CN110903178A - Method for preparing vanillone and application thereof - Google Patents
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Abstract
The invention provides a method for preparing vanillone and application thereof. Specifically, guaiacol is used as raw material, and is reacted with acetyl chloride to produce ester, and then Lewis acid such as AlCl is added3The reaction is catalyzed to generate the vanillone. The method has the advantages of mild reaction conditions, high raw material conversion rate and simple and convenient process flow, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to a method for preparing vanillone and application thereof.
Background
Vanillyl ketone, also called vanilla ketone and acetovanillone, has weak vanilla smell, is used in perfume industry as well as important organic material for synthesizing iloperidone as mental medicine and several new antimalarials. Vanillyl ketone is also a common antioxidant, is a currently recognized specific nicotinamide adenine dinucleotide oxidase inhibitor, and is also commonly used as a cardiotonic and a diuretic in medicine.
In view of the important role of vanillone in the chemical and pharmaceutical industries, there have been many studies reported in recent years for preparing vanillone. For example, the preparation of vanillone from sodium guaiacol (sodium orthomethoxyphenol) which is a petrochemical product reported in dun-riing et al is complicated in process steps, harsh in conditions and relatively low in yield (cellulose science and technology 2009,17(2): 27-33). Zhouyonghong et al reported a method for preparing vanillone by oxidizing lignin compounds using nitrobenzene compounds as an oxidizing agent. The method needs to use p-nitrobenzoic acid or 3-nitrobenzoic acid and the like as oxidants, has high reaction temperature (160-200 ℃), complex post-treatment, low yield and high cost (CN 102295547). Huangwein et al reported that 1-n-propoxy-2-methoxybenzene was obtained by propylation of guaiacol and n-bromo propane, that a mixture of 3-methoxy-4-n-propoxylacetophenone and 3-propoxy-4-methoxyacetophenone was obtained by Friedel-crafts acetylation of 1-n-propoxy-2-methoxybenzene and acetic anhydride, and that the mixture of 3-methoxy-4-n-propoxylacetophenone and 3-propoxy-4-methoxyacetophenone was subjected to selective depropylation with anhydrous aluminum trichloride to synthesize vanillone and isoacetophenone (synthetic chemistry 2013,21(4): 472-475). The method has the most defects of poor selectivity, low atom economy and the concurrent generation of the isoacetophenones while synthesizing the vanillophenones.
The reported processes have technical defects, such as harsh reaction conditions, high reaction temperature, high requirements on process equipment, environmental pollution, poor reaction selectivity, and other side products which are generated simultaneously when the target product is produced.
On the other hand, the iloperidone (formula I) is formed by reacting the intermediate obtained by reacting the starting material of the vanillone with 1-bromo-3-chloropropane and then with the compound E as the key intermediate of the atypical psychotropic drug iloperidone (as shown in US 4366162),
in view of this, there is an urgent need for pharmaceutical researchers to develop a new preparation method of vanillyl ethanone with good environmental friendliness, strong process operability and high yield.
Disclosure of Invention
The invention provides a novel method for preparing vanillone, which comprises the step of adding acetic acid 2-methoxyphenol ester into Lewis acid and nitrobenzene for reaction, and further comprises the steps of cooling after the reaction is finished, adding hydrochloric acid solution, and stirring for dissolving. The process method is good in environmental friendliness, strong in process operability, high in yield and convenient for industrial production.
In some embodiments, the reaction temperature is selected from about 50-80 ℃, including but not limited to 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, or any value between any two values. In the specific scheme, the reaction temperature is directly related to the reaction rate, and further influences the generation amount of the vanillone and the generation amount of corresponding byproducts, such as isoacetophenones and/or 2-methoxyphenol acetate hydrolysate. On the other hand, when the reaction temperature is too high, black flocs appear in the reaction system, presumably due to oxidation of the compound having a phenolic hydroxyl group structure,
In some embodiments, the reaction time is selected from about 7 to 10 hours, including but not limited to 7 hours, 8 hours, 9 hours, 10 hours, or any value between any two values. In the specific scheme, the reaction time influences the yield of the reaction, the reaction time is too short, a large amount of 2-methoxyphenol ester hydrolysis products appear in the reaction process, and the raw material conversion is incomplete.
In another aspect, some embodiments provide a method wherein the lewis acid is selected from at least one of zinc chloride, aluminum chloride, ferric tribromide, tin tetrachloride, titanium tetrachloride, and polyphosphoric acid, preferably aluminum chloride. To ensure that the reaction proceeds smoothly, some embodiments provide a process in which the molar ratio of 2-methoxyphenol acetate to lewis acid is about 1:1.6 to about 1:2.5, including but not limited to 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, or any value in between any two, preferably about 1:2.0 to about 1: 2.5.
Further, in the method of the present invention, the 2-methoxyphenol acetate is formed by reacting guaiacol and acetyl chloride, wherein the molar ratio of guaiacol to acetyl chloride is about 1:1.1 to 1:3, including but not limited to 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3.0 or any value therebetween, preferably about 1:2 to 1:3.
Further, in some embodiments, the reaction temperature of the guaiacol and acetyl chloride is selected from about-5 ℃ to about 25 ℃, including but not limited to-5 ℃, 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃,25 ℃, or any value between any two values, preferably about 15 ℃ to about 25 ℃, and more preferably about 25 ℃. In another aspect, the guaiacol and acetyl chloride are reacted for a time selected from about 1 to about 6 hours, including but not limited to 1,2, 3, 4, 5, 6 hours or any value between any two values, preferably about 4 to about 6 hours, more preferably about 6 hours.
In order to ensure the amidation reaction, guaiacol and acetyl chloride are reacted under the condition of an acid-binding agent selected from at least one of triethylamine, pyridine, 4-dimethylaminopyridine, N-dimethylformamide, N-diisopropylethylamine or tetramethylethylenediamine, preferably triethylamine.
Further, the method for preparing the vanillone also comprises at least one of the steps of organic solvent extraction, drying, concentration or recrystallization.
In some embodiments, the organic solvent used for the extraction reaction is selected from dichloromethane, 1, 2-dichloroethane, chloroform.
In some embodiments, the solvent used for recrystallization is selected from any one or more of acetone, ethanol, isopropanol, ethyl acetate, petroleum ether or toluene in any ratio.
In some embodiments, the methods of the present invention for preparing vanillyl ketone comprise:
1) reacting guaiacol and acetyl chloride to form 2-methoxyphenol acetate, wherein the feeding molar ratio of the guaiacol to the acetyl chloride is 1: 1.1-1: 3, preferably 1: 2-1: 3; the reaction temperature is preferably-5-25 ℃, and more preferably 25 ℃; the reaction time is preferably 1-6 h, and more preferably 6 h;
2) adding 2-methoxyphenol acetate into Lewis acid and nitrobenzene for reaction, and further comprising the steps of cooling after the reaction is finished, adding a hydrochloric acid solution, stirring and dissolving, wherein the reaction temperature is preferably 50-80 ℃; the reaction time is preferably 7 to 10 hours.
3) Organic solvent extraction, drying, concentration or/and recrystallization steps, wherein the organic solvent used for extraction is selected from dichloromethane, 1, 2-dichloroethane, chloroform; the solvent for recrystallization is selected from any one or a mixture of more than one of acetone, ethanol, isopropanol, ethyl acetate, petroleum ether or toluene in any ratio.
In other embodiments, the methods of the present invention for preparing vanillyl ethanone comprise:
1) guaiacol (1 equivalent), triethylamine (2 equivalents) and acetyl chloride (1.5 equivalents) are dissolved in 1, 2-dichloroethane to react at 15-25 ℃, 0.5mol/L hydrochloric acid is used for regulating the system to be acidic, 1, 2-dichloroethane is used for extraction, and the 2-methoxy phenyl acetate is obtained by rectification after concentration.
2) Adding aluminum chloride into nitrobenzene, stirring uniformly, dropwise adding 2-methoxy phenyl acetate, reacting at 80 ℃, cooling a system to room temperature, and adding concentrated hydrochloric acid for acidification;
3) extracting, concentrating the extractive solution under reduced pressure, and recrystallizing to obtain vanillone.
In another aspect, the present invention also provides a process for preparing a compound of formula I, comprising the steps of preparing the aforementioned method for vanillyl ketone, and converting the vanillyl ketone into the compound of formula I,
in some embodiments, the method of preparing the compound of formula I further comprises the step of reacting the vanillone with compound B under basic conditions to form the compound of formula I,
wherein X is selected from a leaving group, preferably halogen (including fluorine, chlorine, bromine or iodine), OTs, OMs, more preferably chlorine or OTs; the alkali is selected from triethylammonium or potassium carbonate.
In some embodiments, the method of preparing the compound of formula I further comprises the step of reacting, under basic conditions, vanillone with compound C to form compound D, and reacting compound D with compound E to form the compound of formula I,
wherein X is selected from a leaving group, preferably halogen (including fluorine, chlorine, bromine or iodine), OTs, OMs, more preferably chlorine or OTs; the alkali is selected from triethylammonium or potassium carbonate.
Further, the specific reaction for the preparation of the compound of formula I is referred to CN102212063A, and the relevant contents are incorporated into the present invention for illustration.
The term "about" as used herein means that a numerical value is within an acceptable error range for the particular value determined by one of ordinary skill in the art, which numerical value depends in part on how the value is measured or determined (i.e., the limits of the measurement system). For example, "about" in each practice in the art may mean within 1 or a standard deviation of more than 1. Alternatively, "about" or "substantially comprising" may mean a range of up to 20%. Furthermore, particularly for biological systems or processes, the term may mean at most an order of magnitude or at most 5 times the value. Unless otherwise indicated, when a particular value appears in the invention and claims, the meaning of "about" or "consisting essentially of" should be assumed to be within an acceptable error range for that particular value.
The structure of a compound can be determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shifts (. delta.) are given in units of 10-6 (ppm). NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument,the solvent can be deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS); MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
The HPLC can be measured by Agilent 1200DAD high pressure liquid chromatograph or Waters 2695-2996 high pressure liquid chromatograph.
Drawings
FIG. 1: the high performance liquid phase spectrum of the vanillone shows that the retention time is 10.713, and the purity is 99.63%.
Detailed Description
Example 1:
guaiacol (200.00g, 1.61mol), pyridine (254.70g, 3.22mol) and acetyl chloride (189.58g, 2.42mol) were dissolved in 500ml of 1, 2-dichloroethane and reacted at-5 ℃ for 6 hours. After the reaction, the system was adjusted to PH 3 with 0.5mol/L hydrochloric acid, extracted with 250ml of 1, 2-dichloroethane, concentrated and then rectified to obtain 2-methoxy phenyl acetate. The purity is 95% and the yield is 92% by liquid chromatography detection.
Example 2:
with reference to the preparation of phenyl 2-methoxyacetate by the method of example 1, different reaction systems were screened in order to obtain optimum reaction conditions, and the specific data are as follows:
note: a represents that the acid-binding agent is triethylamine, b represents that the acid-binding agent is pyridine, c represents that the acid-binding agent is N, N-dimethylformamide, and d represents that the acid-binding agent is 4-dimethylaminopyridine.
And (4) conclusion: when the molar ratio of the guaiacol to the acid-binding agent triethylamine is 1:3 and the reaction is carried out for 6 hours at 25 ℃, the yield of the obtained 2-methoxy phenyl acetate is optimal and the purity is better. Of course, other yields of 90% or more are acceptable.
Example 3:
guaiacol (200.00g, 1.61mol), triethylamine (325.83g, 3.22mol) and acetyl chloride (189.58g, 2.42mol) were dissolved in 500ml of 1, 2-dichloroethane and reacted at 25 ℃ for 6 hours. After the reaction, the system was adjusted to PH 3 with 0.5mol/L hydrochloric acid, extracted with 250ml of 1, 2-dichloroethane, concentrated and then rectified to obtain 2-methoxy phenyl acetate. The purity is 98% and the yield is 96% by liquid chromatography detection.
Example 4:
adding ferric chloride (9.73g, 0.06mol) into 25ml nitrobenzene, stirring uniformly, dropwise adding 2-methoxy phenyl acetate (5.0g, 0.03mol), reacting at 60 ℃ for 8h, cooling the system to room temperature, adding concentrated hydrochloric acid until the system is clear, extracting with 25ml 1, 2-dichloroethane, and combining organic phases. The organic phase is washed with 25ml of 2mol/L sodium hydroxide and the aqueous phase is collected. The aqueous phase is acidified with concentrated hydrochloric acid to pH 2-3, then extracted with 20ml of 1, 2-dichloroethane, the organic phases are combined, concentrated under reduced pressure, and the crude product is recrystallized using 10ml of ethanol. The purity is 99% and the yield is 55% by liquid chromatography detection.
The melting point is 112-114 ℃.
1H NMRδ:7.51～7.54(m,2H,ArH)，δ:6.92～6.95(d,J＝12Hz,1H,ArH)，δ:6.12(s,1H,OH)，δ:3.94(s,3H,CH3)，δ:2.55(s,3H,CH3)。
13C NMRδ:196.85,150.42,146.63,130.23,124.03,113.78,109.72,56.08,26.11。
HR-ESI-MS m/z：[M+H]+＝167.0536。
Example 5
Vacetophenone was prepared according to the method of example 4 and different reaction systems were screened to obtain optimal reaction conditions, and the specific data are as follows:
note: in the diagram, A represents 2-methoxy phenyl acetate; NA is indicated as unreacted.
And (4) conclusion: different Lewis acids are screened under the same reaction condition, and when aluminum chloride is selected, the conversion rate of the target product is the highest and reaches 67.08 percent.
Example 6
Adding 10.00g of aluminum chloride (0.075 mol) into 25ml of nitrobenzene, uniformly stirring, dropwise adding 2-methoxy phenyl acetate (5.0g of 0.03mol), reacting at 80 ℃ for 8 hours, cooling the system to room temperature, adding concentrated hydrochloric acid until the system is clear, extracting with 25ml of 1, 2-dichloroethane, and combining organic phases. The organic phase is washed with 25ml of 2mol/L sodium hydroxide and the aqueous phase is collected. The aqueous phase is acidified to pH 2-3 with concentrated hydrochloric acid, then extracted with 20ml of 1, 2-dichloroethane, the organic phases are combined, the extract is concentrated under reduced pressure, and the crude product is recrystallized using 10ml of ethanol. The separation purity is 99% and the yield is 63% by liquid chromatography detection.
Example 7
Vacetophenone was prepared according to the method of example 6 and different reaction systems were screened to obtain optimal reaction conditions, and the specific data are as follows:
and (4) conclusion: the isomers gradually decrease with increasing temperature, but the higher the temperature, the more black flocs in the system and the more difficult the post-treatment delamination.
Example 8
Vacetophenone was prepared according to the method of example 6 and different reaction systems were screened to obtain optimal reaction conditions, and the specific data are as follows:
and (4) conclusion: other reaction conditions are unchanged, when the feeding molar ratio of the 2-methoxyphenol ester to the aluminum chloride is 1:2.5, the conversion rate of the target product is the highest (84.15%), the dosage of the aluminum chloride is continuously increased, and the conversion rate of the target product is reduced and the isomer is increased.
Example 9
Vacetophenone was prepared according to the method of example 6 and different reaction systems were screened to obtain optimal reaction conditions, and the specific data are as follows:
and (4) conclusion: the other reaction conditions are unchanged, and when the reaction time is 8 hours, the conversion rate of the target product is the highest (80.92%), but the conversion rate of the target product is reduced as the reaction time is prolonged.
Example 10
Adding 10.00g of aluminum chloride (0.075 mol) into 25ml of nitrobenzene, uniformly stirring, dropwise adding 2-methoxy phenyl acetate (5.0g of 0.03mol), reacting at 80 ℃ for 8 hours, cooling the system to room temperature, adding concentrated hydrochloric acid until the system is clear, extracting with 25ml of 1, 2-dichloroethane, and combining organic phases. The organic phase is washed with 25ml of 2mol/L sodium hydroxide and the aqueous phase is collected. The aqueous phase is acidified with concentrated hydrochloric acid to a pH of 2-3, and then extracted with 20ml of 1, 2-dichloroethane, and the organic phases are combined. The extract was concentrated under reduced pressure and the crude product was recrystallized from 10ml of ethyl acetate. The purity is 99 percent and the yield is 78 percent by liquid chromatography detection.
Example 11
Adding aluminum chloride (20.06kg, 150.43mol) into 40L nitrobenzene, stirring uniformly, dropwise adding 2-methoxy phenyl acetate (10.00kg, 60.18mol), reacting at 80 ℃ for 8h, cooling the system to room temperature, adding concentrated hydrochloric acid until the system is clear, extracting with 35L1, 2-dichloroethane, and combining organic phases. The organic phase was washed with 43L of 2mol/L sodium hydroxide and the aqueous phase was collected. The aqueous phase was acidified with concentrated hydrochloric acid to pH 2-3 and extracted with 40L of 1, 2-dichloroethane. The extract was concentrated under reduced pressure and the crude product was recrystallized from 20L of ethyl acetate. The purity is 99 percent and the yield is 82 percent by liquid chromatography detection.
Claims (10)
1. A method for preparing the vanillone comprises the step of adding 2-methoxyphenol acetate into Lewis acid and nitrobenzene for reaction, and further comprises the step of cooling after the reaction is finished, adding hydrochloric acid solution, stirring and dissolving, wherein the reaction temperature is preferably 50-80 ℃, and comprises 50 ℃, 60 ℃, 70 ℃ and 80 ℃; the reaction time is preferably 7-10 hours, including 7 hours, 8 hours, 9 hours and 10 hours.
2. The process of claim 1, wherein the molar charge ratio of 2-methoxyphenol acetate to Lewis acid is 1:1.6 to 1:2.5, preferably 1:2.0 to 1: 2.5.
3. The process of claim 1 or 2, wherein the lewis acid is selected from at least one of zinc chloride, aluminum chloride, ferric trichloride, ferric tribromide, stannic tetrachloride, titanium tetrachloride and polyphosphoric acid, preferably aluminum chloride.
4. A process as claimed in any one of claims 1 to 3, which includes the step of reacting guaiacol with acetyl chloride to form 2-methoxyphenol acetate, wherein the molar ratio of guaiacol to acetyl chloride fed is from 1:1.1 to 1:3, preferably from 1:2 to 1: 3; the reaction temperature is preferably-5-25 ℃, and more preferably 25 ℃; the reaction time is preferably 1-6 h, and more preferably 6 h.
5. A process according to claim 4 wherein guaiacol and acetyl chloride are reacted under acid-binding conditions selected from at least one of triethylamine, pyridine, 4-dimethylaminopyridine, N-dimethylformamide, N-diisopropylethylamine or tetramethylethylenediamine, preferably triethylamine.
6. The method of claim 1, further comprising at least one of an organic solvent extraction, drying, concentration, or recrystallization step.
7. The process of claim 6, wherein the organic solvent is selected from the group consisting of dichloromethane, 1, 2-dichloroethane, chloroform; the solvent used for recrystallization is selected from any one or a mixture of more than one of acetone, ethanol, isopropanol, ethyl acetate, petroleum ether or toluene in any ratio.
8. A process for the preparation of a compound of formula I comprising the steps of preparing vanillone according to the process of any one of claims 1 to 7, and the step of converting vanillone to a compound of formula I,
9. the method of claim 8, further comprising the step of reacting vanillone with Compound B under basic conditions to form a compound of formula I,
wherein X is selected from a leaving group, preferably halogen, OTs, OMs, more preferably chlorine or OTs; the alkali is selected from triethylammonium or potassium carbonate.
10. The method of claim 8, further comprising the step of reacting vanillone with compound C under basic conditions to form compound D, and reacting compound D with compound E to form the compound of formula I,
wherein X is selected from a leaving group, preferably halogen, OTs, OMs, more preferably chlorine or OTs; the alkali is selected from triethylammonium or potassium carbonate.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113197204A (en) * | 2021-05-13 | 2021-08-03 | 何志松 | Preparation method of plant growth regulating compound sodium nitrophenolate |
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| WO2011154860A1 (en) * | 2010-06-08 | 2011-12-15 | Alembic Pharmaceuticals Limited | An improved process for preparing iloperidone |
| WO2014136786A1 (en) * | 2013-03-04 | 2014-09-12 | 国立大学法人九州大学 | Novel compound |
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| US20100076196A1 (en) * | 2008-09-19 | 2010-03-25 | Vertessy Miklos | Process for the preparation of iloperidone |
| WO2010031497A1 (en) * | 2008-09-19 | 2010-03-25 | Miklos Vertessy | New process for the preparation of iloperidone |
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| CN113197204A (en) * | 2021-05-13 | 2021-08-03 | 何志松 | Preparation method of plant growth regulating compound sodium nitrophenolate |
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