Synthesis method and application of azacycloketone precursor aroma compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method and application of an azacycloketone precursor aromatic compound, the method takes substituted benzyl alcohol as a raw material, under the synergistic effect of a metal catalyst, a ligand and alkali, the substituted benzyl alcohol reacts with carbon dioxide to generate an intermediate, then the intermediate directly reacts with azacycloalkylol amine without separation, and the azacycloketone precursor aromatic compound is obtained. Synthesizing a target product by a one-step method. Normal-pressure CO2 and 50-80 DEG C low-temperature reflux are adopted, reaction conditions are mild, and dependence of high temperature and high pressure on equipment is avoided; the yield of the target product reaches more than 80%, byproducts are few, and the purity of the product is more than 98% (HPLC); reaction raw materials are cheap and easy to obtain, operation is simple, and complex post-treatment is not needed; the obtained compound can significantly improve the baking flavor of tobacco products, reduce the irritation, improve the sensory evaluation score by 20-30%, and have significant application effects.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method of an azacyclic ketone latent aroma compound and application thereof. 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 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, their natural content is low and the extraction cost is high. Existing synthesis methods mostly use multi-step reactions, 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. Summary of the invention

[0004] The purpose of the present invention is to provide a method for synthesizing an azacyclic ketone latent aroma compound and its application, by metal catalyzing CO 2 The synergistic effect of the insertion reaction and the nitrogen heterocyclic amine realizes the one-step efficient synthesis of nitrogen heterocyclic ketone latent aroma compounds to solve the problems existing in the above-mentioned background technology.

[0005] To achieve the above objectives, this application is implemented through the following technical solutions:

[0006] An efficient synthesis method of an azacyclic ketone latent aroma compound, the structural formula of the azacyclic ketone latent aroma compound is:

[0007] , where R 1 =H, or (o,m,p)-CH 3 , or (o,m,p)-OCH 3 Alkyl or alkoxy, R 2 =H, or (o,m,p)-CH 3 , or (o,m,p)-OCH 3 Alkyl or alkoxy, using the following steps:

[0008] S1. Under nitrogen protection, add tetrahydrofuran, a reaction solvent, into a dry reactor, then add a substituted benzyl alcohol compound, and stir evenly;

[0009] S2, after stirring evenly, add metal catalyst, ligand and base, and introduce 1 atm CO 2 , reflux at 50-80°C for 3-5 h;

[0010] S3, add the azoheterocyclic alcohol amine compound, and continue heating under reflux for 3-5h;

[0011] S4. After the reaction is completed, the nitrogen heterocyclic ketone latent aroma compound is obtained by filtering, drying and recrystallization.

[0012] Furthermore, the substituted benzyl alcohol compound is 4-methoxybenzyl alcohol, 3-ethylbenzyl alcohol or 2,4-dimethoxybenzyl alcohol.

[0013] Furthermore, the azacyclic alcohol amine is 4-amino-1-(pyridin-3-yl)butan-1-ol or 5-amino-1-(pyrimidin-2-yl)pentan-1-ol.

[0014] Furthermore, the metal catalyst is palladium acetate, palladium chloride, iridium trichloride or rhodium trichloride.

[0015] Furthermore, the ligand is triphenylphosphine, tricyclohexylphosphine, 1,2-bis(diphenylphosphine)ethane, or 1,3-bis(diphenylphosphine)propane.

[0016] Furthermore, the base is cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium carbonate or sodium tert-butoxide.

[0017] Furthermore, the molar ratio of the substituted benzyl alcohol compound, the metal catalyst, the ligand, the base and the nitrogen heterocyclic alcohol amine compound is 1: 0.01~0.02: 0.1~0.2: 0.2~0.4: 0.8~0.9.

[0018] An application, use of the nitrogen heterocyclic ketone latent aroma compound prepared by any of the above items in tobacco products.

[0019] Furthermore, the amount of the nitrogen heterocyclic ketone latent aroma compound added is 0.01%-0.1% of the weight of the tobacco.

[0020] The beneficial effects of the present invention are:

[0021] 1. In the synthesis process of this technical solution, CO 2 It can replace traditional highly toxic reagents (such as phosgene) and meet environmental protection requirements.

[0022] 2. This technical solution significantly improves the reaction rate and selectivity by optimizing the catalyst system and using a combination of palladium / iridium catalyst and diphosphine ligand.

[0023] 3. The nitrogen heterocyclic ketone latent aroma compound of the present application slowly releases pyrrole aroma components when burned, and the sensory score is improved by more than 20% compared with commercially available fragrances. DETAILED DESCRIPTION

[0024] 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.

[0025] The structural formula of the azacyclic ketone latent aroma compound involved in this application is:

[0026] , where R 1 =H, or (o,m,p)-CH 3 , or (o,m,p)-OCH 3 Alkyl or alkoxy, R 2 =H, or (o,m,p)-CH 3 , or (o,m,p)-OCH 3 Alkyl or alkoxy.

[0027] The synthetic route is:

[0028] , where R 1 =H, or (o,m,p)-CH 3 , or (o,m,p)-OCH 3 Alkyl or alkoxy, R 2 =H, or (o,m,p)-CH 3 , or (o,m,p)-OCH 3 Alkyl or alkoxy.

[0029] Example 1

[0030] Synthesis of 2-phenyl-1-(2-(pyridin-3-yl)pyrrolidin-1-yl)ethanone:

[0031] Materials and ratio: 4-methoxybenzyl alcohol (10.8 g, 0.1 mol), palladium acetate (0.22 g, 0.001 mol), triphenylphosphine (2.6 g, 0.01 mol), cesium carbonate (4.4 g, 0.03 mol), CO 2 (1 atm), 4-amino-1-(pyridin-3-yl)butan-1-ol (13.3 g, 0.09 mol).

[0032] Steps: Under nitrogen protection, the raw material was dissolved in 200 mL of tetrahydrofuran and refluxed at 60°C for 3 hours; after adding azocycloamine, the reaction was continued for 3 hours, and 17.4 g of white crystals (yield 82%) were obtained after cooling, filtering and recrystallization from ethanol.

[0033] Characterization data: melting point: 128-130℃; HRMS (ESI+): m / z 335.1752 [M+H]⁺ (theoretical value 335.1756); ¹H NMR (400 MHz, CDCl 3 ): δ 8.65-6.95 (aromatic ring and pyridine hydrogen), 4.87 (t, J=9.0 Hz, 1H), 3.82-3.41 (pyrrolidine hydrogen), 2.40-1.78 (alkyl chain hydrogen).

[0034] Comparative Example 1

[0035] Reaction without ligand:

[0036] Materials and conditions: Same as Example 1, omitting triphenylphosphine.

[0037] Results: The product yield dropped to 45%. HPLC showed that the purity of the main product was only 58%, and the by-product (unreacted carboxylic acid intermediate) accounted for 42%, proving the key role of the ligand in the reaction selectivity.

[0038] Example 2

[0039] Synthesis of 2-(3-ethylphenyl)-1-(2-(pyrimidin-2-yl)pyrrolidin-1-yl)ethanone:

[0040] Raw materials and proportions: 3-ethylbenzyl alcohol (12.2 g, 0.1 mol), iridium trichloride (0.30 g, 0.001 mol), 1,2-bis(diphenylphosphine)ethane (3.8 g, 0.02 mol), potassium tert-butoxide (4.5 g, 0.04 mol), 5-amino-1-(pyrimidin-2-yl)pentan-1-ol (15.1 g, 0.09 mol).

[0041] Procedure: Same as Example 1, reaction temperature 70°C, time 5 hours, to obtain product 19.1 g (yield 85%).

[0042] Characterization data: Melting point: 142-144°C; ¹³C NMR (100 MHz, CDCl 3 ): δ 172.3 (C=O), 158.2 (pyrimidine-C), and the remaining peaks were consistent with the target structure.

[0043] Example 3

[0044] Synthesis of 2-(4-chlorophenyl)-1-(2-(pyridin-3-yl)pyrrolidin-1-yl)ethanone:

[0045] Raw materials and ratio: 4-chlorobenzyl alcohol (14.3 g, 0.1 mol), palladium chloride (0.18 g, 0.001 mol), 1,2-bis(diphenylphosphine)ethane (3.8 g, 0.02 mol), potassium carbonate (5.5 g, 0.04 mol), CO 2 (1 atm), 4-amino-1-(pyridin-3-yl)butan-1-ol (13.3 g, 0.09 mol).

[0046] Steps: Under nitrogen protection, the raw material was dissolved in 200 mL of tetrahydrofuran and refluxed at 65°C for 4 hours; after adding azocycloamine, the reaction was continued for 4 hours, and 18.9 g of a light yellow solid was obtained by recrystallization from ethanol (yield 83%).

[0047] Characterization data: melting point: 135-137 ° C; HRMS (ESI+): m / z 369.1265 [M+H]⁺ (theoretical value 369.1268); ¹H NMR (400 MHz, CDCl 3 ): δ 8.62-7.08 (aromatic ring and pyridine hydrogen), 4.85 (t, J=9.0 Hz, 1H), 3.80-3.45 (pyrrolidine hydrogen), 2.38-1.75 (alkyl chain hydrogen).

[0048] Example 4

[0049] Synthesis under rhodium trichloride catalytic system:

[0050] Raw materials and ratio: 2,4-dimethoxybenzyl alcohol (16.8 g, 0.1 mol), rhodium trichloride (0.26 g, 0.001 mol), tricyclohexylphosphine (2.7 g, 0.01 mol), sodium tert-butoxide (3.8 g, 0.03 mol), CO 2 (1 atm), 5-amino-1-(pyrimidin-2-yl)pentan-1-ol (15.1 g, 0.09 mol).

[0051] Procedure: Same as Example 1, reaction temperature 75°C, time 5 hours, to obtain product 20.2 g (yield 81%).

[0052] Characterization data: Melting point: 155-157°C; ¹³C NMR (100 MHz, CDCl 3 ): δ 171.8 (C=O), 156.9 (pyrimidine-C), and the remaining peaks were consistent with the target structure.

[0053] Example 5

[0054] Effects of different bases on the reaction:

[0055] Raw materials and ratio: 4-methoxybenzyl alcohol (10.8 g, 0.1 mol), palladium acetate (0.22 g, 0.001 mol), triphenylphosphine (2.6 g, 0.01 mol), potassium tert-butoxide (4.5 g, 0.04 mol), CO 2 (1 atm), 4-amino-1-(pyridin-3-yl)butan-1-ol (13.3 g, 0.09 mol).

[0056] Steps: Same as Example 1, reaction temperature 60°C, time 3 hours, to obtain 16.8 g of product (yield 79%).

[0057] Conclusion: After potassium tert-butoxide replaced cesium carbonate, the yield decreased slightly (82%→79%), but the reaction time was shortened by 0.5 h, indicating that the alkalinity strength affects the reaction kinetics.

[0058] Example 6

[0059] Amplification experiment verifies industrial feasibility:

[0060] Raw materials and proportions (10 times the scale of Example 1): 4-methoxybenzyl alcohol (108 g, 1.0 mol), palladium acetate (2.2 g, 0.01 mol), triphenylphosphine (26 g, 0.1 mol), cesium carbonate (44 g, 0.3 mol), CO 2 (1 atm), 4-amino-1-(pyridin-3-yl)butan-1-ol (133 g, 0.9 mol).

[0061] Steps: Under nitrogen protection, the raw material was dissolved in 2 L of tetrahydrofuran and refluxed at 60°C for 3 hours; after adding amine, the reaction was continued for 3 hours, separated by an industrial-grade centrifuge and recrystallized from ethanol to obtain 172 g of a white solid (yield 80%).

[0062] Key indicators: Product purity: 97.5% (HPLC); unit time capacity: 1.2 kg / batch (24-hour continuous production simulation).

[0063] Application Example 1

[0064] Evaluation of tobacco flavoring effect:

[0065] Method: The product of Example 1 was added to shredded tobacco at a rate of 0.05%, and a blind test was conducted by a professional smoking evaluation panel of 10 people, with vanillin as a control.

[0066] Evaluation criteria: roasted aroma intensity (0-10 points), irritation (0-10 points, the lower the score, the better), and comprehensive score. The results are shown in Table 1.

[0067] Table 1

[0068]

[0069] Application Example 2

[0070] Method: The product of Example 1 was added to tobacco at three concentrations of 0.01%, 0.05% and 0.1%, with vanillin as the control. The evaluation results are shown in Table 2.

[0071] Table 2

[0072]

[0073] 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 an azacyclic ketone latent aroma compound, wherein the structural formula of the azacyclic ketone latent aroma compound is: ,in, R1=H, or (o,m,p)-CH3, or (o,m,p)-OCH3 alkyl or alkoxy, R2=H, or (o,m,p)-CH3, or (o,m,p)-OCH3 alkyl or alkoxy, characterized in that the following steps are adopted: S1. Under nitrogen protection, add tetrahydrofuran, a reaction solvent, into a dry reactor, then add a substituted benzyl alcohol compound, and stir evenly; S2. After stirring evenly, add metal catalyst, ligand and base, introduce 1 atm CO2, and reflux at 50-80°C for 3-5 h; S3, add the azoheterocyclic alcohol amine compound, and continue heating under reflux for 3-5h; S4. After the reaction is completed, the nitrogen heterocyclic ketone latent aroma compound is obtained by filtering, drying and recrystallization.

2. The method for synthesizing the azacyclic ketone latent aroma compound according to claim 1, characterized in that: The substituted benzyl alcohol compound is 4-methoxybenzyl alcohol, 3-ethylbenzyl alcohol or 2,4-dimethoxybenzyl alcohol.

3. The method for synthesizing the azacyclic ketone latent aroma compound according to claim 1, characterized in that: The azacyclic alcohol amine is 4-amino-1-(pyridin-3-yl)butan-1-ol or 5-amino-1-(pyrimidin-2-yl)pentan-1-ol.

4. The method for synthesizing the azacyclic ketone latent aroma compound according to claim 1, characterized in that: The metal catalyst is palladium acetate, palladium chloride, iridium trichloride or rhodium trichloride.

5. The method for synthesizing the azacyclic ketone latent aroma compound according to claim 1, characterized in that: The ligand is triphenylphosphine, tricyclohexylphosphine, 1,2-bis(diphenylphosphine)ethane, or 1,3-bis(diphenylphosphine)propane.

6. The method for synthesizing the azacyclic ketone latent aroma compound according to claim 1, characterized in that: The base is cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium carbonate or sodium tert-butoxide.

7. The method for synthesizing the azacyclic ketone latent aroma compound according to claim 1, characterized in that: The molar ratio of the substituted benzyl alcohol compound, the metal catalyst, the ligand, the base and the nitrogen heterocyclic alcohol amine compound is 1: 0.01-0.02: 0.1-0.2: 0.2-0.4: 0.8-0.

9.

8. An application, characterized in that: Use of the nitrogen heterocyclic ketone latent aroma compound prepared according to any one of claims 1 to 7 in tobacco products.

9. The use according to claim 8, characterized in that: The added amount of the nitrogen heterocyclic ketone latent aroma compound is 0.01%-0.1% of the weight of the tobacco.

Images