A method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents
A novel synthesis method for menthyl formic acid using TEMPO, Fe(NO3)3·9H2O, and NHPI catalysts addresses the limitations of existing methods, providing high-yield and industrially viable production of high-purity menthyl formic acid for WS series cooling agents, which are used in food, daily chemicals, tobacco, and medicine.
Patent Information
- Application Number
- CN202311672978.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-07
- Publication Date
- 2024-12-06
- Estimated Expiration
- 2043-12-07
AI Technical Summary
Existing methods for synthesizing menthyl formic acid, a key intermediate for WS series cooling agents, face challenges such as harsh reaction conditions, low yield, use of toxic substances, and poor stereoselectivity, making them unsuitable for large-scale industrial production.
A method involving oxidation of levomenthol with TEMPO, Fe(NO3)3·9H2O, and NaCl, followed by a Wittig reaction with methoxymethyltriphenylphosphonium chloride and subsequent oxidation with NHPI, avoids the use of Grignard reagents and provides a high-yield, simple, and industrially viable process.
The method achieves high purity menthyl formic acid production with mild reaction conditions and easy post-treatment, suitable for industrial applications, and enables the synthesis of WS series cooling agents.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, relates to the synthesis of WS series cooling agent intermediates, and particularly relates to a method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents. Background Art
[0002] Cooling agents are essential additives in people's daily lives. For a long time, L-menthol has been a commonly used cooling agent. It has a refreshing taste and makes people feel cool. It is widely used in products in the fields of food, daily chemicals, tobacco and medicine. However, it also has obvious disadvantages such as volatility, high temperature resistance, short duration of cooling and bitterness. This greatly limits its application field. In order to overcome the above disadvantages, many researchers have tried to modify and transform the structure of L-menthol, thus obtaining WS series cooling agents such as: N-ethyl-p-menthyl-3-carboxamide (WS-3), acetic acid (N-ethyl-p-menthyl-3-carboxamide) ethyl ester (WS-5), N-(4-methoxyphenyl)-p-menthyl-3-carboxamide (WS-12), N-tert-butyl-p-menthyl-3-carboxamide (WS-14), N-cyclopropyl-5-methyl-2-(1-methylethyl) cyclohexanecarboxamide (WS-NA).
[0003]
[0004] The key intermediate for synthesizing the WS series cooling agents is menthyl formic acid, which reacts with dimethyl sulfoxide to generate menthyl formic acid chloride, and then reacts with different amine compounds to obtain the WS series cooling agents we need, as shown below:
[0005]
[0006] Menthyl formic acid is mainly obtained by chemical synthesis. JG Smith and George F. Wright (J. Org. Chem, 1952, 17 (8): 1116-1121) et al. proposed a method of using L-menthol as a raw material, using thionyl chloride or Lucas reagent composed of hydrochloric acid and zinc chloride to perform chlorination substitution, and then preparing it into a Grignard reagent, and then reacting it with dry ice and acid, and finally hydrolyzing it into menthyl formic acid. As shown below:
[0007]
[0008] This route is currently the main route used in industrial production, but the reaction conditions of this method are relatively harsh, and because menthyl chloride is not active enough, it is difficult to prepare Grignard reagents. At the same time, the yield of Grignard reagents hydrolyzed with dry ice and acid to carboxylic acid is also very low.
[0009] Procter & Gamble (WO2010019730) proposed a synthetic route of first converting levomenthol into menthyl sulfonate, which then reacts with a cyaniding agent to obtain menthyl cyanide, which is then hydrolyzed to obtain menthyl formic acid:
[0010]
[0011] This method has a high yield and avoids the grignard reaction that requires anhydrous and oxygen-free operation. However, this method uses the highly toxic substance sodium cyanide, has high safety and environmental protection requirements, and has certain risks, making it difficult to use for large-scale industrial production.
[0012] Renessenz Company (EP2450337A2) of the United States reported another synthetic route of menthyl formic acid:
[0013]
[0014] They used menthone as the raw material, first epoxidized the double bond in menthone, then used Lewis acid to catalyze the rearrangement to menthyl formaldehyde, and finally oxidized the menthyl formaldehyde to menthyl formic acid. This method also avoids the Grignard reaction that requires anhydrous and oxygen-free operation, and is easy to operate. However, the product has poor stereoselectivity, resulting in an impure cool taste of the product, which greatly reduces its application value. Summary of the invention
[0015] In view of the shortcomings of the prior art, the present invention aims to provide a method for synthesizing menthyl formic acid, a key intermediate of the WS series cooling agents. The synthesis method of the present invention avoids the use of synthetic grignard reagents, is simple to operate and post-process, has a high yield, and has industrial value. The synthesis route of the present invention is as follows:
[0016]
[0017] The present invention is achieved through the following technical solutions:
[0018] A method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents, comprises the following steps:
[0019] (1) allowing levomenthol to undergo an oxidation reaction under the catalysis of TEMPO, the action of Fe(NO3)3·9H20 and NaCl in an oxygen atmosphere to generate levomenthone;
[0020] (2) allowing the levomenthone obtained in step (1) to undergo a Wittig reaction with methoxymethyltriphenylphosphonium chloride under the action of a base to generate an enol ether, and the enol ether is hydrolyzed in a solvent to obtain menthyl formaldehyde;
[0021] (3) allowing the menthyl formaldehyde obtained in step (2) to undergo an oxidation reaction in an oxygen atmosphere under the catalysis of NHPI to generate menthyl formic acid.
[0022] A further improvement of the present invention is:
[0023] The molar ratio of levomenthol, TEMPO, Fe(NO3)3·9H20 and NaCl in step (1) is 1:0.05-0.1:0.05-0.1:0.05-0.1.
[0024] Furthermore, the temperature of the oxidation reaction in step (1) is 30 to 80° C., and the time is 20 to 26 hours.
[0025] Furthermore, the base in step (2) is one or a mixture of two or more of n-butyl lithium, potassium tert-butoxide, sodium ethoxide or sodium hydride.
[0026] Furthermore, the solvent in step (2) is one or a mixture of two or more of dimethyl sulfoxide, methanol, acetonitrile, acetone, chloroform, tetrahydrofuran, toluene, dichloromethane, cyclohexane or petroleum ether.
[0027] Furthermore, in step (2), the molar ratio of levomenthone, methoxymethyltriphenylphosphonium chloride and base is 1:1-1.6:1-1.6.
[0028] Furthermore, the temperature of the wittig reaction in step (2) is room temperature and the time is 8 to 12 hours.
[0029] Furthermore, in step (3), the molar ratio of menthyl formaldehyde to NHPI is 1:0.05-0.1.
[0030] Furthermore, the temperature of the oxidation reaction in step (3) is 50 to 90° C., and the time is 2 to 6 hours.
[0031] Compared with the prior art, the present invention has the following beneficial effects:
[0032] The invention avoids the use of a synthetic grignard reagent in the process of preparing menthyl formic acid, has simple operation and post-treatment, mild reaction conditions, high reaction yield and is easy to industrialize; the prepared menthyl formic acid has high purity, reacts with dimethyl sulfoxide to generate menthyl formic acid chloride, and then reacts with different amine compounds to obtain WS series cooling agents. DETAILED DESCRIPTION
[0033] The present invention is described in detail below in conjunction with specific embodiments.
[0034] Example 1
[0035] (1) Synthesis of L-menthone
[0036] 0.156g TEMPO, 0.4g Fe(NO3)3·9H20, 0.05g NaCl and 10ml dichloroethane were added to a 50ml two-necked flask, stirred for five minutes, and then 3.12g (20mmol) of levomenthol was added thereto. The reaction temperature was controlled to 70°C and the reaction was carried out under an oxygen atmosphere for 24h. After the reaction was completed, the mixture was washed with saturated brine, dried, filtered, and the solvent was removed by vacuum distillation. Then, 3.02g of levomenthone was obtained by column chromatography with a yield of 98%.
[0037] (2) Synthesis of Menthyl Formaldehyde
[0038] 7.5 g (22 mmol) of methoxymethyltriphenylphosphonium chloride was added to a 50 ml two-necked flask, and then 22 ml of t BuOK solution in THF (1M t BuOK). After stirring for 30 minutes, 3.1 g (20 mmol) of levulinone was added. The reaction mixture was stirred at room temperature for 10 hours, then the reaction was quenched with 1N HCl, extracted with ether in turn, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by distillation under reduced pressure. The residue was filtered to remove solid triphenylphosphine oxide, and then the filtrate was further concentrated by distillation under reduced pressure. The obtained enol ether was then dissolved in 20 ml of chloroform, and 3 ml of 12N HCl was added. The reaction mixture was stirred at room temperature for 4 hours, and the chloroform was removed by distillation under reduced pressure. Diethyl ether and water were added, the organic phase was separated, the aqueous phase was extracted with diethyl ether 3 times, the organic phases were combined, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. 3.27 g of menthyl formaldehyde was obtained by column chromatography with a yield of 95%.
[0039] (3) Synthesis of Menthyl Formic Acid
[0040] Add 0.163g NHPI, 3.36g (20mmol) menthyl formaldehyde and 80ml acetonitrile to a 250ml two-necked flask, control the reaction temperature to 70℃, and stir for 4h under oxygen atmosphere. After the reaction is completed, remove the solvent by vacuum distillation, then extract with ether and water 3 times, and combine the organic phases. Then extract with 0.5mol / L NaOH aqueous solution 20ml 3 times, collect the aqueous phase, acidify with concentrated hydrochloric acid to pH=1, extract the aqueous phase with ether, combine the organic phases, and dry with anhydrous magnesium sulfate. Filter, remove the solvent by vacuum distillation, and obtain a viscous liquid. After vacuum drying to remove the residual solvent, 3.15g of menthyl formic acid is obtained, with a yield of 85%.
[0041] Example 2
[0042] (1) Synthesis of L-menthone
[0043] 0.312g TEMPO, 0.8g Fe(NO3)3·9H20, 0.1g NaCl and 10ml dichloroethane were added to a 50ml two-necked flask, stirred for five minutes, and then 3.12g (20mmol) of levomenthol was added thereto. The reaction temperature was controlled to 70°C and the reaction was carried out under an oxygen atmosphere for 24h. After the reaction was completed, the mixture was washed with saturated brine, dried, filtered, and the solvent was removed by vacuum distillation. Then, 2.99g of levomenthone was obtained by column chromatography with a yield of 97%.
[0044] (2) Synthesis of Menthyl Formaldehyde
[0045] 7.5 g (22 mmol) of methoxymethyltriphenylphosphonium chloride was added to a 50 ml two-necked flask, and then 22 ml of t BuOK solution in THF (1M t BuOK). After stirring for 30 minutes, 3.1 g (20 mmol) of levulinone was added. The reaction mixture was stirred at room temperature for 10 hours, then the reaction was quenched with 1N HCl, extracted with ether in turn, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by distillation under reduced pressure. The residue was filtered to remove solid triphenylphosphine oxide, and then the filtrate was further concentrated by distillation under reduced pressure. The obtained enol ether was then dissolved in 20 ml of chloroform, and 3 ml of 12N HCl was added. The reaction mixture was stirred at room temperature for 4 hours, and the chloroform was removed by distillation under reduced pressure. Diethyl ether and water were added, the organic phase was separated, the aqueous phase was extracted with ether 3 times, the organic phases were combined, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. 3.3 g of menthyl formaldehyde was obtained by column chromatography with a yield of 96%.
[0046] (3) Synthesis of Menthyl Formic Acid
[0047] Add 0.326g NHPI, 3.36g (20mmol) menthyl formaldehyde and 80ml acetonitrile to a 250ml two-necked flask, control the reaction temperature to 70°C, and stir for 4h under oxygen atmosphere. After the reaction is completed, remove the solvent by vacuum distillation, then extract with ether and water 3 times, and combine the organic phases. Then extract with 0.5mol / L NaOH aqueous solution 20ml 3 times, collect the aqueous phase, acidify to pH=1 with concentrated hydrochloric acid, extract the aqueous phase with ether, combine the organic phases, and dry with anhydrous magnesium sulfate. Filter, remove the solvent by vacuum distillation, and obtain a viscous liquid. After vacuum drying to remove the residual solvent, 3.07g of menthyl formic acid is obtained, with a yield of 83%.
[0048] Example 3: Synthesis of Menthylformyl Chloride
[0049] In a 25 ml round-bottom flask, 3.68 g (20 mmol) of menthyl formic acid prepared in Example 1 and 10 ml of dithionyl chloride were added, and the mixture was heated to reflux at 80° C. for 3 h, and then the excess dithionyl chloride was removed by vacuum distillation to obtain a light yellow oily liquid menthyl formic acid chloride, which was then dissolved in 35 ml of ether solution.
[0050] Example 4: Synthesis of N-ethyl-p-menthyl-3-carboxamide (WS-3)
[0051] Add 40ml of 0.8mol / L NaOH aqueous solution and 5ml of ethylamine aqueous solution [w(EtNH2)=33%] to a 250ml round-bottom flask, then dropwise add the prepared ether solution (35ml) of menthylcarbonyl chloride. After the dropwise addition is complete, stir the reaction mixture at 0℃ for 1h. After the reaction is completed, separate the organic phase, extract the aqueous phase with ether, combine the organic phases, and wash them with dilute hydrochloric acid and saturated brine respectively. Then collect the organic phase, dry it with anhydrous magnesium sulfate, filter it, remove the solvent by vacuum distillation, and then purify the product by recrystallization with a mixture of acetone and water. Obtain 3.47g of N-ethyl-p-menthyl-3-carboxamide (WS-3), with a yield of 82%.
[0052] Example 5: Synthesis of N-cyclopropyl-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide (WS-NA)
[0053] Add 40ml of 0.8mol / L NaOH aqueous solution and 1.16g of cyclopropylamine to a 250ml round-bottom flask, and then dropwise add the prepared ether solution (35ml) of menthylcarbonyl chloride. After the dropwise addition is complete, stir the reaction mixture at 0°C for 1h. After the reaction is completed, separate the organic phase, extract the aqueous phase with ether, combine the organic phases, and wash them once with dilute hydrochloric acid and saturated brine. Then collect the organic phase, dry it with anhydrous magnesium sulfate, filter it, remove the solvent by vacuum distillation, and then recrystallize and purify the product with a mixture of acetone and water. Obtain 3.7g of N-cyclopropyl-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide, with a yield of 83%.
[0054] Example 6: Synthesis of (N-ethyl-p-menthyl-3-carboxamide) ethyl acetate (WS-5)
[0055] Dissolve NaHCO3 (3.5g, 40mmol) and glycine ethyl ester hydrochloride (2.93g, 21mmol) in 40ml water and add to a 250ml round-bottom flask, then dropwise add the prepared ether solution (35ml) of menthylformyl chloride. After the dropwise addition is complete, stir the reaction mixture at room temperature for 2 hours. After the reaction is completed, separate the organic phase, extract the aqueous phase with ether, combine the organic phases, and wash them once with dilute hydrochloric acid and saturated brine. Then collect the organic phase, dry it with anhydrous magnesium sulfate, filter it, remove the solvent by vacuum distillation, and then purify the product by recrystallization with a mixture of acetone and water. Obtain 4.85g of acetic acid (N-ethyl-p-menthyl-3-carboxamide) ethyl ester (WS-5) with a yield of 85%.
[0056] Example 7: Synthesis of N-(4-methoxyphenyl)-p-menthyl-3-carboxamide (WS-12)
[0057] Dissolve NaHCO3 (3.5g, 40mmol) and p-methoxyaniline (2.46g, 20mmol) in 40ml water and add to a 250ml round-bottom flask, then dropwise add the prepared ether solution (35ml) of menthylformyl chloride. After the dropwise addition is complete, stir the reaction mixture at room temperature for 1 hour. After the reaction is completed, separate the organic phase, extract the aqueous phase with ether, combine the organic phases, and wash them once with dilute hydrochloric acid and saturated brine. Then collect the organic phase, dry it with anhydrous magnesium sulfate, filter it, remove the solvent by vacuum distillation, and then recrystallize and purify the product with a mixture of acetone and water. Obtain 3.47g N-(4-methoxyphenyl)-p-menthyl-3-carboxamide (WS-12) with a yield of 82%.
[0058] Example 8: Synthesis of N-tert-butyl-p-menthyl-3-carboxamide (WS-14)
[0059] Add 40ml of 0.8mol / L NaOH aqueous solution and 1.5g of tert-butylamine solution to a 250ml round-bottom flask, and then dropwise add the prepared ether solution (35ml) of menthylformyl chloride. After the dropwise addition is complete, stir the reaction mixture at 0°C for 1h. After the reaction is completed, separate the organic phase, extract the aqueous phase with ether, combine the organic phases, and wash them once with dilute hydrochloric acid and saturated brine. Then collect the organic phase, dry it with anhydrous magnesium sulfate, filter it, remove the solvent by vacuum distillation, and then recrystallize and purify the product with a mixture of acetone and water. Obtain 4.1g of N-tert-butyl p-menthol-3-carboxamide, with a yield of 85%.
[0060] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents, characterized in that: The following steps are involved: (1) Under the catalysis of TEMPO, Fe(NO3)3·9H20 and NaCl, levomenthol undergoes oxidation reaction in an oxygen atmosphere to produce levomenthone; (2) allowing the levomenthone obtained in step (1) to react with methoxymethyltriphenylphosphonium chloride in the presence of a base to produce an enol ether by a wittig reaction, and the enol ether is hydrolyzed in a solvent to produce menthyl formaldehyde; the base is potassium tert-butoxide; (3) The menthyl formaldehyde obtained in step (2) is oxidized under the catalysis of NHPI in an oxygen atmosphere to generate menthyl formic acid.
2. The method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents according to claim 1, characterized in that: The molar ratio of levomenthol, TEMPO, Fe(NO3)3·9H20 and NaCl in step (1) is 1:0.05~0.1:0.05~0.1:0.05~0.
1.
3. The method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents according to claim 1, characterized in that: The temperature of the oxidation reaction in step (1) is 30-80°C and the time is 20-26h.
4. The method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents according to claim 1, characterized in that: The solvent in step (2) is one or a mixture of two or more of dimethyl sulfoxide, methanol, acetonitrile, acetone, chloroform, tetrahydrofuran, toluene, dichloromethane, cyclohexane or petroleum ether.
5. The method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents according to claim 1, characterized in that: The molar ratio of levomenthone, methoxymethyltriphenylphosphonium chloride and base in step (2) is 1:1-1.6:1-1.
6.
6. The method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents according to claim 1, characterized in that: The temperature of the wittig reaction in step (2) is room temperature and the time is 8 to 12 hours.
7. The method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents according to claim 1, characterized in that: The molar ratio of menthyl formaldehyde to NHPI in step (3) is 1:0.05-0.
1.
8. The method for synthesizing menthyl formic acid, a key intermediate of WS series cooling agents according to claim 1, characterized in that: The temperature of the oxidation reaction in step (3) is 50-90°C and the time is 2-6 hours.