Preparation method of cis-6-nonenal and cis-6-nonenol

Abstract

The invention relates to the technical field of compound preparation, and discloses a preparation method of cis-6-nonenal and cis-6-nonenol, and the preparation method of cis-6-nonenal comprises the following steps: mixing 1-halohexyl-3-ene with a catalyst, then adding a Grignard reagent to carry out a coupling reaction, and then carrying out a deprotection reaction to obtain cis-6-nonenal; the preparation method of the cis-6-nonenol comprises the following steps: mixing cis-6-nonenal with a reducing agent, and carrying out a reduction reaction to obtain the cis-6-nonenol. According to the present invention, the low-cost Grignard reagent and the 1-halohexyl-3-ene are adopted as the reactants, the coupling reaction is performed under the catalyst condition, the deprotection reaction is performed to obtain the cis-6-nonenal, the cis-6-nonenal is adopted as the raw material to prepare the cis-6-nonenol, the reaction condition is mild, the yield is high, and the method is suitable for industrial production. The purity of the prepared cis-6-nonenal and cis-6-nonenol is high, and the purity can reach 99% or above.

Description

Technical Field

[0001] The invention relates to the technical field of compound preparation, in particular to a cis-6-nonenal and a preparation method of cis-6-nonenal. Background Art

[0002] Cis-6-nonenal (chemical formula: C9H16O, CAS number: 2277-19-2), also known as (Z)-6-nonenal, has a melon-like aroma, so it is mainly used as a flavoring ingredient in industry and is applied in the food and cosmetics industries. At present, cis-6-nonenal is mainly obtained by oxidation of cis-6-nonenol (molecular formula: C9H18O, CAS number: 35854-86-5). Cis-6-nonenol is also mainly used as a flavoring ingredient in industry. It naturally exists in melons, watermelons and cucumbers, and has the aroma of wax, green, vegetable, melon and fat. It is widely used in the preparation of food flavors, especially in edible flavors such as melons, cucumbers and tomatoes.

[0003] Cis-6-nonenol can be prepared by different synthetic methods, such as patent CN101381282A, which uses leaf alcohol as a raw material to synthesize cis-6-nonenol. Leaf alcohol is first halogenated, then coupled with a hydroxyl-protected Grignard reagent, and deprotected to obtain cis-6-nonenol. However, the cost of coupling and deprotection processes is higher in the method, and the cost of the raw material 3-bromopropanol used is also higher. Therefore, it is urgent to provide a low-cost preparation method of cis-6-nonenol. Summary of the invention

[0004] In view of this, the present invention provides a method for preparing cis-6-nonenal with low-cost raw materials, and using the cis-6-nonenal as a raw material, reducing it with a reducing agent to obtain cis-6-nonenol.

[0005] In order to achieve the above object, the present invention adopts the following technical solution:

[0006] In one aspect, the present invention provides a method for preparing cis-6-nonenal, comprising the following steps: mixing 1-halogenated hex-3-ene with a catalyst, then adding a Grignard reagent to carry out a coupling reaction, and then carrying out a deprotection reaction to obtain cis-6-nonenal;

[0007] The structural formulas of the Grignard reagent and the 1-halogenated hex-3-ene are respectively:

[0008]

[0009] Wherein, R1 is an aldehyde protecting group, and X1 and X2 are each independently chlorine, bromine or iodine.

[0010] Preferably, the molar ratio of the Grignard reagent to the 1-halogenated hex-3-ene is 1.25-1.8:1.

[0011] Preferably, the molar ratio of the 1-halogenated hex-3-ene to the catalyst is 1:0.02-0.05.

[0012] Preferably, the aldehyde protecting group is any one of ketal, thioketal, enol ether and enamine.

[0013] Preferably, the catalyst is a salt or complex of any one of copper, nickel and palladium.

[0014] Preferably, the Grignard reagent is prepared by a method comprising the following steps:

[0015] (1) acrolein is reacted with hydrogen halide to generate 2-haloacrolein, and then the 2-haloacrolein is subjected to an aldehyde group protection reaction to obtain compound A, wherein compound A is R1-C-X1;

[0016] (2) subjecting the compound A to a Grignard reaction with magnesium to obtain a Grignard reagent.

[0017] Preferably, the addition reaction is to introduce hydrogen halide gas into acrolein, and the hydrogen halide gas flow rate is 0.6-0.8 L / (min·kg).

[0018] Preferably, the reactants added in the aldehyde protection reaction include one or more of methanol, ethanol, trimethyl orthoformate, ethylene glycol, and 1,3-propylene glycol.

[0019] Preferably, the temperature of the Grignard reaction in step (2) is 15-30°C.

[0020] Preferably, the 1-halogenated hex-3-ene is prepared by a method comprising the following steps:

[0021] (1) subjecting leaf alcohol to a sulfonylation reaction with benzenesulfonyl chloride to obtain leaf alcohol benzenesulfonate;

[0022] (2) In a polar solvent, the leaf alcohol benzene sulfonate is subjected to a nucleophilic substitution reaction with a halide salt to obtain 1-halogenated hex-3-ene.

[0023] Preferably, the polar solvent includes one or more of methanol, acetone, N,N-dimethylformamide, acetonitrile, an aqueous solution of acetonitrile, and dimethyl sulfoxide.

[0024] Preferably, the halide salt includes any one of sodium bromide, lithium bromide, potassium bromide, magnesium bromide, sodium chloride, potassium chloride, magnesium chloride, potassium iodide, sodium iodide, and magnesium iodide.

[0025] On the other hand, the present invention also provides a method for preparing cis-6-nonenol, comprising the following steps: preparing cis-6-nonenal by any of the above-mentioned preparation methods;

[0026] The cis-6-nonenal is mixed with a reducing agent and subjected to a reduction reaction to obtain cis-6-nonenol.

[0027] Preferably, the molar ratio of the cis-6-nonenal to the reducing agent is 1:1.1-1.5;

[0028] Preferably, the reducing agent includes any one or more of sodium borohydride, potassium borohydride, and aluminum isopropoxide.

[0029] The present invention provides a cis-6-nonenal and a method for preparing cis-6-nonenol using the cis-6-nonenal as a raw material. Compared with the prior art, the present invention has the following beneficial effects:

[0030] First, the present invention adopts a new synthetic route, using a Grignard reagent and 1-halogenated hex-3-ene as reactants, performing a coupling reaction under a catalyst condition, and then performing a deprotection reaction to obtain cis-6-nonenal; then, cis-6-nonenal is used as a raw material to prepare cis-6-nonenol, the reaction conditions are mild, and the prepared cis-6-nonenal and cis-6-nonenol have high purity, which can reach more than 99%.

[0031] Second, the raw materials acrolein and leaf alcohol of the present invention are easy to obtain and have relatively low costs, which can reduce the synthesis cost of the overall process. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0033] Figure 1 The synthetic process route of cis-6-nonenol of the present invention is as follows;

[0034] Figure 2 The synthetic process route of cis-6-nonenol in Example 1 of the present invention is shown in FIG.

[0035] Figure 3 This is the NMR spectrum of cis-6-nonenal prepared in the embodiment of the present invention;

[0036] Figure 4 This is the NMR spectrum of cis-6-nonenol prepared in the embodiment of the present invention. DETAILED DESCRIPTION

[0037] The present invention will be described below by specific examples, and it will be appreciated by those skilled in the art that the following specific examples are only for illustrative purposes, and do not limit the scope of the present invention in any way. In addition, in the following examples, unless otherwise specified, the reagents and equipment used are all commercially available. If in the following examples, specific treatment conditions and treatment methods are not clearly described, then conditions and methods known in the art can be used to process.

[0038] In one aspect of the present invention, Figure 1 As shown, the present invention provides a method for preparing cis-6-nonenal, comprising the following steps: mixing 1-halogenated hex-3-ene with a catalyst, then adding a Grignard reagent for coupling reaction, and then performing a deprotection reaction to obtain cis-6-nonenal;

[0039] The structural formulas of the Grignard reagent and the 1-halogenated hex-3-ene are respectively:

[0040]

[0041] Wherein, R1 is an aldehyde protecting group, and X1 and X2 are each independently chlorine, bromine or iodine.

[0042] In some embodiments of the present invention, the molar ratio of the Grignard reagent to 1-halogenated hex-3-ene is 1.25-1.8:1, for example, 1.25:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, etc., and the molar ratio of 1-halogenated hex-3-ene to the catalyst is 1:0.02-0.05, for example, 1:0.02, 1:0.03, 1:0.04, 1:0.05, etc. It should be noted that in the present invention, 1-halogenated hex-3-ene is first mixed with the catalyst, and then the Grignard reagent is added, otherwise the coupling reaction cannot proceed.

[0043] In some embodiments of the present invention, the catalyst is a salt or complex of any one of copper, nickel and palladium, preferably a copper salt. Among copper salts, cuprous bromide has better stability, so cuprous bromide is more preferred.

[0044] In some specific embodiments of the present invention, the specific steps of mixing 1-halogenated hex-3-ene with a catalyst and then adding a Grignard reagent for coupling reaction are as follows: under nitrogen protection, 1-halogenated hex-3-ene, tetrahydrofuran and a catalyst are mixed, and the tetrahydrofuran solution of the Grignard reagent is added after cooling to 10-20° C., and the reaction is carried out by keeping the temperature after the addition is completed to obtain a crude coupling reaction product with a content of 87-92% and a yield of 80-90%. Preferably, the mass ratio of 1-halogenated hex-3-ene to tetrahydrofuran is 1:3-5, for example, 1:3, 1:4, 1:5, etc., and the concentration of the tetrahydrofuran solution of the Grignard reagent can be 1 mol / L.

[0045] In some embodiments of the present invention, the structural formula of the Grignard reagent is:

[0046]

[0047] In some embodiments of the present invention, the aldehyde protecting group is any one of ketal, thioketal, enol ether and enamine, preferably ketal.

[0048] In some embodiments of the present invention, the deprotection reaction is an acid-catalyzed deprotection reaction, and the catalyst of the acid-catalyzed deprotection reaction is p-toluenesulfonic acid. In some embodiments of the present invention, the deprotection reaction specifically comprises the following steps: dissolving the reactant after the coupling reaction of the Grignard reagent and 1-halogenated hex-3-ene in an acetonitrile aqueous solution, adding a catalyst p-toluenesulfonic acid, and reacting at 45-60°C for 0.5h, then starting reactive distillation, continuously distilling the generated methanol, controlling the reflux ratio to 6:3, stopping the reflux until the conversion rate is greater than 99%, adding a sodium bicarbonate solution to quench the reaction, continuing reactive distillation to remove the acetonitrile, taking the organic phase after stratification, washing with water and continuing distillation to obtain cis-6-nonenal with a purity greater than 99%, a cis-trans ratio greater than 98:2, and a yield of 95-100%. Preferably, the mass ratio of the acetonitrile aqueous solution to the reactants after the coupling reaction is 1:4-6, for example, 1:4, 1:5, 1:6, etc., and the volume ratio of acetonitrile to water in the acetonitrile aqueous solution can be 8:1; the mass ratio of p-toluenesulfonic acid to the reactants after the coupling reaction is 0.02-0.05:1, for example, 0.02:1, 0.03:1, 0.04:1, 0.05:1, etc.; the mass percentage concentration of the sodium bicarbonate solution can be 5%, and the mass ratio of sodium bicarbonate to p-toluenesulfonic acid is 2:1-2, for example, 2:1, 2:1.5, 1:1, etc.

[0049] In some embodiments of the present invention, the Grignard reagent is prepared by a method comprising the following steps:

[0050] (1) Acrolein is reacted with hydrogen halide to generate 2-haloacrolein, and then the 2-haloacrolein is subjected to aldehyde group protection reaction to obtain compound A, wherein compound A is R1-C-X1 and has the structural formula:

[0051]

[0052] (2) subjecting the compound A to a Grignard reaction with magnesium to obtain a Grignard reagent.

[0053] In some embodiments of the present invention, the addition reaction is to introduce hydrogen halide gas into acrolein, and based on the amount of acrolein added, the ventilation rate of the hydrogen halide is 0.6-0.8L / (min·kg), that is, the ventilation rate of hydrogen halide per kilogram of acrolein is 0.6-0.8L / min, and the ventilation method adopts a 1 / 8 tube or a gas distributor. Among them, the specific addition reaction process is a conventional reaction, which will not be repeated here. The present invention mainly lies in the control of the ventilation rate of hydrogen halide, and the hydrogen halide gas can be, for example, hydrogen bromide, hydrogen chloride, hydrogen iodide, etc., preferably hydrogen bromide; the ventilation rate of the hydrogen halide can be, for example, 0.6L / (min·kg), 0.7L / (min·kg), 0.8L / (min·kg), etc. Considering that the reaction process needs to disperse the gas more evenly, the ventilation method is preferably a gas distributor.

[0054] Since acrolein is unstable and easily self-polymerizes, especially under the catalytic action of acid and alkali, the self-polymerization rate of acrolein will be greatly increased, and the introduction of hydrogen halide will make the reaction liquid acidic. If the introduced hydrogen halide cannot be consumed in time, the acidity of the reaction liquid will continue to increase, and the self-polymerization reaction of acrolein and the reaction of the polymer after self-polymerization with hydrogen halide will gradually dominate, reducing the yield of the main reaction. Therefore, in order to ensure the yield of the main reaction, the ventilation rate of hydrogen halide needs to be limited to 0.6-0.8L / (min·kg), and a gas distributor should be used to enhance dispersion.

[0055] In some embodiments of the present invention, the reactants added in the aldehyde protection reaction include one or more of methanol, ethanol, trimethyl orthoformate, ethylene glycol, and 1,3-propylene glycol, preferably trimethyl orthoformate.

[0056] In some embodiments of the present invention, the reaction temperature of the compound A and magnesium is 15-30°C, for example, 15°C, 20°C, 25°C, 30°C, etc. It should be noted that the Grignard reaction of compound A and magnesium to prepare a Grignard reagent can adopt a conventional method for synthesizing a Grignard reagent, for example, first dissolving a portion of compound A in tetrahydrofuran, adding magnesium and an initiator, and after initiation, adding the remaining compound A and tetrahydrofuran under nitrogen protection to react, the reaction temperature is 15-30°C, and compound A is obtained, and the yield of compound A is 92-97%. Among them, the molar ratio of compound A to magnesium is 1:1.9-2.1, for example, it can be 1:1.9, 1:2.0, 1:2.1, etc.; the mass ratio of compound A to tetrahydrofuran is 1:4.0-4.3, for example, it can be 1:4.0, 1:4.1, 1:4.2, 1:4.3, etc.; the amount of compound A added for the first time accounts for about 10% of the total amount, the initiator can be 1,2-dibromoethane, iodomethane or iodine, etc., preferably 1,2-dibromoethane, and the amount of initiator used is generally 1-2mL, which has little to do with the reaction scale.

[0057] In some embodiments of the present invention, the 1-halogenated hex-3-ene is prepared by a method comprising the following steps:

[0058] (1) subjecting leaf alcohol to a sulfonylation reaction with benzenesulfonyl chloride to obtain leaf alcohol benzenesulfonate;

[0059] (2) In a polar solvent, the leaf alcohol benzene sulfonate is subjected to a nucleophilic substitution reaction with a halide salt to obtain 1-halogenated hex-3-ene.

[0060] In some embodiments of the present invention, the steps for synthesizing the leaf alcohol benzene sulfonate are as follows: leaf alcohol, dichloromethane and triethylamine are mixed and cooled to 0-10°C, then benzenesulfonyl chloride is added dropwise, and the temperature is controlled to be 0-15°C. After the addition is completed, the temperature is raised to 15-25°C for insulation reaction. After the reaction is complete, the leaf alcohol benzene sulfonate is obtained by washing with water 1-3 times and desolventizing. The yield is 95-100% and the content is 87-95%. Among them, the mass ratio of leaf alcohol to dichloromethane is 1:3-5, for example, it can be 1:3, 1:4, 1:5, etc.; the molar ratio of leaf alcohol, triethylamine and benzenesulfonyl chloride is 1:1.5-2:1.1-1.2, for example, it can be 1:1.5:1.1, 1:1.6:1.1, 1:1.7:1.1, 1:1.8:1.1, 1:1.9:1.1, 1:2:1.1, 1:1.9:1.2, etc. When the addition amount of triethylamine is increased while the addition amount of leaf alcohol and benzenesulfonyl chloride remains unchanged, the conversion rate of leaf alcohol will increase accordingly.

[0061] In some embodiments of the present invention, the mass ratio of the leaf alcohol benzene sulfonate to the polar solvent is 1:3-5, for example, 1:3, 1:4, 1:5, etc.

[0062] In some embodiments of the present invention, the polar solvent includes one or more of methanol, acetone, N,N-dimethylformamide, acetonitrile, an aqueous solution of acetonitrile, and dimethyl sulfoxide, preferably an aqueous solution of acetonitrile, and the mass content of water in the aqueous solution of acetonitrile is 3-10%, for example, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc.

[0063] In some embodiments of the present invention, the halide salt is a bromide salt, a chloride salt or an iodide salt, for example, it can be any one of sodium bromide, lithium bromide, potassium bromide, magnesium bromide, sodium chloride, potassium chloride, magnesium chloride, potassium iodide, sodium iodide, and magnesium iodide, preferably sodium bromide.

[0064] In some specific embodiments of the present invention, the steps of synthesizing 1-halogenated hex-3-ene from leaf alcohol benzene sulfonate are as follows: using an aqueous solution of acetonitrile as a polar solvent, dissolving leaf alcohol benzene sulfonate in an aqueous solution of acetonitrile in an amount of 3-5 times, adding sodium bromide at 70-80° C. to react, and obtaining 1-halogenated hex-3-ene with a yield of 90-95%. It should be noted that the reaction temperature is determined by the boiling point of the polar solvent. Generally, the reaction temperature is close to and lower than the boiling point of the polar solvent, and there is no special limitation on this. Among them, the mass ratio of leaf alcohol benzene sulfonate and polar solvent is 1:3-5, for example, it can be 1:3, 1:4, 1:5, etc., the mass ratio of acetonitrile and water in the polar solvent is 0.04-0.06:0.95, for example, it can be 0.04:0.95, 0.05:0.95, 0.06:0.95, etc.; the molar ratio of leaf alcohol benzene sulfonate and sodium bromide is 1:1.0-1.2, for example, it can be 1:1.0, 1:1.1, 1:1.2, etc.

[0065] The invention uses acrolein as the raw material of the Grignard reagent and leaf alcohol as the raw material of 1-halogenated hex-3-ene. The prices of acrolein and leaf alcohol are low, and the synthesis cost of cis-6-nonenal is reduced from the source.

[0066] In another aspect of the present invention, the present invention also provides a method for preparing cis-6-nonenol, comprising the following steps: preparing cis-6-nonenal by using any of the above-mentioned preparation methods, mixing the cis-6-nonenal with a reducing agent, and performing a reduction reaction to obtain cis-6-nonenol. The present invention synthesizes cis-6-nonenol from cis-6-nonenal under milder reaction conditions.

[0067] In some embodiments of the present invention, the molar ratio of the cis-6-nonenal to the reducing agent is 1:1.1-1.5, for example, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc., and the reducing agent includes any one or more of sodium borohydride, potassium borohydride, and aluminum isopropoxide.

[0068] In some specific embodiments of the present invention, the preparation method of cis-6-nonenol comprises the following steps: under nitrogen protection, at 0-10° C., adding an ethanol solution of cis-6-nonenal to an ethanol solution of sodium borohydride, returning the mixture to room temperature for reaction after the addition is complete, adding dilute hydrochloric acid to quench the reaction after the reaction is complete, adjusting the pH value to 5-7, then adding n-heptane for extraction 1-3 times, combining the organic phases, washing with alkali to weak alkalinity, desolventizing and distilling to obtain cis-6-nonenol with a purity greater than 99%, a cis-trans ratio greater than 98:2, and a yield of 80-83%. Among them, the molar ratio of cis-6-nonenal to sodium borohydride is 1:1.1-1.5, for example, it can be 1:1.1, 1:1.2, 1:1.3, 1:4.1, 1:1.5, etc., the mass ratio of cis-6-nonenal to the ethanol solution of cis-6-nonenal is 1:1-3, for example, it can be 1:1, 1:2, 1:3, etc., and the mass ratio of sodium borohydride to the ethanol solution of sodium borohydride is 1:4-6, for example, it can be 1:4, 1:5, 1:6, etc.

[0069] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments. The embodiments of the present application are only used as examples, and all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0070] Example 1

[0071] This embodiment provides a method for preparing cis-6-nonenol. The synthetic process diagram is as follows: Figure 2 shown.

[0072] The specific preparation steps of cis-6-nonenol are as follows:

[0073] (1) Preparation of Compound 1: Hydrogen bromide gas was introduced into 156.6 g of acrolein to carry out an addition reaction, and then trimethyl orthoformate was added to carry out an aldehyde protection reaction, wherein the molar ratio of acrolein to trimethyl orthoformate was 1.1, and the reaction gave Compound 1 with a yield of 56.43% and a conversion rate of acrolein of 96.71%. The hydrogen bromide was introduced at a rate of 0.7 L / (min·kg), and a gas distributor was used for the ventilation.

[0074] (2) Preparation of Compound 2: 1 mol of Compound 1 was dissolved in tetrahydrofuran, and magnesium and initiator 1,2-dibromoethane (1 ml) were added for initiation. When bubbles were observed, stirring was started and external circulation was used for cooling. The temperature was controlled below 50°C. After stabilization, the temperature was controlled at 25°C for standby use.

[0075] The remaining compound 1 and tetrahydrofuran were added under nitrogen protection, the reaction temperature was 25°C, and the reaction was kept warm for 1 hour, then the reaction was quenched with water. The organic phase was taken for gas chromatography detection, and the proportion of compound 1 was less than 1%. The reaction was completed, and sampling was performed for titration. The concentration of compound 2 was 1 mol / L, and the yield was 97%.

[0076] (3) Preparation of compound 4: Compound 3 leaf alcohol (3 kg), dichloromethane and triethylamine were mixed, cooled to 5°C, and 5.8 kg of p-toluenesulfonyl chloride was added dropwise after nitrogen replacement. The reaction temperature was maintained at 5-20°C. After the addition was completed, the reaction was kept at 20°C for 2 hours. Gas chromatography detected that the proportion of leaf alcohol was <1%, and the reaction was completed. The mixture was washed with water twice and the concentrated solution of compound 4 was obtained after desolventizing. The internal standard yield was 97.8%.

[0077] (4) Preparation of Compound 5: The concentrated solution of Compound 4 was dissolved in an acetonitrile-water solution (the mass content of water was 5%), the mass of the acetonitrile-water solution being 4 times the mass of Compound 4, and 3.3 kg of sodium bromide was added. After nitrogen substitution, the temperature was raised to 75° C. and stirred for reaction for 2 h. The reaction was terminated when the gas phase proportion of Compound 4 was less than 1%. The temperature was cooled to room temperature, filtered, and the filtrate was distilled to obtain Compound 5 with a purity of 96% and a yield of 92.4%.

[0078] (5) Preparation of compound 6: Under nitrogen protection, 1.3 kg of compound 5, tetrahydrofuran and 41.5 g of catalyst copper chloride were mixed and stirred at room temperature for 10 min. After cooling to 15°C, 1 mol / L tetrahydrofuran solution of compound 2 was added dropwise for 4 h. After the addition was complete, the mixture was kept warm for 2 h. According to gas chromatography, the reaction was completed when the proportion of compound 5 was less than 1%. Water was added to quench the reaction. After separation, the upper organic phase was taken. After desolvation, 5% sodium bicarbonate was used for alkaline washing, and then washed once with water. Desolvation gave compound 6 with an internal standard yield of 87.1%.

[0079] (6) Preparation of compound 7: 145.4 g crude compound 6, 73.5 g water, and 581.6 g acetonitrile were mixed, 3.5 g p-toluenesulfonic acid was added, the temperature was raised to 50°C, and the reaction was stirred for 0.5 h. Then, the methanol was continuously removed by reactive distillation. A 0.5 m stainless steel packed tower was used to control the reflux ratio to 6:3. The kettle temperature was maintained at 55°C. After 3 h of reaction, the gas phase proportion of compound 6 was less than 0.5%. A 5% sodium bicarbonate solution was added to quench the reaction. The acetonitrile was removed by distillation and desolventization. After layering, the organic phase was taken and then distilled (80°C, 0.4 kPa). A 0.5 m stainless steel packed tower was used to obtain compound 7 (92.1 g) with a purity of 99%, a cis-trans ratio of 90.2:9.8, and a yield of 96.3%. Figure 3 Shown is the NMR spectrum of compound 7 cis-6-nonenal.

[0080] (7) Preparation of compound 8: 69.6 g of sodium borohydride was mixed with anhydrous ethanol, nitrogen was replaced, and the mixture was stirred evenly. 184.2 g of compound 7 was mixed with ethanol, and the mixture was added dropwise to the ethanol solution of sodium borohydride at 5°C. After the addition was completed, the mixture was slowly restored to room temperature. After reacting for 1 hour, the gas phase ratio of compound 7 was less than 1% as determined by gas chromatography. The reaction was completed, and 1% dilute hydrochloric acid was added dropwise for quenching. The pH was adjusted to 6, and the mixture was extracted twice with n-heptane. After the organic phases were combined, 5% sodium bicarbonate was added for alkaline washing. After desolventizing, the concentrate was distilled (92°C, 0.3 kPa) and a 0.5 m stainless steel packed tower was used to obtain compound 8 (155.3 g) with a purity of 99%. The cis-trans ratio was 89.4:10.6, and the yield was 83%. Figure 4 Shown is the NMR spectrum of compound 8 cis-6-nonenol.

[0081] Example 2

[0082] This embodiment is basically the same as embodiment 1, with the only difference being that in step (3), the molar ratio of leaf alcohol, triethylamine and benzenesulfonyl chloride is 1:1.8:1.1, and the mixture of compound 3 leaf alcohol, dichloromethane and triethylamine is cooled to 10°C, and after nitrogen substitution, benzenesulfonyl chloride is added dropwise, and the reaction temperature is maintained at 10-20°C. After the addition is completed, the reaction is kept at 20°C for 2h.

[0083] Example 3

[0084] This embodiment is substantially the same as embodiment 1, the only difference being that the acetonitrile-water solution is replaced by dimethylformamide in step (4).

[0085] Example 4

[0086] This embodiment is substantially the same as embodiment 1, the only difference being that the acetonitrile-water solution is replaced by dimethyl sulfoxide in step (4).

[0087] Example 5

[0088] This embodiment is substantially the same as embodiment 1, except that the molar ratio of compound 5 to copper chloride in step (5) is 1:0.05.

[0089] Example 6

[0090] This embodiment is basically the same as embodiment 1, the only difference being that in step (5), the catalyst cupric chloride is replaced by cuprous bromide, and the molar ratio of compound 5 to cuprous bromide is 1:0.06.

[0091] Example 7

[0092] This embodiment is basically the same as embodiment 1, the only difference being that in step (5), the catalyst cupric chloride is replaced by cuprous bromide, and the molar ratio of compound 5 to cuprous bromide is 1:0.05.

[0093] Example 8

[0094] This example is basically the same as Example 1, except that trimethyl orthoformate is replaced by ethylene glycol in step (1). The yield of compound 1 is 50.78%, and the conversion rate of acrolein is 90.25%.

[0095] Comparative Example 1

[0096] This comparative example is substantially the same as Example 1, except that the ventilation rate of hydrogen bromide in step (1) is 1.2 L / (min·kg).

[0097] Comparative Example 2

[0098] This comparative example is basically the same as Example 1, except that the ventilation rate of hydrogen bromide in step (1) is 1.2 L / (min·kg), and the ventilation method adopts a 1 / 8 tube.

[0099] Comparative Example 3

[0100] This comparative example is basically the same as Example 1, except that the ventilation rate of hydrogen bromide in step (1) is 3.0 L / (min·kg), and the ventilation method adopts a 1 / 8 tube.

[0101] The reaction conditions of compound 1 in Example 1 and Comparative Examples 1-3 were detected and counted. The results are shown in Table 1:

[0102] Table 1

[0103]

[0104] As can be seen from Table 1, in the present application, the gas distributor is selected as the ventilation method, and when the ventilation rate is controlled at 0.7 L / min, the conversion rate of acrolein and the yield of compound 1 are optimal.

[0105] Comparative Example 4

[0106] This comparative example is basically the same as Example 1, with the only difference being that in step (3), the molar ratio of leaf alcohol, triethylamine and benzenesulfonyl chloride is 1:1.5:1.1, and the leaf alcohol, dichloromethane and triethylamine of compound 3 are mixed and then cooled to -10°C, and after nitrogen substitution, benzenesulfonyl chloride is added dropwise, and the reaction temperature is maintained at -10 to 5°C. After the addition is completed, the reaction is kept at 5°C for 1.5 hours.

[0107] Comparative Example 5

[0108] This comparative example is basically the same as Example 1, with the only difference being that in step (3), the molar ratio of leaf alcohol, triethylamine and benzenesulfonyl chloride is 1:1.15:1.1, and the mixture of compound 3 leaf alcohol, dichloromethane and triethylamine is cooled to -10°C, and after nitrogen substitution, benzenesulfonyl chloride is added dropwise, and the reaction temperature is maintained at -10 to 5°C. After the addition is complete, the reaction is kept at 5°C for 4 hours.

[0109] The molar ratio of leaf alcohol, triethylamine and benzenesulfonyl chloride is 1:1.15:1.1, the reaction temperature is -10 to 5°C, and the reaction time is 4 hours.

[0110] The reaction conditions of compound 4 in Examples 1-2 and Comparative Examples 4-5 were detected and counted. The results are shown in Table 2:

[0111] Table 2

[0112]

[0113] It can be seen from Table 2 that the conversion rate of compound 3 and the yield of compound 4 can be improved by increasing the amount of triethylamine added.

[0114] Comparative Example 6

[0115] This comparative example is substantially the same as Example 1, except that the acetonitrile-water solution is replaced by acetonitrile in step (4).

[0116] Comparative Example 7

[0117] This comparative example is basically the same as Example 1, the only difference being that the acetonitrile-water solution is replaced by methanol in step (4).

[0118] Comparative Example 8

[0119] This comparative example is substantially the same as Example 1, except that the acetonitrile-water solution is replaced by acetone in step (4).

[0120] The reaction conditions of compound 5 in Examples 1, 3-4 and Comparative Examples 6-8 were detected and counted. The results are shown in Table 3:

[0121] Table 3

[0122] Solvents Reaction time (h) Conversion rate (%) Selectivity (%) Example 1 Acetonitrile-water solution 2 93.65 98.54 Example 3 dimethylformamide 1 99.87 96.81 Example 4 Dimethyl sulfoxide 1 99.71 99.33 Comparative Example 6 Acetonitrile 1 10.82 99.69 Comparative Example 7 Methanol 2 91.94 87.87 Comparative Example 8 acetone 1.5 89.78 99.3

[0123] In current research, in order to reduce the complexity of solvent separation, acetonitrile is usually used as a solvent, and lithium bromide is used for substitution reaction, but the cost of lithium bromide is relatively high. This application considers reducing the cost and selects sodium bromide with lower cost, but the reaction conversion rate of sodium bromide in acetonitrile solution is very low. It was found through experiments that in an aqueous solution of acetonitrile, at 70-80°C, the substitution reaction can also be achieved using sodium bromide with lower cost, and the conversion rate of compound 4 and the selectivity of compound 5 are both good.

[0124] Comparative Example 9

[0125] This comparative example is basically the same as Example 1, except that in step (5), the catalyst cupric chloride is replaced by nickel chloride-1,3-butadiene, and the molar ratio of compound 5 to nickel chloride-1,3-butadiene is 1:0.05.

[0126] Comparative Example 10

[0127] This comparative example is basically the same as Example 1, except that in step (5), the catalyst cupric chloride is replaced by nickel acetylacetonate, and the molar ratio of compound 5 to nickel acetylacetonate is 1:0.05.

[0128] The reaction conditions of compound 6 in Examples 1, 5-7 and Comparative Examples 9-10 were detected and statistically analyzed. The results are shown in Table 4:

[0129] Table 4

[0130]

[0131] In the present invention, copper salts have a certain catalytic effect on the synthesis of compound 6, but considering the comprehensive conversion rate and selectivity, the catalyst is preferably cuprous bromide and cupric chloride. Considering that cuprous bromide is more stable than cupric chloride, cuprous bromide is preferably used as the catalyst.

[0132] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for preparing cis-6-nonenal, characterized in that: The method comprises the following steps: mixing 1-halogenated hex-3-ene with a catalyst, then adding a Grignard reagent to carry out a coupling reaction, and then carrying out a deprotection reaction to obtain cis-6-nonenal; The structural formulas of the Grignard reagent and the 1-halogenated hex-3-ene are respectively: Wherein, R1 is an aldehyde protecting group, and X1 and X2 are each independently chlorine, bromine or iodine.

2. The method for preparing cis-6-nonenal according to claim 1, characterized in that: The molar ratio of the Grignard reagent to the 1-halogenated hex-3-ene is 1.25-1.8:1; The molar ratio of the 1-halogenated hex-3-ene to the catalyst is 1:0.02-0.

05.

3. The method for preparing cis-6-nonenal according to claim 1, characterized in that: The aldehyde protecting group is any one of ketal, thioketal, enol ether and enamine; The catalyst is a salt or complex of any one of copper, nickel and palladium.

4. The method for preparing cis-6-nonenal according to claim 1, characterized in that: The Grignard reagent is prepared by a method comprising the following steps: (1) acrolein is reacted with hydrogen halide to generate 2-haloacrolein, and then the 2-haloacrolein is subjected to an aldehyde group protection reaction to obtain compound A, wherein compound A is R1-C-X1; (2) subjecting the compound A to a Grignard reaction with magnesium to obtain a Grignard reagent.

5. The method for preparing cis-6-nonenal according to claim 4, characterized in that: The addition reaction is to introduce hydrogen halide gas into acrolein, and the hydrogen halide gas flow rate is 0.6-0.8L / (min·kg); The reactants added in the aldehyde protection reaction include one or more of methanol, ethanol, trimethyl orthoformate, ethylene glycol, and 1,3-propylene glycol.

6. The method for preparing cis-6-nonenal according to claim 4, characterized in that: The temperature of the Grignard reaction in step (2) is 15-30°C.

7. The method for preparing cis-6-nonenal according to claim 4, characterized in that: The 1-halogenated hex-3-ene is prepared by a method comprising the following steps: (1) subjecting leaf alcohol to a sulfonylation reaction with benzenesulfonyl chloride to obtain leaf alcohol benzenesulfonate; (2) In a polar solvent, the leaf alcohol benzene sulfonate is subjected to a nucleophilic substitution reaction with a halide salt to obtain 1-halogenated hex-3-ene.

8. The method for preparing cis-6-nonenal according to claim 7, characterized in that: The polar solvent includes one or more of methanol, acetone, N,N-dimethylformamide, acetonitrile, an aqueous solution of acetonitrile, and dimethyl sulfoxide; The halide salt includes any one of sodium bromide, lithium bromide, potassium bromide, magnesium bromide, sodium chloride, potassium chloride, magnesium chloride, potassium iodide, sodium iodide, and magnesium iodide.

9. A method for preparing cis-6-nonenol, characterized in that: The following steps are involved: The method according to any one of claims 1 to 8 is used to prepare cis-6-nonenal; The cis-6-nonenal is mixed with a reducing agent and subjected to a reduction reaction to obtain cis-6-nonenol.

10. The method for preparing cis-6-nonenol according to claim 9, characterized in that: The molar ratio of the cis-6-nonenal to the reducing agent is 1:1.1-1.5; The reducing agent includes any one or more of sodium borohydride, potassium borohydride, and aluminum isopropoxide.

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