A preparation method of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran

Abstract

The invention discloses a preparation method of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran, which belongs to the field of organic synthesis technology. The present invention uses 2-hexenal as raw material, first undergoes addition reaction with hydrogen chloride, and then replaces and prepares Bunte salt with sodium thiosulfate in the presence of a phase catalyst. The last pot method is hydrolyzed under acidic conditions and directly condensed with 2-hexenal to form a ring to obtain 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran. The raw materials used in this route are cheap and easy to obtain, have high safety, are convenient for industrial production, have a high yield, can reach 89%, and are suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] 3-Formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran has a strong, fruity, leafy, minty, and uniquely tropical aroma. It is widely used in food, chewing gum, perfume, cosmetics, oral, and pharmaceutical products for flavoring and aromatherapy. Its synthesis is relatively rare, primarily based on two patents.

[0004] Patent EP3025591A1 discloses the use of 3-acetylthio-1-hexanal in the presence of sodium methoxide for the cyclization synthesis of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran. The raw material in this synthesis route is thioacetic acid, which is relatively expensive, and column chromatography purification is required, resulting in a complex processing process.

[0005] Patent US4629799A discloses the synthesis of 3-formyl-5,6-dihydro-2,6-dimethyl-2H-thiopyran by condensing hydrogen sulfide with enal. This synthesis method can be used to prepare 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran according to the description. However, this synthesis method requires the use of highly toxic hydrogen sulfide gas, which poses a high safety risk.

[0006] Therefore, it is necessary to develop a new synthetic route for 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran, starting from low-cost raw materials, to simply, safely and efficiently synthesize 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran. Summary of the Invention

[0007] In order to address the deficiencies of the prior art, the present invention aims to provide a method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran. The method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran provided by the present invention has the advantages of cheap and readily available raw materials, high safety, and high yield.

[0008] In order to achieve the above object, the technical solution of the present invention is:

[0009] In a first aspect of the present invention, a method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran is provided, comprising:

[0010] 3-Chloro-1-hexanal reacts with sodium thiosulfate to obtain an intermediate;

[0011] The intermediate reacts with 2-hexenal to give 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran;

[0012] The structure of the intermediate is:

[0013]

[0014] The synthetic route of the present invention is as follows:

[0015]

[0016] In some embodiments of the present invention, the molar ratio of 3-chloro-1-hexanal, sodium thiosulfate and 2-hexenal is 1:(1-1.5):(1-1.5).

[0017] In some embodiments of the present invention, the preparation method comprises:

[0018] Under the catalysis of a phase catalyst, 3-chloro-1-hexanal reacts with sodium thiosulfate to obtain an intermediate;

[0019] The intermediate is hydrolyzed under acidic conditions and then reacted with 2-hexenal to obtain 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran.

[0020] In some embodiments of the present invention, the intermediate can be isolated or not before participating in the reaction with 2-hexenal.

[0021] In some embodiments of the present invention, the phase catalyst is selected from one of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, polyethylene glycol 2000 (PEG2000) or cyclodextrin, preferably TBAB, with high yield.

[0022] In some embodiments of the present invention, the amount of the catalyst is 1-5% of the amount of 3-chloro-1-hexanal, specifically 1%, 2%, 3%, 4%, 5%, etc., preferably 3%.

[0023] In some embodiments of the present invention, the acidic condition is a pH of the reaction system of 1-2.

[0024] In some embodiments of the present invention, the preparation method further comprises the step of separating and purifying the intermediate after the reaction with 2-hexenal to obtain 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran;

[0025] The separation and purification method comprises the following steps: after the reaction of the intermediate and 2-hexenal is completed, dichloromethane is added to the reaction system for liquid-liquid extraction, the organic phase is collected, washed, the solvent is removed, and distilled.

[0026] In some embodiments of the present invention, the preparation method further comprises the following steps:

[0027] 3-Chloro-1-hexanal is obtained by reacting 2-hexenal with hydrogen chloride.

[0028] In some embodiments of the present invention, the molar ratio of 2-hexenal to hydrogen chloride is 1:(1-1.5).

[0029] The beneficial effects of the present invention are:

[0030] The present invention provides a novel method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran. Using 2-hexenal as a raw material, the raw material is first subjected to an addition reaction with hydrogen chloride, followed by substitution with sodium thiosulfate in the presence of a phase catalyst to prepare a Bunte salt. Finally, the product is hydrolyzed under acidic conditions and then directly condensed with 2-hexenal to form a ring, thereby obtaining 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran. This route uses inexpensive and readily available raw materials, is highly safe to use, is convenient for industrial production, and has a high yield of up to 89%, making it suitable for large-scale industrial production. DETAILED DESCRIPTION

[0031] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0032] Example 1

[0033] A method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran, the synthetic route is as follows:

[0034]

[0035] The specific method includes the following steps:

[0036] (1) In a 500 mL three-necked flask equipped with a thermometer and a reflux condenser, 250 g of dichloromethane and 147 g (1.5 mol) of 2-hexenal were added, accompanied by deep cooling, and the reaction temperature was controlled at 15-20°C. 60 g (1.65 mol) of hydrogen chloride gas was introduced. After the addition was completed, the reaction was stirred for 2 h. The solvent was removed to obtain 196 g of 3-chloro-1-hexanal intermediate with a purity of 97.5% and a yield of 96%, which could be directly used in the next synthesis.

[0037] (2) In a 1000 mL three-necked flask, add 150 g of water, 20 g of ethanol, 100 g (0.74 mol) of the intermediate 3-chloro-1-hexanal, and then add 7.2 g (0.03 eq) of the phase transfer catalyst TBAB. Control the kettle temperature at 42-46 ° C and add 430 g of 30% (0.82 mol) of sodium thiosulfate aqueous solution, after completion of the dropwise addition, stirring and reacting for 4 h; 115 g (0.82 mol) of 2-hexenal was added dropwise, and 32% hydrochloric acid was continued to be added dropwise to adjust the pH of the reaction solution to 1-2. After completion of the dropwise addition, the reaction was kept at 42-46 ° C for 3 h, cooled to room temperature, extracted twice with 300 g of dichloromethane, and then washed once with 100 g of saturated sodium bicarbonate aqueous solution, desolventized to obtain 161.6 g of a crude product, which was distilled and collected at 1 mmHg and 105-108 ° C to obtain 146.1 g of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran with a purity of 99.2% and a yield of 93%.

[0038] H NMR

[0039] 1 H NMR (CDCl3, 400MHz): 9.32 (s, 1H), 6.79 (dd, 1H, J = 5.3, 2.8Hz), 3.51 (m, 1H), 2.92-3.05 (m, 1H), 2. 61-2.75(m,1H), 2.22-2.38(m,1H), 1.35-1.7(6m,8H), 0.95(t,3H,J=7.1Hz), 0.93(t3H,J=6.9Hz).

[0040] Example 2

[0041] A method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran comprises the following steps:

[0042] (1) In a 500 mL three-necked flask equipped with a thermometer and a reflux condenser, 250 g of dichloromethane and 147 g (1.5 mol) of 2-hexenal were added, accompanied by deep cooling, and the reaction temperature was controlled at 15-20°C. 54.5 g (1.5 mol) of hydrogen chloride gas was introduced. After the addition was completed, the reaction was stirred for 2 h. The solvent was removed to obtain 179 g of 3-chloro-1-hexanal intermediate with a purity of 95.2% and a yield of 85.6%, which could be directly used in the next synthesis.

[0043] (2) In a 1000 mL three-necked flask, 150 g of water, 20 g of ethanol, 100 g (0.74 mol) of the intermediate 3-chloro-1-hexanal were added, and then 7.2 g (0.03 eq) of the phase transfer catalyst TBAB was added. The kettle temperature was controlled at 42-46° C., and 38830% (0.74 mol) of sodium thiosulfate aqueous solution was added dropwise. After the addition was complete, the reaction was continued with stirring for 4 h. 104 g (0.74 mol) of 2-hexenal was added dropwise, and 32% of salt was continued to be added dropwise. Acid, adjust the pH of the reaction solution to 1-2, after the addition is complete, keep the reaction at 42-46 ° C for 3h, cool to room temperature, extract twice with 300g of dichloromethane, wash once with 100g of saturated sodium bicarbonate aqueous solution, desolvate to obtain 161.6g of crude product, distill, collect the fraction at 105-108 ° C under 1mmHg, and obtain 131g of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran with a purity of 99.1% and a yield of 83.4%.

[0044] The H NMR spectrum of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran obtained in Example 2 was consistent with that in Example 1.

[0045] Example 3

[0046] A method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran comprises the following steps:

[0047] (1) In a 500 mL three-necked flask equipped with a thermometer and a reflux condenser, 250 g of dichloromethane and 147 g (1.5 mol) of 2-hexenal were added, accompanied by deep cooling, and the reaction temperature was controlled at 15-20°C. 82 g (2.25 mol) of hydrogen chloride gas was introduced. After the addition was completed, the reaction was stirred for 2 h. The solvent was removed to obtain 188 g of 3-chloro-1-hexanal intermediate with a purity of 94.6% and a yield of 89.3%, which could be directly used in the next synthesis.

[0048] (2) In a 1000 mL three-necked flask, add 150 g of water, 20 g of ethanol, 100 g (0.74 mol) of the intermediate 3-chloro-1-hexanal, and then add 7.2 g (0.03 eq) of the phase transfer catalyst TBAB. Control the kettle temperature at 42-46 ° C and add 582 g of 30% (1.11 mol) of sodium thiosulfate aqueous solution, after completion of the dropwise addition, stirring and reacting for 4 h; 155 g (1.11 mol) of 2-hexenal was added dropwise, and 32% hydrochloric acid was continued to be added dropwise to adjust the pH of the reaction solution to 1-2. After completion of the dropwise addition, the reaction was kept warm at 42-46 ° C for 3 h, cooled to room temperature, extracted twice with 300 g of dichloromethane, and then washed once with 100 g of saturated sodium bicarbonate aqueous solution, desolventized to obtain 161.6 g of a crude product, which was distilled and collected at 1 mmHg and 105-108 ° C to obtain 141 g of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran with a purity of 99.1% and a yield of 89.8%.

[0049] The H NMR spectrum of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran obtained in Example 3 was consistent with that in Example 1.

[0050] Example 4

[0051] A method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran was described, which differed from Example 1 in that TEBA was used as the phase transfer catalyst, and the remaining steps were the same as those in Example 1. Finally, 139 g of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran was obtained with a purity of 99.1% and a yield of 88.5%.

[0052] The H NMR spectrum of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran obtained in Example 4 was consistent with that in Example 1.

[0053] Example 5

[0054] A method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran was disclosed, which differed from Example 1 in that tetrabutylammonium chloride was used as the phase transfer catalyst, and the remaining steps were the same as those in Example 1. Finally, 143 g of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran was obtained with a purity of 99.2% and a yield of 91.1%.

[0055] The H NMR spectrum of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran obtained in Example 5 was consistent with that in Example 1.

[0056] Example 6

[0057] A method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran was described. The method differed from Example 1 in that tetrabutylammonium hydrogen sulfate was used as the phase transfer catalyst, and the remaining steps were the same as those in Example 1. Finally, 135 g of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran was obtained with a purity of 99.0% and a yield of 86.0%.

[0058] The H NMR spectrum of 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran obtained in Example 6 was consistent with that in Example 1.

[0059] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A method for preparing 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran, characterized in that: include: Under the catalysis of phase transfer catalyst, 3-chloro-1-hexanal reacts with sodium thiosulfate to obtain an intermediate; The intermediate is hydrolyzed under acidic conditions and reacted with 2-hexenal to obtain 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran; The structure of the intermediate is: The intermediate is not isolated; The phase transfer catalyst is selected from one of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate; The acidic condition is that the pH of the reaction system is 1-2.

2. The preparation method according to claim 1, wherein The molar ratio of 3-chloro-1-hexanal, sodium thiosulfate and 2-hexenal is 1:(1-1.5):(1-1.5).

3. The preparation method according to claim 1, wherein The amount of the catalyst is 1-5% of the amount of 3-chloro-1-hexanal.

4. The preparation method according to claim 1, wherein The preparation method further comprises the step of separating and purifying after the reaction is completed to obtain 3-formyl-5,6-dihydro-2,6-dipropyl-2H-thiopyran; The separation and purification method comprises the following steps: after the reaction is completed, adding dichloromethane to the reaction system for liquid-liquid extraction, collecting the organic phase, washing, removing the solvent, and rectifying.

5. The preparation method according to any one of claims 1 to 4, characterized in that The preparation method further comprises the following steps: 3-Chloro-1-hexanal is obtained by reacting 2-hexenal with hydrogen chloride.

6. The preparation method according to claim 5, wherein The molar ratio of 2-hexenal to hydrogen chloride is 1:(1-1.5).

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