Synthesis method and application of nitrogen heterocyclic precursor aromatic compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method and application of an azacyclo precursor aromatic compound, the method takes substituted heterocyclic alcohol amine and a 2-phenethyl alcohol compound as raw materials, adopts a one-step method to directly synthesize a target product without separation, uses cheap iron, cobalt and manganese salt catalysts to replace noble metals, and reduces the cost; the reaction temperature is low, the reaction is normal pressure reaction, the reaction condition is milder, the operation is simpler and more convenient, the yield can reach 80% or above, and the method is very beneficial to actual industrial production; after the target product is added into the cigarette product, the compound slowly releases aroma components, and the sensory score is improved by 20% or above compared with that of commercially available spices.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method and application of a nitrogen heterocyclic latent aroma compound. Background Art

[0002] Nitrogen heterocyclic compounds have a unique aroma or aromatic taste. Many nitrogen heterocyclic compounds such as pyrrole, pyridine, pyrazine, etc. are present in tobacco aroma precursors. Although such substances are rarely found in various foods, they have a strong odor and a very low critical value; and give tobacco leaves a strong roasted aroma, which has a significant effect on enhancing and improving the flavor of tobacco, so they are considered to be tobacco flavors.

[0003] Pyrrole derivatives naturally exist in the fermentation process of microorganisms and the Maillard reaction. Most of these compounds have special aroma substances and are a large category of heterocyclic spices. Studies have shown that there are also some natural N-substituted pyrrole and acyl pyrrole derivatives in tobacco and smoke. These compounds are an important class of tobacco aroma components, which have the effects of increasing the unique aroma of tobacco, improving the aftertaste, and reducing irritation. However, its natural content is low and the extraction cost is high. The existing synthesis methods mostly use multi-step reactions (such as CN105837528A), which have problems such as low yield (<60%), high temperature and high pressure (>100°C) and complex purification steps. In addition, traditional spices (such as vanillin) are prone to increase the irritation of smoke. Therefore, there is an urgent need to develop efficient and mild synthesis processes and new latent aroma compounds.

[0004] Therefore, efficiently synthesized pyrrole derivatives are diluted and applied to tobacco to correct the flavor and enhance the aroma of cigarettes, thereby maintaining the inherent special style of tobacco products. Summary of the invention

[0005] The purpose of the present invention is to provide a synthesis method and application of nitrogen heterocyclic latent aroma compounds to solve the problems existing in the above-mentioned background technology.

[0006] To achieve the above objectives, this application is implemented through the following technical solutions:

[0007] A method for synthesizing a nitrogen heterocyclic latent aroma compound, wherein the structural formula of the nitrogen heterocyclic latent aroma compound is:

[0008] ,in, ,

[0009] , using the following steps:

[0010] S1. Under the protection of inert gas, add tetrahydrofuran, a reaction solvent, into a reactor, then add a heterocyclic alcohol amine compound, and stir evenly;

[0011] S2. After stirring evenly, add a metal catalyst and a base, and heat under reflux at 60-80°C for 3-5h;

[0012] S3, adding 2-phenylethanol compounds, continuing heating and reflux for 3-5 hours, after the reaction is completed, filtering, drying and recrystallizing to obtain nitrogen heterocyclic latent aroma compounds.

[0013] Furthermore, the heterocyclic alcohol amine compound is an alkyl or alkoxy substituted pyridinolamine.

[0014] Furthermore, the metal catalyst is one or more of ferrous chloride, ferrous acetate, cobalt dichloride or manganese dichloride.

[0015] Furthermore, the 2-phenylethanol compound is alkyl- or alkoxy-substituted 2-phenylethanol.

[0016] Furthermore, the molar ratio of the heterocyclic alcohol amine compound, the metal catalyst, the base and the 2-phenylethanol compound is 1: 0.05~0.10: 0.15~0.30: 1.0~1.2.

[0017] An application, use of the nitrogen heterocyclic latent aroma compound prepared by any of the above items in tobacco products.

[0018] Furthermore, the amount of the nitrogen heterocyclic latent aroma compound added to the tobacco product is 0.01%-0.1% of the weight of the tobacco.

[0019] The beneficial effects of the present invention are:

[0020] This technical solution directly adopts a one-step method to directly synthesize the target product without separation, and uses cheap iron, cobalt, and manganese salt catalysts instead of precious metals to reduce costs; the reaction temperature is low and it is a normal pressure reaction, the reaction conditions are milder, the operation is simpler, and the yield can reach more than 80%, which is very beneficial for actual industrial production; after adding the target product to the cigarette product, the compound slowly releases the aroma component, and the sensory score is improved by more than 20% compared with commercially available flavors. DETAILED DESCRIPTION

[0021] The technical solution of the present invention is described in detail below through examples. The following examples are merely exemplary and can only be used to explain and illustrate the technical solution of the present invention, but cannot be construed as limiting the technical solution of the present invention.

[0022] The structural formula of the nitrogen heterocyclic latent aroma compound involved in this application is:

[0023] ,in, ,

[0024] .

[0025] The synthetic route is:

[0026] ,in, ,

[0027] .

[0028] Example 1

[0029] Synthesis of 3-(1-(1-phenylethyl)pyrrolidin-2-yl)pyridine:

[0030] Under nitrogen protection, 200 mL of tetrahydrofuran was added as the reaction solvent to a dry reactor, and then 16.6 g (0.1 mol) of 4-amino-1-(pyridin-3-yl)butan-1-ol (2a) was added. After stirring, 1.3 g (0.01 mol) of ferrous chloride and 2.7 g (0.02 mol) of potassium carbonate were added. After heating and reflux at 70°C for 3 h, 12.2 g (0.1 mol) of 2-phenylethanol (3a) was added. The mixture was heated and refluxed for 3 h. After the reaction was completed, the reaction was stopped, filtered, dried and recrystallized to obtain 20 g (yield 80%) of a latent aromatic nitrogen heterocyclic compound 3-(1-(1-phenylethyl)pyrrolidin-2-yl)pyridine (1a).

[0031] Characterization data:

[0032] Melting point: 142-144℃, 1 H NMR (400 MHz; CDCl 3 ) 1.35 (3H, d), 1.62–1.72 (1H,m), 1.75–1.85 (1H, m), 1.85–1.97 (1H, m), 2.15–2.27 (1H, m), 2.63 (1H, dd), 3.05 (1H, td), 3.65–3.80 (2H, m), 7.10–7.25 (6H, m), 7.62 (1H, br d), 8.40 (1H, dd), 8.47 (1H, d).

[0033] Comparative Example 1

[0034] No ferrous chloride was added to the raw materials, and other reaction conditions were the same as those in Example 1.

[0035] As a result, the product yield was less than 20%, and the HPLC analysis results showed that a large amount of unreacted raw materials remained, indicating the necessity of adding a catalyst.

[0036] Example 2

[0037] Synthesis of 3-(1-(1-(p-tolyl)ethyl)pyrrolidin-2-yl)pyridine:

[0038] Raw materials and proportions: 4-amino-1-(pyridin-3-yl)butan-1-ol (16.6 g, 0.1 mol), cobalt dichloride (1.3 g, 0.01 mol), potassium tert-butoxide (2.7 g, 0.02 mol), 1-(p-tolyl)ethanol (13.6 g, 0.1 mol).

[0039] Steps: Same as Example 1, reaction temperature 80°C, time 5 hours, to obtain product 22.6 g (yield 85%).

[0040] Characterization data:

[0041] Melting point: 155-157°C; 13 C NMR (100 MHz, CDCl 3 ): δ 21.5 (methyl-C), 126.5-148.2 (aromatic ring-C).

[0042] Example 3

[0043] Halogenated substrate expansion (4-chlorophenylethanol):

[0044] Raw materials and ratio:

[0045] 4-Amino-1-(pyridin-3-yl)butan-1-ol (16.6 g, 0.1 mol), manganese dichloride (1.3 g, 0.01 mol), sodium carbonate (2.7 g, 0.02 mol), 1-(4-chlorophenyl)ethanol (15.1 g, 0.1 mol).

[0046] Procedure: Same as Example 1, react at 75°C for 4 hours to obtain 21.8 g of product (yield 83%).

[0047] Characterization data: Melting point: 138-140°C; HRMS (ESI+): m / z 369.1265 [M+H]⁺ (theoretical value 369.1268).

[0048] Example 4

[0049] Amplification experiment verifies industrial feasibility:

[0050] Raw materials and proportions (scaled up 10 times based on Example 1):

[0051] 4-Amino-1-(pyridin-3-yl)butan-1-ol (166 g, 1.0 mol), ferrous chloride (13 g, 0.1 mol), potassium carbonate (27 g, 0.2 mol), 2-phenylethanol (122 g, 1.0 mol).

[0052] Steps: Under nitrogen protection, the raw material was dissolved in 2 L of tetrahydrofuran, reacted at 70°C for 3 hours, and industrial-grade centrifugal purification was performed to obtain 198 g of the product (yield 79%).

[0053] Key indicators: Product purity: 97.8% (HPLC); Unit production capacity: 1.5 kg / batch (24-hour continuous production).

[0054] The product of Example 1 was added to shredded tobacco at a weight percentage of 0.05%, and a blind test was conducted by a professional smoking evaluation panel. The evaluation results are shown in Table 1.

[0055] Table 1

[0056]

[0057] The nitrogen heterocyclic latent aroma compounds prepared by the preparation method of the present application include by-products. In order to improve the purity of the nitrogen heterocyclic latent aroma compounds in the product, a purification process may also be included. Specifically, the nitrogen heterocyclic latent aroma compounds obtained after drying and recrystallization are dissolved in tetrahydrofuran again at -10-0°C, and then saturated brine is added (the nitrogen heterocyclic latent aroma compounds of this product can be dissolved in water, but when saturated brine is used, extraction separation can be adopted, and the removed saturated brine, through detection, basically does not contain the main product of the prepared nitrogen heterocyclic latent aroma compounds) and stirred and mixed, and then the saturated brine layer is removed after standing for 10-48 hours, and then the drying and recrystallization process is adopted again to obtain nitrogen heterocyclic latent aroma compounds with higher purity.

[0058] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing a nitrogen heterocyclic latent aroma compound, wherein the structural formula of the nitrogen heterocyclic latent aroma compound is: ,in, ， , characterized in that the following steps are adopted: S1. Under the protection of inert gas, add tetrahydrofuran, a reaction solvent, into a reactor, then add a heterocyclic alcohol amine compound, and stir evenly; S2. After stirring evenly, add a metal catalyst and a base, and heat under reflux at 60-80°C for 3-5h; S3, adding 2-phenylethanol compounds, continuing heating and reflux for 3-5 hours, after the reaction is completed, filtering, drying and recrystallizing to obtain nitrogen heterocyclic latent aroma compounds.

2. The method for synthesizing the nitrogen heterocyclic latent aroma compound according to claim 1, characterized in that: The heterocyclic alcohol amine compound is a pyridinolamine substituted with an alkyl group or an alkoxy group.

3. The method for synthesizing the nitrogen heterocyclic latent aroma compound according to claim 1, characterized in that: The metal catalyst is one or more of ferrous chloride, ferrous acetate, cobalt dichloride or manganese dichloride.

4. The method for synthesizing the nitrogen heterocyclic latent aroma compound according to claim 1, characterized in that: The 2-phenylethanol compound is 2-phenylethanol substituted with an alkyl group or an alkoxy group.

5. The method for synthesizing the nitrogen heterocyclic latent aroma compound according to claim 1, characterized in that: The molar ratio of the heterocyclic alcohol amine compound, the metal catalyst, the base and the 2-phenylethanol compound is 1: 0.05~0.10: 0.15~0.30: 1.0~1.

2.

6. An application, characterized in that: Use of the nitrogen heterocyclic latent aroma compound prepared according to any one of claims 1 to 5 in tobacco products.

7. The use according to claim 6, characterized in that: The amount of the nitrogen heterocyclic latent aroma compound added to the tobacco product is 0.01%-0.1% of the weight of the tobacco.

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