A method for preparing 5-alkyl resorcinols

Abstract

The present application relates to a kind of preparation method of 5-alkyl resorcinols compound. Specifically, the method includes the following steps: under the action of catalyst and persulfate, compound of formula (2) is subjected to dehydroaromatization reaction, and 5-alkyl resorcinols compound shown in formula (1) is obtained.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical synthesis, and particularly relates to a preparation method of 5-alkyl resorcinols. BACKGROUND

[0002] 5-alkyl resorcinols are a kind of medical intermediates with high activity and wide application. 5-methyl resorcinol can be used for synthesizing bratticanol with anti-tumor invasion activity, and can also be used for detecting antimony, chromium, nitrate and nitrite, pentose, lignin, sugar gum, aldehyde sugar, beet sugar, sucrose and amylase, etc. 5-pentyl resorcinol can be used for synthesizing cannabidiol compounds. The structural formula of 5-pentyl resorcinol is shown in the following formula (3):

[0003]

[0004] At present, the routes for synthesizing the compound shown in formula (3) mainly include the following routes:

[0005] Route one

[0006]

[0007] The aldehyde reagent is subjected to Witting reaction, Michael addition reaction and Claisen condensation reaction in sequence to obtain a sodium salt intermediate, which is reacted with cuprous bromide to obtain a bromination product. Then, the bromination and decarboxylation are performed to obtain 5-pentyl resorcinol, and the final yield is about 50% (J. Org. Chem. 1972, 37, 18). The Witting reagent used in the route is expensive, so that the route has high cost. In addition, the bromination reaction in the route produces polybrominated substitutes, and it is difficult to obtain high-purity products meeting market demand.

[0008] Route two

[0009]

[0010] The α,β-unsaturated ketone reagent is subjected to Michael addition and Claisen condensation to obtain an α,β-unsaturated cyclohexanone intermediate, which is then subjected to aromatization and decarboxylation under the action of bromine and DMF one-pot method to obtain 5-pentyl resorcinol (J. Org. Chem., 1977, 42, 21). When the bromination is performed using an equivalent of bromine, the route also produces polybrominated substitutes, which leads to purification difficulty and makes it difficult to obtain high-purity products meeting market demand.

[0011] Route three

[0012]

[0013] Bn-protected 3,5-dihydroxybenzaldehyde is subjected to Witting reaction, debenzylization and reductive hydrogenation to obtain 5-pentylresorcinol (Journal of Chemical Research 2009, 183). There is a problem in this route that the starting material is not commercially available, which is not suitable for the starting material of industrialized production of 5-pentylresorcinol.

[0014] Route four

[0015]

[0016] Bromo-methyl-protected resorcinol compound is subjected to coupling reaction, reductive hydrogenation and demethylation in sequence to obtain 5-pentylresorcinol (European Journal of Medicinal Chemistry 2020, 204, 112620). This route uses expensive metal palladium catalyst and a large amount of boron tribromide, which is not conducive to industrialized production.

[0017] In summary, there are still many shortcomings in the existing synthesis methods, such as low total yield, high cost, many by-products, difficult purification, and many waste products, which are not suitable for industrialized production. SUMMARY

[0018] TECHNICAL PROBLEM

[0019] The purpose of the present application is to provide a synthesis method of 5-alkylresorcinol compounds, which reduces the amount of catalyst, reduces the generation of reaction waste, and improves the total yield of target products, so as to be suitable for industrial large-scale production.

[0020] TECHNICAL SCHEME

[0021] In one aspect, the present application provides a preparation method of 5-alkylresorcinol compounds represented by formula (1), which comprises the following steps:

[0022] Under the action of a catalyst and a persulfate, the compound of formula (2) is subjected to dehydrogenation aromatization reaction to obtain 5-alkylresorcinol compounds represented by formula (1):

[0023]

[0024] In formula (1) and formula (2), R 1 selected from C1-C 10 linear or branched alkyl; R 2 selected from hydrogen, -CO2R, wherein R is selected from C1-C 10 linear or branched alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C6-C 10one or more substituents in the substituted benzyl group or the substituted aryl group can be selected from methoxy, halogen;

[0025] wherein the catalyst can be selected from one or more of iodine, potassium iodide, sodium iodide, bromine, potassium bromide, sodium bromide.

[0026] In a particular embodiment, in formula (1) and formula (2), R 1 is selected from one of methyl, ethyl, n-propyl, n-butyl, n-pentyl.

[0027] In a particular embodiment, in formula (1) and formula (2), R 2 is hydrogen or -CO2R, wherein R is selected from one of C1-C 10 one of linear or branched alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, and substituted or unsubstituted naphthyl, the substituted benzyl group can be selected from p-methoxybenzyl, 2,4-dimethoxybenzyl, and monochlorobenzyl, the substituted phenyl group can be selected from phenyl substituted with methoxy or halogen, and the substituted naphthyl group can be selected from naphthyl substituted with methoxy or halogen; in particular, R 2 is hydrogen or -CO2R, wherein R is selected from one of methyl, ethyl, n-propyl, n-butyl, n-pentyl.

[0028] In a particular embodiment, the persulfate salt can be selected from one or more of sodium persulfate, potassium persulfate, and ammonium persulfate.

[0029] In a particular embodiment, the molar ratio of the catalyst to the compound of formula (2) can be 1 :20 to 1 :2.5, preferably 1 :20 to 1 :5, for example 1 :15 to 1 :5 or 1 :10 to 1 :5.

[0030] In a particular embodiment, the molar ratio of the persulfate salt to the compound of formula (2) can be 0.9:1 to 2.0:1, preferably 1 :1 to 1.5:1.

[0031] In a particular embodiment, the dehydroaromatization reaction is carried out in the presence of a solvent, and the solvent can be selected from one or more of water, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, chlorobenzene, acetonitrile, benzonitrile, t-butanol, n-hexane, n-heptane, cyclohexane.

[0032] In a particular embodiment, the reaction temperature of the dehydroaromatization reaction can be 20 to 120°C, preferably 30 to 90°C.

[0033] In the specific embodiment, the reaction time of the dehydroaromatization reaction can be 3-24 hours, preferably 6-12 hours.

[0034] According to the present application, the halogen includes fluorine, chlorine, bromine, and iodine.

[0035] Advantages

[0036] An important feature of the present application is that cheap and readily available raw materials are used to directly oxidize and aromatize under the action of an oxidant and a catalyst, which is low in price and mild in reaction conditions. The preparation method of 5-alkyl resorcinols designed in the present application is suitable for the industrial production of 5-alkyl resorcinols and can well meet the market demand for 5-alkyl resorcinols.

[0037] The present application uses readily available chemical products as starting materials to prepare 5-alkyl resorcinols, which has the advantages of readily available raw materials, less by-products, easy purification, and high total yield in the synthesis process, and is suitable for development as an industrial production process. DETAILED DESCRIPTION

[0038] The advantages of the present application will be further described by the following examples, which should be understood as being for illustrative purposes only and do not limit the scope of the present application, and obvious changes and modifications made by those skilled in the art according to the present application are also included within the scope of the present application.

[0039] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the present application are conventional or known raw materials, reagents, methods in the art.

[0040] Example 1: Preparation of methyl 2,4-dihydroxy-6-methylbenzoate

[0041] Methyl 2-hydroxy-4-oxo-6-methylcyclohex-2-ene-1-carboxylate (1.84 g, 1.0 equivalent) and potassium iodide (332 mg, 0.2 equivalent) were placed in a 50 mL reaction bottle, acetonitrile (10 mL) was added, and then potassium persulfate (3.24 g, 1.2 equivalent) was added. The mixture was stirred at 80°C for 12 hours, the solid was removed by filtration, and all the solvent was removed by concentration under reduced pressure. Column chromatography (petroleum ether, ethyl acetate (100:1-10:1)) was performed to obtain methyl 2,4-dihydroxy-6-methylbenzoate (1.31 g, yield 72%). 1 H NMR (500 MHz, CDCl3): δ 11.73 (s, 1H), 6.29 (d, J = 2.5 Hz, 1H), 6.24 (t, J = 2.5 Hz, 1H), 5.57 (s, 1H), 3.93 (s, 3H), 2.50 (s, 3H). ESI m / z: (M+H) + 183.1.

[0042] Example 2: Preparation of methyl 2,4-dihydroxy-6-methylbenzoate

[0043] Methyl 2-hydroxy-4-oxo-6-methylcyclohex-2-ene-1-carboxylate (1.84 g, 1.0 eq) was taken in a 50 mL reaction flask, acetonitrile (10 mL) and iodine (253 mg, 0.1 eq) were added, then potassium persulfate (3.24 g, 1.2 eq) was added, stirred at 70 °C for 12 h, the solid was removed by filtration, all the solvent was removed by concentration under reduced pressure, column chromatography to obtain methyl 2,4-dihydroxy-6-methylbenzoate (1.53 g, yield 84%). 1 H NMR (500 MHz, CDC13): δ 11.73 (s, 1H), 6.29 (d, J = 2.5 Hz, 1H), 6.24 (t, J = 2.5 Hz, 1H), 5.57 (s, 1H), 3.93 (s, 3H), 2.50 (s, 3H). ESI m / z: (M+H) + 183.1.

[0044] Example 3: Preparation of methyl 2,4-dihydroxy-6-n-pentylbenzoate

[0045] Methyl 2-hydroxy-4-oxo-6-pentylcyclohex-2-ene-1-carboxylate (2.4 g, 1.0 eq) and potassium iodide (332 mg, 0.2 eq) were taken in a 50 mL reaction flask, acetonitrile (10 mL) was added, then potassium persulfate (3.24 g, 1.2 eq) was added, stirred at 70 °C for 6 h, the solid was removed by filtration, all the solvent was removed by concentration under reduced pressure, column chromatography to obtain methyl 2,4-dihydroxy-6-pentylbenzoate (1.42 g, yield 60%). 1 H NMR (400 MHz, CDC13): δ 0.9 (s, 3H), 1.2-1.7 (b, 6H), 2.8 (m, 2H), 4.0 (s, 3H), 6.2 (s, 2H). ESI m / z: (M+H) + 238.1.

[0046] Example 4: Preparation of methyl 2,4-dihydroxy-6-n-pentylbenzoate

[0047] Methyl 2-hydroxy-4-oxo-6-pentylcyclohex-2-ene-1-carboxylate (1.9 g, 1.0 eq) and potassium iodide (270 mg, 0.2 eq) were taken in a 50 mL reaction flask, toluene (10 mL) was added, then potassium persulfate (2.6 g, 1.2 eq) was added, stirred at 80 °C for 12 h, the solid was removed by filtration, all the solvent was removed by concentration under reduced pressure, column chromatography to obtain methyl 2,4-dihydroxy-6-pentylbenzoate (833 g, yield 60%).1 H NMR (400 MHz, CDC13): δ 0.9 (s, 3H), 1.2-1.7 (b, 6H), 2.8 (m, 2H), 4.0 (s, 3H), 6.2 (s, 2H). ESI m / z: (M+H) + 238.1.

[0048] Example 5: Preparation of 2,4-dihydroxy-6-n-pentyl benzoic acid methyl ester

[0049] 2-hydroxy-4-oxo-6-pentylcyclohex-2-ene-1-carboxylic acid methyl ester (2.4 g, 1.0 eq) was taken in a 50 mL reaction flask, acetonitrile (10 mL) and iodine (253 mg, 0.1 eq) were added, then potassium persulfate (3.24 g, 1.2 eq) was added, stirred at 60 °C for 6 hours, the solid was removed by filtration, all the solvent was removed by concentration under reduced pressure, column chromatography to obtain 2,4-dihydroxy-6-pentyl benzoic acid methyl ester (1.90 g, yield 80%). 1 H NMR (400 MHz, CDC13): δ 0.9 (s, 3H), 1.2-1.7 (b, 6H), 2.8 (m, 2H), 4.0 (s, 3H), 6.2 (s, 2H). ESI m / z: (M+H) + 238.1.

[0050] Example 6: Preparation of 2,4-dihydroxy-6-n-pentyl benzoic acid ethyl ester

[0051] 2-hydroxy-4-oxo-6-pentylcyclohex-2-ene-1-carboxylic acid ethyl ester (2.54 g, 1.0 eq) was taken in a 50 mL reaction flask, acetonitrile (10 mL) and iodine (253 mg, 0.1 eq) were added, then potassium persulfate (3.24 g, 1.2 eq) was added, stirred at 80 °C for 12 hours, the solid was removed by filtration, all the solvent was removed by concentration under reduced pressure, column chromatography to obtain 2,4-dihydroxy-6-pentyl benzoic acid ethyl ester (2.06 g, yield 82%). ESI m / z: (M+H) + 255.3.

[0052] Example 7: Preparation of 2,4-dihydroxy-6-n-pentyl benzoic acid methyl ester

[0053] 2-hydroxy-4-oxo-6-pentylcyclohex-2-ene-1-carboxylic acid methyl ester (2.4 g, 1.0 eq) was taken in a 50 mL reaction flask, acetonitrile (10 mL) and bromine (160 mg, 0.1 eq) were added, then sodium persulfate (2.85 g, 1.2 eq) was added, stirred at 80 °C for 12 hours, the solid was removed by filtration, all the solvent was removed by concentration under reduced pressure, column chromatography to obtain 2,4-dihydroxy-6-pentyl benzoic acid methyl ester (1.55 g, yield 65%).1 H NMR (400 MHz, CDC13): δ 0.9 (s, 3H), 1.2-1.7 (b, 6H), 2.8 (m, 2H), 4.0 (s, 3H), 6.2 (s, 2H). ESI m / z: (M+H) + 238.1.

[0054] Example 8: Preparation of 2,4-dihydroxy-6-n-pentylbenzoic acid methyl ester

[0055] Take 2-hydroxy-4-oxo-6-n-pentylcyclohex-2-en-1-carboxylic acid methyl ester (2.4 g, 1.0 equivalent) in a 50 mL reaction bottle, add acetonitrile (10 mL) and potassium bromide (238 mg, 0.2 equivalent), then add sodium persulfate (2.85 g, 1.2 equivalent), stir at 90°C for 6 hours, filter to remove the solid, remove all solvents under reduced pressure, column chromatography to obtain 2,4-dihydroxy-6-n-pentylbenzoic acid methyl ester (1.38 g, yield 58%). 1 H NMR (400 MHz, CDC13): δ 0.9 (s, 3H), 1.2-1.7 (b, 6H), 2.8 (m, 2H), 4.0 (s, 3H), 6.2 (s, 2H). ESI m / z: (M+H) + 238.1.

[0056] Example 9: Preparation of 5-n-pentyl-1,3-benzenediol

[0057] Take 3-hydroxy-5-n-pentylcyclohex-2-en-1-one (1.82 g, 1.0 equivalent) in a 50 mL reaction bottle, add acetonitrile (10 mL) and bromine (160 mg, 0.1 equivalent), then add sodium persulfate (2.85 g, 1.2 equivalent), stir at 80°C for 12 hours, filter to remove the solid, remove all solvents under reduced pressure, column chromatography to obtain 5-n-pentyl-1,3-benzenediol (0.87 g, yield 70%). 1 H NMR (400 MHz, CDC13): δ 6.26 (t, J = 2.2 Hz, 1H), 6.19 (t, J = 2.2 Hz, 1H), 2.50-2.38 (m, 2H), 1.36-1.21 (m, 4H), 0.87 (q, J = 6.6 Hz, 3H). ESI m / z: (M+H) + 181.2.

[0058] Example 10: Preparation of 5-n-pentyl-1,3-benzenediol

[0059] Take 3-hydroxy-5-n-pentylcyclohex-2-en-1-one (1.82 g, 1.0 equivalent) into a 50 mL reaction bottle, add acetonitrile (10 mL) and iodine (253 mg, 0.1 equivalent), then add sodium persulfate (2.85 g, 1.2 equivalent), stir at 80°C for 12 hours, filter to remove the solid, concentrate to remove all solvents under reduced pressure, column chromatography to obtain 5-n-pentyl-1,3-benzenediol (1.53 g, yield 85%). 1 H NMR (400 MHz, CDC13): δ 6.26 (t, J = 2.2 Hz, 1H), 6.19 (t, J = 2.2 Hz, 1H), 2.50-2.38 (m, 2H), 1.36-1.21 (m, 4H), 0.87 (q, J = 6.6 Hz, 3H). ESI m / z: (M+H) + 181.2.

Claims

1. A method for preparing a 5-alkylresorcinol compound, comprising the steps of: subjecting a compound of formula (2) to a dehydroaromatization reaction in the presence of a catalyst and a persulfate salt to obtain a 5-alkylresorcinol compound of formula (1) : wherein, in formulae (1) and (2), R 1 is selected from the group consisting of a substituted benzyl group, a substituted phenyl group, and a substituted naphthyl group, and R 2 is selected from the group consisting of a hydrogen atom, a substituted benzyl group, a substituted phenyl group, and a substituted naphthyl group. The dehydroaromatization reaction is carried out in the presence of a solvent, and the solvent is selected from one or more of water, dichloromethane, dichloroethane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, chlorobenzene, acetonitrile, benzonitrile, t-butanol, n-hexane, n-heptane, and cyclohexane. The dehydroaromatization reaction is carried out at a reaction temperature of 20 to 120℃. R 1 selected from C1-C 10 linear or branched alkyl; R 2 Selected from hydrogen, -CO2R, where R is selected from C1 to C2. 10 Straight-chain or branched alkyl groups, substituted or unsubstituted benzyl groups, substituted or unsubstituted C6-C6 groups. 10 One of the aryl groups, wherein the substituents in the substituted benzyl or substituted aryl group can be one or more, and are selected from methoxy and halogen; The dehydroaromatization reaction is carried out at a reaction temperature of 30 to 90℃. The dehydroaromatization reaction is carried out for a reaction time of 3 to 24 hours.

2. The method of claim 1, wherein, In formula (1) and formula (2), R 1 is one selected from methyl, ethyl, n-propyl, n-butyl or n-pentyl.

3. The method of claim 1, wherein, In formula (1) and formula (2), R 2 is hydrogen or -CO2R, wherein R is selected from the group consisting of C1-C 10 straight-chain or branched alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl, The dehydroaromatization reaction is carried out for a reaction time of 6 to 12 hours.

4. The method of claim 1, wherein, In formula (1) and formula (2), R 2 is hydrogen or -CO2R, wherein R is one selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl.

5. The method of claim 1, wherein, ​ 6. The method of claim 1, wherein, ​ 7. The method of claim 1, wherein, ​ 8. The method of claim 1, wherein, ​ 9. The method of claim 1, wherein, ​ 10. The method of claim 1, wherein, ​ 11. The method of claim 1, wherein, ​ 12. The method of claim 1, wherein, ​

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