Method for synthesizing carveol hydrate by using 2, 3-epoxy pinane

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a method for synthesizing carveol hydrate by using 2, 3-epoxy pinane, which comprises the following steps: by using 2, 3-epoxy pinane as a raw material, adding deionized water in a solvent in the presence of organic phosphoric acid as a catalyst and a micro-channel reactor as reaction equipment, carrying out ring-opening rearrangement reaction on the 2, 3-epoxy pinane to obtain carveol hydrate. Under the combined action of the catalyst and the microchannel reactor, high-yield and high-purity carveol hydrate is obtained; the method is mild in reaction condition, simple and convenient to operate, capable of effectively avoiding violent heat release of epoxy ring opening and generated by-products, high in reaction efficiency and good in industrial application prospect, the product yield can reach 98%, and the content can reach 99%.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and relates to the synthesis of hydrated carvone, a pharmaceutical and fragrance intermediate. In particular, it relates to a method for the mild synthesis of hydrated carvone in a microchannel reactor using 2,3-epoxypine as a raw material and an organophosphate catalyst. Background Technology

[0002] Sobrerol, also known as carvone hydrate, has the molecular formula C1. 10 H 18 O2, belonging to the terpene diol class of compounds, is a mucolytic agent with expectorant and antiasthmatic effects, primarily used to treat bronchitis and asthma. Recent studies have discovered that this compound possesses pharmacological effects inducing tumor cell apoptosis, potentially making it a novel anticancer drug. Furthermore, this compound can serve as an important intermediate for flavorings (such as carvacrol and carvone). Its usage is continuously increasing, and its synthesis methods have therefore attracted considerable attention.

[0003] Currently, there are three main methods for synthesizing hydrated carvacrol. The most important and commonly used method is to use 2,3-epoxypine as a raw material and perform ring-opening in an aqueous phase via acid catalysis or RuCl3 catalysis. Tetrahedron 1998 54 (593-598) The disadvantages of this method are numerous side reactions, low chemical yield (<15%), and low optical purity of the product; another method is to use lipase catalysis to kinetically resolve the racemic mixture to obtain an optically pure product, but this method is not suitable for large-scale preparation. Tetrahedron Asymmetry , 1991, 2 (931-934). The third method uses readily available methyl 3,5-dihydroxy-4-methylbenzoate as a starting material to efficiently synthesize optically pure trans-(+)-hydrated pinol through a 7-step reaction (overall yield 27%). This method has few side reactions, is easy to operate, and has high chemical yield and optical purity (ee > 99%), but the reaction has drawbacks such as lengthy steps and low overall yield. Chemical Journal of Chinese Universities , 2004, 25 (1069-1072), which limited its further application in production. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing hydrated carvacrol from 2,3-epoxypinene. The present invention uses an organophosphate catalyst combined with continuous flow microchannel technology to synthesize hydrated carvacrol, which has the advantages of mild reaction conditions, chemical selectivity and high yield.

[0005] This invention is achieved through the following technical solution: A method for synthesizing hydrated carvacrol from 2,3-epoxypinene includes the following steps: Using 2,3-epoxypinene as a raw material, in a solvent, with organophosphoric acid as a catalyst, and a microchannel reactor as the reaction equipment, deionized water was added to induce a ring-opening rearrangement reaction of 2,3-epoxypinene. Under the combined action of the catalyst and the microchannel reactor, hydrated carvacrol was obtained in high yield and high purity. The organic phosphoric acid is selected from the following structures: .

[0006] The reaction equation is:

[0007] A further improvement to the present invention is as follows: The solvent is one or a mixture of two of toluene, anisole, methanol, ethanol, cyclohexane, 1,4-dioxane, tetrahydrofuran, or dichloroethane.

[0008] Furthermore, the molar ratio of the 2,3-epoxypinene to the organophosphoric acid catalyst is 10000:1 to 5.

[0009] Furthermore, the reaction temperature is 10–60°C.

[0010] Furthermore, the microchannel reactor is a continuous flow microreactor.

[0011] Furthermore, the 2,3-epoxypinene and the organophosphoric acid catalyst need to be dissolved in solvents separately, mixed at -25 to 0°C, and then transported to a microchannel reactor for reaction.

[0012] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides a novel method for synthesizing hydrated carvone. By utilizing the combined effect of an organophosphate catalyst and a continuous flow microreaction channel, the chemoselectivity of the ring-opening rearrangement of 2,3-epoxypine is improved, the adverse thermal effects of the ring-opening reaction are reduced, and a new route for obtaining hydrated carvone in high yield is provided. Attached Figure Description

[0013] Figure 1 This is a flow chart of the continuous flow microreactor device of the present invention. Detailed Implementation

[0014] The present invention will now be described in detail with reference to specific embodiments.

[0015] This invention provides a method for synthesizing hydrated carvacrol from 2,3-epoxypine, comprising the following steps: 2,3-Epoxypinene was dissolved in a solvent, and the organophosphate catalyst was also dissolved in the solvent to prepare a solution of a certain concentration. The 2,3-Epoxypinene solution and the catalyst solution were pumped separately into a continuous flow microchannel reactor. The reaction temperature was controlled. Under the action of the catalyst, 2,3-Epoxypinene underwent ring-opening rearrangement to form hydrated carvyl alcohol. The reaction product flowed out of the microchannel reactor along with the reaction solution. Gas chromatography analysis of the reaction solution showed that the starting material disappeared, indicating high reaction selectivity, and the reaction was terminated. After the reaction was completed, an alkaline solution was added to neutralize the alkalinity. The reaction solution was then distilled under reduced pressure to recover the solvent, and further filtered to obtain the hydrated carvyl alcohol product.

[0016] The catalyst used in this invention is an organophosphate with different acidity, including common organophosphates based on the BINOL and H8-BINOL skeletons, specifically selected from the following compounds:

[0017] Comparative Example 1

[0018] 2,3-Epoxypine (304 g, 2 mol) was dissolved in toluene (3000 mL) in a 10 L glass-jacketed reactor. Simultaneously, 600 mL of water was added to the reactor. A circulating chilled brine solution was circulated through the reactor jacket to maintain the temperature at 5–10 °C. Organophosphate catalyst I (70 mg, 0.2 mmol) was diluted with toluene (100 mL) to prepare a solution, which was then slowly added dropwise to the reactor. The temperature was maintained for 12 h. After the reaction, the reaction solution was neutralized with sodium carbonate aqueous solution, and the organic and aqueous phases were separated. The toluene was concentrated to obtain 265 g of crude hydrated carvone, with a yield of 78%. GC analysis showed the sample purity to be 80%.

[0019] Comparative Example 2 2,3-epoxypine (304 g, 2 mol) was diluted with toluene (15000 mL) to prepare solution A; p-toluenesulfonic acid (34 mg, 0.2 mmol) was diluted with toluene (2100 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After the reactor pipeline was flushed with toluene, it was fed through pump 1 and pump 2 respectively. Pump 1 delivers solution A (flow rate 15 mL / min), and pump 2 delivers solution B (flow rate 2.1 mL / min). A temperature control module maintains the micromixer at -15 to -10°C. After mixing, solutions A and B enter a PFR reactor (plug flow reactor, 316L material, 225 mL volume). Simultaneously, 600 mL of deionized water is pumped into the PFR reactor at a flow rate of 0.6 mL / min using pump 4. The reaction is carried out at 35°C for 3.5 minutes. After the reaction, the mixture enters a CSTR reactor (continuous stirred tank reactor, 50 L volume, internal temperature -10 to 5°C). At the same time, pump 3 injects quenching alkali at a flow rate of 8 mL / min for quenching. Finally, the product is extracted with toluene, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the toluene flushing system is switched on, and the entire system is cleaned using an online cleaning (CIP) procedure. The reaction yielded 289 g of hydrated carvacrol, with a yield of 85%, and the sample purity was 87% according to GC analysis.

[0020] Example 1 2,3-epoxypine (304 g, 2 mol) was diluted with toluene (15000 mL) to prepare solution A; organophosphoric acid catalyst I (70 mg, 0.2 mmol) was diluted with toluene (2100 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After the reactor pipeline was flushed with toluene, it was fed through pumps 1 and 2 respectively. Pump 1 delivers solution A (flow rate 15 mL / min), and pump 2 delivers solution B (flow rate 2.1 mL / min). A temperature control module maintains the micromixer at -15 to -10°C. After mixing, solutions A and B enter a PFR reactor (plug flow reactor, 316L material, 225 mL volume). Simultaneously, 600 mL of deionized water is pumped into the PFR reactor at a flow rate of 0.6 mL / min using pump 4. The reaction is carried out at 35°C for 3.5 minutes. After the reaction, the mixture enters a CSTR reactor (continuous stirred tank reactor, 50 L volume, internal temperature -10 to 5°C). At the same time, pump 3 injects quenching alkali at a flow rate of 8 mL / min for quenching. Finally, the product is extracted with toluene, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the toluene flushing system is switched on, and the entire system is cleaned using an online cleaning (CIP) procedure. The reaction yielded 323g of pure white carvone hydrate, with a yield of 95%, and GC analysis showed that the sample purity was 98%.

[0021] Example 2 2,3-epoxypine (304 g, 2 mol) was diluted with cyclohexane (20000 mL) to prepare solution A; organophosphate catalyst II (140 mg, 0.2 mmol) was diluted with cyclohexane (3000 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After the reactor pipeline was flushed with cyclohexane, it was fed through pumps 1 and 2 respectively. Pump 1 delivers solution A (flow rate 20 mL / min), and pump 2 delivers solution B (flow rate 3 mL / min). A temperature control module maintains the micromixer at -20 to -15°C. After mixing, solutions A and B enter a PFR reactor (316L material, 225 mL volume). Simultaneously, 600 mL of deionized water is pumped into the PFR reactor at a flow rate of 0.6 mL / min using pump 4. The reaction is carried out at 25°C for 5 minutes. After the reaction, the mixture enters a CSTR reactor (50 L volume, internal temperature -10 to 5°C), while quenching alkali is injected at a flow rate of 8 mL / min using pump 3. The product is finally collected using cyclohexane, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the cyclohexane flushing system is switched on, and the entire system is cleaned using an online cleaning (CIP) procedure. The reaction yields 326 g of pure white hydrated carvyl alcohol, with a yield of 96%, and GC analysis shows a sample purity of 99%.

[0022] Example 3 2,3-epoxypine (304 g, 2 mol) was diluted with methanol (10000 mL) to prepare solution A; organophosphate catalyst III (232 mg, 0.3 mmol) was diluted with methanol (1500 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After the reactor pipeline was flushed with methanol, it was fed through pumps 1 and 2 respectively. Pump 1 delivers solution A (flow rate 10 mL / min), and pump 2 delivers solution B (flow rate 1.5 mL / min). A temperature control module maintains the micromixer at -10 to -5°C. After mixing, solutions A and B enter a PFR reactor (316L material, 225 mL volume). Simultaneously, 600 mL of deionized water is pumped into the PFR reactor at a flow rate of 0.6 mL / min using pump 4. The reaction is carried out at 10°C for 3 minutes. After the reaction, the mixture enters a CSTR reactor (50 L volume, internal temperature -10 to 5°C), while quenching alkali is injected at a flow rate of 5 mL / min using pump 3. The product is then extracted with ethyl acetate, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the system is flushed with methanol, and a complete system cleaning process (CIP) is performed. The reaction yields 334 g of pure white carvone hydrate, with a yield of 98%, and GC analysis shows a sample purity of 97%.

[0023] Example 4 2,3-Epoxypine (304 g, 2 mol) was diluted with 1,4-dioxane (12000 mL) to prepare solution A; organophosphate catalyst IV (151 mg, 0.2 mmol) was diluted with 1,4-dioxane (1800 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After flushing the reactor pipeline with 1,4-dioxane, the feed was introduced through pumps 1 and 2, respectively. Pump 1 delivers solution A (flow rate 12 mL / min), and pump 2 delivers solution B (flow rate 1.8 mL / min). A temperature control module maintains the micromixer at -15 to -10°C. After mixing, solutions A and B enter the PFR reactor (316L material, 225 mL volume). Simultaneously, 600 mL of deionized water is pumped into the PFR reactor at a flow rate of 0.6 mL / min using pump 4. The reaction is carried out at 40°C for 1.5 minutes. After the reaction, the mixture enters the CSTR reactor (50 L volume, internal temperature -10 to 5°C). At the same time, quenching alkali is injected at a flow rate of 6 mL / min using pump 3. The product is finally extracted with ethyl acetate, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the 1,4-dioxane flushing system is switched on, and the entire system is cleaned using an online cleaning (CIP) procedure. The reaction yielded 327g of pure white carvone hydrate, with a yield of 96%, and GC analysis showed that the sample purity was 99%.

[0024] Example 5 2,3-epoxypine (304 g, 2 mol) was diluted with ethanol (15000 mL) to prepare solution A; organophosphate catalyst V (228 mg, 0.4 mmol) was diluted with ethanol (2000 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After flushing the reactor pipeline with ethanol, the feed was introduced through pumps 1 and 2, respectively. Pump 1 delivers solution A (flow rate 15 mL / min), and pump 2 delivers solution B (flow rate 2.0 mL / min). A temperature control module maintains the micromixer temperature between -5 and 0°C. After mixing, solutions A and B enter a PFR reactor (316L material, 225 mL volume). Simultaneously, 600 mL of deionized water is pumped into the PFR reactor at a flow rate of 0.6 mL / min using pump 4. The reaction is carried out at 30°C for 4 minutes. After the reaction, the mixture enters a CSTR reactor (50 L volume, internal temperature -10 to 5°C), while quenching alkali is injected at a flow rate of 4 mL / min using pump 3. The product is finally extracted with ethyl acetate, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the ethanol flushing system is switched on, and the entire system is cleaned using an online cleaning (CIP) procedure. The reaction yields 324 g of pure white carvone hydrate, with a yield of 95%, and GC analysis shows a sample purity of 96%.

[0025] Example 6 2,3-epoxypine (456 g, 3 mol) was diluted with anisole (20000 mL) to prepare solution A; organophosphate catalyst VI (524 mg, 0.6 mmol) was diluted with anisole (2500 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After flushing the reactor pipeline with anisole, the feed was introduced through pumps 1 and 2, respectively. Pump 1 delivers solution A (flow rate 20 mL / min), and pump 2 delivers solution B (flow rate 2.5 mL / min). A temperature control module maintains the micromixer at -20 to -15°C. After mixing, solutions A and B enter a PFR reactor (316L material, 225 mL volume). Simultaneously, 900 mL of deionized water is pumped into the PFR reactor at a flow rate of 0.9 mL / min using pump 4. The reaction is carried out at 35°C for 2 minutes. After the reaction, the mixture enters a CSTR reactor (50 L volume, internal temperature -10 to 5°C), while quenching alkali is injected at a flow rate of 8 mL / min using pump 3. The product is then extracted with anisole, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the anisole flushing system is switched on, and the entire system is cleaned using an online cleaning (CIP) procedure. The reaction yields 486 g of pure, off-white carvone hydrate, with a yield of 95%, and GC analysis confirms a sample purity of 95%.

[0026] Example 7 2,3-Epoxypine (456 g, 3 mol) was diluted with toluene:anisole at a ratio of 1:1 (20000 mL) to prepare solution A; organophosphate catalyst VI (524 mg, 0.6 mmol) was diluted with toluene:anisole at a ratio of 1:1 (2500 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After flushing the reactor pipeline with the toluene:anisole 1:1 mixture, the feed was introduced through pumps 1 and 2, respectively. Pump 1 delivers solution A (flow rate 20 mL / min), and pump 2 delivers solution B (flow rate 2.5 mL / min). A temperature control module maintains the micromixer at -20 to -15°C. After mixing, solutions A and B enter the PFR reactor (316L material, 225 mL volume). Simultaneously, 900 mL of deionized water is pumped into the PFR reactor at a flow rate of 0.9 mL / min using pump 4. The reaction is carried out at 35°C for 2 minutes. After the reaction, the mixture enters the CSTR reactor (50 L volume, internal temperature -10 to 5°C). At the same time, quenching alkali is injected by pump 3 at a flow rate of 8 mL / min. Finally, the product is extracted with toluene, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the piping system is flushed with a 1:1 toluene:anisole mixture, and the entire system is cleaned via a continuous in-system cleaning (CIP) procedure. The reaction yielded 496g of pure white carvacrol hydrate, with a yield of 97%, and GC analysis showed that the sample purity was 98%.

[0027] Example 8 2,3-epoxypine (456 g, 3 mol) was diluted with toluene:methanol = 4:1 (15000 mL) to prepare solution A; organophosphate catalyst I (104 mg, 0.3 mmol) was diluted with toluene:methanol = 4:1 (2000 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After flushing the reactor pipeline with the toluene:methanol = 4:1 mixture, the feed was introduced through pumps 1 and 2, respectively. Pump 1 delivers solution A (flow rate 15 mL / min), and pump 2 delivers solution B (flow rate 2.0 mL / min). A temperature control module maintains the micromixer at -25 to -20°C. After mixing, solutions A and B enter the PFR reactor (316L material, 225 mL volume). Simultaneously, 900 mL of deionized water is pumped into the PFR reactor at a flow rate of 0.9 mL / min using pump 4. The reaction is carried out at 30°C for 3 minutes. After the reaction, the mixture enters the CSTR reactor (50 L volume, internal temperature -15 to -5°C). At the same time, quenching alkali is injected at a flow rate of 5 mL / min using pump 3. The product is finally extracted with toluene, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the piping system is flushed with a toluene:methanol = 4:1 mixture, and the entire system is cleaned using an online cleaning (CIP) procedure. The reaction yielded 496g of pure white hydrated carvyl alcohol, with a yield of 97%. GC analysis showed that the sample purity was 97%.

[0028] Example 9 2,3-Epoxypine (608 g, 4 mol) was diluted with 1,4-dioxane:ethanol = 5:1 (24000 mL) to prepare solution A; organophosphate catalyst IV (301 mg, 0.4 mmol) was diluted with 1,4-dioxane:ethanol = 5:1 (2400 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After flushing the reactor pipeline with the 1,4-dioxane:ethanol = 5:1 mixture, the feed was introduced through pumps 1 and 2, respectively. Pump 1 delivers solution A (flow rate 12 mL / min), and pump 2 delivers solution B (flow rate 1.2 mL / min). A temperature control module maintains the micromixer at -20 to -15°C. After mixing, solutions A and B enter the PFR reactor (316L material, 225 mL volume). Simultaneously, 1200 mL of deionized water is pumped into the PFR reactor at a flow rate of 0.6 mL / min using pump 4. The reaction is carried out at 35°C for 5 minutes. After the reaction, the mixture enters the CSTR reactor (50 L volume, internal temperature -5 to 0°C), while quenching alkali is injected at a flow rate of 6 mL / min using pump 3. The product is finally extracted with ethyl acetate, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the piping system is flushed with a 5:1 mixture of 1,4-dioxane and ethanol, and the entire system is cleaned using an online cleaning (CIP) procedure. The reaction yielded 648g of pure, grayish-white carvacrol hydrate, with a yield of 95%. GC analysis showed the sample purity to be 95%.

[0029] Example 10 2,3-Epoxypine (608 g, 4 mol) was diluted with toluene:anisole:methanol = 2:2:1 (25000 mL) to prepare solution A; organophosphate catalyst VI (524 mg, 0.6 mmol) was diluted with toluene:anisole:methanol = 2:2:1 (2500 mL) to prepare solution B. A one-way valve was installed before the reactor unit to prevent backflow. After flushing the reactor pipeline with the toluene:anisole:methanol = 2:2:1 mixture, the feed was introduced through pumps 1 and 2 respectively. Pump 1 delivers solution A (flow rate 25 mL / min), and pump 2 delivers solution B (flow rate 2.5 mL / min). A temperature control module maintains the micromixer at -20 to -15°C. After mixing, solutions A and B enter the PFR reactor (316L material, 225 mL volume). Simultaneously, 1200 mL of deionized water is pumped into the PFR reactor at a flow rate of 1.2 mL / min using pump 4. The reaction is carried out at 50°C for 1.5 minutes. After the reaction, the mixture enters the CSTR reactor (50 L volume, internal temperature -10 to -5°C), while quenching alkali is injected at a flow rate of 10 mL / min using pump 3. The product is finally extracted with toluene, and the flow rates and ratios of solutions A and B are adjusted via an analytical feedback system. Finally, the piping system is flushed with a toluene:anisole:methanol mixture of 2:2:1, and the entire system is cleaned using an online cleaning (CIP) procedure. The reaction yielded 668g of pure white hydrated carvyl alcohol, with a yield of 98%, and GC analysis showed that the sample purity was 98%.

[0030] The above description of the embodiments is only for illustrating the technical concept and features of the present invention. Its purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. Those skilled in the art can obviously easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative effort. Therefore, the above embodiments should not be used to limit the scope of protection of the present invention. All improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for synthesizing hydrated carvacrol from 2,3-epoxypinene, characterized in that, The process includes the following steps: using 2,3-epoxypinene as a raw material, in a solvent, with organic phosphoric acid as a catalyst, a microchannel reactor as the reaction equipment, and deionized water added, 2,3-epoxypinene undergoes a ring-opening rearrangement reaction to obtain hydrated carvacrol. The organic phosphoric acid is selected from the following structures: 。 2. The method for synthesizing hydrated carvacrol from 2,3-epoxypine as described in claim 1, characterized in that: The solvent is one or a mixture of two of toluene, anisole, methanol, ethanol, cyclohexane, 1,4-dioxane, tetrahydrofuran, or dichloroethane.

3. The method for synthesizing hydrated carvacrol from 2,3-epoxypine as described in claim 1, characterized in that: The molar ratio of 2,3-epoxypine to the organophosphoric acid catalyst is 10000:1-5.

4. The method for synthesizing hydrated carvacrol from 2,3-epoxypine as described in claim 1, characterized in that: The reaction temperature is 10–60°C.

5. The method for synthesizing hydrated carvone from 2,3-epoxypine as described in claim 1, characterized in that: The microchannel reactor is a continuous flow microreactor.

6. The method for synthesizing hydrated carvone from 2,3-epoxypine as described in claim 1, characterized in that: The 2,3-epoxypinene and the organophosphate catalyst need to be dissolved in solvents separately, mixed at -25 ~ 0℃, and then transported to a microchannel reactor for reaction.

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