A method for synthesizing sandalore from melonal

Abstract

The application provides a method for synthesizing sandalwood ether from melonal, comprising the following steps: melonal is subjected to etherification reaction with methanol under the action of a catalyst to obtain methoxymelonal, and a metal methoxide reagent is added to the methoxymelonal to obtain sandalwood ether. The synthesis route is novel and short, melonal which is cheap and easy to obtain is used as a raw material, sandalwood ether product is obtained through two-step reactions of etherification and Grignard addition, and the method has the advantages of high reaction yield, less waste, simple operation and the like, and is easy to scale up. Compared with the traditional route of using dihydromyrcene, the method does not involve high-pressure hydrogenation and does not produce methoxymethyl chavicol by-product, and the route yield is significantly improved.

Description

Technical Field

[0001] This invention belongs to the fields of fine chemicals and fragrances, specifically relating to a method for synthesizing sandalwood ether using melon aldehyde as a raw material. Background Technology

[0002] Sandalwood is a rare plant native to overseas regions, and only sandalwood trees over 30 years old can yield high-quality natural sandalwood oil. Natural sandalwood oil has a rich, elegant aroma with a slightly cooling sensation; it not only diffuses well but also has a long-lasting fragrance, making it a highly prized raw material. Currently, the world's most valuable sandalwood oil comes from eastern India. Due to the extremely limited sandalwood resources and the strict controls imposed by the Indian government in recent years, the supply of natural sandalwood oil has fallen short of demand, causing prices to soar. This has led many downstream customers to seek substitutes for natural sandalwood oil, significantly promoting the research, development, and application of synthetic sandalwood.

[0003] The main aromatic components of natural santalol are α-santalol and β-santalol, with β-santalol being the primary source of its aroma. Their structural formulas are shown below. Due to the highly complex chemical structure of β-santalol, its artificial synthesis requires multiple steps, resulting in high costs and limited practical applications. To obtain a cheaper sandalwood aroma, synthetic chemists have developed various substitutes for santalol, such as santalol 208, santalol 210, santalinol, and ebonyol. These substitutes possess the characteristic aroma of sandalwood and are inexpensive, thus promoting the widespread use and application of sandalwood fragrances.

[0004]

[0005] Sandalwood ether is an important monomeric fragrance compound with sandalwood and floral aromas, possessing a rich and pleasing scent. It is also a substitute for β-santalol, initially discovered by Bush Boake Allen in 1973, and is currently the only known linear sandalwood fragrance compound. Sandalwood ether is a colorless, transparent liquid at room temperature, chemically stable, and does not easily cause discoloration when added to downstream products. It has a fresh, elegant, and delicate sandalwood aroma with a hint of floral notes, exhibiting excellent diffusion properties, and is widely used in various daily chemical products such as soaps, cosmetics, and perfumes.

[0006] The main synthetic route for santal ether is shown below (DE2255119). First, natural dihydromyrcene reacts with methanol under an acid catalyst to obtain methoxydihydromyrcene. This is followed by a further epoxidation reaction to obtain an epoxide, and finally, a hydrogenation reduction reaction to obtain the santal ether product. This is currently the mainstream synthetic route for santal ether, as its raw material, dihydromyrcene, is inexpensive and readily available, making large-scale production feasible. However, it is worth noting that this route also has some significant drawbacks, such as a relatively long synthetic route, low hydrogenation selectivity, and a large amount of byproduct methoxycitronellol. These factors result in a high cost for santal ether, making it unable to compete with relatively inexpensive products such as santal 803 and santal 210, thus limiting the widespread use of santal ether.

[0007]

[0008] In summary, santalyl ether is an excellent synthetic sandalwood product, possessing an elegant and delicate aroma, stable chemical properties, and no discoloration. Currently, the main synthetic route for santalyl ether uses dihydromyrcene as a raw material, involving three steps: etherification, epoxidation, and hydrogenation. This long synthetic route and poor hydrogenation selectivity result in high costs for santalyl ether, limiting its widespread use.

[0009] To prepare santalyl ether products more economically, it is urgent to develop new synthetic routes, improve the synthesis yield, and reduce the production cost of santalyl ether. Summary of the Invention

[0010] The purpose of this invention is to provide a simple and efficient method for synthesizing santalin ether using melon aldehyde as a raw material. This method achieves efficient and low-cost synthesis of santalin ether. Using inexpensive and readily available melon aldehyde as a raw material, the santalin ether product is obtained through a two-step reaction involving etherification and Grignard addition. It features high overall synthetic yield, low waste generation, and simple operation, making it easy to scale up for production. Furthermore, compared to the traditional route using dihydromyrcene, this method does not involve high-pressure hydrogenation and produces no methoxycitronellol byproduct.

[0011] To achieve the above objectives and technical effects, the present invention adopts the following technical solution:

[0012] A method for synthesizing santalyl ether from melon aldehyde includes the following steps:

[0013] S1. Cucurbitaldehyde undergoes an etherification reaction with methanol under the action of a catalyst to yield methoxycucurbitaldehyde;

[0014] S2, methyl metal reagents are added to methoxycucurbitaldehyde to give santalyl ether.

[0015] The reaction equation for the synthesis of santalyl ether from melon aldehyde according to the present invention is shown below:

[0016]

[0017] In this invention, the reactor in S1 is a bed reactor or a tubular reactor, in which the catalyst is loaded; the feed method of the reactants is either top-in, bottom-out or bottom-in, top-out.

[0018] In this invention, the catalyst used in S1 is an acid resin solid catalyst, which may be one or more of sulfonic acid resin, phosphoric acid resin, carboxylic acid resin, and phenolic hydroxyl resin, with sulfonic acid resin being preferred.

[0019] In this invention, the reaction temperature of the etherification reaction in S1 is 60–110°C, preferably 70–80°C; and / or, the reaction pressure is 0.1–0.5 MPaG, preferably 0.1–0.2 MPaG; and / or, the mass hourly space velocity is 0.2–6.0 h⁻¹. -1 .

[0020] In this invention, the feed liquid in S1 is composed of melon aldehyde, methanol, and water, wherein the feed molar ratio of melon aldehyde to methanol is 1:13 to 1:30; the feed molar ratio of melon aldehyde to water is 1:0.3 to 1:1; preferably, the feed liquid also includes a small amount of silanol, and the molar ratio of melon aldehyde to silanol is 20 to 200:1; more preferably, the feed temperature is room temperature.

[0021] In this invention, the methyl metal reagent in S2 is selected from at least one of methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, dimethyl zinc, trimethyl aluminum, and methyllithium, preferably methyl magnesium chloride or methyl magnesium bromide; preferably, the amount of the methyl metal reagent is 80-150 mol of the molar amount of methoxycucurbitaldehyde.

[0022] In this invention, the reaction in S2 is carried out in the presence of an aprotic solvent, preferably selected from one or more of diethyl ether, propyl ether, isopropyl ether, butyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, and toluene, more preferably tetrahydrofuran and diethyl ether; preferably, the amount of the solvent used is 1.5 to 4.0 times the mass of methoxycucurbitaldehyde.

[0023] In this invention, the reaction temperature of the S2 addition reaction is -20 to 50°C, preferably 0 to 20°C, and / or the reaction pressure is atmospheric pressure, and the reaction time is 2 to 4 hours.

[0024] In this invention, after the addition reaction is complete, a step of adding a quencher to quench the reaction is further included. The quencher can be, but is not limited to, water, aqueous ammonium chloride solution, aqueous ammonium sulfate solution, aqueous ammonium phosphate solution, aqueous acetic acid solution, dilute hydrochloric acid, etc. The volume of the quencher added is 0.22 to 0.70 times the volume of the methyl metal reagent.

[0025] The present invention, by adopting the above technical solution, has the following positive effects:

[0026] 1. The synthetic route of this invention is novel and concise. It uses inexpensive and readily available melon aldehyde as raw material and obtains sandalwood ether product through two-step reaction of etherification and Grignard addition. It has the advantages of high reaction yield, low "three wastes" (waste gas, wastewater, and solid waste), and simple operation, and is easy to scale up for production.

[0027] 2. In the etherification reaction, the present invention adopts a fixed-bed continuous process and uses a solid acid catalyst, which has the advantages of stable process and high raw material conversion.

[0028] 3. In this invention, a small amount of water is added to the feed liquid of the etherification reaction to inhibit the formation of acetal byproducts, thereby effectively improving the selectivity of methoxycucurbitaldehyde. Detailed Implementation

[0029] The present invention is described in detail below through embodiments, but the present invention is not limited to the embodiments described below.

[0030] The main raw material information is as follows:

[0031] Cucurbitaldehyde, Beida Zhengyuan, 85%, used after distillation purification; Strong acid cation exchange resins 001*7, 001*4, D201, Dandong Mingzhu, industrial grade; Strong acid cation exchange resins Diaion PLK228, Amberlite IR-120, Sigma-Aldrich reagents. Methanol, Aladdin reagent, chromatographic grade; Trimethylsilanol, 97%, Xianghui Pharmaceutical.

[0032] Anhydrous tetrahydrofuran, diethyl ether, and methyl tert-butyl ether, chromatographic grade, Aladdin reagent. Methylmagnesium chloride, West Asia reagent, 2M THF solution; methylmagnesium bromide, Merrill reagent, 1M THF solution; dimethylzinc, Aladdin reagent, 1M toluene solution; trimethylaluminum, Echo reagent, 2M toluene solution; methylmagnesium iodide, Aladdin reagent, 3M diethyl ether solution; methyllithium, Aladdin reagent, 1.6M THF solution. Anhydrous ammonium chloride, sodium sulfate, and sodium chloride, Sinopharm reagent, AR.

[0033] The gas chromatography test conditions of this invention are as follows:

[0034] Instrument model: Agilent 7890B; Column: HP-5 capillary column (60m × 0.30mm × 0.25μm); Initial temperature 40.0℃, increased to 100.0℃ at a rate of 5.0℃ / min; then increased to 200.0℃ at a rate of 10.0℃ / min and held for 15.0min; then increased to 240.0℃ at a rate of 20.0℃ / min and held for 5.0min. Carrier gas: high-purity nitrogen, split ratio 30:1, split flow rate 42.0mL / min. Carrier gas savings: 28.0mL / min, initial waiting time 5.0min. Injection temperature 250.0℃, detector: FID, detector temperature 280.0℃, air flow rate 350.0mL / min, hydrogen flow rate 30.0mL / min, make-up gas flow rate 50.0mL / min, injection volume 0.2μL.

[0035] Example 1

[0036] Resin-catalyzed synthesis of methoxycucurbitaldehyde from melonaldehyde

[0037] First, prepare the feed solution by adding methanol (100.9g, 3.15mol), melon aldehyde (29.5g, 0.21mol), water (1.13g, 0.063mol), and trimethylsilanol (0.2g, 0.0021mol) sequentially to a wide-mouth bottle. After all materials have been added, place a magnetic stir bar in the wide-mouth bottle and stir thoroughly until a clear, transparent, and homogeneous feed solution with a slightly yellow tint is obtained.

[0038] This reaction step was carried out in a tubular reactor. The reactor tube was 60 cm long and 2.2 cm in inner diameter. The middle section of the reactor tube was filled with 100 g of Dandong Mingzhu 001*7 strong acid resin catalyst (99% purity). The top and bottom of the reactor tube were filled with ceramic ball packing material to fix and support the resin catalyst. Temperature measuring lines were evenly distributed throughout the reactor tube, with a total of four temperature measuring points. After the catalyst filling was complete, the power to the fixed-bed reactor was turned on, and the previously prepared feed solution was added to the feed tank. The circulating oil bath in the reactor tube jacket was turned on to raise the temperature of the reactor tube to 60°C. After the temperature stabilized, the feed horizontal flow pump was turned on, and the feed solution entered the tubular reactor at a rate of 3.3 g / min, with bottom inlet and top outlet, and a weight hourly space velocity (WHSV) of 2.0 h⁻¹. -1 Maintaining a constant feed rate and temperature, the continuous reaction begins. After exiting the reaction tube, the reaction liquid is cooled by a condenser and then enters a reaction liquid collection tank. A sampler is installed on the connecting pipeline between the condenser and the collection tank. Once the reaction is running smoothly, samples are taken periodically from the sampler. The extracted reaction liquid is then mixed with the internal standard n-octane and analyzed by GC chromatography. The results show that the conversion rate of the raw material melon aldehyde is 96%, and the selectivity of methoxymelon aldehyde is 98%.

[0039] The product, methoxycucurbitaldehyde, is a known compound. Its GC elution time is consistent with the standard. High-resolution mass spectrometry data are as follows: HRMS-EI M + Calcd for C 10 H 20 O2:172.1463,found 172.1462.

[0040] Example 2

[0041] Resin-catalyzed synthesis of methoxycucurbitaldehyde from melonaldehyde

[0042] First, prepare the feed solution by adding methanol (147.4g, 4.6mol), melon aldehyde (32.3g, 0.23mol), water (4.1g, 0.23mol), and trimethylsilanol (0.21g, 0.0023mol) sequentially to a wide-mouth bottle. After all materials have been added, place a magnetic stir bar in the wide-mouth bottle and stir thoroughly until the mixture is homogeneous, resulting in a clear, transparent, and uniform feed solution with a slightly yellow tint.

[0043] This reaction step was carried out in a tubular reactor. The reactor tube was 60 cm long and 2.2 cm in inner diameter. The middle section of the reactor tube was filled with 100 g of Dandong Mingzhu 001*7 strong acid resin catalyst (99% purity). The top and bottom of the reactor tube were filled with ceramic ball packing material to fix and support the resin catalyst. Temperature measuring lines were evenly distributed throughout the reactor tube, with a total of four temperature measuring points. After the catalyst filling was complete, the power to the fixed-bed reactor was turned on, and the previously prepared feed solution was added to the feed tank. The circulating oil bath in the reactor tube jacket was turned on to raise the temperature of the reactor tube to 80°C. After the temperature stabilized, the feed horizontal flow pump was turned on, and the feed solution entered the tubular reactor at a rate of 5.0 g / min, with bottom inlet and top outlet, and a weight hourly space velocity (WHSV) of 3.0 h⁻¹. -1 Maintaining a constant feed rate and temperature, the continuous reaction begins. After exiting the reaction tube, the reaction liquid is cooled by a condenser and then enters a reaction liquid collection tank. A sampler is installed on the connecting pipeline between the condenser and the collection tank. Once the reaction is running smoothly, samples are taken periodically from the sampler. The extracted reaction liquid is then mixed with the internal standard n-octane and analyzed by GC chromatography. The results show that the conversion rate of the raw material melon aldehyde is 99%, and the selectivity of methoxymelon aldehyde is 98%.

[0044] Example 3

[0045] Resin-catalyzed synthesis of methoxycucurbitaldehyde from melonaldehyde

[0046] First, prepare the feed solution by adding methanol (1268.9g, 39.6mol), melon aldehyde (185.1g, 1.32mol), water (11.9g, 0.66mol), and trimethylsilanol (5.95g, 0.066mol) sequentially to a wide-mouth bottle. After all materials have been added, place a magnetic stir bar in the wide-mouth bottle and stir thoroughly until the mixture is homogeneous, resulting in a clear, transparent, and uniform feed solution with a slightly yellow tint.

[0047] This reaction step was carried out in a tubular reactor. The reactor tube was 60 cm long and 2.2 cm in inner diameter. The middle section of the reactor tube was filled with 80 g of Dandong Mingzhu 001*4 strong acid resin catalyst (99% purity). The top and bottom ends of the reactor tube were filled with ceramic ball packing material to fix and support the resin catalyst. Temperature measuring lines were evenly distributed throughout the reactor tube, with a total of four temperature measuring points. After the catalyst filling was completed, the power to the fixed-bed reactor was turned on, and the previously prepared feed solution was added to the feed tank. The circulating oil bath in the reactor tube jacket was turned on to raise the temperature of the reactor tube to 110°C. After the temperature stabilized, the feed horizontal flow pump was turned on, and the feed solution entered the tubular reactor at a rate of 8.0 g / min, with bottom inlet and top outlet, and a weight hourly space velocity (WHSV) of 6.0 h⁻¹. -1 Maintaining a constant feed rate and temperature, the continuous reaction begins. After exiting the reaction tube, the reaction liquid is cooled by a condenser and then enters a reaction liquid collection tank. A sampler is installed on the connecting pipeline between the condenser and the collection tank. Once the reaction is running smoothly, samples are taken periodically from the sampler. The extracted reaction liquid is then mixed with the internal standard n-octane and analyzed by GC chromatography. The results show that the conversion rate of the raw material melon aldehyde is 96%, and the selectivity of methoxymelon aldehyde is 98%.

[0048] Example 4

[0049] Resin-catalyzed synthesis of methoxycucurbitaldehyde from melonaldehyde

[0050] First, prepare the feed solution by adding methanol (842.1g, 26.3mol), melon aldehyde (204.7g, 1.46mol), water (13.2g, 0.73mol), and trimethylsilanol (1.32g, 0.0146mol) sequentially to a wide-mouth bottle. After all materials have been added, place a magnetic stir bar in the wide-mouth bottle and stir thoroughly until the mixture is homogeneous, resulting in a clear, transparent, and uniform feed solution with a slightly yellow tint.

[0051] This reaction step was carried out in a tubular reactor. The reactor tube was 60 cm long and 2.2 cm in inner diameter. The middle section of the reactor tube was filled with 110 g of Dandong Mingzhu D201 strong acid resin catalyst (99% purity). The top and bottom of the reactor tube were filled with ceramic ball packing material to fix and support the resin catalyst. Temperature measuring lines were evenly distributed throughout the reactor tube, with a total of four temperature measuring points. After the catalyst filling was completed, the power to the fixed-bed reactor was turned on, and the previously prepared feed solution was added to the feed tank. The circulating oil bath in the reactor tube jacket was turned on to raise the temperature of the reactor tube to 60°C. After the temperature stabilized, the feed horizontal flow pump was turned on, and the feed solution entered the tubular reactor at a rate of 2.75 g / min, with bottom inlet and top outlet, and a weight hourly space velocity (WHSV) of 1.5 h⁻¹. -1 Maintaining a constant feed rate and temperature, the continuous reaction begins. After exiting the reaction tube, the reaction liquid is cooled by a condenser and then enters a reaction liquid collection tank. A sampler is installed on the connecting pipeline between the condenser and the collection tank. Once the reaction is running smoothly, samples are taken periodically from the sampler. The extracted reaction liquid is then mixed with the internal standard n-octane and analyzed by GC chromatography. The results show that the conversion rate of the raw material melon aldehyde is 97%, and the selectivity of methoxymelon aldehyde is 98%.

[0052] Example 5

[0053] Resin-catalyzed synthesis of methoxycucurbitaldehyde from melonaldehyde

[0054] First, prepare the feed solution by adding methanol (182.6g, 5.7mol), melon aldehyde (53.3g, 0.38mol), water (4.1g, 0.23mol), and trimethylsilanol (0.34g, 0.0038mol) sequentially to a wide-mouth bottle. After all materials have been added, place a magnetic stir bar in the wide-mouth bottle and stir thoroughly until the mixture is homogeneous, resulting in a clear, transparent, and uniform feed solution with a slightly yellow tint.

[0055] This step of the reaction was carried out in a tubular reactor. The reactor tube was 60 cm long and 2.2 cm in inner diameter. The middle section of the reactor tube was filled with Diaion PLK228 strong acid resin catalyst (121 g, 99% purity). The top and bottom ends of the reactor tube were filled with ceramic ball packing material to fix and support the resin catalyst. Temperature measuring lines were evenly distributed throughout the reactor tube, with a total of four temperature measuring points. After the catalyst filling was complete, the power to the fixed-bed reactor was turned on, and the previously prepared feed solution was added to the feed tank. The circulating oil bath in the reactor tube jacket was turned on to raise the temperature of the reactor tube to 60°C. After the temperature stabilized, the feed horizontal flow pump was turned on, and the feed solution entered the tubular reactor at a rate of 0.4 g / min, with bottom inlet and top outlet, and a weight hourly space velocity (WHSV) of 0.2 h⁻¹. -1Maintaining a constant feed rate and temperature, the continuous reaction begins. After exiting the reaction tube, the reaction liquid is cooled by a condenser and then enters a reaction liquid collection tank. A sampler is installed on the connecting pipeline between the condenser and the collection tank. Once the reaction is running smoothly, samples are taken periodically from the sampler. The extracted reaction liquid is then mixed with the internal standard n-octane and analyzed by GC chromatography. The results show that the conversion rate of the raw material melon aldehyde is 99%, and the selectivity of methoxymelon aldehyde is 98%.

[0056] Example 6

[0057] Resin-catalyzed synthesis of methoxycucurbitaldehyde from melonaldehyde

[0058] First, prepare the feed solution by adding methanol (495.7g, 15.5mol), melon aldehyde (166.9g, 1.19mol), water (15.0g, 0.83mol), and trimethylsilanol (0.54g, 0.006mol) sequentially to a wide-mouth bottle. After all materials have been added, place a magnetic stir bar in the wide-mouth bottle and stir thoroughly until the mixture is homogeneous, resulting in a clear, transparent, and uniform feed solution with a slightly yellow tint.

[0059] This reaction step was carried out in a tubular reactor. The reactor tube was 60 cm long and 2.2 cm in inner diameter. The middle section of the reactor tube was filled with 106 g of Amberlite IR-120 strong acid resin catalyst (99% purity). The top and bottom of the reactor tube were filled with ceramic ball packing material to fix and support the resin catalyst. Temperature measuring lines were evenly distributed throughout the reactor tube, with a total of four temperature measuring points. After the catalyst filling was complete, the power to the fixed-bed reactor was turned on, and the previously prepared feed solution was added to the feed tank. The circulating oil bath in the reactor tube jacket was turned on to raise the temperature of the reactor tube to 90°C. After the temperature stabilized, the feed horizontal flow pump was turned on, and the feed solution entered the tubular reactor at a rate of 5.3 g / min, with bottom inlet and top outlet, and a weight hourly space velocity (WHSV) of 3.0 h⁻¹. -1 Maintaining a constant feed rate and temperature, the continuous reaction begins. After exiting the reaction tube, the reaction liquid is cooled by a condenser and then enters a reaction liquid collection tank. A sampler is installed on the connecting pipeline between the condenser and the collection tank. Once the reaction is running smoothly, samples are taken periodically from the sampler. The extracted reaction liquid is then mixed with the internal standard n-octane and analyzed by GC chromatography. The results show that the conversion rate of the raw material melon aldehyde is 97%, and the selectivity of methoxymelon aldehyde is 99%.

[0060] Example 7

[0061] Preparation of santalyl ether by reaction of methoxycucurnal and Grignard reagent

[0062] First, place a 1L three-necked flask in ice water. Place a magnetic stir bar inside the flask, and connect nitrogen gas and a constant-pressure dropping funnel to the flask opening. Replace the air in the flask with nitrogen gas. Then, add the solvent tetrahydrofuran (33.6g) and the raw material methoxycucurbitaldehyde (22.4g, 0.13mol) sequentially to the flask. Start stirring and mix thoroughly to obtain a clear, transparent liquid. Add a tetrahydrofuran solution of methyl magnesium chloride (71.5mL, 2.0M) to the three-necked flask with a constant-pressure dropping funnel and stir rapidly. Control the dropping rate of methyl magnesium chloride to maintain the reaction solution in the flask at approximately 0°C, not exceeding 5°C. Complete the addition within 1 hour; the reaction solution is pale gray and slightly turbid. Continue stirring for another hour, then take a sample for analysis. GC detection shows that the raw material methoxycucurbitaldehyde reacted almost completely, with a conversion rate >99.0%, and the selectivity of the product santalyl ether >99.0%.

[0063] Saturated ammonium chloride aqueous solution (50 mL) was added dropwise to the reaction solution using a constant-pressure dropping funnel to quench any unreacted Grignard reagent. The reaction solution initially became turbid, then gradually became clear and separated into phases. For post-processing, the reaction solution was first placed in a separatory funnel to separate the oil and water phases. The organic phase was then washed sequentially with saturated ammonium chloride aqueous solution and saturated brine. After drying the organic phase with anhydrous sodium sulfate, it was filtered and distilled to obtain the santalyl ether product.

[0064] The obtained santalyl ether product is a known compound. Its GC elution time is consistent with the standard. High-resolution mass spectrometry data are as follows: HRMS-EI M + Calcd for C 11 H 24 O2:188.1776,found 188.1778.

[0065] Example 8

[0066] Preparation of santalyl ether by reaction of methoxycucurnal and Grignard reagent

[0067] First, place a 1L three-necked flask in a low-temperature bath. Place a magnetic stir bar inside the flask, and connect nitrogen gas and a constant-pressure dropping funnel to the flask opening. Replace the air in the flask with nitrogen gas. Then, add the solvent tetrahydrofuran (103.2g) and the raw material methoxycucurbitaldehyde (25.8g, 0.15mol) sequentially to the flask. Start stirring and mix thoroughly to obtain a clear, transparent liquid. Add a tetrahydrofuran solution of methyl magnesium bromide (225.0mL, 1.0M) to the three-necked flask with a constant-pressure dropping funnel and stir rapidly. Control the dropping rate of methyl magnesium bromide to maintain the reaction solution in the flask at approximately -20°C, not exceeding -15°C. Complete the addition within 1 hour. The reaction solution is pale gray and slightly turbid. Continue stirring for 3 hours, then take samples for analysis. GC detection shows that the raw material methoxycucurbitaldehyde reacted almost completely, with a conversion rate >99.0%, and the selectivity of the product santalyl ether >99.0%.

[0068] Saturated ammonium chloride aqueous solution (50 mL) was added dropwise to the reaction solution using a constant-pressure dropping funnel to quench any unreacted Grignard reagent. The reaction solution initially became turbid, then gradually became clear and separated into phases. For post-processing, the reaction solution was first placed in a separatory funnel to separate the oil and water phases. The organic phase was then washed sequentially with saturated ammonium chloride aqueous solution and saturated brine. After drying the organic phase with anhydrous sodium sulfate, it was filtered and distilled to obtain the santalyl ether product.

[0069] Example 9

[0070] Santal ether is prepared by reacting methoxycucurnal with dimethyl zinc reagent.

[0071] First, place a 1L three-necked flask in ice water. Place a magnetic stir bar inside the flask, and connect nitrogen gas and a constant-pressure dropping funnel to the flask opening. Replace the air in the flask with nitrogen gas. Then, add the solvent diethyl ether (48.2g) and the raw material methoxycucurbitaldehyde (24.1g, 0.14mol) sequentially to the flask. Start stirring and mix thoroughly to obtain a clear, transparent liquid. Add a toluene solution of dimethyl zinc (154.0mL, 1.0M) to the constant-pressure dropping funnel and add it dropwise to the three-necked flask with rapid stirring. Control the dropping rate of the dimethyl zinc solution to maintain the reaction solution in the three-necked flask at approximately 0°C, not exceeding 5°C. Complete the addition within 1 hour; the reaction solution is pale gray and slightly turbid. Raise the temperature of the reaction solution to 50°C and continue stirring for 2 hours. Samples are taken for analysis. GC detection shows that the raw material methoxycucurbitaldehyde reacted almost completely, with a conversion rate >99.0%, and the selectivity of the product santalyl ether >99.0%.

[0072] A 10% ammonium acetate aqueous solution (50 mL) was added dropwise to the reaction solution using a constant-pressure dropping funnel to quench the unreacted dimethyl zinc reagent. The reaction solution initially became turbid, then gradually became clear and separated into phases. For post-processing, the reaction solution was first placed in a separatory funnel to separate the oil and water phases. The organic phase was then washed sequentially with saturated ammonium chloride aqueous solution and saturated brine. After drying the organic phase with anhydrous sodium sulfate, it was filtered and distilled to obtain the santalyl ether product.

[0073] Example 10

[0074] Santal ether is prepared by reacting methoxycucurnal with trimethylaluminum reagent.

[0075] First, place a 1L three-necked flask in ice water. Place a magnetic stir bar inside the flask, and connect nitrogen gas and a constant-pressure dropping funnel to the flask opening. Replace the air in the flask with nitrogen gas. Then, add the solvent methyl tert-butyl ether (88.7g) and the raw material methoxycucurbitaldehyde (35.3g, 0.205mol) sequentially to the flask. Start stirring and mix thoroughly to obtain a clear, transparent liquid. Add a trimethylaluminum toluene solution (82.0mL, 2.0M) to the constant-pressure dropping funnel and add it dropwise to the three-necked flask with rapid stirring. Control the dropping rate of the trimethylaluminum solution to maintain the reaction solution in the flask at approximately 0°C, not exceeding 5°C. Complete the addition within 1 hour; the reaction solution is pale gray and slightly turbid. Raise the temperature of the reaction solution to 50°C and continue stirring for 3 hours. Samples are taken for analysis. GC detection shows that the raw material methoxycucurbitaldehyde reacted almost completely, with a conversion rate >99.0%, and the selectivity of the product santalyl ether >99.0%.

[0076] Saturated ammonium chloride aqueous solution (50 mL) was added dropwise to the reaction solution using a constant-pressure dropping funnel to quench the unreacted trimethylaluminum reagent. The reaction solution initially became turbid, then gradually became clear and separated into phases. For post-processing, the reaction solution was first placed in a separatory funnel to separate the oil and water phases. The organic phase was then washed sequentially with saturated ammonium chloride aqueous solution and saturated brine. After drying the organic phase with anhydrous sodium sulfate, it was filtered and distilled to obtain the santalyl ether product.

[0077] Example 11

[0078] Preparation of santalyl ether by reaction of methoxycucurnal and Grignard reagent

[0079] First, place a 1L three-necked flask in ice water. Place a magnetic stir bar inside the flask, and connect nitrogen gas and a constant-pressure dropping funnel to the flask opening. Replace the air in the flask with nitrogen gas. Then, add the solvent diethyl ether (98.1g) and the raw material methoxycucurbitaldehyde (32.7g, 0.19mol) sequentially to the flask. Start stirring and mix thoroughly to obtain a clear, transparent liquid. Add a 69.7mL (3.0M) solution of magnesium methyl iodide in diethyl ether to the constant-pressure dropping funnel and add it dropwise to the three-necked flask with rapid stirring. Control the dropping rate of the magnesium methyl iodide solution to maintain the reaction solution in the three-necked flask at approximately 0°C, not exceeding 5°C. Complete the addition within 1 hour; the reaction solution is pale gray and slightly turbid. Continue stirring for 2 hours, then take a sample for analysis. GC detection shows that the raw material methoxycucurbitaldehyde reacted almost completely, with a conversion rate >99.0%, and the selectivity of the product santalyl ether >99.0%.

[0080] 10% acetic acid aqueous solution (40 mL) was added dropwise to the reaction solution using a constant pressure dropping funnel to quench any unreacted Grignard reagent. The reaction solution initially became turbid, then gradually became clear and separated into phases. For post-processing, the reaction solution was first placed in a separatory funnel to separate the oil and water phases. The organic phase was then washed sequentially with saturated ammonium chloride aqueous solution and saturated brine. After drying the organic phase with anhydrous sodium sulfate, it was filtered and distilled to obtain the santalyl ether product.

[0081] Example 12

[0082] Santal ether is prepared by reacting methoxycucurnal with methyl lithium reagent.

[0083] First, place a 1L three-necked flask in ice water. Place a magnetic stir bar inside the flask, and connect nitrogen gas and a constant-pressure dropping funnel to the flask opening. Replace the air in the flask with nitrogen gas. Then, add the solvent tetrahydrofuran (33.6g) and the raw material methoxycutanal (29.3g, 0.17mol) sequentially to the flask. Start stirring and mix thoroughly to obtain a clear, transparent liquid. Add a 159.4mL (1.6M) solution of lithium methyl ether to the constant-pressure dropping funnel and add it dropwise to the three-necked flask with rapid stirring. Control the dropping rate of the lithium methyl ether solution and maintain the reaction solution in the flask at approximately 0°C, not exceeding 5°C. Complete the addition within 1 hour; the reaction solution is pale gray and slightly turbid. Continue stirring for 3 hours, then take a sample for analysis. GC detection shows that the raw material methoxycutanal reacted almost completely, with a conversion rate >99.0%, and the selectivity of the product santalyl ether >99.0%.

[0084] Saturated ammonium chloride aqueous solution (50 mL) was added dropwise to the reaction solution using a constant-pressure dropping funnel to quench the unreacted methyllithium reagent. The reaction solution initially became turbid, then gradually became clear and separated into phases. For post-processing, the reaction solution was first placed in a separatory funnel to separate the oil and water phases. The organic phase was then washed sequentially with saturated ammonium chloride aqueous solution and saturated brine. After drying the organic phase with anhydrous sodium sulfate, it was filtered and distilled to obtain the santalyl ether product.

Claims

1. A method for synthesizing santalyl ether from melon aldehyde, characterized in that, Includes the following steps: S1. Cucurbitaldehyde undergoes an etherification reaction with methanol under the action of a catalyst to yield methoxycucurbitaldehyde; the feed liquid in S1 consists of cucurbitaldehyde, methanol, water, and silanol. S2, methyl metal reagents are added to methoxycucurbitaldehyde to give santalyl ether.

2. The method according to claim 1, characterized in that, In S1, the reactor is either a bed reactor or a tubular reactor, and the catalyst is loaded into it.

3. The method according to claim 2, characterized in that, The reactants are fed in either from top to bottom or from bottom to top.

4. The method according to claim 1, 2, or 3, characterized in that, The catalyst described in S1 is an acidic resin solid catalyst.

5. The method according to claim 4, characterized in that, The catalyst mentioned in S1 is one or more of sulfonic acid resin, phosphoric acid resin, carboxylic acid resin, and phenolic hydroxyl resin.

6. The method according to claim 5, characterized in that, The catalyst mentioned in S1 is a sulfonic acid resin.

7. The method according to claim 4, characterized in that, The etherification reaction in S1 is carried out at a temperature of 60–110 °C; and / or, The reaction pressure is 0.1~0.5 MPaG; and / or, The mass hourly space velocity is 0.2 to 6.0 h⁻¹.

8. The method according to claim 7, characterized in that, The etherification reaction in S1 is carried out at a temperature of 70-80℃; and / or, The reaction pressure is 0.1~0.2 MPaG.

9. The method according to claim 1, characterized in that, The feed molar ratio of meconaldehyde to methanol in S1 is 1:13 to 1:30; the feed molar ratio of meconaldehyde to water is 1:0.3 to 1:1; and the molar ratio of meconaldehyde to silanol is 20 to 200:

1.

10. The method according to claim 9, characterized in that, The feed liquid in S1 is fed at room temperature.

11. The method according to claim 1, characterized in that, The methyl metal reagent in S2 is selected from at least one of methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, dimethyl zinc, trimethyl aluminum, and methyl lithium.

12. The method according to claim 11, characterized in that, The methyl metal reagent in S2 is selected from methyl magnesium chloride and methyl magnesium bromide.

13. The method according to claim 11, characterized in that, The amount of the methyl metal reagent used is 80-150 mol of the molar amount of methoxycucurbitaldehyde.

14. The method according to claim 1 or 11, characterized in that, The reaction in S2 proceeds in the presence of an aprotic solvent.

15. The method according to claim 14, characterized in that, The aprotic solvent is selected from one or more of diethyl ether, propyl ether, isopropyl ether, butyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, and toluene.

16. The method according to claim 15, characterized in that, The aprotic solvent is tetrahydrofuran or diethyl ether.

17. The method according to claim 15, characterized in that, The amount of the aprotic solvent used is 1.5 to 4.0 times the mass of methoxycucurbitaldehyde.

18. The method according to claim 14, characterized in that, The reaction temperature for the S2 addition reaction is -20 to 50°C, and / or, The reaction pressure is atmospheric pressure, and the reaction time is 2 to 4 hours.

19. The method according to claim 18, characterized in that, The reaction temperature for the S2 addition reaction is 0~20℃.

20. The method according to claim 1, characterized in that, After the addition reaction is complete, the process also includes the step of adding a quencher to quench the reaction.

21. The method according to claim 20, characterized in that, The quenching agent is selected from any one of water, ammonium chloride aqueous solution, ammonium sulfate aqueous solution, ammonium phosphate aqueous solution, acetic acid aqueous solution, and dilute hydrochloric acid.

22. The method according to claim 21, characterized in that, The volume of the quenching agent added is 0.22 to 0.70 times the volume of the methyl metal reagent.

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