkanone in a ratio of about 2:1; after about 20 hours, the ratio is higher than 10:1, and as the equilibrium stabilizes, the desired isomer suitable for rearrangement reaction (i.e., 1,3-dibromo-2-alkanone) reaches about 70% (GC area %).

[0027] During the bromine addition and subsequent hold period, evolution of hydrogen bromide occurs; this gas is absorbed into a suitable aqueous medium and collected as aqueous hydrobromic acid.

[0028] To recover the crude 1,3-dibromo-2-alkanone, the reaction mixture was treated by adding water and then separated into an aqueous phase (containing about 48% w / w hydrobromic acid) and an organic phase (containing the crude product). Typically, as shown by the data listed in Table A, the recovered crude product contained about 70% (GC area) of 1,3-dibromo-2-alkanone.

[0029] Therefore, the 1,3-dibromo-2-alkanone used in the rearrangement reaction is crude 1,3-dibromo-2-alkanone obtained by the following steps:

[0030] Bromination of the corresponding 2-alkanone in concentrated hydrobromic acid by addition of elemental bromine to form 1,3-dibromo-2-alkanone accompanied by 3,3-dibromo-2-alkanone in the reaction mixture;

[0031] The reaction mixture is maintained for a holding time adjusted to maximize conversion of 3,3-dibromo-2-alkanone to 1,3-dibromo-2-alkanone (e.g., to achieve >65%, >67%, >69% (GC area %) of 1,3-dibromo-2-alkanone); and crude 1,3-dibromo-2-alkanone is collected.

[0032] The crude 1,3-dibromo-2-alkanone can be subjected to the rearrangement reaction without further purification. However, the present invention is not limited to the rearrangement of 1,3-dibromo-2-alkanone obtained by brominating 2-alkanone in concentrated hydrobromic acid; other methods for preparing 1,3-dibromo-2-alkanone reported in the literature can be used, for example, brominating 2-alkanone with the aid of an acceptable brominating agent in an organic solvent (such as a halogenated hydrocarbon CH2Cl2 or CH2Br2).

[0033] A convenient way to carry out the rearrangement reaction comprises gradually adding 1,3-dibromo-2-alkanone to a reaction vessel previously charged with a basic aqueous solution (e.g., comprising 10% to 30% w / w Na2CO3, K2CO3 or a mixture thereof (dissolved in water), or a carbonate / bicarbonate mixture) and a catalytically effective amount of an alkali metal salt of a cis-2-enoic acid, at an elevated temperature (e.g., ≥35° C., such as ≥40° C.), for example, when the reaction mixture is maintained at a temperature in the range of 40° C. to 60° C. The molar ratio of the added 1,3-dibromo-2-alkanone to the carbonate is 1:2 to 1:4, such as about 1:3 to 1:3.5.

[0034] The use of potassium carbonate, for example, is preferred over sodium carbonate because, as shown below, the corresponding alkali metal bicarbonate is a by-product of the rearrangement reaction. When potassium salts are used, fewer difficulties may be encountered in the work-up stage of the reaction mixture due to the higher solubility of potassium bicarbonate in water than sodium bicarbonate.

[0035] The reaction occurs during the addition of 1,3-dibromo-2-alkanone to the alkaline reaction mixture in the presence of an alkali metal salt of a cis-2-enoic acid. The reaction occurs with a decrease in pH (i.e., during the addition of 1,3-dibromo-2-alkanone, the initial strongly alkaline pH of 12-14 decreases by at least 2 pH units, such as by 2-4 pH units) and a temperature increase of about 5°C to 10°C (i.e., ΔT 反应器 ) as the logo.

[0036] In contrast, if 1,3-dibromo-2-alkanone is added to the alkaline solution without the cis-2-enoic acid alkali metal salt, the rearrangement of 1,3-dibromo-2-alkanone progresses slowly and the added 1,3-dibromo-2-alkanone accumulates in the reaction vessel. The experimental results shown below show that during the addition of crude 1,3-dibromo-2-alkanone, the rearrangement of 1,3-dibromo-2-heptanone, 1,3-dibromo-2-octanone and 1,3-dibromo-2-nonanone does not occur. Only after the addition of crude 1,3-dibromo-2-alkanone is complete, the pH begins to drop and T R The reaction proceeds as the reactor temperature begins to rise spontaneously. The rearrangement of higher homologues (e.g., 1,3-dibromo-2-decanone and 1,3-dibromo-2-undecanone) is more difficult and makes little progress without the aid of a catalytically effective amount of an alkali metal salt of a cis-2-enoic acid.

[0037] After the slow addition of crude 1,3-dibromo-2-alkanone is complete (on a laboratory scale this can last from 30 minutes to 120 minutes), the reaction mixture is kept under stirring at a temperature in the range of 50°C to 55°C for a period of time, i.e. a cooking period of several (1 to 3) hours, to allow the reaction to complete. A pH drop of about 0.5 to 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 1,3-dibromo-2-alkanone, i.e. a drop to ≤ 1%, area %).

[0038] After the rearrangement reaction is complete, the reaction mixture is cooled to room temperature and separated into an aqueous phase (heavy phase) and an organic phase (light phase). The organic phase (which contains unreacted bromoisomers accompanying 1,3-dibromo-2-alkanone, primarily 3-bromo-2-alkanone and 3,3-dibromo-2-alkanone; as well as some condensation by-products formed during the rearrangement reaction) can be discarded. The aqueous phase (which contains the cis-2-enoic acid in the form of its alkali metal salt (i.e., sodium or potassium salt, depending on the base selected)) is treated to isolate the product.

[0039] An exemplary rearrangement reaction is illustrated by the scheme described below, using K2CO3 to convert 1,3-dibromo-2-decanone (1,3-DBD) to the potassium salt of cis-2-decenoic acid (abbreviated CDA-K):

[0040] AP-RM represents a catalytically effective amount of a cis-2-enoic acid alkali metal salt added in advance to start the rearrangement reaction. As noted above, a catalytically effective amount of a cis-2-enoic acid alkali metal salt is supplied to the reaction in aqueous form, for example, by removing a relatively small portion of the aqueous phase collected after phase separation, and retaining this small portion for addition in the next round of testing of the process. Typically, this small portion accounts for 1wt% to 10wt% of the total weight of the aqueous phase, for example, 3wt% to 7wt% (about 5wt%). Based on the concentration of the cis-2-enoic acid alkali metal salt, it can be understood that the catalytically effective amount of the salt added in the alkaline solution before the rearrangement reaction begins is preferably 1 mole percent to 5 mole percent relative to 1,3-dibromo-2-alkanone.

[0041] However, it should be mentioned that there are other ways of supplying the cis-2-enoic acid alkali metal salt for the rearrangement reaction, for example by direct addition of the free acid or a salt from another source (if the free acid is added instead of an alkali metal salt, the acid will react in a basic solution to form the corresponding basic salt in situ).

[0042] Next, the major portion of the aqueous phase is treated by washing with a water-immiscible organic solvent (eg, a halogenated hydrocarbon such as dichloromethane) (repeated washing cycles may be required) to extract and remove organic impurities from the aqueous solution containing the product.

[0043] When the reaction mixture obtained cannot be separated into an aqueous phase and an organic phase, it is (optionally) diluted with water and washed with an organic solvent immiscible with water, followed by phase separation to collect a purified aqueous phase containing the product, which can be divided into a minor portion and a major portion as described above. The minor portion is used for the next round of experiments, while the major portion is processed to recover the product therefrom.

[0044] In order to recover the product in the form of the free acid, the purified aqueous solution is acidified, for example with the aid of concentrated hydrochloric acid (e.g., commercially available 32% HCl solution), which is slowly added to the aqueous solution to reach a strongly acidic pH (e.g., 1 to 2). The acidified reaction mixture is separated into an aqueous phase (heavy phase) and an organic phase (light phase). The former comprises bromide salts and chloride salts; the latter comprises crude cis-2-decenoic acid and possibly some residual organic solvent used in the washing stage, as well as water, which are removed, for example, by evaporation under vacuum, to obtain crude cis-2-enoic acid.

[0045] The sequence of reactions that occur when the aqueous solution is acidified (specifically, in the preparation of the potassium salt of cis-2-decenoic acid) is as follows: (1)3KHCO3+3HCl→3KCl+3CO2↑+3H2O

[0046] Therefore, the process for preparing crude cis-2-enoic acid further comprises acidification of the purified aqueous phase (i.e. after extraction with an organic solvent) to obtain a biphasic medium comprising a heavy aqueous phase containing salts and a light organic phase consisting essentially of cis-2-enoic acid in the free acid form.

[0047] The corresponding alkali metal salt can be prepared by conventional methods, for example, by reacting the free acid with potassium hydroxide in a suitable solvent and isolating it by crystallization and filtration, followed by drying.

[0048] As indicated above, the crude cis-2-enoic acids obtained by the process of the present invention do not require further purification, i.e., the purity of these acids is sufficient for use as biodispersants in bromine-based water treatment, i.e., their purity levels are >80%, >85%, >87%, such as 80% to 95% (in GC area %). Characteristic purity levels of the crude acids are listed in Table B below. However, if desired, the crude acids can be purified by conventional techniques (e.g., chromatography or distillation) or by the method of the present invention, which is now described in detail.

[0049] Table B

[0050] Purification of crude cis-2-enoic acid by various methods was investigated. In the study shown below, CDA with a HPLC assay value of ˜70% (absolute quantification based on calibration with a commercial external standard (≥97%)) was purified by chromatography and thermal separation techniques such as vacuum distillation and wiped film evaporation. The goal of this study was to achieve high purity CDA (≥90% based on the HPLC assay value above, or ≥95% HPLC purity (relative) based on area %), and industrially acceptable yields (≥60%; ≥70%; ≥75%; e.g., 60% to 80% or 80% to 90%-95%).

[0051] The experimental results reported below show that very high purity levels were achieved by liquid-solid column chromatography, but the yields were often unsatisfactory. For example, using silica gel as adsorbent, saturated hydrocarbons (heptane or hexane) and esters (ethyl acetate) as solvents, similar to Preparation 3 of WO 2020 / 240559, purity levels of up to 99% HPLC area% were achieved, but the yields of the final product were quite low (~25%-40% yield).

[0052] In contrast, purification by thermal separation, such as wiped film evaporation (thin film evaporation), has been found to be suitable for large-scale production because it compromises high purity product with acceptable yield. Although cis-2-enoic acid is thermally instable, process variables such as reduced pressure, temperature and time can be adjusted to suppress the formation of undesirable impurities driven by high temperature. The evaluation of the impurity profile of CDA reported below shows that at high temperature and reduced pressure, the major impurities include the trans isomer of the acid (produced by isomerization of the desired cis isomer) and bromomethylenenonanoic acid (present in crude CDA and originates from the intermediate impurity 1,3,3-dibromodecane formed during bromination of decanone). The latter is usually the major impurity, but the trans isomer is also not insignificant and can exceed 1.0% if the evaporation / distillation is not properly controlled. Therefore, by carrying out wiped film evaporation at a temperature not lower than 150° C. (e.g., in the range of 150° C. to 180° C. or 150° C. to 190° C.), the preparation of a product with a high assay value (≥90%) and excellent production yield (60%-80%) can be achieved. When the pressure is reduced as much as possible (<5 mbar), the isomerization of the cis isomer to the trans isomer is effectively suppressed (<3%, e.g., <1%) without showing a decrease in product yield.

[0053] For example, efficient purification of cis-2-enoic acid can be achieved by thermal separation with the aid of a wiped film evaporator or a short path evaporator, operating at a feed rate in the range of 14 ml / min to 25 ml / min, a heating temperature of 150° C. to 180° C., wherein the evaporator is maintained at a low vacuum (down to 2 mbar-5 mbar), and the evaporator size is 0.12 m 2 The wetted materials are usually made of stainless steel or glass. The film thickness formed is usually <1mm. The vapor is condensed on the condenser and the distillate is collected.

[0054] In wiped film evaporation (WFE), the feed flow rate is also another adjustable process variable. For example, in a small pilot scale, an industrially desirable D / F ratio (defined as the ratio between the distillate flow leaving the distillation unit and the feed flow entering the unit) of not less than 50% (e.g., >60%) was achieved when the feed flow rate was maintained in the range of 13 ml / min-25 ml / min (e.g., 14 ml / min-18 ml / min; ˜14 ml / min-15 ml / min) at 150° C. and in the range of 32 ml / min-37 ml / min (e.g., 33 ml / min-35 ml / min) at 180° C. Higher feed flow rates can be used for larger sized evaporators (as shown in the pilot study reported below).

[0055] Vacuum pumps that can be used to reduce the pressure to <4.5 mbar include oil pumps, such as Edwards two-stage oil pumps. The pump used to deliver the feed is, for example, a peristaltic pump, such as a Watson-Marlow 505U pump.

[0056] Thus, the process for preparing cis-2-enoic acid as described herein is optionally followed by a purification step, which comprises thermal separation by wiped film evaporation; for example, the crude cis-2-enoic acid is subjected to wiped film evaporation while maintaining a temperature-reduced pressure profile during the wiped film evaporation, thereby suppressing isomerization of the cis-2-enoic acid to the trans isomer (e.g., less than 1.0% by HPLC area %) while increasing the yield (e.g., >60%, >70%, >80%, 90%). For example, the temperature-reduced pressure-time profile is maintained by adjusting the temperature, vacuum, and feed flow rate as described above.

[0057] In large-scale production, two-stage wiped film evaporation can be advantageous, performing two distillations in one test, e.g., collecting the condensate and returning the condensate to the feed stream, to achieve good results, e.g., evaporation yields of 60%-90% (e.g., 70%-90%), and high purity (HPLC assay value>90%).

[0058] CDA produced by different synthetic methods can benefit from the purification techniques described herein. Therefore, another aspect of the invention is a method of purifying cis-2-enoic acid (eg, CDA) by thermal separation (eg, wiped film evaporation (using the conditions described above)) and vacuum distillation. In the attached figure

[0059] Figure 1A , Figure 1B and Figure 1C is the CDA of Example 1 1 H-NMR spectrum.

[0060] Figure 2A , Figure 2B and Figure 2C is the CDA of Example 2 1 H-NMR spectrum.

[0061] Figure 3A , Figure 3B and Figure 3C The CUDA of Example 4 is 1 H-NMR spectrum.

[0062] Figure 4A , Figure 4B and Figure 4C is the CNA of Example 5 1 H-NMR spectrum.

[0063] Figure 5A , Figure 5B and Figure 5C is the COA of Example 6 1 H-NMR spectrum.

[0064] Fig. 6A , Figure 6B and Figure 6C is the CHA of Example 7 1 H-NMR spectrum.

[0065] Fig. 7A , Figure 7B and Figure 7C is the CDA of Example 8B 1 H-NMR spectrum.

[0066] Fig. 8A and Figure 8B is the CDA of Example 8B 13 C-NMR spectrum.

[0067] Fig.9A , Fig. 9B and Fig. 9C is the CDA of Example 11 1 H-NMR spectrum.

[0068] Fig. 10A and Fig. 10B is the CDA of Example 11 13 C-NMR spectrum.

[0069] Fig.11A and Fig. 11B The isomerization of the cis isomer to the trans isomer is shown at 150°C and 180°C, respectively. Example

[0070] method

[0071] GC: Gas Chromatograph HP 7890A

[0072] Method (CDA): Initial temperature 50°C, hold for 2 minutes, then increase to 280°C at 10°C / min and hold for 5 minutes, then increase to 300°C at 10°C / min and hold for 2 minutes.

[0073] Injector: 250℃

[0074] Detector: 300℃

[0075] Split ratio: 1:40

[0076] Product sample concentration: ~20 mg / ml DCM

[0077] Injection volume: 1 μl sample

[0078] Column: Agilent J&W Columns, HP-5, 30m x 0.32mm x 0.25μ

[0079] Part No. 19091J-413, Serial No. USF302346H

[0080] 1 H-NMR spectroscopy

[0081] Spectra were collected on an Avance III, 500 MHz instrument.

[0082] HPLC: Agilent 1220 LC system

[0083] Chromatographic conditions for CDA

[0084] Wavelength: λ = 214nm

[0085] Column: Akzo Nobel, Kromasil, 250mm*4.6mm ID*5μm+pre-column C18

[0086] Mobile phase: [A] H2O + 0.1% H3PO4 (conc. 85%):

[0087] [B] Acetonitrile (AcN)

[0088] Gradient curve:

[0089]

[0090] Follow-up time: 9 minutes

[0091] Flow rate: 1.0ml / min

[0092] Injection volume: 5.0 μl

[0093] Column temperature: 25°C

[0094] Sample temperature: 20℃

[0095] CDA retention time: 14.6 minutes

[0096] Example 1

[0097] Preparation of cis-2-decenoic acid

[0098] Step 1:

[0099] Bromine (410 g, 2.56 mol) was added dropwise over 2 hours to a mixture of 2-decanone (200 g, 1.28 mol) and 48% aqueous HBr (300 g) stirred and cooled to ~10° C. The reaction started immediately with the start of bromine addition, and no accumulation of bromine was observed.

[0100] The reaction is exothermic and is accompanied by the emission of HBr gas (before the end of bromine addition), which is absorbed in a scrubber.

[0101] Most of the reaction occurred during the bromine addition and was cooked at room temperature (~20°C) for 6 hours. After standing overnight (~15 hours) at room temperature without stirring, the composition of the reaction mixture stabilized. Partial conversion of 3,3-dibromo-2-decanone (3,3-DBD) to the desired product 1,3-dibromo-2-decanone (1,3-DBD) occurred. Water (160 g) was added to the reaction mixture at room temperature, stirred for 30 minutes, and the phases separated.

[0102] An aqueous phase (627 g) containing -50% HBr (d = 1.51 g / ml) and crude DBD (404 g, d = 1.43 g / ml) was obtained. The concentration of 1,3-DBD in the crude product was 69.6% (GC, area %).

[0103] Step 2:

[0104] In a 1 L stirred reactor, a 25% w / w concentration of K2CO3 aqueous solution was prepared by adding K2CO3 (200 g) in portions to water (600 g). The reaction was exothermic. To this solution was added a portion of the aqueous phase (containing CDA-K) of the reaction mixture (50 g) remaining from the previous run (referred to as AP-RM, see Comparative Example 3). The resulting clear solution was heated to 40°C and crude DBD (200 g) from step 1 was added dropwise to the solution over 60 minutes. The progress of the reaction was monitored by GC and pH changes. The reaction was completed by boiling at 50°C for 3.0 hours under mechanical stirring.

[0105] It should be noted that without the addition of AP-RM, the reaction started spontaneously only two hours after the addition of crude DBD.

[0106] The end of the reaction was determined by pH (pH dropped from 13.3 to 9.3) and GC analysis of the reaction mixture (1,3-DBD disappeared to ≤1%, area %). After the reaction was completed, it was cooled to room temperature and stirring was stopped. An organic phase appeared above the aqueous phase, which contained unreacted 3-bromo-2-decanone (3-BD) and 3,3-DBD, as well as by-products formed by the condensation reaction of crude DBD. The phases were separated. The organic phase (39 g) was an organic waste. 50 g of the aqueous phase was taken for the next round of testing.

[0107] To reduce the amount of impurities to a minimum, the remaining aqueous phase (950 g) was washed three times with dichloromethane (DCM, 3 x 250 g).

[0108] After the washing stage, an aqueous phase containing cis-2-decenoic acid potassium salt (CDA-K), organic byproducts, KBr and KHCO3 is obtained. To obtain crude cis-2-decenoic acid (CDA), the aqueous phase is acidified by dropwise addition of 32% aqueous HCl solution (193 g) over 1 hour. During the acidification (final pH = 1.1), CO2 (calculated as 63 g) is emitted.

[0109] After stopping stirring, an aqueous phase (955 g) containing salts (KCl and KBr) (heavy phase, d=1.19 g / ml) and wet crude CDA (light phase, 71 g, d=1.07 g / ml) were obtained.

[0110] Under vacuum (T B =50°C) to evaporate DCM and light fractions from wet CDA to give crude CDA (50.5 g), which was analyzed by GC and 1 H-NMR analysis (see Figure 1A , Figure 1B and Figure 1C of 1H-NMR spectrum). The calculated yield of crude CDA is -68% based on 1,3-DBD or 46.8% based on 2-decanone.

[0111] The purity of the obtained crude CDA was 88.2% (in terms of GC area %). The main impurity in the crude product was 2-bromomethylenenonanoic acid (BMNA): 8.8% (in terms of GC area %).

[0112] Example 2

[0113] Preparation of cis-2-decenoic acid

[0114] Step 1:

[0115] Bromine (800 g, 5 mol) was added dropwise over 5 hours to a mixture of 2-decanone (400 g, 2.564 mol) and 48% aqueous HBr (600 g) stirred and cooled to ~10°C. The reaction started immediately with the start of bromine addition, and no accumulation of bromine was observed. The reaction was exothermic and accompanied by the emission of HBr gas (before the end of bromine addition), which was absorbed in a scrubber.

[0116] Most of the reaction occurred during the bromine addition, and the composition of the reaction mixture stabilized after standing overnight at room temperature without stirring. Partial conversion of 3,3-dibromo-2-decanone (3,3-DBD) to the desired product 1,3-dibromo-2-decanone (1,3-DBD) occurred. Water (300 g) was added to the reaction mixture at room temperature, stirred for 30 minutes, and the phases were separated.

[0117] An aqueous phase (1207 g) containing -49.5% HBr (d = 1.51 g / ml) and crude DBD (789 g, d = 1.42 g / ml) was obtained. The concentration of 1,3-DBD in the crude product was 70.4% (GC, area %).

[0118] Step 2:

[0119] In a 2 L stirred reactor, a 25% w / w concentration of K2CO3 in water was prepared by adding K2CO3 (400 g) in portions to water (1200 g). The reaction was exothermic. To this solution was added a portion of the aqueous phase of the CDA-K reaction mixture (50 g) remaining from the previous run. The resulting clear solution was heated to 40°C and crude DBD (step 1, 400 g) was added dropwise to the solution over 70 minutes. The progress of the reaction was monitored by GC and pH changes. The reaction was completed by cooking at 40°C for 1.0 hour and then at 50°C for 2.0 hours under mechanical stirring.

[0120] The end of the reaction was determined by pH (pH dropped from 12.7 to 9.6) and GC analysis of the reaction mixture (1,3-DBD disappeared to ≤1%, area %). After the reaction was completed, the mixture was cooled to room temperature and stirring was stopped. An organic phase appeared above the aqueous phase, which contained unreacted 3-BD and 3,3-DBD, as well as by-products formed by the condensation reaction of crude DBD. The phases were separated. 50 g of the aqueous phase was taken for the next round of experiments.

[0121] To reduce the amount of impurities to a minimum, the aqueous phase (1943 g) was washed three times with dichloromethane (DCM, 3 x 500 g).

[0122] After the washing stage, an aqueous phase containing cis-2-decenoic acid potassium salt (CDA-K), organic byproducts, KBr and KHCO3 is obtained. To obtain crude cis-2-decenoic acid (CDA), the aqueous phase is acidified by dropwise addition of 32% aqueous HCl solution (401 g) over 1 hour. During the acidification (final pH = 1.9), CO2 (calculated to be 127 g) is emitted.

[0123] After stopping stirring, a salt (KCl and KBr)-containing aqueous phase (2017 g) (heavy phase, d=1.19 g / ml) and wet crude CDA (light phase, 128 g, d=1.03 g / ml) were obtained.

[0124] Under vacuum (T B =50°C) DCM and light fractions were evaporated from wet CDA to give crude CDA (102 g), which was then analyzed by GC, HPLC and 1 H-NMR analysis ( Figure 2A , Figure 2B and Figure 2C of 1 H-NMR spectrum).

[0125] According to the results, the purity of the obtained crude CDA was 89.7% (GC area %) and 90.0% (HPLC area %). The calculated yield of the crude CDA was ˜67% based on 1,3-DBD.

[0126] Example 3 (Comparative)

[0127] Preparation of cis-2-decenoic acid

[0128] Step 1 is carried out according to Example 1. However, the rearrangement reaction of Step 2 is carried out without adding an alkali metal salt of a cis-2-enoic acid.

[0129] Step 2: In a 1 L stirred reactor, a 25% w / w concentration of K3CO3 aqueous solution was prepared by adding K2CO3 (200 g) in portions to water (600 g). The reaction was exothermic. The resulting clear solution was heated to 40°C and crude DBD (200 g, obtained as described previously) was added dropwise to the solution over 60 minutes. The reaction progress was monitored by GC and pH changes.

[0130] The mixture of aqueous K2CO3 and crude DBD was stirred for 3 hours at 50°C. Based on the pH (unchanged at ~13) and GC, it was seen that the reaction did not occur.

[0131] Then, the temperature in the reactor suddenly began to rise spontaneously, reaching 76°C within 10 minutes. The end of the reaction was determined by pH (pH dropped from 13.3 to 9.5) and GC analysis of the reaction mixture (1,3-DBD disappeared to ≤1%, area %). The phases were separated and 50 g of the aqueous phase was used for the next run (i.e., the procedure of Example 1).

[0132] Example 4

[0133] Preparation of cis-2-undecenoic acid

[0134] Step 1:

[0135] Bromine (410 g, 2.56 mol) was added dropwise over 3 hours to a mixture of 2-undecanone (218 g, 1.28 mol) and 48% aqueous HBr (300 g) stirred and cooled to ~10°C. The reaction started immediately with the start of bromine addition, and no accumulation of bromine was observed. The reaction was exothermic and accompanied by the release of HBr gas (before the end of bromine addition), which was absorbed with a scrubber.

[0136] Most of the reaction occurred during the bromine addition and cooked at room temperature (~20°C) for 3.5 hours. After standing at room temperature overnight (~16.5 hours) without stirring, the composition of the reaction mixture stabilized. Partial conversion of 3,3-dibromo-2-undecanone (3,3-DBUD) to the desired product 1,3-dibromo-2-undecanone (1,3-DBUD) occurred. Water (160 g) was added to the reaction mixture at room temperature, stirred for 30 minutes, and the phases separated.

[0137] An aqueous phase (627 g) containing -50% HBr (d = 1.50 g / ml) and crude DBUD (415 g, d = 1.39 g / ml) was obtained. The concentration of 1,3-DBUD in the crude product was 69.1% (GC, area %).

[0138] Step 2:

[0139] In a 1 L stirred reactor, a 25% w / w concentration of K2CO3 aqueous solution was prepared by adding K2CO3 (200 g) portionwise to water (600 g). The reaction was exothermic. The resulting clear solution was heated to 40°C and crude DBUD (200 g) from step 1 was added dropwise to the solution over 20 minutes. The reaction progress was monitored by GC and pH changes.

[0140] The mixture of aqueous K2CO3 and crude DBUD was stirred at 50°C for 1 hour, at 60°C for 1.5 hours, and then at 70°C for another 1.5 hours. Based on the pH (unchanged at ~13) and GC, it was seen that the reaction did not occur.

[0141] Next, a portion (~10 g) of the aqueous phase of the CDA-K reaction mixture was added dropwise to the reaction mixture over 15 minutes. At the end of the addition, the temperature in the reactor began to rise and reached 82°C within 10 minutes. The mixture was then stirred at 70°C for another 2 hours.

[0142] The completion of the reaction was determined by pH (pH dropped from 13 to 10) and GC analysis of the reaction mixture (disappearance of 1,3-DBUD to ≤ 1%, area %).

[0143] To reduce the amount of impurities to a minimum, the reaction mixture (960 g) was washed three times with dichloromethane (DCM, 3 x 250 g) at room temperature. It should be noted that the first phase separation was slow.

[0144] After the washing stage, an aqueous phase containing cis-2-undecenoic acid potassium salt (CUDA-K), organic byproducts, KBr and KHCO3 is obtained. To obtain crude cis-2-undecenoic acid (CUDA), the aqueous phase is acidified by dropwise addition of 32% aqueous HCl solution (132 g) over 1 hour. During the acidification, CO2 is emitted.

[0145] After stopping stirring, the aqueous phase (762 g) containing salt (KCl and KBr) (heavy phase, d = 1.15 g / ml) and wet crude CUDA (light phase, 53 g, d = 1.07 g / ml) were obtained and analyzed by GC and 1 H-NMR analysis (see Figure 3A , Figure 3B and Figure 3C of 1 H-NMR spectrum). The purity of the obtained crude CUDA was 89.6% (in terms of GC area %). The main impurity in the crude product was 2-bromomethylenedecanoic acid (BMDA): 5.2% (in terms of GC area %).

[0146] Under vacuum (T B=50°C) DCM and light fractions were evaporated from wet CUDA to give crude CUDA (35 g).

[0147] It can be seen that in this example, a small amount of alkali metal salt of homologous acid (CDA-K) was used to promote the preparation of CUDA. The obtained aqueous phase containing potassium salt of cis-2-undecenoic acid (CUDA-K) and trace amounts of CDA-K can be used to supply a catalytically effective amount of CUDA-K for the next run, which is added to the alkaline K2CO3 solution before starting to slowly add crude DBUD to ensure efficient and easy-to-control reactions.

[0148] Example 5 (Comparative)

[0149] Preparation of cis-2-nonenoic acid

[0150] Step 1:

[0151] Bromine (410 g, 2.56 mol) was added dropwise over 3 hours to a mixture of 2-nonanone (from Sigma-Aldrich; 182 g, 1.28 mol) and 48% aqueous HBr (300 g) stirred and cooled to ~10°C. The reaction started immediately with the start of bromine addition, and no accumulation of bromine was observed. The reaction was exothermic with the release of HBr gas (before the end of bromine addition), which was absorbed with a scrubber.

[0152] Most of the reaction occurred during the bromine addition and was cooked at room temperature (~20°C) for 2.0 hours. After standing at room temperature overnight (~17 hours) with stirring, the composition of the reaction mixture stabilized. Partial conversion of 3,3-dibromo-2-nonanone (3,3-DBN) to the desired product 1,3-dibromo-2-nonanone (1,3-DBN) occurred. Water (160 g) was added to the reaction mixture at room temperature, stirred for 30 minutes, and the phases separated.

[0153] An aqueous phase (624 g) containing -50% HBr (d = 1.50 g / ml) and crude DBN (382 g, d = 1.47 g / ml) was obtained. The concentration of 1,3-DBN in the crude product was 70.6% (GC, area %).

[0154] Step 2:

[0155] In a 1 L stirred reactor, a 25% w / w concentration of K2CO3 aqueous solution was prepared by adding K2CO3 (200 g) in portions to water (600 g). The reaction was exothermic. The resulting clear solution was heated to 46°C and crude DBN (191 g) from step 1 was added dropwise to the solution over 45 minutes. The pH and T were varied by HPLC. RMonitor the reaction progress by measuring the changes in

[0156] Based on the pH (unchanged at ~13) and GC, it can be seen that no reaction occurred during the addition of crude DBN. The pH immediately began to drop after the addition of crude DBN, and T R Start rising immediately.

[0157] The end of the reaction was determined by pH (pH dropped from 13.3 to 9.1) and GC analysis of the reaction mixture (disappearance of 1,3-DBN to ≤ 1%, area %). The phases were separated. The organic phase (42.6 g) was organic waste.

[0158] To reduce the amount of impurities to a minimum, the aqueous phase (948 g) was washed three times with dichloromethane (DCM, 3 x 250 g).

[0159] After the washing stage, an aqueous phase containing cis-2-nonenoic acid potassium salt (CNA-K), organic byproducts, KBr and KHCO3 is obtained. To obtain crude cis-2-nonenoic acid (CNA), the aqueous phase is acidified by dropwise addition of 32% aqueous HCl solution (227 g) over 1 hour. During the acidification, CO2 is emitted.

[0160] After stopping stirring, the aqueous phase (978 g) containing salt (KCl and KBr) (heavy phase, d = 1.19 g / ml) and wet crude CNA (light phase, 51 g, d = 1.02 g / ml) were obtained and analyzed by GC and 1 H-NMR analysis (see Figure 4A , Figure 4B and Figure 4C of 1 H-NMR spectrum). The purity of the obtained CNA was 92.0% (based on GC area %).

[0161] Under vacuum (T B =50°C) DCM and light fractions were evaporated from wet CNA to give crude CNA (46.6 g).

[0162] Example 6 (Comparative)

[0163] Preparation of cis-2-octenoic acid

[0164] Step 1:

[0165] Bromine (410 g, 2.56 mol) was added dropwise over 3 hours to a mixture of 2-octanone (from Sigma-Aldrich; 164 g, 1.28 mol) and 48% aqueous HBr (300 g) stirred and cooled to ~10°C. The reaction started immediately with the start of bromine addition, and no accumulation of bromine was observed. The reaction was exothermic and accompanied by the emission of HBr gas (before the end of bromine addition), which was absorbed with a scrubber.

[0166] Most of the reaction occurred during the bromine addition and was cooked at room temperature (~20°C) for 2.5 hours. After standing at room temperature overnight (~15 hours) with stirring, the composition of the reaction mixture stabilized. Partial conversion of 3,3-dibromo-2-octanone (3,3-DBO) to the desired product 1,3-dibromo-2-octanone (1,3-DBO) occurred. Water (160 g) was added to the reaction mixture at room temperature, stirred for 30 minutes, and the phases separated.

[0167] An aqueous phase (636 g) containing -50% HBr (d = 1.51 g / ml) and crude DBO (358 g, d = 1.54 g / ml) was obtained. The concentration of 1,3-DBO in the crude product was 71.0% (GC, area %).

[0168] Step 2:

[0169] In a 1 L stirred reactor, a 25% w / w concentration of K2CO3 aqueous solution was prepared by adding K2CO3 (200 g) in portions to water (600 g). The reaction was exothermic. The resulting clear solution was heated to 49°C and crude DBO (182 g) from step 1 was added dropwise to the solution over 1 hour. The pH and T were varied by HPLC. R Monitor the reaction progress by measuring the changes in

[0170] Based on the pH (unchanged at ~13) and GC, it can be seen that no reaction occurred during the addition of crude DBO. The pH immediately began to drop after the addition of crude DBO, and T R Start rising immediately.

[0171] The completion of the reaction was determined by pH (pH dropped from 13.7 to 9.3) and GC analysis of the reaction mixture (disappearance of 1,3-DBO to ≤ 1%, area %).

[0172] Before starting the washing, water (75 g) was added to the reaction mixture (982 g).To reduce the amount of impurities to a minimum, the reaction mixture was washed four times with dichloromethane (DCM, 4 x 250 g).

[0173] After the washing stage, an aqueous phase containing cis-2-octenoic acid potassium salt (COA-K), organic byproducts, KBr and KHCO3 is obtained. To obtain crude cis-2-octenoic acid (COA), the aqueous phase is acidified by dropwise addition of 32% aqueous HCl solution (178 g) over 1 hour. During the acidification, CO2 is emitted.

[0174] After stopping stirring, the aqueous phase (938 g) containing salt (KCl and KBr) (heavy phase, d = 1.18 g / ml) and wet crude COA (light phase, 44 g, d = 1.00 g / ml) were obtained and analyzed by GC and 1 H-NMR analysis (see Figure 5A , Figure 5B and Figure 5C of 1 H-NMR spectrum). The purity of the obtained crude COA was 89.6% (based on GC area %).

[0175] Under vacuum (T B =50°C) DCM and light fractions were evaporated from wet COA to give crude COA (41.3 g).

[0176] Example 7 (Comparative)

[0177] Preparation of cis-2-heptenoic acid

[0178] Step 1:

[0179] Bromine (410 g, 2.56 mol) was added dropwise over 3 hours to a mixture of 2-heptanone (from Sigma-Aldrich; 146 g, 1.28 mol) and 48% aqueous HBr (300 g) stirred and cooled to ~10°C. The reaction started immediately with the start of bromine addition, and no accumulation of bromine was observed. The reaction was exothermic with the emission of HBr gas (before the end of bromine addition), which was absorbed with a scrubber.

[0180] Most of the reaction occurred during the bromine addition and was cooked at room temperature (~20°C) for 4.5 hours. After standing at room temperature overnight (~17 hours) with stirring, the composition of the reaction mixture stabilized. Partial conversion of 3,3-dibromo-2-heptanone (3,3-DBH) to the desired product 1,3-dibromo-2-heptanone (1,3-DBH) occurred. Water (160 g) was added to the reaction mixture at room temperature, stirred for 30 minutes, and the phases separated.

[0181] An aqueous phase (631 g) containing -50% HBr (d=1.52 g / ml) and crude DBH (351 g, d=1.60 g / ml) was obtained. The concentration of 1,3-DBH in the crude product was 72.6% (GC, area %).

[0182] Step 2:

[0183] In a 1 L stirred reactor, a 25% w / w concentration of K2CO3 aqueous solution was prepared by adding K2CO3 (200 g) in portions to water (600 g). The reaction was exothermic. The resulting clear solution was heated to 49°C and crude DBH (173 g) from step 1 was added dropwise to the solution over 1 hour. The pH and T R Monitor the reaction progress by measuring the changes in

[0184] Based on the pH (which remained constant at ~13), it can be seen that no reaction occurred during the addition of crude DBH. The pH immediately began to drop after the addition of crude DBH, and T R Start rising immediately.

[0185] The end of the reaction was determined by pH (pH dropped from 13.5 to 9.3) and GC analysis of the reaction mixture (1,3-DBH disappeared to ≤1%, area %). After the reaction was completed, the mixture was cooled to room temperature and stirring was stopped, and an organic phase appeared above the aqueous phase, which contained unreacted 3-BH and 3,3-DBH, and by-products formed by the condensation reaction of crude DBH. The phases were separated. The organic phase (24 g) was an organic waste.

[0186] Before starting the washing, water (50 g) was added to the reaction mixture (948 g).To reduce the amount of impurities to a minimum, the reaction mixture (998 g) was washed three times with dichloromethane (DCM, 3 x 250 g).

[0187] After the washing stage, an aqueous phase containing cis-2-heptenoic acid potassium salt (CHA-K), organic byproducts, KBr and KHCO3 is obtained. To obtain crude cis-2-heptenoic acid (CHA), the aqueous phase is acidified by dropwise addition of 32% aqueous HCl solution (193 g) over 1 hour. During the acidification, CO2 is emitted.

[0188] After stopping stirring, the aqueous phase (1014 g) containing salt (KCl and KBr) (heavy phase, d = 1.18 g / ml) and wet crude CHA (light phase, 45 g, d = 1.00 g / ml) were obtained and analyzed by GC and 1 H-NMR analysis (see Fig. 6A , Figure 6B and Figure 6C of 1 H-NMR spectrum). The purity of the obtained CHA was 95.6% (based on GC area %).

[0189] Under vacuum (T B =50°C) DCM and light fractions were evaporated from wet CHA to give crude CHA (44 g).

[0190] Example 8A-Example 8B (Comparative)

[0191] Purification of crude cis-2-decenoic acid by silica gel column chromatography

[0192] 8A

[0193] 1.54 g of crude CDA was placed in The top of a glass column of 1.50 mm in diameter filled with 75 ml of silica gel 60 (Merck 0.04-0.063 mm). The initial eluent was hexane, and the first 240 ml of eluent were discarded. The eluent was then changed to 5% ethyl acetate-95% hexane. The additional 140 ml of eluent were discarded, and 60 ml fractions were collected. The solvent was removed under reduced pressure to obtain 0.36 g of pure CDA (by HPLC area %: 99%).

[0194] 8B

[0195] 2.35 g of crude CDA was placed in The top of a glass column of 1.50 mm diameter filled with 100 ml of silica gel 60 (Merck 0.04-0.063 mm). The initial eluent was hexane, and the first 300 ml of eluent was discarded. The eluent was then changed to 5% ethyl acetate-95% hexane. The additional 210 ml of eluent was discarded, and 65 ml fractions were then collected.

[0196] This fraction was combined with the fraction of 8A, and the solvent was removed under reduced pressure to obtain 0.95 g of pure CDA (HPLC area %: 99%), which was analyzed by GC and 1 H-NMR analysis (see Fig. 7A , Figure 7B and Figure 7C of 1 H-NMR spectra and Fig. 8A and Figure 8B of 13 C-NMR).

[0197] Example 9

[0198] Purification of crude cis-2-decenoic acid by distillation (laboratory scale)

[0199] Crude CDA (70% CDA content according to HPLC determination) was distilled under reduced pressure. The distillation apparatus consisted of a 100 ml three-necked flask connected to a short Vigreux column via a Y-connector. A water-cooled condenser and a four-flasks rotating receiver were connected to a vacuum pump (2 mbar). Crude CDA (79.7 g) was placed in a distillation flask, vacuum was applied and heating was applied. The vapor temperature at the distillation head was 77°C-83°C; pure CDA was obtained at a vapor temperature of 95°C-105°C (bottom temperature of 130°C-140°C). 43 g of CDA was collected, with a CDA content of 96.7% (according to HPLC determination). The CDA after distillation was 97.6% pure according to GC (area %), accompanied by 0.6% trans-decenoic acid and about 0.5% bromomethylenenonanoic acid. The distillation yield was 75%.

[0200] Example 10

[0201] Purification of crude cis-2-decenoic acid by wiped film evaporation (small pilot scale)

[0202] A small pilot scale study was performed to determine the evaporation conditions to achieve purification of crude CDA in order to achieve high CDA assay values ​​(≥90%) and good yields (≥90%).

[0203] For CDA purification, 0.12 m 2 The WFE was a 1 L bottom flask for the residue and a 200 ml flask for collecting the distillate. Heating was performed by hot oil circulated to the WFE jacket through the LAUDA system. The vapor passed through a condenser and was cooled by ethylene glycol-water cooled to 7°C. The crude CDA was fed to the WFE by a peristaltic pump (via 1 / 2" Teflon tubing). In order to monitor the feed and distillation rates during the experiment, laboratory measuring cylinders were used for the crude product inlet and distillate outlet. The vacuum was achieved by an oil vacuum pump, equipped with an acetone-dry ice cold trap to prevent DCM from entering the pump.

[0204] A series of tests were performed, varying the conditions (temperature, reduced pressure, feed flow rate, rotation speed and D / F ratio) and testing the influence of the conditions on the measured values ​​and impurity profiles. The operating conditions and test results are listed in Table C.

[0205] Table C

[0206] The results listed in Table C show that by subjecting the crude product to wiped film evaporation at temperatures above 150°C (e.g., 150°C to 180°C), products with high CDA assays (≥90%) and excellent production yields (in the range of 80%-90%) can be obtained. Although good assay results were observed in several runs (A4, B4) when deep vacuum was not achieved, these runs were shown to result in low productivity / low yield. Therefore, it is advantageous to maintain the evaporation runs at low pressure (<4.5 mbar). In order to obtain the desired D / F ratio close to 71%, the feed flow rate was maintained in the range of 14 ml / min-15 ml / min at 150°C and 35 ml / min at 180°C.

[0207] Embodiment 11

[0208] Purification of crude cis-2-decenoic acid by wiped film evaporation (pilot scale)

[0209] The WFE system used for crude product purification consisted of a 0.4 m 2 WFE and 100 L bottom tank, both made of 316 stainless steel. WFE is heated with hot oil from an electric heater ("Lauda", 48 kW); bottom tank is not heated. CDA crude is fed from a 200 L drum by a peristaltic pump and placed on a WI-1 balance on top of the WFE system. The residue is collected in the bottom tank and vented at the end of each run. Vapor is heated at 0.75 m 2 The distillate was condensed in a stainless steel condenser cooled by water from a cooling tower. The distillate was collected in a 100 L glass distillate receiver and pumped out with a diaphragm pump P-3 at the end of each test. The condenser and the distillate receiver were connected to a deep vacuum dry pump CXS250 (from "Edwards").

[0210] To determine the optimal evaporation conditions for crude CDA (63.6 kg, assay 67% w / w, HPLC), several exploratory trials were performed.

[0211] Good results (HPLC assay value of recovered pure CDA ≥ 90% (by HPLC)) were obtained by operating a two-stage distillation mode at 175°C-180°C and 1 mbar, with a feed rate of 27 kg / hr (189°C top, pressure ~1 mbar) for the first stage distillation, yielding 40 kg of CDA (assay value 77% w / w), and a feed rate of 55 kg / hr (180°C top, pressure 1 mbar) for the second stage distillation, yielding 23.8 kg of CDA on specification (98% assay value). The bottom material (11 kg) of the second stage distillation was also distilled at 175°C-180°C and a feed rate of 60 kg / hr to give 7 kg of CDA on specification (93%). The total yield of the WFE purification was 72% CDA on specification (assay value > 95%) in the crude CDA product. Fig.9A , Fig. 9B and Fig. 9C The obtained CDA 1 H-NMR spectrum, Fig. 10A and Fig. 10B The obtained CDA 13 C-NMR spectrum.

[0212] Example 12

[0213] Thermal isomerization of CDA

[0214] A study was conducted to determine the thermal isomerization of CDA.CDA was charged into a flask equipped with a magnetic stirrer, thermocouple and condenser. Fig.11A and Fig. 11B The isomerization of the cis isomer to the trans isomer (TDA) at 150°C and 180°C at atmospheric pressure is shown based on sampling at different times and HPLC analysis. It can be seen that CDA is thermally unstable and undergoes very rapid and significant isomerization.

Claims

1. A method for purifying crude cis-2-enoic acid by thermal separation, the method comprising subjecting the crude cis-2-enoic acid to wiped film evaporation or vacuum distillation under a temperature-reduced pressure curve to minimize isomerization of cis-2-enoic acid to trans-2-enoic acid.

2. The process of claim 1 comprising subjecting a crude cis-2-enoic acid having the formula R-CH=CH-COOH, wherein R is a linear alkyl group CH3-(CH2) n -, 3≤n≤10.

3. The process according to claim 2, wherein the cis-2-enoic acid is cis-2-decenoic acid, and wherein the wiped film evaporation is carried out at a temperature of not less than 150°C and a reduced pressure of <5 mbar.

4. The process according to claim 3, wherein the temperature is in the range of 150°C to 180°C and the reduced pressure is 1 mbar to 5 mbar, thereby suppressing the isomerization of the cis isomer to the trans isomer so that the level of the trans isomer is less than 1.0% by HPLC area.

5. The process according to any one of claims 1 to 4, wherein the wiped film evaporation comprises the step of collecting condensate and returning it to the feed stream of the wiped film evaporator.

6. The method according to any one of claims 1 to 5, wherein the crude cis-2-enoic acid is prepared by a process comprising the following steps: The 2-alkanone is brominated to give a 1,3-dibromo-2-alkanone; and the 1,3-dibromo-2-alkanone is rearranged to the cis-2-enoic acid.

7. The method according to any one of claims 1 to 6, wherein the crude cis-2-enoic acid is prepared by a process comprising the following steps: 1,3-dibromo-2-alkanone is rearranged in a basic environment in the presence of a catalytically effective amount of an alkali metal salt of a cis-2-enoic acid, and the cis-2-enoic acid is isolated from the reaction mixture in the form of a free acid or an alkali metal salt.

8. The method of claim 7, wherein the crude cis-2-enoic acid is prepared by a process comprising the following steps: At elevated temperature, 1,3-dibromo-2-alkanone is gradually added to a reaction vessel previously charged with an alkaline aqueous solution of Na2CO3, K2CO3 or a mixture thereof and a catalytically effective amount of an alkali metal salt of a cis-2-enoic acid.

9. The method according to claim 7 or 8, wherein the process for preparing the crude cis-2-enoic acid comprises separating the reaction mixture into an aqueous phase and an organic phase, and treating the aqueous phase to recover cis-2-enoic acid therefrom, wherein the cis-2-enoic acid is in the form of a free acid or in the form of an alkali metal salt.

10. The method according to claim 9, wherein the process of preparing the crude cis-2-enoic acid comprises treating the aqueous phase by washing with an organic solvent, followed by phase separation to obtain a purified aqueous phase.

11. The method according to claim 7 or 8, wherein the process of preparing the crude cis-2-enoic acid comprises optionally diluting the reaction mixture with water and washing with an organic solvent, followed by phase separation to obtain a purified aqueous phase.

12. The method according to claim 10 or 11, wherein the process for preparing the crude cis-2-enoic acid further comprises acidifying the purified aqueous phase to obtain a biphasic medium comprising a salt-containing heavy aqueous phase and a light organic phase consisting essentially of cis-2-enoic acid in the free acid form.

13. The method according to any one of claims 6 to 12, wherein the process for preparing the crude cis-2-enoic acid comprises rearranging 1,3-dibromo-2-alkanone, wherein the 1,3-dibromo-2-alkanone is selected from the group consisting of: 1,3-Dibromo-2-heptanone 1,3-Dibromo-2-octanone 1,3-Dibromo-2-nonanone 1,3-Dibromo-2-decanone 1,3-Dibromo-2-undecanone.

14. The method according to claim 13, wherein the 1,3-dibromo-2-alkanone used in the rearrangement reaction is crude 1,3-dibromo-2-alkanone obtained by the following steps: brominating the corresponding 2-alkanone selected from the group consisting of 2-heptanone, 2-octanone, 2-nonanone, 2-decanone and 2-undecanone in concentrated hydrobromic acid by adding elemental bromine to form 1,3-dibromo-2-alkanone accompanied by 3,3-dibromo-2-alkanone in the reaction mixture; maintaining the reaction mixture for a hold time, the hold time being adjusted to maximize conversion of 3,3-dibromo-2-alkanone to 1,3-dibromo-2-alkanone; And the crude 1,3-dibromo-2-alkanone was collected by phase separation.

15. The process according to any one of claims 6 to 14, wherein the process for preparing the crude cis-2-enoic acid comprises rearranging 1,3-dibromo-2-alkanone in the presence of a catalytically effective amount of an alkali metal salt of cis-2-enoic acid, the catalytically effective amount being up to 10 mol % based on 1,3-dibromo-2-alkanone.

16. The method according to any one of claims 8 to 15, wherein the process for preparing the crude cis-2-enoic acid comprises removing a small portion of the aqueous phase before or after treating the aqueous phase and using the portion of the aqueous phase to supply the catalytically effective amount of the cis-2-enoic acid alkali metal salt in the rearrangement reaction of the corresponding 1,3-dibromo-2-alkanone.

17. The method according to any one of claims 7 to 16, wherein the process of preparing the crude cis-2-enoic acid comprises supplying the catalytically effective amount of the cis-2-enoic acid alkali metal salt to the rearrangement reaction in the form of an aqueous solution recovered from a previous rearrangement reaction.

18. A process according to any one of the preceding claims, wherein the cis-2-enoic acid is cis-2-decenoic acid.

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