Synthesis method of 8-methylnonanoic acid

Abstract

The invention discloses a synthesis method of 8-methylnonanoic acid, which takes halogenated isobutane and 1-bromo-6-chlorohexane as raw materials, and comprises the following steps: converting the halogenated isobutane into an organic metal reagent, and coupling the organic metal reagent with the 1-bromo-6-chlorohexane under the catalysis of transition metal salt to obtain chlorinated isodecane; and oxidizing chloromethyl at the tail end of the chloro-isodecane into carboxyl to obtain 8-methylnonanoic acid. The reaction activity difference of bromine and chlorine is utilized, a target carbon skeleton is constructed in one step through direct selective coupling, terminal oxidizable sites are reserved at the same time, active functional groups such as carboxyl do not need to be protected and deprotected, synthesis steps are simplified, and harsh reaction conditions and use of expensive reagents are avoided. The method is safe, simple and convenient to operate, the obtained 8-methylnonanoic acid is high in purity and ideal in yield, and an economic, green and efficient intermediate synthesis scheme is provided for industrial production of dihydrocapsaicin.

Description

Technical Field

[0001] This invention relates to the field of organic compound synthesis technology, and in particular to a method for synthesizing 8-methylnonanoic acid, a key intermediate of dihydrocapsaicin. Background Technology

[0002] Chili peppers contain a variety of nutrients beneficial to human health, with high levels of vitamin A, vitamin C, dietary fiber, and capsaicin. Capsaicin compounds are the main active ingredients in chili peppers that cause their spiciness, but the content of dihydrocapsaicin has a significant impact on the overall spiciness and taste of chili peppers, making it one of the important indicators for evaluating chili pepper quality. In the food industry, accurately understanding its content helps control the flavor characteristics of products and meet the diverse spiciness preferences of consumers. In the pharmaceutical and cosmetic fields, due to its various physiological activities, its content is also a key parameter for related product development and quality control.

[0003] The chemical structure of dihydrocapsaicin can be viewed as the product of hydrogenation of the double bonds in the capsaicin molecule. Its molecular structure includes a vanillyl (o-methoxyphenol), an amide bond, and an aliphatic side chain. The side chain is a saturated structure, a characteristic that gives it both similarities and differences in chemical properties compared to capsaicin. With increasing consumer demand for health, safety, and environmental protection, the market demand for dihydrocapsaicin, as a compound combining mild irritation with high safety, will continue to grow. Especially in the food, cosmetics, and medical fields, dihydrocapsaicin has broad application prospects. In the future, with continuous technological advancements and expanded applications, dihydrocapsaicin is expected to play an important role in even more fields.

[0004] Dihydrocapsaicin has broad application prospects and its demand will continue to rise. However, extracting dihydrocapsaicin from chili peppers is difficult and cannot meet market demand. Therefore, it is imperative to conduct research on its artificial synthesis.

[0005] As shown in the above formula, the chemical synthesis of dihydrocapsaicin typically involves amide condensation using vanillinamine and 8-methylnonanoic acid as key intermediates. Currently, vanillinamine has been industrially produced and is inexpensive and readily available; however, the synthesis process of 8-methylnonanoic acid is still in the pilot-scale research and development stage, and suffers from problems such as lengthy steps, expensive raw materials, harsh conditions, low yield, or environmental pollution, which limit the low-cost large-scale production of dihydrocapsaicin. Summary of the Invention

[0006] This invention provides a method for synthesizing 8-methylnonanoic acid, which solves the aforementioned problems in the synthesis of 8-methylnonanoic acid in the prior art.

[0007] To solve the above-mentioned technical problems, the present invention provides a method for synthesizing 8-methylnonanoic acid, using haloisobutane of general formula I and 1-bromo-6-chlorohexane as raw materials, comprising the following steps: (1) The haloisobutane shown in general formula I is converted into an organometallic reagent, and the organometallic reagent is coupled with 1-bromo-6-chlorohexane under the catalysis of a transition metal salt to obtain the intermediate chloroisodecane; (2) In the presence of an oxidant, the chloroisodecane obtained in step (1) is oxidized to convert the terminal chloromethyl group into a carboxyl group, thereby obtaining the 8-methylnonanoic acid; Wherein, the general formula I is: X-CH2-CH(CH3)2, where X is a chlorine atom or a bromine atom.

[0008] In a preferred embodiment of the present invention, the organometallic reagent is a Grignard reagent prepared by reacting the haloisobutane with metallic magnesium in the presence of an initiator.

[0009] In a preferred embodiment of the present invention, the molar ratio of the haloisobutane to the magnesium metal is 1:1 to 1:1.1.

[0010] In a preferred embodiment of the present invention, the initiator is selected from at least one of iodine, iodomethane, 1,2-dibromoethane, trimethylchlorosilane, or diisobutylaluminum hydride.

[0011] In a preferred embodiment of the present invention, in step (1), the temperature of the coupling reaction is -80 to -50°C.

[0012] In a preferred embodiment of the present invention, in step (1), the molar ratio of the organometallic reagent to the 1-bromo-6-chlorohexane is 1:1 to 1:1.1.

[0013] In a preferred embodiment of the present invention, in step (1), the transition metal salt is lithium tetrachlorocopper(II)ate.

[0014] In a preferred embodiment of the present invention, in step (2), the oxidant is selected from at least one of sodium hypochlorite, sodium chlorite, or ferric nitrate-potassium chloride-oxygen system.

[0015] In a preferred embodiment of the present invention, in step (2), the temperature of the oxidation reaction is 80-120°C.

[0016] In a preferred embodiment of the present invention, in step (2), the oxidation reaction is carried out in the presence of bicarbonate and alkali metal iodide.

[0017] The beneficial effects of this invention are as follows: This invention provides a method for synthesizing 8-methylnonanoic acid, using readily available and inexpensive bulk chemical products haloisobutane and 1-bromo-6-chlorohexane as raw materials. It cleverly utilizes the difference in reactivity between bromine and chlorine, directly and selectively coupling to construct the target carbon skeleton in one step while simultaneously retaining the terminal oxidizable sites. This eliminates the need for protection and deprotection of active functional groups such as carboxyl groups, significantly simplifying the synthesis steps and avoiding harsh reaction conditions and expensive reagents. This invention employs conventional reaction and post-processing operations, is safe and simple, yields high-purity 8-methylnonanoic acid with ideal yield, and offers significant advantages in raw material and production costs. It is highly practical, can be stably scaled up, and provides an economical, green, and efficient intermediate synthesis scheme for the industrial production of dihydrocapsaicin. Attached Figure Description

[0018] Figure 1 This is the 1H NMR spectrum of 8-methylnonanoic acid, the final product obtained in Example 4 of this invention. Detailed Implementation

[0019] The preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby providing a clearer and more explicit definition of the scope of protection of the present invention.

[0020] This invention discloses a method for synthesizing 8-methylnonanoic acid, using haloisobutane of general formula I and 1-bromo-6-chlorohexane as raw materials. The general formula I is: X-CH2-CH(CH3)2, where X is a chlorine atom or a bromine atom; The method steps are as follows: (1) The haloisobutane is converted into an organometallic reagent, and the organometallic reagent and the 1-bromo-6-chlorohexane are coupled in a molar ratio of 1:1 to 1:1.1 in a first organic solvent and under the catalysis of a transition metal salt, at a reaction temperature of -80 to -50°C, to obtain the intermediate chloroisodecane. Specifically, the first organic solvent is selected from at least one of diethyl ether, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, chloroform, or dichloromethane, preferably at least one of N-methylpyrrolidone, tetrahydrofuran, or methyl tert-butyl ether.

[0021] The organometallic reagent is a Grignard reagent prepared by reacting the haloisobutane with metallic magnesium in a second organic solvent at a molar ratio of 1:1 to 1:1.1, in the presence of an initiator and at 50–80°C.

[0022] The second organic solvent is selected from at least one of toluene, trifluoromethylbenzene, fluorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, or N-methylpyrrolidone, preferably at least one of tetrahydrofuran, 2-methyltetrahydrofuran, or N-methylpyrrolidone.

[0023] The initiator is selected from at least one of iodine, iodomethane, 1,2-dibromoethane, trimethylchlorosilane or diisobutylaluminum hydride, preferably iodine or DIBAL-H.

[0024] The transition metal salt is a copper salt, specifically lithium tetrachlorocopper(II)ate.

[0025] (2) In the presence of an oxidant, the chloroisodecane obtained in step (1) is oxidized in a third organic solvent at a temperature of 80-120°C, preferably 90-100°C, so that the terminal chloromethyl group is converted into a carboxyl group, thereby obtaining the 8-methylnonanoic acid; The oxidant is selected from at least one of sodium hypochlorite, sodium chlorite, or ferric nitrate-potassium chloride-oxygen.

[0026] Furthermore, this oxidation reaction can also be carried out in the presence of bicarbonates, such as sodium bicarbonate, and sodium iodide.

[0027] The reaction equation for the above reaction is: .

[0028] The specific technical solutions of the present invention will be described in detail below through specific embodiments.

[0029] Example 1 Under an inert gas atmosphere (such as nitrogen, to isolate oxygen, the same below), add activated magnesium strips (1.32 g, 55 mmol) and 100 mL of tetrahydrofuran to a dry reaction flask, along with a catalytic amount of iodine. While stirring at room temperature, slowly add a small amount of isobutyl bromoisobutane (6.85 g, 50 mmol) dissolved in 50 mL of anhydrous tetrahydrofuran through a constant-pressure dropping funnel. Initiate the reaction by heating, and continue adding the isobutyl bromoisobutane-tetrahydrofuran solution while maintaining the temperature below 25 °C. After the addition is complete, continue stirring the reaction mixture at 50 °C for 1 hour until the magnesium scrap is almost completely consumed, yielding a Grignard reagent solution of isobutyl magnesium bromide for later use. Under inert gas protection, add 1-bromo-6-chlorohexane (10 g, 50 mmol), 80 mL tetrahydrofuran and 20 mL N-methylpyrrolidone to another dry reaction flask, stir for 30 minutes to mix evenly, and then add a THF solution of dilithium tetrachlorocopper(II) acid (1 mL, concentration approximately 0.1 mol / L).

[0030] Subsequently, the reaction flask was cooled to -75°C in a dry ice-acetone bath. Maintaining this temperature, the prepared isobutylmagnesium bromide Grignard reagent solution was slowly added dropwise to the reaction flask using a constant-pressure dropping funnel. After the addition was complete, the reaction was stirred at -75°C for another 5 hours. Gas chromatography (GC) monitoring confirmed that the peak area of ​​the starting material 1-bromo-6-chlorohexane had decreased to below 1%, indicating that the reaction was essentially complete.

[0031] Remove the cold bath, quench the reaction by adding 100 mL of saturated ammonium chloride aqueous solution dropwise to the reaction flask, extract twice with ethyl acetate, combine the organic phases and wash with brine. Dry the washed organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate by rotary evaporation under reduced pressure at 40 °C, and purify the residue by column chromatography [eluent: V(petroleum ether):V(ethyl acetate) = 80:1] to give 7.79 g of the target product, yield 88%; 1H NMR (400 MHz, CDCl3): 3.64 (t, J = 6.6 Hz, 2H), 1.59–1.39 (m, 3H), 1.38–1.30 (m, 8H), 1.20–1.12 (m, 2H), 0.86 (d, J = 6.4 Hz, 6H). The data are consistent with the target structure chloroisodecane.

[0032] Example 2 Under inert gas protection, add activated magnesium strip (1.32 g, 55 mmol) and 100 mL tetrahydrofuran to a dry reaction flask, then add DIBAL-H (0.5 mL, 1 M). Maintain the temperature below 25 °C, and slowly add chloroisobutane (4.65 g, 50 mmol) / 80 mL tetrahydrofuran solution dropwise through a constant-pressure dropping funnel. After the addition is complete, continue stirring until a Grignard reagent solution is obtained and set aside. Under inert gas protection, add 1-bromo-6-chlorohexane (10 g, 50 mmol) and 100 mL tetrahydrofuran / 25 mL N-methylpyrrolidone to another dry reaction flask, stir well, and then add 2 mL of dilithium tetrachlorocopper(II)ate THF solution (approximately 0.1 mol / L concentration).

[0033] Subsequently, the reaction flask was cooled to -60°C in a dry ice-acetone bath, and the Grignard reagent was added dropwise to the reaction flask through a constant pressure dropping funnel, completing the addition within 1 hour. After the addition was complete, the reaction was stirred at -60°C for 5 hours. Gas chromatography (GC) monitoring confirmed that the peak area of ​​the starting material 1-bromo-6-chlorohexane had decreased to below 1%, indicating that the reaction was essentially complete.

[0034] Remove the cold bath, add 100 mL of saturated ammonium chloride aqueous solution to the reaction flask to quench the reaction, extract twice with ethyl acetate, combine the organic phases and wash with brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate by rotary evaporation under reduced pressure at 40 °C, and purify the residue by column chromatography [eluent: V(petroleum ether):V(ethyl acetate) = 80:1] to obtain 7.43 g of the target product, with a yield of 84%; the 1H NMR detection data of the product are consistent with the detection data of the product in Example 1. Example 3 Under inert gas protection, add activated magnesium strip (52.8 g, 2.2 mol) and 250 mL tetrahydrofuran to a dry reaction flask, add DIBAL-H (10 mL, 1 M), and dropwise add a small amount of bromoisobutane (274 g, 2 mol) / 2000 mL tetrahydrofuran solution. Initiate the reaction by gentle heating, and continue to dropwise add bromoisobutane-tetrahydrofuran solution while controlling the temperature below 25 °C. After the addition is complete, continue stirring the reaction until the Grignard reagent is completely obtained and set aside for later use. Under inert gas protection, 400 g (2 mol) of 1-bromo-6-chlorohexane and 2500 mL of tetrahydrofuran / 500 mL of N-methylpyrrolidone solution were added to another dry reaction vessel. The mixture was stirred for 30 minutes, and then 50 mL of dilithium tetrachlorocopper(II)ate THF solution (approximately 0.1 mol / L) was added. The mixture was cooled to -60°C, and the Grignard reagent was added dropwise while maintaining this temperature. After the addition was complete, the mixture was stirred at -60°C for 5 hours, and the reaction was detected as complete by gas chromatography. The reaction was quenched by adding 1000 mL of saturated ammonium chloride aqueous solution. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by vacuum distillation to obtain 325.6 g of the target product, with a yield of 92%. The 1H NMR detection data of the product were consistent with those of the product in Example 1. Example 4 Add 17.7 g (0.1 mol) of chloroisodecane prepared in Example 1 and 200 mL of dimethyl sulfoxide to a 500 mL round-bottom flask, stir until dissolved, and then add sodium bicarbonate (16.8 g, 0.2 mol) and sodium iodide (3.8 g, 0.025 mol). Heat the mixture to 110 °C and react for 2 hours. Then, add an aqueous solution of sodium hypochlorite (140 g, 0.15 mol) dropwise with stirring. After the addition is complete, continue the reaction at 110 °C for 2 hours.

[0035] After the reaction was complete, the reaction solution was cooled to room temperature and removed by rotary evaporation under reduced pressure at 40°C to remove most of the dimethyl sulfoxide solvent. The remaining viscous substance was diluted with 200 mL of water, adjusted to pH 1-2 with 6N hydrochloric acid, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography [eluent: V(petroleum ether):V(ethyl acetate) = 8:1] to give 14.1 g of the target product, yield 82%. ¹H NMR (400 MHz, CDCl₃): 2.39 (t, J = 8 Hz, 2H), 1.67–1.58 (m, 2H), 1.56–1.51 (m, 1H), 1.38–1.26 (m, 6H), 1.21–1.16 (m, 2H), 0.89 (d, J = 8 Hz, 6H). The spectrum is attached. Figure 1 As shown. Example 5 Sodium bicarbonate (336 g, 4 mol), sodium iodide (75 g, 0.5 mol), and 2000 mL of dimethyl sulfoxide were added to a 5 L reaction flask. The mixture was heated to 110 °C, and chloroisodecane (354 g, 2 mol) prepared in Example 3 was added dropwise. After the addition was complete, the mixture was stirred and reacted at 110 °C for 1 hour. Then, sodium chlorite (338 g, 3 mol, 80%) in a 1000 mL aqueous solution was added dropwise, and the reaction was continued at 110 °C with stirring for 3 hours. The reaction was monitored by TLC until complete.

[0036] After the reaction was completed, the mixture was cooled to room temperature and removed by rotary evaporation under reduced pressure at 40°C to remove most of the solvent. 1000 mL of water was added to the remaining viscous substance for dilution, and the pH was adjusted to 1-2 with 6N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to obtain 313 g of the target product, with a yield of 91%. The 1H NMR detection data of the product were consistent with those of the product in Example 4.

[0037] Comparative Example 1 The difference from Example 4 is that sodium iodide was not added, while all other conditions remained the same. The reaction conversion rate was low, and the final yield of 8-methylnonanoic acid was only about 24%.

[0038] Comparative Example 2 The difference from Example 4 is that sodium bicarbonate was not added, while all other conditions remained the same. The reaction selectivity was poor, and the product purity was low; after purification, the yield was approximately 55%.

[0039] The above test results show that sodium bicarbonate and sodium iodide have a significant synergistic promoting effect in the oxidation step of this invention, and their co-existence is key to achieving high yield and high selectivity oxidation. The above descriptions are merely embodiments of this invention and do not limit the patent scope of this invention. Any equivalent structural or procedural transformations made based on the description and drawings of this invention, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of this invention.

Claims

1. A method for synthesizing 8-methylnonanoic acid, characterized in that, Using haloisobutane of general formula I and 1-bromo-6-chlorohexane as raw materials, the process includes the following steps: (1) The haloisobutane shown in general formula I is converted into an organometallic reagent, and the organometallic reagent is coupled with 1-bromo-6-chlorohexane under the catalysis of a transition metal salt to obtain the intermediate chloroisodecane; (2) In the presence of an oxidant, the chloroisodecane obtained in step (1) is oxidized to convert the terminal chloromethyl group into a carboxyl group, thereby obtaining the 8-methylnonanoic acid; Wherein, the general formula I is: X-CH2-CH(CH3)2, where X is a chlorine atom or a bromine atom.

2. The method for synthesizing 8-methylnonanoic acid according to claim 1, characterized in that, The organometallic reagent is a Grignard reagent prepared by reacting the haloisobutane with metallic magnesium in the presence of an initiator.

3. The method for synthesizing 8-methylnonanoic acid according to claim 2, characterized in that, The molar ratio of the haloisobutane to the magnesium metal is 1:1 to 1:1.

1.

4. The method for synthesizing 8-methylnonanoic acid according to claim 2, characterized in that, The initiator is selected from at least one of iodine, iodomethane, 1,2-dibromoethane, trimethylchlorosilane, or diisobutylaluminum hydride.

5. The method for synthesizing 8-methylnonanoic acid according to any one of claims 1 to 4, characterized in that, In step (1), the temperature of the coupling reaction is -80 to -50°C.

6. The method for synthesizing 8-methylnonanoic acid according to any one of claims 1 to 4, characterized in that, In step (1), the molar ratio of the organometallic reagent to the 1-bromo-6-chlorohexane is 1:1 to 1:1.

1.

7. The method for synthesizing 8-methylnonanoic acid according to any one of claims 1 to 4, characterized in that, In step (1), the transition metal salt is lithium tetrachlorocopper(II) acid.

8. The method for synthesizing 8-methylnonanoic acid according to any one of claims 1 to 4, characterized in that, In step (2), the oxidant is selected from at least one of sodium hypochlorite, sodium chlorite, or ferric nitrate-potassium chloride-oxygen system.

9. The method for synthesizing 8-methylnonanoic acid according to any one of claims 1 to 4, characterized in that, In step (2), the temperature of the oxidation reaction is 80-120℃.

10. A method for synthesizing 8-methylnonanoic acid according to any one of claims 1 to 4, characterized in that, In step (2), the oxidation reaction is carried out in the presence of bicarbonate and alkali metal iodide.

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