Preparation of cis-2-alkenonic acid

Abstract

A method for preparing cis-2-alkenyl acid or its alkali metal salt, comprising rearranging 1,3-dibromo-2-alkenone in an alkaline environment in the presence of a catalytically effective amount of the cis-2-alkenyl acid alkali metal salt, and separating the cis-2-alkenyl acid in free acid form or alkali metal salt form from the reaction mixture.

Description

[0001] This application relates to the synthesis of long-chain cis-α,β-unsaturated acids of the formula R-CH=CH-COOH, namely cis-2-chain enoic acids, wherein R represents an alkyl residue (straight chain or branched chain) consisting of not less than, for example, 4 carbon atoms.

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

[0003] In the jointly assigned PCT / IL2020 / 050591 (=WO 2020 / 240559), cis-2-decenoic acid was demonstrated as an effective adjuvant to brominated biocides in treating biofilms and planktonic bacteria on water systems and water-contacting surfaces, significantly enhancing the killing of bacteria commonly found in pure and mixed cultures in industrial and natural waters compared to treatment with brominated biocides alone. Notably, PCT / IL2020 / 050591 shows that cis-2-decenoic acid of moderate purity, such as 80-95% (by gas chromatography, GC area %), can satisfactorily enhance brominated water treatment.

[0004] We have now developed a method for synthesizing long-chain cis-2-enoic acids or their salts, and the recovered crude products have acceptable levels of purity, suitable for bromine-based water treatment without further purification.

[0005] The synthesis is based on a two-step process, involving the bromination of the corresponding 2-alkane to give crude 1,3-dibromo-2-alkane as the major product and other isomers, followed by rearrangement of the 1,3-dibromo-2-alkane to yield an unsaturated acid, as shown in the following scheme:

[0006]

[0007] [Where R' is an alkyl group, such as C2H5, C3H7, C4H9, C5H] 11 and C6H 13The two-step synthesis described above was first described by Rappe et al. [Acta Chemica Scandinavica (1965), Vol. 19, pp. 383-389]. The rearrangement occurs in an alkaline environment, using alkali metal carbonates or alkali metal bicarbonates as bases. A similar method was reported by the same research group in Organic Syntheses (1973), Vol. 53, pp. 123-127.

[0008] An attempt to modify the two-step synthetic route was found in US 8,748,486, which explained that alkali metal bicarbonates could only effectively promote the preparation of short-chain cis-α,β-unsaturated acids. The authors reported that the rearrangement reactions of long-chain brominated ketones (e.g., 1,3-dibromo-2-decanone) were very slow in the presence of alkali metal bicarbonates, failing to yield the target fatty acid even with extended reaction times. The authors instead used alkali metal hydroxides to promote the preparation of long-chain cis-α,β-unsaturated acids (the terms "cis-α,β-unsaturated acid" and "cis-2-olefinic acid" are used interchangeably).

[0009] The experimental results reported below are consistent with the observations in US 8,748,486: the rearrangement reaction of long-chain 1,3-dibromo-2-alkylones shows almost no progress at alkaline pH, even at high reaction temperatures, and is prone to thermal runaway (a sudden and rapid increase in reaction temperature). Such reaction profiles are unacceptable for processes operated on an industrial scale.

[0010] However, it has now been found that providing a quantitative amount of the alkali metal salt of the target cis-2-enoic acid to the reaction mixture can effectively and controllably promote the rearrangement reaction of 1,3-dibromo-2-alkylone to give the cis-2-enoic acid. As shown below, the added alkali metal salt of the cis-2-enoic acid can be provided for the rearrangement reaction from previous steps. A controllable method is provided by adding a small amount of the cis-2-enoic acid or its salt at the start of the rearrangement reaction.

[0011] Therefore, this application mainly relates to a method for preparing cis-2-alkenonic acid [R-CH=CH-COOH] or its alkali metal salt [R-CH=CH-COOM, where M is an alkali metal], comprising rearranging 1,3-dibromo-2-alkenone [R-CHBr-C(O)-CH2Br] in an alkaline environment (e.g., generated from an alkali metal carbonate or a mixture of alkali metal carbonate / bicarbonate) in the presence of a catalytically effective amount of the cis-2-alkenonic acid alkali metal salt, and separating the cis-2-alkenonic acid in free acid form or alkali metal salt form 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-alkenonic acid in free acid form or alkali metal salt form).

[0012] R is selected from an alkyl group with not less than 4 carbon atoms, for example, not less than 5 carbon atoms, for example, R is C4-C. 11 Alkyl groups. For example, cis-2-decenoic acid in its free acid form (R is C7H). 15 It is collected in an oily form. When the cis-2-decenoic acid thus formed reacts with an alkali metal hydroxide such as KOH, the corresponding potassium salt is given in a paste-like solid form.

[0013] The cis-2-chain enoic acid R-CH=CH-COOH prepared in this application is preferably straight-chain. That is, R is usually a straight-chain alkyl group CH3-(CH2). n -(3≤n, e.g., 3≤n≤10). For example, the preparation of cis-2-alkenyl acids by rearrangement reactions of the corresponding 1,3-dibromo-2-alkenones as described below has been investigated (but it should be noted that R is not limited to straight chains and may be branched alkyl groups, e.g., isoalkyl groups):

[0014]

[0015] All of this was found to be due to the addition of a catalytically effective amount of the target cis-2-alkenonic acid or its alkali metal salt to the basic reaction mixture. The “catalytically effective amount” refers to an amount of up to 15 mol%, for example, up to 10 mol%, for example, 1-5 mol%, based on 1,3-dibromo-2-alkenone.

[0016] The 1,3-dibromo-2-alkanone that undergoes the rearrangement reaction is 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) in concentrated hydrobromic acid (e.g., a 30%-48% HBr solution by weight) with the slow addition of elemental bromine (stoichiometrically, the molar ratio of Br2 to 2-alkanone is about 2:1).

[0017] The weight ratio of the 2-alkylone starting material to the HBr aqueous solution was 1:1 to 1:2. The reaction medium was cooled to a temperature in the range of 5-20°C, for example, about 5-10°C. Under these conditions, elemental bromine was readily added to the 2-alkylone, and most of the reaction occurred during the addition of bromine; no accumulation of bromine was observed (characteristic yellow markings obtained from the reaction mixture).

[0018] On a laboratory scale, the bromine addition time is typically 1–5 hours. After the elemental bromine is added, the reaction mixture is held at room temperature (15–25 °C), optionally with stirring, for a period of time (“holding time”). The holding time can last from 6 to 24 hours, for example 6–12 hours. A longer holding time appears to be beneficial because the bromination of 2-alkylones produces some isomeric byproducts, primarily 3,3-dibromo-2-alkylone. GC analysis of the reaction mixture shows that, over time, the target isomer 1,3-dibromo-2-alkylone gradually becomes the major product; that is, a prolonged holding time enables significant interconversion of 3,3-dibromo-ketones to 1,3-dibromo-ketones.

[0019] To illustrate the importance of extending the retention time in altering the distribution of isomeric mixtures of 1,3-dibromo-2-alkylone and 3,3-dibromo-2-alkylone at the expense of the latter, Table A lists experimental data based on procedures using 2-nonanone, 2-decanone, or 2-undecanone bromide (reported in the Working Example below):

[0020] Table A

[0021]

[0022] *In T R The time elapsed after bromine addition at approximately 20°C

[0023] Other impurities consisting of 3-bromo-2-alkylone and tribromo-2-alkylone are also present.

[0024] It can be seen that the product mixtures obtained by brominating various 2-alkaneones in hydrobromic acid exhibit a similar behavior after prolonged holding time. Initially, the mixture of 1,3-dibromo-2-alkaneone and 3,3-dibromo-2-alkaneone was in a ratio of approximately 2:1; after approximately 20 hours, the ratio increased to over 10:1, equilibrium stabilized, and approximately 70% (GC, area%) of the target isomer, 1,3-dibromo-2-alkaneone, was suitable for the rearrangement reaction.

[0025] Hydrogen bromide is released during the bromine addition and subsequent holding phases; the gas is absorbed by a suitable aqueous medium and collected as an aqueous solution of hydrobromic acid.

[0026] To recover crude 1,3-dibromo-2-alkylone, the reaction mixture was post-treated by adding water, followed by separation into an aqueous phase (consisting of approximately 48% w / w hydrobromic acid) and an organic phase (consisting of the crude product). Typically, as shown in the data listed in Table A, the recovered crude product contains approximately 70% (GC, area) of 1,3-dibromo-2-alkylone.

[0027] Therefore, in a preferred embodiment of this application, 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 in concentrated hydrobromic acid by adding elemental bromine, thereby forming 1,3-dibromo-2-alkanone and 3,3-dibromo-2-alkanone together in the reaction mixture;

[0028] The reaction mixture is maintained for an adjusted holding time to maximize the interconversion 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.

[0029] The crude 1,3-dibromo-2-alkanone requires no further purification and can now proceed with the rearrangement reaction. However, this application is not limited to obtaining the rearrangement of 1,3-dibromo-2-alkanone by brominating 2-alkanone in concentrated hydrobromic acid; other methods reported in the literature for the preparation of 1,3-dibromo-2-alkanone can be used, for example, brominating 2-alkanone in an organic solvent such as a haloalkane (CH2Cl2 or CH2Br2) with the aid of an acceptable brominating agent.

[0030] A simple method for carrying out the rearrangement reaction involves gradually adding 1,3-dibromo-2-alkanone to a reaction vessel pre-filled with an alkaline aqueous solution (e.g., consisting of 10-30% w / w Na₂CO₃, K₂CO₃, or a mixture thereof or a carbonate / bicarbonate mixture dissolved in water) and a catalytically effective amount of cis-2-alkenyl acid at an elevated temperature (e.g., ≥35°C, e.g., ≥40°C), for example, while the reaction mixture is maintained at a temperature in the range of 40°C-60°C. 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.

[0031] For example, potassium carbonate is preferred over sodium carbonate because, as shown below, the corresponding alkali metal bicarbonate is a byproduct of the rearrangement reaction. When using potassium salts, fewer difficulties may be encountered in the post-processing stages of the reaction mixture because potassium bicarbonate is more soluble in water than sodium bicarbonate.

[0032] In the presence of an alkali metal salt of cis-2-olefinic acid, the reaction occurs during the addition of 1,3-dibromo-2-alkylone to a basic reaction mixture. The reaction proceeds with a decrease in pH (i.e., a decrease of at least 2 pH units, for example 2-4 pH units, in the initial strongly basic pH of 12-14 during the addition of 1,3-dibromo-2-alkylone) and an increase in temperature (i.e., Δ...). T The reactor temperature is approximately 510°C.

[0033] Conversely, if 1,3-dibromo-2-alkanone is added to an alkaline solution in the absence of an alkali metal salt of cis-2-alkenylic acid, the rearrangement of 1,3-dibromo-2-alkanone proceeds poorly, and the added 1,3-dibromo-2-alkanone accumulates in the reaction vessel. The experimental results shown below indicate that during the addition of crude 1,3-dibromo-2-alkanone, no rearrangement occurred in 1,3-dibromo-2-heptanone, 1,3-dibromo-2-octanone, and 1,3-dibromo-2-nonanone. The pH only began to decrease after the addition of crude 1,3-dibromo-2-alkanone was complete, and T... R The spontaneous rise in reactor temperature marks the commencement of the reaction. The rearrangement of higher homologues, such as 1,3-dibromo-2-decanone and 1,3-dibromo-2-undecanone, is even more difficult; progress is virtually impossible without the aid of an effective amount of alkali metal salts of cis-2-enoic acids.

[0034] After the slow addition of crude 1,3-dibromo-2-alkylone is complete (this may take 30-120 min on a laboratory scale), the reaction mixture is kept stirred for a period of time, i.e., cooked for several (1-3) hours at a temperature in the range of 50-55°C, to allow the reaction to complete. A pH decrease of approximately 0.5-1.5 units is observed during cooking. Reaction progress can be monitored by pH measurement (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-alkylone, i.e., a decrease to ≤1% by area).

[0035] 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 (containing unreacted brominated isomers, accompanied by 1,3-dibromo-2-alkanones, primarily 3-bromo-2-alkanones and 3,3-dibromo-2-alkanones; and some condensation byproducts formed during the rearrangement reaction) can be discarded. The aqueous phase containing cis-2-alkeny acids in the form of alkali metal salts (i.e., sodium or potassium salts, depending on the chosen base) is post-treated to separate the products.

[0036] An exemplary rearrangement reaction is illustrated by the scheme described below: using K₂CO₃ to convert 1,3-dibromo-2-decanoone (1,3-DBD) to the potassium salt of cis-2-decenoic acid (abbreviated as CDA-K):

[0037]

[0038] AP-RM indicates that a catalytically effective amount of the cis-2-alkenoic acid alkali metal salt is pre-added to initiate the rearrangement reaction. As described above, the catalytically effective amount of the cis-2-alkenoic acid alkali metal salt is provided to the reaction in an aqueous form, for example, by removing a relatively small portion of the aqueous phase collected after phase separation, retaining this small portion for use in the next operation. Typically, the small portion constitutes 1%-10% by weight of the total weight of the aqueous phase, for example, 3%-7% (about 5%). Based on the concentration of the cis-2-alkenoic acid alkali metal salt, it can be understood that the catalytically effective amount of the salt added to the alkaline solution before the start of the rearrangement reaction is preferably 1-5 mol% relative to the 1,3-dibromo-2-alkane.

[0039] However, it should be mentioned that there are alternative methods for providing cis-2-alkenyl alkali metal salts for rearrangement reactions, for example, by directly adding free acids or salts from other sources (if a free acid is added instead of an alkali metal salt, the acid reacts in an alkaline solution, forming the corresponding alkali metal salt in situ).

[0040] Next, most of the aqueous phase is post-treated by washing with an organic solvent immiscible with water, such as a halogenated hydrocarbon (e.g., dichloromethane) (this may require repeated washing cycles) to extract and remove organic impurities from the aqueous solution containing the product.

[0041] If the reaction mixture thus obtained cannot be separated into an aqueous 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, as described above, can be divided into a smaller fraction and a larger fraction. The smaller fraction is dedicated to the next operation, while the larger fraction is processed to recover the product from it.

[0042] To recover the product in its free acid form, the purified aqueous solution is acidified, for example, by slowly adding concentrated hydrochloric acid (e.g., a commercially available 32% HCl solution) to the aqueous solution to achieve a strongly acidic pH (e.g., from 1-2). The acidified reaction mixture is separated into an aqueous (heavy) phase and an organic (light) phase. The former contains bromide and chloride salts; the latter consists of crude cis-2-decenoic acid and some residual organic solvents and water, which may have been used in the washing stage, and is removed, for example, by vacuum evaporation, thereby obtaining crude cis-2-decenoic acid.

[0043] The sequence of reactions following acidification of the aqueous solution (especially in the preparation of potassium cis-2-decenoate) is as follows:

[0044]

[0045] Therefore, the method of this application further includes acidifying and purifying the aqueous phase (i.e., after extraction with an organic solvent) to obtain a biphase medium comprising a heavy saline phase and a light organic phase, said organic phase being primarily composed of cis-2-olefinic acids in the form of free acids.

[0046] The corresponding alkali metal salts can be prepared by conventional methods, such as by reacting free acid with potassium hydroxide in a suitable solvent and separating by crystallization and filtration, followed by drying.

[0047] As described above, the crude cis-2-enoic acids provided by the method of this application do not require further purification; that is, these acids are pure enough to act as biodispersants in bromine-based water treatment, i.e., their purity levels are >80%, >85%, >87%, for example, from 80%–95% (by 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 such as chromatography or distillation.

[0048] Table B

[0049]

[0050] Attached Figure Description

[0051] Figure 1A , 1B And 1C is the CDA of Example 1. 1 H-NMR spectrum.

[0052] Figure 2A , 2B And 2C is the CDA of Example 2. 1 H-NMR spectrum.

[0053] Figure 3A , 3B And 3C is the CUDA of Example 4. 1 H-NMR spectrum.

[0054] Figure 4A , 4B And 4C is the CNA of Example 5. 1 H-NMR spectrum.

[0055] Figure 5A , 5B And 5C is the COA of Example 6 1 H-NMR spectrum.

[0056] Figure 6A , 6B And 6C is the CHA of Example 7 1 H-NMR spectrum. Example

[0057] method:

[0058] GC: HP 7890A Gas Chromatograph

[0059] Method (CDA): Initial temperature 50℃, hold for 2 min, then increase to 280℃ at 10℃ / min and hold for 5 min, then increase to 300℃ at 10℃ / min and hold for 2 min.

[0060] Injector: 250℃

[0061] Detector: 300℃

[0062] Flow split ratio: 1:40

[0063] Product sample concentration: approximately 20 mg / ml DCM

[0064] Injection volume: 1 μl sample

[0065] Chromatographic column: Agilent J&W column, HP-5, 30m x 0.32mm x 0.25μm.

[0066] Part number 19091J-413, serial number USF302346H

[0067] 1 H-NMR spectrum

[0068] Spectroscopic analysis was performed on an Avance III, 500MHz instrument (Spectra).

[0069] Example 1: Preparation of cis-2-decenoic acid

[0070] Step 1:

[0071] Bromine (410 g, 2.56 mol) was added dropwise over 2 hours to a mixture of 2-decanone (200 g, 1.28 mol) stirred and cooled to about 10 °C and 48% HBr aqueous solution (300 g). The reaction started immediately upon the addition of bromine, and no accumulation of bromine was observed.

[0072] The reaction is exothermic and accompanied by the emission of HBr gas. Just before the addition of bromine is complete, the bromine is absorbed in the scrubber.

[0073] Most of the reaction occurred during the addition of bromine and cooking at room temperature (approximately 20°C) for 6 hours. After standing overnight (approximately 15 hours) at room temperature without stirring, the composition of the reaction mixture stabilized. 3,3-Dibromo-2-decanone (3,3-DBD) was partially converted to the target product 1,3-dibromo-2-decanone (1,3-DBD). Water (160 g) was added to the reaction mixture at room temperature with stirring for 30 minutes, followed by phase separation.

[0074] An aqueous phase (627 g) containing approximately 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 %).

[0075] Step 2:

[0076] A 25% w / w aqueous solution of K₂CO₃ was prepared in a 1 L stirred reactor by adding K₂CO₃ (200 g) in portions to water (600 g). The reaction was exothermic. A portion of the aqueous phase (containing CDA-K) of the remaining reaction mixture (50 g) from the previous operation (named AP-RM; see Comparative Example 3) was added to this solution. The resulting clear solution was heated to 40 °C, and crude DBD (200 g) from step 1 was added dropwise over 60 min. The reaction progress was monitored by changes in GC and pH. The reaction was completed by cooking at 50 °C for 3.0 h with mechanical stirring.

[0077] It should be noted that, without the addition of AP-RM, the reaction only begins spontaneously two hours after the addition of crude DBD.

[0078] The reaction was terminated by pH (pH decreasing from 13.3 to 9.3) and GC analysis of the reaction mixture (disappearance of 1,3-DBD to ≤1%, area %). After the reaction was complete, the mixture was cooled to room temperature, stirring was stopped, and an organic phase appeared above the aqueous phase, containing unreacted 3-bromo-2-decanone (3-BD) and 3,3-DBD, as well as byproducts formed from the condensation reaction of crude DBD. The phases were separated. The organic phase (39 g) was organic waste. 50 g of the aqueous phase was used for the next operation.

[0079] To minimize the amount of impurities, the remaining aqueous phase (950g) was washed three times with dichloromethane (DCM, 3 × 250g).

[0080] Following the washing stage, an aqueous phase containing potassium cis-2-decenoate (CDA-K), organic byproducts, KBr, and KHCO3 was obtained. To obtain crude cis-2-decenoic acid (CDA), the aqueous phase was acidified by adding 193 g of a 32% HCl aqueous solution dropwise over 1 hour. During the acidification process (final pH = 1.1), CO2 (calculated as 63 g) was emitted.

[0081] After stirring was stopped, 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.

[0082] In a vacuum (T) B DCM and light components were evaporated from wet CDA at 50°C to obtain crude CDA (50.5 g), which was then subjected to GC and... 1 H-NMR analysis (see [reference]) Figure 1A , 1B And 1C 1 (H-NMR spectra). The calculated yields of crude CDA were approximately 68% based on 1,3-DBD, or 46.8% based on 2-decanone.

[0083] The purity of the crude CDA obtained was 88.2% (by GC, area %). The major impurity in the crude product was 2-bromomethylene nonanoic acid (BMNA): 8.8% (by GC, area %).

[0084] Example 2: Preparation of cis-2-decenoic acid

[0085] Step 1:

[0086] Bromine (800 g, 5 mol) was added dropwise over 5 hours to a mixture of 2-decanone (400 g, 2.564 mol) stirred and cooled to about 10 °C and 48% HBr aqueous solution (600 g). The reaction started immediately upon the addition of bromine, and no accumulation of bromine was observed. The reaction was exothermic, accompanied by the emission of HBr gas, which was absorbed into the scrubber just before the addition of bromine was complete.

[0087] Most of the reaction occurred during the addition of bromine. After standing overnight at room temperature without stirring, the composition of the reaction mixture remained stable. 3,3-Dibromo-2-decanone (3,3-DBD) was partially converted to the target product 1,3-dibromo-2-decanone (1,3-DBD). Water (300 g) was added to the reaction mixture at room temperature and stirred for 30 min, after which the phases were separated.

[0088] 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 %).

[0089] Step 2:

[0090] A 25% w / w aqueous solution of K₂CO₃ was prepared in a 2L stirred reactor by adding K₂CO₃ (400 g) in portions to water (1200 g). The reaction was exothermic. A portion of the aqueous phase of the remaining reaction mixture CDA-K (50 g) from the previous operation was added to this solution. The resulting clear solution was heated to 40 °C, and crude DBD (step 1, 400 g) was added dropwise over 70 min. The reaction progress was monitored by changes in GC and pH. The reaction was completed by cooking at 40 °C for 1.0 h and then at 50 °C for 2.0 h with mechanical stirring.

[0091] The reaction was terminated by pH (decrease from 12.7 to 9.6) and GC analysis of the reaction mixture (disappearance of 1,3-DBD to ≤1%, area %). After the reaction was complete, the mixture was cooled to room temperature and stirring was stopped. An organic phase containing unreacted 3-BD and 3,3-DBD, as well as byproducts from the condensation reaction of crude DBD, appeared above the aqueous phase. The phases were separated. 50 g of the aqueous phase was used for the next operation.

[0092] To minimize the amount of impurities, the aqueous phase (1943g) was washed three times with dichloromethane (DCM, 3×500g).

[0093] Following the washing stage, an aqueous phase containing potassium cis-2-decenoate (CDA-K), organic byproducts, KBr, and KHCO3 was obtained. To obtain crude cis-2-decanoic acid (CDA), the aqueous phase was acidified by adding 401 g of a 32% HCl aqueous solution dropwise over 1 hour. During the acidification process (final pH = 1.9), CO2 (calculated as 127 g) was emitted.

[0094] After stirring was stopped, 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.

[0095] In a vacuum (T) B DCM and light components were evaporated from wet CDA at 50℃ to obtain crude CDA (102 g), which was then analyzed by GC, HPLC and... 1 H-NMR ( Figure 2A , 2B and in 2C 1It was analyzed using H-NMR spectroscopy.

[0096] Based on these results, the purity of the crude CDA obtained was 89.7% (by GC, area %) and 90.0% (by HPLC, area %). Based on 1,3-DBD, the calculated yield of the crude CDA was approximately 67%.

[0097] Example 3 (Comparative): Preparation of cis-2-decenoic acid

[0098] Step 1 was performed as in Example 1. However, the rearrangement reaction in step 2 was carried out without the addition of a cis-2-alkenyl alkali metal salt.

[0099] Step 2:

[0100] A 25% w / w aqueous solution of K₂CO₃ was prepared in a 1 L stirred reactor 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 previously described) was added dropwise over 60 min. The reaction progress was monitored by changes in GC and pH.

[0101] The mixture of K2CO3 aqueous solution and crude DBD was stirred at 50°C for 3 hours. Based on pH (which showed no change at approximately 13) and GC, it can be seen that no reaction occurred.

[0102] Then suddenly, the temperature inside the reactor began to rise spontaneously, reaching 76°C within ten minutes. The end of the reaction was determined by pH (pH decreased 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 taken for the next operation (i.e., the procedure of Example 1).

[0103] Example 4: Preparation of cis-2-undecenoic acid

[0104] Step 1:

[0105] Bromine (410 g, 2.56 mol) was added dropwise over 3 h to a mixture of 2-undecone (218 g, 1.28 mol) stirred and cooled to approximately 10 °C and 48% HBr aqueous solution (300 g). The reaction started immediately upon the addition of bromine, and no accumulation of bromine was observed. The reaction was exothermic, accompanied by the emission of HBr gas, which was absorbed into the scrubber just before the addition of bromine was complete.

[0106] Most of the reaction occurred during the addition of bromine and cooking at room temperature (approximately 20°C) for 3.5 hours. After standing overnight (approximately 16.5 hours) at room temperature without stirring, the composition of the reaction mixture stabilized. 3,3-Dibromo-2-undecanone (3,3-DBUD) was partially converted to the target product 1,3-dibromo-2-undecanone (1,3-DBUD). Water (160 g) was added to the reaction mixture at room temperature with stirring for 30 minutes, followed by phase separation.

[0107] An aqueous phase (627 g) containing approximately 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 %).

[0108] Step 2:

[0109] A 25% w / w K₂CO₃ aqueous solution was prepared in a 1 L stirred reactor 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 DBUD (200 g) from step 1 was added dropwise over 20 min. The reaction progress was monitored by changes in GC and pH.

[0110] The mixture of K2CO3 aqueous solution and crude DBUD was stirred at 50°C for 1 h, at 60°C for 1.5 h, and at 70°C for another 1.5 h. Based on pH (which showed no change at approximately 13) and GC, it can be seen that no reaction occurred.

[0111] Next, a portion of the aqueous phase of the CDA-K reaction mixture (approximately 10 g) was added dropwise to the reaction mixture over 15 minutes. At the end of the addition, the temperature inside the reactor began to rise and reached 82°C within 10 minutes. The mixture was then stirred at 70°C for another 2 hours.

[0112] The end of the reaction was determined by pH (pH decreasing from 13 to 10) and GC analysis of the reaction mixture (disappearance of 1,3-DBUD to ≤1%, area%).

[0113] 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.

[0114] Following the washing stage, an aqueous phase containing potassium cis-2-undecenoic acid (CUDA-K), organic byproducts, KBr, and KHCO3 was obtained. To obtain crude cis-2-undecenoic acid (CUDA), the aqueous phase was acidified by adding 132 g of an aqueous HCl solution dropwise over 1 hour. CO2 was emitted during the acidification process.

[0115] After stirring was stopped, 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, which was then subjected to GC and 1 H-NMR analysis (see [reference]) Figure 3A , 3B and 3C 1 (H-NMR spectrum). The purity of the crude CUDA obtained was 89.6% (by GC, area %). The major impurity in the crude product was 2-bromomethylenedecanoic acid (BMDA): 5.2% (by GC, area %).

[0116] In a vacuum (T) B DCM and light components were evaporated from wet CUDA at 50°C to obtain crude CUDA (35g).

[0117] As can be seen, in this embodiment, a small amount of the alkali metal salt of the homologous acid (CDA-K) is used to advance the preparation of CUDA. The resulting aqueous phase containing potassium cis-2-undecenoate (CUDA-K) and an insignificant amount of CDA-K can be used to provide a catalytically effective amount of CUDA-K for the next operation. This is added to an alkaline K2CO3 solution before the slow addition of crude DBUD to ensure an effective and controlled reaction.

[0118] Example 5 (Comparative): Preparation of cis-2-nonenoic acid

[0119] Step 1:

[0120] Bromine (410 g, 2.56 mol) was added dropwise over 3 h to a mixture of 2-nonanone (from Sigma-Aldrich; 182 g, 1.28 mol) and 48% HBr aqueous solution (300 g) that had been stirred and cooled to about 10 °C. The reaction started immediately upon the addition of bromine, and no accumulation of bromine was observed. The reaction was exothermic, accompanied by the emission of HBr gas, which was absorbed into the scrubber just before the addition of bromine was complete.

[0121] Most of the reaction occurred during the addition of bromine and cooking at room temperature (approximately 20°C) for 2.0 hours. After standing overnight (approximately 17 hours) at room temperature, the composition of the reaction mixture stabilized under stirring. 3,3-Dibromo-2-nonanone (3,3-DBN) was partially converted to the target product 1,3-dibromo-2-nonanone (1,3-DBN). Water (160 g) was added to the reaction mixture at room temperature and stirred for 30 minutes, after which the phases were separated.

[0122] An aqueous phase (624 g) containing approximately 50% HBr (d = 1.50 g / ml) and crude DBN (382 g, d = 147 g / ml) was obtained. The concentration of 1,3-DBN in the crude product was 70.6% (GC, area %).

[0123] Step 2:

[0124] A 25% w / w K₂CO₃ aqueous solution was prepared in a 1 L stirred reactor 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 over 45 min. The solution was then analyzed by pH and T. R Changes are used to monitor the reaction process.

[0125] Based on the pH value (which remained unchanged at approximately 13) and GC, it can be seen that no reaction occurred during the addition of crude DBN. Immediately after the addition of crude DBN, the pH value began to decrease, and T... R It has begun to rise.

[0126] The reaction was terminated by pH (pH decreasing 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.

[0127] To minimize the amount of impurities, the aqueous phase (948 g) was washed three times with dichloromethane (DCM, 3 x 250 g).

[0128] Following the washing stage, an aqueous phase containing potassium cis-2-nonenoic acid (CNA-K), organic byproducts, KBr, and KHCO3 was obtained. To obtain crude cis-2-nonenoic acid (CNA), the aqueous phase was acidified by adding 227 g of a 32% HCl aqueous solution dropwise over 1 hour. CO2 was emitted during the acidification process.

[0129] After stirring was stopped, an aqueous phase (978 g) was obtained, which contained salts: KCl and KBr (heavy phase, d = 1.19 g / ml) and wet crude CNA (light phase, 51 g, d = 1.02 g / ml), which was then subjected to GC and... 1 H-NMR (see H-NMR) Figure 4A , 4B The 1H-NMR spectrum of 4C was analyzed. The purity of the obtained CNA was 92.0% (by GC, area %).

[0130] In a vacuum (T) B DCM and light components were evaporated from wet CNA at 50°C to obtain crude CNA (46.6 g).

[0131] Example 6 (Comparative): Preparation of cis-2-octenic acid

[0132] Step 1:

[0133] Bromine (410 g, 2.56 mol) was added dropwise over 3 h to a mixture of 2-octanone (from Sigma-Aldrich; 164 g, 1.28 mol) and 48% HBr aqueous solution (300 g) that had been stirred and cooled to about 10 °C. The reaction started immediately upon the addition of bromine, and no accumulation of bromine was observed. The reaction was exothermic, accompanied by the emission of HBr gas, which was absorbed into the scrubber just before the addition of bromine was complete.

[0134] Most of the reaction occurred during the addition of bromine and cooking at room temperature (approximately 20°C) for 2.5 hours. After standing overnight (approximately 15 hours) at room temperature, the composition of the reaction mixture stabilized under stirring. 3,3-Dibromo-2-octanone (3,3-DBO) was partially converted to the target product 1,3-dibromo-2-octanone (1,3-DBO). Water (160 g) was added to the reaction mixture at room temperature and stirred for 30 minutes, after which the phases were separated.

[0135] An aqueous phase (636 g) containing approximately 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 %).

[0136] Step 2:

[0137] A 25% w / w K₂CO₃ aqueous solution was prepared in a 1 L stirred reactor 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 over 1 h. The solution was then analyzed by pH and T. R Changes are used to monitor the reaction process.

[0138] Based on the pH value (which remained unchanged at approximately 13) and GC, it can be seen that no reaction occurred during the addition of crude DBO. Immediately after the addition of crude DBO, the pH value began to decrease, and T... R It has begun to rise.

[0139] The end of the reaction was determined by pH (pH decreasing from 13.7 to 9.3) and by GC analysis of the reaction mixture (disappearance of 1,3-DBO to ≤1%, area%).

[0140] Before starting the washing, add water (75 g) to the reaction mixture (982 g). To minimize the amount of impurities, wash the reaction mixture four times with dichloromethane (DCM, 4 x 250 g).

[0141] Following the washing stage, an aqueous phase containing potassium cis-2-octenate (COA-K), organic byproducts, KBr, and KHCO3 was obtained. To obtain crude cis-2-octenate (COA), the aqueous phase was acidified by adding 178 g of a 32% HCl aqueous solution dropwise over 1 hour. CO2 was emitted during the acidification process.

[0142] After stirring was stopped, an aqueous phase (938 g) was obtained, which contained salts: KCl and KBr (heavy phase, d = 1.18 g / ml) and wet crude COA (light phase, 44 g, d = 1.00 g / ml), which was analyzed by GC and 1H-NMR (see [link to GC-NMR analysis]). Figure 5A , 5B (1H-NMR spectrum of 5C). The purity of the obtained COA was 89.6% (by GC, area %).

[0143] In a vacuum (T) B DCM and light components were evaporated from the wet COA at 50°C to obtain crude COA (41.3 g).

[0144] Example 7 (Comparative): Preparation of cis-2-heptenoic acid

[0145] Step 1:

[0146] Bromine (410 g, 2.56 mol) was added dropwise over 3 h to a mixture of 2-heptanone (from Sigma-Aldrich; 146 g, 1.28 mol) and 48% HBr aqueous solution (300 g) that had been stirred and cooled to about 10 °C. The reaction started immediately upon the addition of bromine, and no accumulation of bromine was observed. The reaction was exothermic, accompanied by the emission of HBr gas, which was absorbed into the scrubber just before the addition of bromine was complete.

[0147] Most of the reaction occurred during the addition of bromine and cooking at room temperature (approximately 20°C) for 4.5 hours. After standing overnight (approximately 17 hours) at room temperature, the composition of the reaction mixture stabilized under stirring. 3,3-Dibromo-2-heptanone (3,3-DBH) was partially converted to the target product 1,3-dibromo-2-heptanone (1,3-DBH). Water (160 g) was added to the reaction mixture at room temperature and stirred for 30 minutes, after which the phases were separated.

[0148] 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 %).

[0149] Step 2:

[0150] A 25% w / w K₂CO₃ aqueous solution was prepared in a 1 L stirred reactor 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 over 1 h. The pH and T were then compared with the K₂CO₃ solution. R Changes are used to monitor the reaction process.

[0151] Based on the pH value (which remained unchanged at approximately 13), it can be seen that no reaction occurred during the addition of crude DBH. Immediately after the addition of crude DBH, the pH value began to decrease, and T... R It has begun to rise.

[0152] The reaction was terminated by pH (pH decreasing from 13.5 to 9.3) and by GC analysis of the reaction mixture (disappearance of 1,3-DBH to ≤1%, area %). After the reaction was complete, the mixture was cooled to room temperature and stirring was stopped. An organic phase appeared above the aqueous phase, containing unreacted 3-BH and 3,3-DBH, as well as byproducts formed from the condensation reaction of crude DBH. The phases were separated. The organic phase (24 g) was organic waste.

[0153] Before starting the washing, add water (50 g) to the reaction mixture (948 g). To minimize the amount of impurities, wash the diluted reaction mixture (998 g) three times with dichloromethane (DCM, 3 x 250 g).

[0154] Following the washing stage, an aqueous phase containing potassium cis-2-heptenate (CHA-K), organic byproducts, KBr, and KHCO3 was obtained. To obtain crude cis-2-heptenic acid (CHA), the aqueous phase was acidified by adding 193 g of a 32% HCl aqueous solution dropwise over 1 hour. CO2 was emitted during the acidification process.

[0155] After stirring was stopped, an aqueous phase (1014 g) was obtained, which contained salts: KCl and KBr (heavy phase, d = 1.18 g / ml) and wet crude CHA (light phase, 45 g, d = 1.00 g / ml), which was subjected to GC and 1 H-NMR analysis (see [reference]) Figure 6A , 6B And 6C 1 (H-NMR spectrum). The purity of the obtained CHA was 95.6% (by GC, area %).

[0156] In a vacuum (T) B DCM and light components were evaporated from wet CHA at 50°C to obtain crude CHA (44g).

Claims

1. A method for preparing cis-2-alkenonic acid or its alkali metal salt, wherein the general formula of the cis-2-alkenonic acid is R-CH=CH-COOH, where R is a straight-chain alkyl group CH3-(CH2). n - where 3≤n≤10, the method comprises, in the presence of a catalytically effective amount of an alkali metal salt of cis-2-alkenyl acid, rearranging 1,3-dibromo-2-alkenone by adding cis-2-alkenyl acid or a salt thereof at the start of the rearrangement reaction in an alkaline environment, and separating cis-2-alkenyl acid in free acid form or alkali metal salt form from the reaction mixture.

2. The method according to claim 1, comprising gradually adding the 1,3-dibromo-2-alkylone to a reaction vessel pre-filled with an alkaline aqueous solution of Na2CO3, K2CO3 or a mixture thereof and a catalytically effective amount of a cis-2-alkenyl alkali metal salt at an elevated temperature.

3. The method according to claim 1, further comprising separating the reaction mixture into an aqueous phase and an organic phase, and post-treating the aqueous phase to recover cis-2-olefinic acid in the form of a free acid or an alkali metal salt.

4. The method of claim 3, wherein the aqueous phase is post-treated by washing with an organic solvent, followed by phase separation to obtain a purified aqueous phase.

5. The method of claim 1, wherein the reaction mixture is optionally diluted with water and washed with an organic solvent, followed by phase separation to obtain a purified aqueous phase.

6. The method of claim 4, further comprising acidifying the purified aqueous phase to obtain a biphase medium comprising a heavy saline phase and a light organic phase consisting substantially of cis-2-olefinic acids in the form of free acids.

7. The method according to claim 1, wherein the 1,3-dibromo-2-alkylone is selected from:

8. The method according to claim 1, wherein the 1,3-dibromo-2-alkylone used in the rearrangement reaction is crude 1,3-dibromo-2-alkylone obtained by the following steps: By adding elemental bromine to bromate the corresponding 2-alkane in concentrated hydrobromic acid, 1,3-dibromo-2-alkane and 3,3-dibromo-2-alkane are formed in the reaction mixture. The reaction mixture is maintained for an adjusted holding time to maximize the interconversion of 3,3-dibromo-2-alkanone to 1,3-dibromo-2-alkanone; and Collect crude 1,3-dibromo-2-alkylone.

9. The method according to claim 8, wherein the 2-alkane is selected from 2-heptanone, 2-octanone, 2-nonanone, 2-decanone, and 2-undecanone.

10. The method of claim 8, wherein the holding time is adjusted to achieve not less than 65% of 1,3-dibromo-2-alkylone, as measured by gas chromatography as area % 11. The method according to claim 1, wherein, Based on 1,3-dibromo-2-alkylone, the catalytically effective amount of the cis-2-alkenyl alkali metal salt is at most 10 mol.

12. The method according to claim 3, wherein a small portion of the aqueous phase is removed before or after post-treatment of the aqueous phase and used to provide a catalytically effective amount of the cis-2-alkenyl alkali metal salt in the corresponding 1,3-dibromo-2-alkenone rearrangement reaction.

13. The method of claim 1, wherein the catalytically effective amount of the cis-2-alkenyl alkali metal salt is provided to the rearrangement reaction in the form of an aqueous solution recovered from the earlier rearrangement reaction.

14. The method according to claim 1, wherein the 1,3-dibromo-2-alkylone is 1,3-dibromo-2-decanoone, such that the cis-2-enoic acid is cis-2-decenoic acid.

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