Preparation and purification of cis-2-alkenoic acid

Abstract

A method for purifying crude cis-2-alkenoic acid by thermal separation, which includes wiped film evaporation or vacuum distillation of the crude cis-2-alkenoic acid under a temperature-drop pressure profile, and minimizes the isomerization of cis-2-alkenoic acid to trans-2-alkenoic acid.

Description

Technical Field

[0001] The present invention relates to the synthesis and purification of long-chain cis-α,β-unsaturated acids of the formula R-CH=CH-COOH, i.e., cis-2-alkenoic acids, wherein R represents an alkyl residue (linear or branched) consisting of, for example, 4 or more carbon atoms.

Background Art

[0002] Long-chain cis-2-alkenoic acids have been reported to act as biocides. For example, in International Publication No. 2008 / 143889 and Journal of Bacteriology 191:1393-1403 (2009), cis-2-decenoic acid produced by the bacterium Pseudomonas aeruginosa can induce Pseudomonas aeruginosa, other Gram-negative bacteria, Gram-positive bacteria, and fungi to undergo a physiologically mediated dispersion reaction, resulting in the dispersion of aggregates and communities of microorganisms formed on surfaces known as biofilms.

[0003] In International Publication No. 2020 / 240559 assigned to the same applicant as the present application, cis-2-decenoic acid acts as an effective adjuvant to bromine-containing biocides in the treatment of biofilms and planktonic bacteria in aqueous systems and on surfaces in contact with water, and it has been demonstrated that the killing of bacteria is significantly enhanced in both pure and mixed cultures commonly found in industrial and natural waters compared to treatment with brominated biocides alone. In particular, International Publication No. 2020 / 240559 shows that a sufficient enhancement of bromine-based water treatment can be achieved using cis-2-decenoic acid of medium purity, for example, 80-95% (gas chromatography, GC area%).

[0004] International Publication No. 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 not satisfactory. For example, when silica gel is used as the adsorbent and saturated hydrocarbons (heptane or hexane) and esters (ethyl acetate) are used as solvents, a high purity level of 99% in HPLC area% is achieved as in Preparation 3 of International Publication No. 2020 / 240559, but the yield of the final product is very low (the yield is about 25% - 40%).

[0005] Cahiez et al., "Stereospecific syntheses of alkenyllithium reagents from alkenyl iodides", Synthesis, 1976, 4, 245 - 8 reports the synthesis and purification by distillation of cis-2-decenoic acid, showing that the boiling point is 102 - 103 ° / 0.5 torr.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Brief Description of the Drawings

[0008]

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Mode for Carrying Out the Invention

[0009] It has been found that cis-2-alkenoic acids such as cis-2-decenoic acid can be isomerized from the cis isomer to the trans isomer by purifying with a thermal separation method. If the thermal separation by evaporation / distillation is not properly controlled, the amount of the trans isomer may exceed 1.0% (HPLC area). However, even though cis-2-alkenoic acids are thermally unstable, by adjusting process variables (such as reduced pressure, temperature, time, etc.), the formation of undesirable impurities caused by high temperature can be suppressed. The experimental results shown below indicate that high analytical values (≧90%) and good purification yields (70 - 90%) can be achieved, especially with wiped film evaporation.

[0010] Accordingly, the present invention is mainly a method for purifying crude cis-2-alkenoic acid by thermal separation, which includes wiped film evaporation or vacuum distillation of the crude cis-2-alkenoic acid under a temperature-drop pressure profile, thereby minimizing the isomerization of cis-2-alkenoic acid to trans-2-alkenoic acid.

[0011] The cis-2-alkenoic acid is preferably cis-2-decenoic acid and is purified by wiped film evaporation carried out at a temperature of 150 °C or higher (for example, 150 - 180 °C) and a reduced pressure of less than 5 mbar (for example, 1 - 5 mbar, or 2 - 5 mbar, for example, 2 - 4 mbar), whereby the isomerization of the cis isomer to the trans isomer is suppressed, and the level of the trans isomer is less than 1.0% in HPLC area. The wiped film evaporation may include the step of collecting the condensate and returning it to the feed stream (in order to reach the target analytical value).

[0012] The crude cis-2-alkenoic acid obtained by various synthetic routes can be purified by the thermal separation method (for example, wiped film evaporation) of the present invention. However, the crude cis-2-alkenoic acid prepared by a two-step process including brominating 2-alkanone to obtain 1,3-dibromo-2-alkanone and rearranging 1,3-dibromo-2-alkanone to cis-2-alkenoic acid may particularly benefit from purification by wiped film evaporation. This synthetic route is described in detail in our previous international patent application PCT / IL2021 / 051423 (≡ International Publication No. WO 2022 / 118309).

[0013] The synthesis is based on a two-step process in which the corresponding 2-alkanone is brominated to obtain crude 1,3-dibromo-2-alkanone as the main product together with other isomers, and then 1,3-dibromo-2-alkanone is rearranged to an unsaturated acid, as shown in the following scheme.

[0014]

Chemical formula

[0015] (Here, R’ is alkyl, such as C2H5, C3H7, C4H9, C5H 11 , and C6H 13 .) The above two-step synthesis was first described by Rappe et al. in [Acta Chemica Scandinavica (1965), Vol. 19, p. 383 - 389]. The rearrangement was carried out in an alkaline environment using an alkali carbonate or alkali bicarbonate as a base. A similar approach was reported by the same research group in Organic Syntheses (1973), Vol. 53, p. 123 - 127.

[0016] Attempts to modify the two-step synthesis route can be found in U.S. Patent No. 8,748,486, which explains that alkali bicarbonate can only effectively promote the preparation of short-chain cis-α,β-unsaturated acids. The authors reported that the rearrangement reaction of long-chain brominated ketones, such as 1,3-dibromo-2-decanone, was very slow in the presence of alkali bicarbonate, and the desired fatty acid could not be obtained even with an extended reaction time. The authors switched to an alkali hydroxide to promote the preparation of long-chain cis-α,β-unsaturated acids (the terms "cis-α,β-unsaturated acid" and "cis-2-alkenoic acid" can be used interchangeably).

[0017] The experimental results reported below regarding this synthesis route are consistent with the observations made in U.S. Patent No. 8,748,486. The rearrangement reaction of long-chain 1,3-dibromo-2-alkanone under alkaline pH hardly proceeds even at high reaction temperatures, and thermal runaway (a sudden and rapid increase in reaction temperature) is likely to occur. Such a reaction profile is unacceptable for processes carried out on an industrial scale.

[0018] However, it has been found that in order to promote the rearrangement reaction of 1,3-dibromo-2-alkanone in an effective and controllable manner to obtain cis-2-alkenoic acid, it is necessary to supply a certain amount of the alkali salt of the target cis-2-alkenoic acid to the reaction mixture. As shown below, the alkali salt of cis-2-alkenoic acid added may be supplied to the rearrangement reaction from the previous run. A small amount of cis-2-alkenoic acid or its salt added at the start of the rearrangement reaction provides a controllable process.

[0019] Therefore, this synthesis is based on a process for the preparation of cis-2-alkenoic acid [R-CH=CH-COOH] or its alkali metal salt [R-CH=CH-COOM, where M is an alkali metal], and the preparation process is carried out in an alkaline environment (e.g., generated by an alkali carbonate or an alkali carbonate / bicarbonate mixture) in the presence of a catalytically effective amount of the alkali metal salt of cis-2-alkenoic acid, by rearranging 1,3-dibromo-2-alkanone [R-CHBr-C(O)-CH2Br], and isolating the cis-2-alkenoic acid in the form of the free acid or the alkali metal salt from the reaction mixture (e.g., by separating the reaction mixture into an aqueous phase and an organic phase, and post-treating the aqueous phase to recover the cis-2-alkenoic acid in the form of the free acid or the alkali metal salt).

[0020] R is an alkyl group consisting of 4 or more carbon atoms, for example 5 or more carbon atoms. For example, R is C4-C 11 alkyl. For example, cis-2-decenoic acid in the form of the free acid (where R is C7H 15 is) is collected as an oil. When the cis-2-decenoic acid thus produced is reacted with an alkali hydroxide, for example KOH, the corresponding potassium salt is obtained as a pasty solid.

[0021] The cis-2-alkenoic acid R-CH=CH-COOH prepared by the above synthetic route and purified by the present invention is preferably linear. That is, R is usually a linear alkyl chain CH3-(CH2) n-(3 ≤ n, for example, 3 ≤ n ≤ 10, 3 ≤ n ≤ 6). For example, the preparation of cis-2-alkenoic acid by the rearrangement reaction of the corresponding 1,3-dibromo-2-alkanone shown below was studied (however, it should be noted that R is not limited to a straight chain and may be a branched alkyl group, such as isoalkyl).

[0022]

Chemical formula

[0023] It has been found that all can benefit by adding a catalytically effective amount of the target cis-2-alkenoic acid or its alkali metal salt to the alkali reaction mixture. "Catalytically effective amount" means that the added amount is up to 15 mol%, for example up to 10 mol%, for example 1 - 5 mol% with respect to 1,3-dibromo-2-alkanone.

[0024] The 1,3-dibromo-2-alkanone undergoing the rearrangement reaction is most conveniently prepared by slowly adding elemental bromine (stoichiometrically, the molar ratio of Br2:2-alkanone is about 2:1) to the corresponding 2-alkanone [R-CH2-C(O)-CH3] (for example, 2-heptanone, 2-octanone, 2-nonanone, 2-decanone, or 2-undecanone) in concentrated hydrobromic acid (for example, an HBr solution with a weight ratio of 30% - 48%).

[0025] The weight ratio of the 2-alkanone starting material to aqueous HBr is 1:1 - 1:2. The reaction medium is cooled to a temperature of 5 - 20 °C, for example about 5 - 10 °C. Under these conditions, elemental bromine is smoothly added to the 2-alkanone, and most of the reaction occurs during the addition of bromine. The accumulation of bromine (indicated by the reaction mixture turning a characteristic yellow color) is not observed.

[0026] The bromine addition time on a laboratory scale is usually 1 to 5 hours. After the addition of elemental bromine is completed, the reaction mixture is held at room temperature (15 to 25 °C) for a certain period of time (the "holding time") with optional stirring. The holding time is 6 to 24 hours, for example, 6 to 12 hours. Since several isomeric by-products such as 3,3-dibromo-2-alkanone are mainly produced by the bromination reaction of 2-alkanone, it is effective to increase the holding time. In the GC analysis of the reaction mixture, the desired isomer 1,3-dibromo-2-alkanone gradually becomes the main product over time, that is, it has been shown that increasing the holding time enables a significant interconversion from 3,3-dibromo ketone to 1,3-dibromo ketone.

[0027] To illustrate the importance of extending the holding time when shifting the distribution of the isomer mixture consisting of 1,3-dibromo-2-alkanone and 3,3-dibromo-2-alkanone in favor of the former and at the expense of the latter, the experimental data based on the bromination procedure of 2-nonanone, 2-decanone, or 2-undecanone (reported in the following examples) are summarized in Table A.

[0028]

Table A

[0029] It can be seen that the product mixture obtained by brominating various 2-alkanones in hydrobromic acid shows a similar reaction when held for a long time. Initially, the ratio of the mixture consisting of 1,3-dibromo-2-alkanone and 3,3-dibromo-2-alkanone is about 2:1, and after about 20 hours, the ratio exceeds 10:1, the equilibrium is stabilized, and the desired isomer suitable for the rearrangement reaction, that is, 1,3-dibromo-2-alkanone, reaches about 70% (GC area%).

[0030] The generation of hydrogen bromide occurs during the addition of bromine and the subsequent holding stage, and the gas is absorbed into an appropriate aqueous medium and collected as aqueous hydrobromic acid.

[0031] To recover the crude 1,3-dibromo-2-alkanone, the reaction mixture is worked up by adding water and subsequently separated into an aqueous phase (consisting of about 48% w / w hydrobromic acid) and an organic phase consisting of the crude product. Typically, as shown by the data summarized in Table A, the recovered crude product contains about 70% (GC area) of 1,3-dibromo-2-alkanone.

[0032] Accordingly, the 1,3-dibromo-2-alkanone used in the rearrangement reaction is the crude 1,3-dibromo-2-alkanone, and the crude 1,3-dibromo-2-alkanone forming 1,3-dibromo-2-alkanone together with 3,3-dibromo-2-alkanone in the reaction mixture by adding elemental bromine to brominate the corresponding 2-alkanone in concentrated hydrobromic acid, maintaining the reaction mixture for a holding time adjusted to maximize the interconversion of 3,3-dibromo-2-alkanone to 1,3-dibromo-2-alkanone (e.g., reaching >65%, >67%, >69% (GC area %) of 1,3-dibromo-2-alkanone), and collecting the crude 1,3-dibromo-2-alkanone.

[0033] The crude 1,3-dibromo-2-alkanone can proceed 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, and other preparation methods of 1,3-dibromo-2-alkanone reported in the literature, for example, using an acceptable brominating reagent to brominate 2-alkanone in an organic solvent such as a halogenated hydrocarbon (CH2Cl2 or CH2Br2) may also be used.

[0034] A convenient method for performing the rearrangement reaction involves gradually adding 1,3-dibromo-2-alkanone to a reaction vessel pre-filled with an aqueous alkaline solution (e.g., consisting of 10 - 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 cis-2-alkenoic acid at an elevated temperature, e.g., ≥35 °C, e.g., ≥40 °C. For example, when maintaining the reaction mixture at a temperature in the range of 40 °C to 60 °C, 1,3-dibromo-2-alkanone is gradually added. The molar ratio of 1,3-dibromo-2-alkanone added to the carbonate is 1:2 to 1:4, e.g., about 1:3 to 1:3.5.

[0035] As shown below, since the corresponding alkali bicarbonate is a by-product of the rearrangement reaction, it is preferable to use, for example, potassium carbonate rather than sodium carbonate. Potassium bicarbonate has a higher solubility in water than sodium bicarbonate, so when using the potassium salt, the difficulties encountered in the post-treatment stage of the reaction mixture may be reduced.

[0036] When an alkali metal salt of cis-2-alkenoic acid is present, the reaction occurs during the addition of 1,3-dibromo-2-alkanone to the alkaline reaction mixture. The occurrence of the reaction is characterized by a decrease in pH (i.e., the initial strong alkaline pH of 12 - 14 decreases by at least 2 pH units, e.g., 2 - 4 pH units during the addition of 1,3-dibromo-2-alkanone) and a temperature increase of about 5 - 10 °C (i.e., ΔT 反応器 ).

[0037] In contrast, when 1,3-dibromo-2-alkanone is added to an alkaline solution in the absence of the alkali metal salt of cis-2-alkenoic acid, the rearrangement of 1,3-dibromo-2-alkanone does not proceed sufficiently, and the added 1,3-dibromo-2-alkanone accumulates in the reaction vessel. The experimental results shown below indicate that no rearrangement of 1,3-dibromo-2-heptanone, 1,3-dibromo-2-octanone, and 1,3-dibromo-2-nonanone occurred during the addition of the crude 1,3-dibromo-2-alkanone. Only after the addition of the crude 1,3-dibromo-2-alkanone was completed did the pH begin to decrease and T R (the reactor temperature) began to rise spontaneously, indicating that the reaction was proceeding. The rearrangement of higher homologues such as 1,3-dibromo-2-decanone and 1,3-dibromo-2-undecanone is more difficult to proceed, and substantially, it cannot be achieved without the assistance of a catalytically effective amount of the alkali metal salt of cis-2-alkenoic acid.

[0038] After the slow addition of the crude 1,3-dibromo-2-alkanone is completed (which may take 30 - 120 min on a laboratory scale), the reaction mixture is held for a certain period with stirring, that is, heated at a temperature in the range of 50 - 55 °C for several hours (1 - 3 hours) to complete the reaction. During the heating period, it is observed that the pH decreases by about 0.5 - 1.5 units. 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 (identifying the disappearance of 1,3-dibromo-2-alkanone, i.e., a decrease to ≤ 1% in area %).

[0039] After the rearrangement reaction is completed, the reaction mixture is cooled to room temperature and separated into an aqueous phase (heavy) and an organic phase (light). The organic phase (containing unreacted brominated isomers associated with 1,3-dibromo-2-alkanone, mainly 3-bromo-2-alkanone and 3,3-dibromo-2-alkanone, and some condensation by-products formed during the rearrangement reaction) may be discarded. The aqueous phase containing cis-2-alkenoic acid in the form of an alkali metal salt (sodium salt or potassium salt determined by the selected base) is post-treated to isolate the product.

[0040] An example of the rearrangement reaction is shown by the following scheme, in which 1,3-dibromo-2-decanone (1,3-DBD) is converted to the potassium salt of cis-2-decenoic acid (abbreviated CDA-K) using K2CO3.

[0041]

Chemical formula

[0042] AP-RM refers to a catalytically effective amount of an alkali metal salt of cis-2-alkenoic acid that is added in advance to initiate the rearrangement reaction. As pointed out above, the catalytically effective amount of the alkali metal salt of cis-2-alkenoic acid 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 run of the process. Usually, the small portion constitutes 1 to 10% by weight, for example 3 to 7% by weight (about 5% by weight) of the total weight of the aqueous phase. Based on the concentration of the alkali metal salt of cis-2-alkenoic acid, it can be seen that the catalytically effective amount of the salt added to the alkali solution before the start of the rearrangement reaction is preferably 1 to 5 mol% with respect to 1,3-dibromo-2-alkanone.

[0043] However, it should be mentioned that there is also another way to supply the alkali metal salt of cis-2-alkenoic acid to the rearrangement reaction, for example, by directly adding the free acid or salt from other sources (when adding the free acid instead of the alkali metal salt, the acid reacts in the alkali solution and forms the corresponding alkali salt in situ).

[0044] Next, the major part of the aqueous phase is post-treated by washing with an immiscible organic solvent such as a halogenated hydrocarbon such as dichloromethane (it may be necessary to repeat the washing cycle) to extract and remove organic impurities from the product-containing aqueous solution.

[0045] If the resulting reaction mixture cannot be separated into an aqueous phase and an organic phase, it is (optionally) diluted with water, washed with a water-immiscible organic solvent, and then phase-separated to collect a purified product-containing aqueous phase that can be divided into a small portion and a major portion as described above. The small portion is used for the next run, and the major portion is processed to recover the product therefrom.

[0046] To recover the product in the form of the free acid, for example, the purified aqueous solution is acidified using concentrated hydrochloric acid (e.g., commercially available 32% HCl solution) that is slowly added to the purified aqueous solution to reach a strongly acidic pH (e.g., 1 - 2). The acidified reaction mixture is separated into an aqueous phase (heavy phase) and an organic phase (light phase). The former contains bromide and chloride salts, and the latter consists of crude cis-2-decenoic acid, possibly a portion of the residual organic solvent subjected to the washing step, and water, which are removed, for example, by evaporation under vacuum to obtain crude cis-2-alkenoic acid.

[0047] A series of reactions that occur during the acidification of the aqueous solution (specifically, the preparation of the potassium salt of cis-2-decenoic acid) are shown below.

[0048]

Chemical formula

[0049] Therefore, the process for preparing crude cis-2-alkenoic acid further includes acidifying the purified aqueous phase (i.e., after extraction with an organic solvent) to obtain a biphasic medium comprising a heavy salt-containing aqueous phase and a light organic phase consisting essentially of cis-2-alkenoic acid in the form of the free acid.

[0050] The corresponding alkali salt can be prepared by conventional methods such as reacting the free acid with potassium hydroxide in a suitable solvent, separating by crystallization and filtration, and then drying.

[0051] As pointed out above, the crude cis-2-alkenoic acid obtained by the process of the present invention does not require further purification. That is, this acid has a purity sufficient to act as a biocide in bromine-based water treatment, i.e., its purity level is >80%, >85%, >87%, for example, 80-95% (GC area %). The characteristic purity levels of the crude acid are summarized in Table B below. However, if necessary, the crude acid can be purified by conventional techniques such as chromatography or distillation, or by the method of the present invention described in detail below.

[0052]

Table B

[0053] The purification of crude cis-2-alkenoic acid by several methods was studied. In the studies shown below, approximately 70% CDA (absolute quantification based on calibration with a commercially available external standard (≥97%)) by HPLC analysis was purified by chromatography and thermal separation techniques such as vacuum distillation and wiped film evaporation. The goal of this study was to achieve an industrially acceptable yield (≥60%, ≥70%, ≥75%, for example 60-80% or 80 to 90-95%) and high purity CDA (≥90% by the above HPLC analysis or HPLC purity ≥95% by area % (relative)).

[0054] The experimental results reported below show that very high purity levels are achieved by liquid-solid column chromatography, but the yields are not satisfactory. For example, when silica gel was used as the adsorbent and saturated hydrocarbons (heptane or hexane) and esters (ethyl acetate) were used as the solvents, a high purity level of 99% by HPLC area % was achieved as in Preparation 3 of WO 2020 / 240559, but the yield of the final product was very low (the yield was about 25%-40%).

[0055] On the one hand, purification by thermal separation, for example wiped film evaporation (thin film evaporation), has been found to be suitable for large-scale production because it combines high-purity products with acceptable yields. Despite the thermal instability of cis-2-alkenoic acid, by adjusting process variables (such as reduced pressure, temperature, time, etc.), the formation of undesirable impurities caused by high temperatures can be suppressed. According to the evaluation of the impurity profile of CDA reported below, at high temperatures and reduced pressure, the main impurities consist of the trans isomer of the acid (formed by isomerization of the desired cis isomer) and bromomethylene nonanoic acid (present in the crude CDA and derived from the intermediate impurity 1,3,3-dibromodecane formed during decanone bromination). The latter is generally the main impurity, but the trans isomer is non-negligible, and if evaporation / distillation is not properly controlled, the amount of the trans isomer may exceed 1.0%. Therefore, by performing wiped film evaporation at temperatures in the range of 150 °C or higher, for example 150 - 180 °C or 150 - 190 °C, high-purity (≥90%) products can be prepared with good production yields (60 - 80%). Lowering the pressure as much as possible (<5 mbar) effectively suppresses the isomerization of the cis isomer to the trans isomer (<3%, for example <1%) without showing a decrease in the product yield.

[0056] For example, effective purification of cis-2-alkenoic acid can be achieved by thermal separation using a wiped film evaporator or a short path evaporator operating at a feed flow rate of 14 - 25 ml / min and a heating temperature of 150 - 180 °C. The evaporator is maintained at a low vacuum of 2 - 5 mbar, and the size is 0.12 m 2 . The wetted material is usually made of stainless steel or glass. The thickness of the formed film is usually <1 mm. The vapor is condensed in a condenser, and the distillate is collected.

[0057] In a wiped film evaporator (WFE), the feed flow rate is another adjustable process variable. For example, in a mini-pilot scale where the feed flow rate is maintained in the range of 13 - 25 ml / min (e.g., 14 - 18 ml / min, about 14 - 15 ml / min) at 150 °C and 32 - 37 ml / min (e.g., 33 - 35 ml / min) at 180 °C, industrially, the desired D / F ratio (defined as the ratio of the distillate stream exiting the distillation unit to the feed stream entering the unit) reaches 50% or more, e.g., > 60%. (As shown in the pilot studies reported below), the larger the evaporator size, the higher the feed flow rate that can be used.

[0058] <Examples of vacuum pumps that can be used to obtain a pressure of 4.5 mbar include oil pumps such as the Edwards two-stage oil pump. Examples of pumps for feeding the feed material include peristaltic pumps such as the Watson-Marlow 505U pump.

[0059] Therefore, after the process for preparing cis-2-alkenoic acid described in this specification, a purification step including thermal separation by wiped film evaporation is optionally carried out. For example, the crude cis-2-alkenoic acid is subjected to wiped film evaporation, and by maintaining a temperature-drop pressure profile during the wiped film evaporation, isomerization to the trans isomer of cis-2-alkenoic acid is suppressed (e.g., less than 1.0% by HPLC area %), and the yield is increased (e.g., > 60%, > 70%, > 80%, 90%). For example, the temperature-drop pressure-time profile is maintained by adjusting the temperature, vacuum, and feed flow rate as described above.

[0060] In large-scale production, a two-stage wiped film evaporation where two distillation passes are carried out in one run, for example, by collecting the condensate and returning the condensate to the feed stream, can be beneficial to obtain good results such as an evaporation yield of 60% - 90%, e.g., 70 - 90%, and high purity (analysis by HPLC > 90%).

[0061] CDA produced by different synthesis methods can benefit from the purification techniques described herein. Thus, another aspect of the present invention is a method for purifying cis-2-alkenoic acids such as CDA by thermal separation such as wiped film evaporation (using the above conditions) and vacuum distillation.

Example

[0062] Method GC: Gas chromatograph HP 7890A Method (CDA): Hold at an initial temperature of 50 °C for 2 min, then increase the temperature to 280 °C at a rate of 10 °C / min and hold for 5 min, then increase the temperature to 300 °C at a rate of 10 °C / min and hold for 2 min. Injector: 250 °C Detector: 300 °C Split ratio: 1:40 Concentration of product sample: approximately 20 mg / ml DCM Injection volume: 1 μl of sample Column: Agilent J&W column, HP-5, 30 m × 0.32 mm × 0.25 μ Part number: 19091J-413, Manufacturing number: USF302346H

[0063] 1 H-NMR spectroscopy The spectrum was acquired with an Avance III, 500 MHz instrument.

[0064] HPLC: Agilent 1220 LC system Chromatography conditions for CDA: Wavelength: λ = 214 nm Column: Akzo Nobel, Kromasil, 250 mm * 4.6 mm ID * 5 μm + precolumn C18 Mobile phase: [A] H2O + 0.1% H3PO4 (concentration 85%): [B] Acetonitrile (AcN) Gradient profile:

Table 1

[0065] (Example 1) (Preparation of cis-2-decenoic acid) In Step 1, A mixture of 2-decanone (200 g, 1.28 mol) and 48% aqueous HBr solution (300 g) was stirred, cooled to about 10 °C, and bromine (410 g, 2.56 mol) was added dropwise over 2 hours. As soon as the addition of bromine was started, the reaction began immediately, and no accumulation of bromine was observed.

[0066] The reaction was an exothermic reaction, accompanied by the evolution of HBr gas immediately before the addition of bromine was completed, and this gas was absorbed by a scrubber.

[0067] During the addition of bromine and heating at room temperature (about 20 °C) for 6 hours, most of the reaction occurred. After standing at room temperature overnight (about 15 hours), the composition of the reaction mixture stabilized without stirring. A partial conversion from 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 min, and the phases were separated.

[0068] An aqueous phase (627 g) containing about 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%).

[0069] In Step 2, In a 1 L stirred reactor, K2CO3 (200 g) was added portionwise to water (600 g) to prepare an aqueous K2CO3 solution with a concentration of 25% w / w. The reaction was an exothermic reaction. To this solution, a part (50 g) of the aqueous phase (containing CDA-K) of the reaction mixture remaining from the previous run (named AP-RM, see Comparative Example 3) was added. The resulting clear solution was heated to 40 °C, and the crude DBD (200 g) from Step 1 was added dropwise to this solution over 60 min. The progress of the reaction was monitored by GC and the change in pH. While mechanically stirring, the reaction was completed by heating at 50 °C for 3.0 h.

[0070] It should be noted that when AP-RM is not added, the reaction does not spontaneously start until 2 hours after the addition of the crude DBD.

[0071] The end of the reaction was determined by pH (the pH decreased from 13.3 to 9.3) and GC analysis of the reaction mixture (1,3-DBD disappeared to ≤ 1% in area %). After the reaction was completed, it was cooled to room temperature and stirring was stopped. An organic phase containing unreacted 3-bromo-2-decanone (3-BD) and 3,3-DBD, as well as by-products formed by the condensation reaction of the crude DBD, appeared on top of the aqueous phase. The phases were separated. The organic phase (39 g) was organic waste. 50 g of the aqueous phase was taken out for use in the next run.

[0072] To minimize the amount of impurities, the remaining aqueous phase (950 g) was washed three times with dichloromethane (DCM, 3 × 250 g).

[0073] After the washing step, an aqueous phase containing potassium cis-2-decenoate (CDA-K), organic by-products, KBr, and KHCO3 was obtained. To obtain crude cis-2-decenoic acid (CDA), a 32% HCl aqueous solution (193 g) was added dropwise over 1 h to acidify the aqueous phase. CO2 (calculated at 63 g) was released during acidification (final pH = 1.1).

[0074] After stopping the 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) was obtained.

[0075] Under vacuum (T B = 50 °C), DCM and light components were evaporated from the wet CDA to obtain crude CDA (50.5 g), which was analyzed by GC and 1 1H-NMR ([Reference is made to Figures 1A, 1B, and 1C for the 1H-NMR spectrum). The calculated yield of the crude CDA was approximately 68% based on 1,3-DBD and 46.8% based on 2-decanone. 1 For the 1H-NMR spectrum, see Figures 1A, 1B, and 1C). The calculated yield of the crude CDA was approximately 68% based on 1,3-DBD and 46.8% based on 2-decanone.

[0076] The purity of the obtained crude CDA was 88.2% (GC area %). The main impurity of the crude product, 2-bromomethylene nonanoic acid (BMNA), was 8.8% (GC area %).

[0077] (Example 2) (Preparation of cis-2-decenoic acid) In Step 1, A mixture of 2-decanone (400 g, 2.564 mol) and 48% aqueous HBr (600 g) was stirred and cooled to about 10 °C, and bromine (800 g, 5 mol) was added dropwise over 5 hours. As soon as the addition of bromine started, the reaction began immediately, and no accumulation of bromine was observed. The reaction was exothermic and was accompanied by the evolution of HBr gas just before the addition of bromine was completed, and this gas was absorbed by a scrubber.

[0078] Most of the reaction occurred during the addition of bromine. After leaving the reaction mixture at room temperature overnight without stirring, the composition of the reaction mixture became stable. A partial conversion from 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 min, and the phases were separated.

[0079] An aqueous phase (1207 g) containing approximately 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 %).

[0080] In Step 2, K2CO3 (400 g) was added portionwise to water (1200 g) in a 2 L stirred reactor to prepare an aqueous K2CO3 solution with a concentration of 25% w / w. The reaction was an exothermic reaction. A portion (50 g) of the aqueous phase (containing CDA-K) of the reaction mixture remaining from the previous run was added to this solution. The resulting clear solution was heated to 40 °C, and crude DBD (400 g, Step 1) was added dropwise to this solution over 70 min. The progress of the reaction was monitored by GC and the change in pH. The reaction was completed by heating at 40 °C for 1.0 h and then at 50 °C for 2.0 h while stirring mechanically.

[0081] The end of the reaction was determined by pH (the pH decreased from 12.7 to 9.6) and GC analysis of the reaction mixture (1,3-DBD disappeared to ≤ 1% in area %). After the reaction was completed, it was cooled to room temperature and stirring was stopped, and an organic phase containing unreacted 3-BD and 3,3-DBD, as well as by-products formed by the condensation reaction of crude DBD, appeared on top of the aqueous phase. The phases were separated. 50 g of the aqueous phase was taken out for use in the next run.

[0082] To minimize the amount of impurities, the aqueous phase (1943 g) was washed three times with dichloromethane (DCM, 3 × 500 g).

[0083] After the washing step, an aqueous phase containing potassium cis-2-decenoate (CDA-K), organic by-products, KBr, and KHCO3 was obtained. To obtain crude cis-2-decanoic acid (CDA), a 32% HCl aqueous solution (401 g) was added dropwise over 1 h to acidify the aqueous phase. During acidification (final pH = 1.9), CO2 (calculated at 127 g) was released.

[0084] After stopping the stirring, an aqueous phase (2017 g) containing salts KCl and KBr (heavy phase, d = 1.19 g / ml) and wet crude CDA (light phase, 128 g, d = 1.03 g / ml) was obtained.

[0085] Under vacuum (T B = 50 °C), DCM and light components were evaporated from the wet CDA to obtain crude CDA (102 g), which was analyzed by GC, HPLC, and 1 1H-NMR (1H-NMR spectra in Figures 2A, 2B, and 2C). 1 Based on the results, the purity of the obtained crude CDA was 89.7% (GC area%) and 90.0% (HPLC area%). The calculated yield of crude CDA was approximately 67% based on 1,3-DBD.

[0086]

[0087] (Example 3 Comparative Example) <Preparation of cis-2-decenoic acid> Step 1 was carried out in the same manner as in Example 1. However, the rearrangement reaction in Step 2 was carried out without adding the alkali metal salt of cis-2-alkenoic acid.

[0088] In Step 2, In a 1 L stirred reactor, K2CO3 (200 g) was added portionwise to water (600 g) to prepare an aqueous K2CO3 solution with a concentration of 25% w / w. The reaction was an exothermic reaction. The resulting clear solution was heated to 40 °C, and crude DBD (200 g, obtained as described above) was added dropwise to this solution over 60 min. The progress of the reaction was monitored by GC and the change in pH.

[0089] The mixture of the aqueous K2CO3 solution and crude DBD was stirred at a temperature of 50 °C for 3 hours. Based on the pH (which did not change at approximately 13) and GC, it was found that no reaction occurred.

[0090] Next, the temperature inside the reactor began to rise rapidly naturally and reached 76 °C within 10 minutes. The end of the reaction was determined by pH (the pH decreased from 13.3 to 9.5) and GC analysis of the reaction mixture (1,3-DBD disappeared to ≤ 1% in area %). The phases were separated and 50 g of the aqueous phase was taken out for use in the next run (i.e., the procedure of Example 1).

[0091] (Example 4) (Preparation of cis-2-undecenoic acid) In Step 1, A mixture of 2-undecanone (218 g, 1.28 mol) and 48% aqueous HBr solution (300 g) was stirred and cooled to about 10 °C, and bromine (410 g, 2.56 mol) was added dropwise over 3 hours. As soon as the addition of bromine started, the reaction began immediately and no accumulation of bromine was observed. The reaction was an exothermic reaction and was accompanied by the evolution of HBr gas immediately before the addition of bromine was completed, and this gas was absorbed by a scrubber.

[0092] Most of the reaction occurred during the addition of bromine and heating at room temperature (about 20 °C) for 3.5 hours. After standing at room temperature overnight (about 16.5 hours), the composition of the reaction mixture was stable without stirring. A partial conversion from 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 min, and the phases were separated.

[0093] An aqueous phase (627 g) containing about 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 %).

[0094] In Step 2, In a 1 L stirred reactor, K2CO3 (200 g) was added portionwise to water (600 g) to prepare an aqueous K2CO3 solution with a concentration of 25% w / w. The reaction was an exothermic reaction. The resulting clear solution was heated to 40 °C, and the crude DBUD (200 g) from Step 1 was added dropwise to this solution over 20 min. The progress of the reaction was monitored by changes in GC and pH.

[0095] The mixture of the aqueous K2CO3 solution and the crude DBUD was stirred at a temperature of 50 °C for 1 hour, at 60 °C for 1.5 hours, and further at 70 °C for 1.5 hours. Based on the pH (which did not change at about 13) and GC, it was found that no reaction occurred.

[0096] Next, a portion (about 10 g) of the aqueous phase (containing CDA-K) of the reaction mixture was added dropwise to the reaction mixture over 15 min. When the addition was completed, the temperature inside the reactor began to rise and reached 82 °C within 10 min. Thereafter, this mixture was stirred at 70 °C for an additional 2 hours.

[0097] The end of the reaction was determined by pH (the pH decreased from 13 to 10) and GC analysis of the reaction mixture (the disappearance of 1,3-DBUD to ≤ 1% in area %).

[0098] To minimize the amount of impurities, the reaction mixture (960 g) was washed three times with dichloromethane (DCM, 3 × 250 g) at room temperature. It should be noted that the first phase separation was slow.

[0099] After the washing step, an aqueous phase containing potassium cis-2-undecenoate (CUDA-K), organic by-products, KBr, and KHCO3 was obtained. To obtain crude cis-2-undecenoic acid (CUDA), a 32% aqueous HCl solution (132 g) was added dropwise over 1 hour to acidify the aqueous phase. CO2 was released during the acidification.

[0100] After stopping the stirring, an aqueous phase (762 g) containing salts KCl and KBr (heavy phase, d = 1.15 g / ml) and wet crude CUDA (light phase, 53 g, d = 1.07 g / ml) was obtained and analyzed by GC and 1 1H-NMR (1 For the 1H-NMR spectrum, see Figures 3A, 3B and 3C. The purity of the obtained crude CUDA was 89.6% (GC area%). The main impurity of the crude product, 2-bromomethylidene decanoic acid (BMDA), was 5.2% (GC area%).

[0101] Under vacuum (T B = 50 °C), DCM and light components were evaporated from the moist CUDA to obtain crude CUDA (35 g).

[0102] As can be seen in this example, the preparation of CUDA was carried out using a small amount of the alkali metal salt of the homologous acid (CDA-K). The obtained aqueous phase contained potassium cis-2-undecenoate (CUDA-K) together with a trace amount of CDA-K, which was used to supply a catalytically effective amount of CUDA-K to the alkali K2CO3 solution before starting the slow addition of crude DBUD at the next run, ensuring an efficient and easily manageable reaction.

[0103] (Example 5 Comparative Example) (Preparation of cis-2-nonenoic acid) In Step 1, A mixture of 2-nonanone (manufactured by Sigma-Aldrich, 182 g, 1.28 mol) and 48% aqueous HBr solution (300 g) was stirred, cooled to about 10 °C, and bromine (410 g, 2.56 mol) was added dropwise over 3 hours. As soon as the addition of bromine started, the reaction began immediately and no accumulation of bromine was observed. The reaction was exothermic and was accompanied by the release of HBr gas immediately before the addition of bromine was completed, and this gas was absorbed by a scrubber.

[0104] Most of the reaction occurred during the addition of bromine and heating at room temperature (about 20 °C) for 2.0 hours. After standing at room temperature overnight (about 17 hours), the composition of the reaction mixture was stabilized by stirring. A partial conversion from 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 min, and the phases were separated.

[0105] An aqueous phase (624 g) containing about 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 %).

[0106] In Step 2, K2CO3 (200 g) was added portionwise to water (600 g) in a 1 L stirred reactor to prepare an aqueous K2CO3 solution with a concentration of 25% w / w. The reaction was exothermic. The resulting clear solution was heated to 46 °C, and the crude DBN (191 g) from Step 1 was added dropwise to this solution over 45 min. The progress of the reaction was monitored by the changes in pH and T R of the reaction.

[0107] Based on the pH (which did not change at about 13) and GC, it was found that no reaction occurred during the addition of the crude DBN. Immediately after the addition of the crude DBN, the pH began to decrease and T R began to increase.

[0108] The end of the reaction was determined by the pH (the pH decreased from 13.3 to 9.1) and GC analysis of the reaction mixture (the disappearance of 1,3-DBN to ≤ 1% in area %). The phases were separated. The organic phase (42.6 g) was organic waste.

[0109] To minimize the amount of impurities, the aqueous phase (948 g) was washed three times with dichloromethane (DCM, 3 × 250 g).

[0110] After the washing step, an aqueous phase containing potassium cis-2-nonenoate (CNA-K), organic by-products, KBr, and KHCO3 was obtained. To obtain crude cis-2-nonenoic acid (CNA), a 32% aqueous HCl solution (227 g) was added dropwise over 1 hour to acidify the aqueous phase. CO2 was released during the acidification.

[0111] After stopping the stirring, an aqueous phase (978 g) containing salts KCl and KBr (heavy phase, d = 1.19 g / ml) and wet crude CNA (light phase, 51 g, d = 1.02 g / ml) was obtained, and GC and 1Analyzed by H-NMR ( 1 For the H-NMR spectrum, see Figures 4A, 4B, and 4C). The purity of the obtained CNA was 92.0% (GC area%).

[0112] Under vacuum (T B = 50 °C), DCM and light components were evaporated from the moist CNA to obtain crude CNA (46.6 g).

[0113] (Example 6 Comparative Example) (Preparation of cis-2-octenoic acid) In Step 1, A mixture of 2-octanone (manufactured by Sigma-Aldrich, 164 g, 1.28 mol) and 48% aqueous HBr solution (300 g) was stirred and cooled to about 10 °C, and bromine (410 g, 2.56 mol) was added dropwise over 3 hours. As soon as the addition of bromine started, the reaction immediately began, and no accumulation of bromine was observed. The reaction was an exothermic reaction, accompanied by the release of HBr gas immediately before the addition of bromine was completed, and this gas was absorbed by a scrubber.

[0114] Most of the reaction occurred during the addition of bromine and heating at room temperature (about 20 °C) for 2.5 hours. After standing at room temperature overnight (about 15 hours), the composition of the reaction mixture was stabilized by stirring. A partial conversion from 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 min, and the phases were separated.

[0115] An aqueous phase (636 g) containing about 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%).

[0116] In Step 2, In a 1 L stirred reactor, K2CO3 (200 g) was added portionwise to water (600 g) to prepare an aqueous K2CO3 solution with a concentration of 25% w / w. The reaction was an exothermic reaction. The resulting clear solution was heated to 49 °C, and the crude DBO (182 g) from Step 1 was added dropwise to this solution over 1 hour. The progress of the reaction was monitored by the changes in pH and T R .

[0117] Based on pH (which did not change at about 13) and GC, it was found that no reaction occurred during the addition of the crude DBO. Immediately after adding the crude DBO, the pH began to decrease and T R began to increase.

[0118] The end of the reaction was determined by pH (the pH decreased from 13.7 to 9.3) and GC analysis of the reaction mixture (1,3-DBO disappeared to ≤ 1% in area %).

[0119] Before starting the washing, water (75 g) was added to the reaction mixture (982 g). To minimize the amount of impurities, the reaction mixture was washed 4 times with dichloromethane (DCM, 4 × 250 g).

[0120] After the washing step, an aqueous phase containing potassium cis-2-octenoate (COA-K), organic by-products, KBr, and KHCO3 was obtained. To obtain crude cis-2-octenoic acid (COA), a 32% aqueous HCl solution (178 g) was added dropwise over 1 hour to acidify the aqueous phase. CO2 was released during the acidification.

[0121] After stopping the stirring, an aqueous phase (938 g) containing salts KCl and KBr (heavy phase, d = 1.18 g / ml) and wet crude COA (light phase, 44 g, d = 1.00 g / ml) was obtained and analyzed by GC and 1 1H-NMR ( 1 For the 1H-NMR spectrum, see Figures 5A, 5B, and 5C). The purity of the obtained COA was 89.6% (GC area %).

[0122] Under vacuum (T BThe DCM and light components were evaporated from the moist COA at (≤50 °C) to obtain crude COA (41.3 g).

[0123] (Example 7 Comparative Example) (Preparation of cis-2-Heptenoic Acid) In Step 1, A mixture of 2-heptanone (manufactured by Sigma-Aldrich, 146 g, 1.28 mol) and 48% aqueous HBr solution (300 g) was stirred, cooled to approximately 10 °C, and bromine (410 g, 2.56 mol) was added dropwise over 3 hours. As soon as the addition of bromine was started, the reaction immediately began, and no accumulation of bromine was observed. The reaction was exothermic, and the evolution of HBr gas was accompanied immediately before the addition of bromine was completed, and this gas was absorbed by a scrubber.

[0124] Most of the reaction occurred during the addition of bromine and heating at room temperature (about 20 °C) for 4.5 hours. After standing at room temperature overnight (about 17 hours), the composition of the reaction mixture was stabilized by stirring. Partial conversion from 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 min, and the phases were separated.

[0125] An aqueous phase (631 g) containing approximately 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%).

[0126] In Step 2, K2CO3 (200 g) was added portionwise to water (600 g) in a 1 L stirred reactor to prepare an aqueous K2CO3 solution with a concentration of 25% w / w. The reaction was exothermic. The resulting clear solution was heated to 49 °C, and the crude DBH from Step 1 (173 g) was added dropwise to this solution over 1 hour. The progress of the reaction was monitored by the change in pH and T R .

[0127] Based on the pH (which did not change at about 13), it can be seen that no reaction occurred during the addition of the crude DBH. Immediately after the addition of the crude DBH, the pH began to decrease and T R began to increase.

[0128] The end of the reaction was determined by the pH (the pH decreased from 13.5 to 9.3) and the GC analysis of the reaction mixture (1,3-DBH disappeared to ≤ 1% in area %). After the reaction was completed, it was cooled to room temperature and stirring was stopped, and an organic phase containing unreacted 3-BH and 3,3-DBH, as well as by-products formed by the condensation reaction of the crude DBH, appeared on top of the aqueous phase. The phases were separated. The organic phase (24 g) is organic waste.

[0129] Before starting the washing, water (50 g) was added to the reaction mixture (948 g). To minimize the amount of impurities, the diluted reaction mixture (998 g) was washed three times with dichloromethane (DCM, 3 × 250 g).

[0130] After the washing step, an aqueous phase containing potassium cis-2-heptenoate (CHA-K), organic by-products, KBr and KHCO3 was obtained. To obtain crude cis-2-heptenoic acid (CHA), a 32% aqueous HCl solution (193 g) was added dropwise over 1 hour to acidify the aqueous phase. CO2 was released during the acidification.

[0131] After stopping the stirring, an aqueous phase (1014 g) containing salts KCl and KBr (heavy phase, d = 1.18 g / ml) and wet crude CHA (light phase, 45 g, d = 1.00 g / ml) was obtained and analyzed by GC and 1 1H-NMR ( 1 For the 1H-NMR spectrum, see Figures 6A, 6B and 6C). The purity of the obtained CHA was 95.6% (GC area %).

[0132] Under vacuum (T B = 50 °C), DCM and light components were evaporated from the wet CHA to obtain crude CHA (44 g).

[0133] (Examples 8A and 8B Comparative Examples) <Purification of Crude Cis-2-Decenoic Acid by Silica Gel Column Chromatography> 8A 1.54 g of crude CDA was placed on top of a 24 cm long glass column with a diameter of Φ22 mm packed 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 was discarded. Next, the eluent was changed to 5% ethyl acetate - 95% hexane. A further 140 mL of eluent was discarded, and 60 mL fractions were collected. The solvent was removed under reduced pressure to obtain 0.36 g of pure CDA (99% by HPLC area %).

[0134] 8B 2.35 g of crude CDA was placed on top of a 35 cm long glass column with a diameter of Φ22 mm packed 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. Next, the eluent was changed to 5% ethyl acetate - 95% hexane. A further 210 mL of eluent was discarded, and 65 mL fractions were collected.

[0135] This fraction was combined with the 8A fraction, and the solvent was removed under reduced pressure to obtain 0.95 g of pure CDA (99% by HPLC area %), which was analyzed by GC and 1 1H-NMR ( 1 For the 1H-NMR spectrum, see Figures 7A, 7B, 7C, 13 For 13C-NMR, see Figures 8A, 8B).

[0136] (Example 9) <Purification of Crude Cis-2-Decenoic Acid by Distillation (Laboratory Scale)> Crude CDA (70% CDA content by HPLC analysis) was distilled under reduced pressure. The distillation apparatus consisted of a 100 mL three-necked flask connected via a Y-connector to a short Vigreux column. A rotary receiver equipped with a water condenser and four flasks was attached to the vacuum pump (2 mbar). Crude CDA (79.7 g) was placed in the distillation flask, and vacuum and heating were applied. Distillation was started at a vapor temperature of 77 - 83 °C at the distillation head, and pure CDA was obtained at a vapor temperature of 95 - 105 °C (bottom temperature 130 - 140 °C). 43 g of CDA was collected, and the CDA content was 96.7% (analysis by HPLC). The distilled CDA had a purity of 97.6% by GC (area %), contained 0.6% trans-decenoic acid and approximately 0.5% bromomethylidenenonanoic acid. The distillation yield was 75%.

[0137] (Example 10) <Purification of Crude cis-2-Decenoic Acid by wiped film evaporation (mini-pilot scale)> Mini-pilot scale studies were conducted to determine the evaporation conditions for purifying crude CDA to achieve high CDA assay values (≥90%) and good yields (≥90%).

[0138] 0.12 m 2 CDA purification was carried out using a glass WFE of 0.12 m, a 1 L bottom flask for residues, and a 200 ml flask for distillate collection. Heating was carried out by hot oil circulating through the WFE jacket by a LAUDA system. The vapor was passed through a condenser and cooled by chilled ethylene glycol water at 7 °C. Crude CDA was fed to the WFE by a peristaltic pump (via 1 / 2’’ Teflon tubing). Laboratory graduated cylinders were used at the crude CDA inlet and distillate outlet to monitor the feed flow rate and distillation rate during operation. Vacuum was achieved by an oil vacuum pump, and an acetone dry ice trap was attached to prevent DCM from reaching the pump.

[0139] In a series of runs, conditions (temperature, vacuum pressure, feed flow rate, rotation speed, D / F ratio) were varied to test the effect of these conditions on the analytical and impurity profiles. The operating conditions and test results are summarized in Table C.

[0140] [Table C]

[0141] From the results summarized in Table C, it can be seen that wiped film evaporation of the crude product at temperatures above 150 °C, for example, between 150 °C and 180 °C, results in products with high CDA assays (≥ 90%) and good product yields of 80-90%. Some runs where deep vacuum was not created (A4, B4) showed good assays, but these runs showed low productivity / yields. It is therefore beneficial to keep the evaporation runs at low pressures (< 4.5 mbar). To obtain the desired D / F ratio near 71%, the feed flow rate is kept in the range of 14-15 ml / min at 150 °C and 35 ml / min at 180 °C.

[0142] Example 11 <Purification of crude cis-2-decenoic acid by wiped film evaporation (pilot scale)> The WFE systems for crude purification were all 0.4 m 2 The system included a 100 L bottom tank and a "Canzler" WFE. The WFE was heated with hot oil from an electric heater ("Lauda", 48 kW), but the bottom tank was not heated. Crude CDA was fed from a 200 L drum by a peristaltic pump and placed on the balance WI-1 at the top of the WFE system. The residue was collected in the bottom tank and discharged at the end of each run. Steam was pumped to a 0.75 m 2 The distillate was collected in a 100 L glass distillate receiver and removed by diaphragm pump P-3 at the end of each run. The condenser and distillate receiver were connected to an Edwards deep vacuum dry pump CXS250.

[0143] Several trials were conducted to define the optimal evaporation conditions for crude CDA (63.6 kg, analytical value 67% w / w, HPLC).

[0144] The two-pass distillation mode was performed in the first pass at 175 - 180 °C, 1 mbar, feed flow rate 27 kg / h (189 °C, top pressure approximately 1 mbar) to obtain 40 kg of CDA (analytical value 77% w / w), and then in the second pass at 55 kg / h (180 °C, top pressure 1 mbar) to obtain 23.8 kg of in-specification CDA (analytical value 98%), and good results (recovery of pure CDA with analytical value ≥ 90% by HPLC) were obtained. The bottom of the second pass (11 kg) was also distilled at 175 - 180 °C and a feed flow rate of 60 kg / h to obtain 7 kg of in-specification CDA (93%). The overall yield of purification by WFE was 72% in-specification (analytical value > 95%) CDA from the crude CDA product. Figures 9A, 9B, and 9C are the 1 1H-NMR spectra of the obtained CDA, and Figures 10A and 10B are the 13 13C-NMR spectra of the obtained CDA.

[0145] (Example 12) (Thermal Isomerization of CDA) Studies were conducted to determine the thermal isomerization of CDA. CDA was charged into a flask equipped with a magnetic stirrer, a thermocouple, and a condenser. Figures 11A and 11B show the isomerization of the cis isomer to the trans isomer (TDA) at 150 °C and 180 °C respectively at atmospheric pressure as a result of sampling at different times and analyzing by HPLC. It can be seen that CDA is unstable to heat and very large isomerization occurs rapidly.

Claims

1. A method for purifying crude cis-2-alkenoic acid by thermal separation, comprising wiped film evaporation or vacuum distillation of the crude cis-2-alkenoic acid under a temperature-drop pressure profile, and minimizing the isomerization of cis-2-alkenoic acid to trans-2-alkenoic acid.

2. Formula R-CH=CH-COOH (wherein R is a straight alkyl chain CH ３ - (CH ２ ) ｎ -, and 3≦n≦10), comprising wiping film evaporation of the crude cis-2-alkenoic acid.

3. The method according to claim 2, wherein the cis-2-alkenoic acid is cis-2-decenoic acid, and the wiped film evaporation is carried out at a temperature of 150 °C or higher and a reduced pressure of < 5 mbar.

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

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

6. The crude cis-2-alkenoic acid is prepared by a process comprising brominating 2-alkanone to obtain 1,3-dibromo-2-alkanone, and rearranging the 1,3-dibromo-2-alkanone to the cis-2-alkenoic acid, the method according to any one of claims 1 to 5.

7. The crude cis-2-alkenoic acid is prepared by a process comprising rearranging 1,3-dibromo-2-alkanone in an alkaline environment in the presence of a catalytically effective amount of an alkali metal salt of cis-2-alkenoic acid, and isolating cis-2-alkenoic acid in the form of a free acid or an alkali metal salt from the reaction mixture, the method according to any one of claims 1 to 6.

8. The crude cis-2-alkenoic acid is Na ２ CO ３ , K ２ CO ３ The method according to claim 7, prepared by a process comprising the step of gradually adding 1,3-dibromo-2-alkanone at an elevated temperature to a reaction vessel pre-filled with an aqueous alkali solution of Na, CO, ２ , K, CO, ２ , or a mixture thereof and an alkali metal salt of cis-2-alkenoic acid in a catalytically effective amount.

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

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

11. The process for preparing the crude cis-2-alkenoic acid according to claim 7 or 8 includes optionally diluting the reaction mixture with water, washing it with an organic solvent, and subsequently performing phase separation to obtain a purified aqueous phase.

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

13. The process for preparing the crude cis-2-alkenoic acid [Chemical Formula 2] includes rearranging a 1,3-dibromo-2-alkanone selected from the group consisting of, according to the method of any one of claims 6 to 12.

14. The 1,3-dibromo-2-alkanone used in the rearrangement reaction is a crude 1,3-dibromo-2-alkanone, and the crude 1,3-dibromo-2-alkanone includes forming 1,3-dibromo-2-alkanone together with 3,3-dibromo-2-alkanone in the reaction mixture by brominating a corresponding 2-alkanone selected from the group consisting of 2-heptanone, 2-octanone, 2-nonanone, 2-decanone, and 2-undecanone by adding elemental bromine in concentrated hydrobromic acid; maintaining the reaction mixture for a holding time adjusted to maximize the interconversion of 3,3-dibromo-2-alkanone to 1,3-dibromo-2-alkanone; collecting the crude 1,3-dibromo-2-alkanone by phase separation, according to the method of claim 13.

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

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

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

18. The method according to any one of claims 1 to 17, wherein the cis-2-alkenoic acid is cis-2-decenoic acid.

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