A green synthesis of polysubstituted benzyl ethers and polysubstituted benzaldehydes

Abstract

The application discloses a preparation method of a polysubstituted benzyl ether, which comprises the following steps: dissolving a compound III in a polar protic solvent, adding a base, and reacting under the action of an oxidant at a temperature of 15-100 DEG C for 1-48 h to obtain a compound I; the preparation method of the polysubstituted benzyl ether is a green synthesis method, the reaction condition is warm and environment-friendly, the alcohol used can be recycled, the use of expensive metal catalysts is avoided, the cost is low, the reaction steps are few, the yield is high, the discharge of three wastes is reduced, and there is no metal residue, so the method is suitable for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a preparation method of a polysubstituted benzyl ether and a polysubstituted benzaldehyde. BACKGROUND

[0002] Benzyl ether is an important fragment existing in many drug molecules and natural products, and has important applications in medicine, pesticides and the like.

[0003] At present, the synthesis routes of benzyl ether mainly include the following:

[0004] 1) C-O bond is constructed through Ullmann type C-O bond coupling reaction or Williamson reaction. Specifically, C-O bond coupling is realized by SN2 reaction of O-nucleophile and a substrate having an alcohol derivative or halogen as a good leaving group at the benzyl position.

[0005]

[0006] 2) Benzyl ether is realized through direct realization of cross-coupling reaction of benzyl C-H and alcohol through chemical oxidation, electrochemical oxidation and transition metal catalysis.

[0007]

[0008] Syringaldehyde is a key intermediate of many drugs, and is mainly applied to the synthesis of classic antibacterial agent methoxybenzyl and podophyllotoxin.

[0009] At present, the synthesis routes of syringaldehyde mainly include the following:

[0010] The patent application with the publication number CN101575269A discloses that 3,5-dibromo-4-hydroxybenzaldehyde is used as raw material, sodium methoxide methanol solution is used as methoxylation reagent and reaction solvent, and syringaldehyde is obtained through cuprous salt-carbon monoxide or cuprous salt-methyl formate catalysis.

[0011]

[0012] 2,6-dimethoxy-4-methylphenol is used as raw material, and direct oxidation of benzyl C-H bond is realized through transition metal copper or cobalt catalysis to obtain syringaldehyde.

[0013] SUMMARY

[0014] The application aims to provide a preparation method of a polysubstituted benzyl ether, which has mild reaction conditions, is environmentally friendly, belongs to a green synthesis method, uses recyclable alcohol, avoids the use of expensive metal catalysts, has low cost, few reaction steps, high yield, reduced three waste emissions, no metal residues, and is suitable for industrial production.

[0015] Another object of the application is to provide a preparation method of a polysubstituted benzaldehyde.

[0016] To achieve the above object, the application adopts the following technical solutions:

[0017] In a first aspect of the application, a preparation method of a polysubstituted benzyl ether is provided, which comprises the following steps:

[0018]

[0019] Compound III is dissolved in an excess of a polar protic solvent, a base is added, and the mixture is reacted under the action of an oxidant at a temperature of 15-100 DEG C (preferably 60-95 DEG C, and most preferably 60 DEG C, 65 DEG C or 95 DEG C) for 1-48 h (preferably 24 h) to obtain compound I; the molar ratio of compound III to the base is 1:0.05-1 (preferably 1:0.3 or 1:0.5);

[0020] The polar protic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, ethylene glycol, 3-buten-1-ol, cyclopropylmethanol, benzyl alcohol, ethylene glycol monomethyl ether, phenethyl alcohol, phenylpropanol, 4-methoxybenzyl alcohol, acetonitrile, 4-chlorobenzyl alcohol, 2-bromobenzyl alcohol, 3-bromobenzyl alcohol, 2-methoxybenzyl alcohol, 2-bromo-phenethyl alcohol, 2-naphthalene ethanol, and deuterated methanol;

[0021] The base is selected from at least one of potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, potassium methoxide, potassium carbonate, potassium bicarbonate, sodium bicarbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), and 1,4-diazabicyclo[2.2.2]octane (DABCO);

[0022] The oxidant is selected from oxygen and air;

[0023] In the compound III,

[0024] R1 is selected from hydrogen, C1-C20 alkyl, and C1-C20 alkoxy;

[0025] R2 is selected from hydrogen, C1-C20 alkyl, and C1-C20 alkoxy;

[0026] R3is selected from the group consisting of hydrogen, C1-C20alkyl, R6is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R7is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R8is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R9is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R 10 R6is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R7is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R8is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R9is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R

[0027] R1is selected from the group consisting of hydrogen, C1-C20alkyl, C1-C20alkoxy;

[0028] R2is selected from the group consisting of hydrogen, C1-C20alkyl, C1-C20alkoxy;

[0029] R3is selected from the group consisting of hydrogen, C1-C20alkyl, R6is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R7is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R8is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R9is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R 10 R6is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R7is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R8is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R9is selected from the group consisting of hydrogen, C1-C10alkyl, C1-C10alkoxy, halogen (fluorine, chlorine, bromine, iodine); R 11 C1-C20alkyl, deuterium-substituted C1-C20alkyl,

[0030]

[0031] n1is a positive integer from 1 to 10 (e.g. 1, 2, 3, 4, 5, 6);

[0032] R 11 selected from the group consisting of hydrogen, C1-C10alkyl;

[0033] n2is a positive integer from 0 to 10 (e.g. 0, 1, 2, 3, 4, 5, 6);

[0034] n3is a positive integer from 0 to 10 (e.g. 0, 1, 2, 3, 4, 5, 6);

[0035] n4is a positive integer from 0 to 10 (e.g. 0, 1, 2, 3, 4, 5, 6);

[0036] n5is a positive integer from 0 to 10 (e.g. 0, 1, 2, 3, 4, 5, 6);

[0037] R 12 selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, halogen (fluorine, chlorine, bromine, iodine);

[0038] R 13 selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, halogen (fluorine, chlorine, bromine, iodine);

[0039] R 14 selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, halogen (fluorine, chlorine, bromine, iodine);

[0040] R 15 selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, halogen (fluorine, chlorine, bromine, iodine);

[0041] R 16 selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, halogen (fluorine, chlorine, bromine, iodine).

[0042] The molar ratio of the compound III to the polar protic solvent is 1:1-200.

[0043] More preferably, in the compound III,

[0044] R1is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, n-hexyloxy;

[0045] R2is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, n-hexyloxy;

[0046] R3is selected from the group consisting of hydrogen, hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl,

[0047]

[0048] More preferably, in the compound I,

[0049] R1is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, n-hexyloxy;

[0050] R2is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy;

[0051] R3is selected from the group consisting of hydrogen, hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl,

[0052]

[0053] R4is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CD3, -CH2CD3, -CH2CH2OCD3,

[0054]

[0055] Most preferably, the compound III is selected from one of the following structures:

[0056]

[0057] Most preferably, the compound I is selected from one of the following structures:

[0058]

[0059]

[0060]

[0061] In a second aspect of the present application, a method for preparing a polysubstituted benzaldehyde is provided, comprising the steps of:

[0062]

[0063] dissolving compound IV in an excess of a polar protic solvent, adding a base, reacting under the action of a first oxidizing agent at a temperature of 15-100°C (preferably 60-95°C, most preferably 60°C, 65°C, 95°C) for 1-48h (preferably 24h), adding a second oxidizing agent, reacting under the action of a second oxidizing agent at a temperature of 15-100°C (preferably 60-95°C, most preferably 60°C, 65°C, 95°C) for 1-48h (preferably 24h), to obtain a compound of formula II;

[0064] The molar ratio of compound IV to base is 1:0.05-1 (preferably 1:0.3, 1:0.5);

[0065] The molar ratio of compound IV to the second oxidizing agent is 1 :0.05 to 1.5 (preferably 1 :1);

[0066] The polar protic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, ethylene glycol, 3-buten-1-ol, cyclopropylmethanol, benzyl alcohol, ethylene glycol monomethyl ether, phenethyl alcohol, phenylpropanol, 4-methoxybenzyl alcohol, acetonitrile, 4-chlorobenzyl alcohol, 2-bromobenzyl alcohol, 3-bromobenzyl alcohol, 2-methoxybenzyl alcohol, 2-bromo-phenethyl alcohol, 2-naphthaleneethanol, deuterated methanol;

[0067] The base is selected from at least one of potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, potassium methoxide, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), 1,4-diazabicyclo[2.2.2]octane (DABCO);

[0068] The first oxidizing agent is selected from the group consisting of oxygen, air;

[0069] The second oxidizing agent is selected from the group consisting of oxygen, air, hydrogen peroxide, potassium permanganate, manganese dioxide, tert-butyl hydroperoxide, ozone, potassium dichromate, sodium hypochlorite, meta-chloroperoxybenzoic acid, peroxyacetic acid, 2,3-dichloro-5,6-dicyano-p-benzoquinone, lead tetraacetate and the like.

[0070] In the compound IV,

[0071] R1is selected from the group consisting of hydrogen, C1-C20alkyl, C1-C20alkoxy;

[0072] R2is selected from the group consisting of hydrogen, C1-C20alkyl, C1-C20alkoxy;

[0073] In the compound II,

[0074] R1is selected from the group consisting of hydrogen, C1-C20alkyl, C1-C20alkoxy;

[0075] R2is selected from the group consisting of hydrogen, C1-C20alkyl, C1-C20alkoxy.

[0076] More preferably, in the compound IV,

[0077] R1is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexyloxy;

[0078] R2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy.

[0079] More preferably, in the compound II,

[0080] R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy;

[0081] R2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy.

[0082] The molar ratio of the compound IV to the polar protic solvent is 1:1-200.

[0083] Most preferably, the compound IV is selected from one of the following structures:

[0084]

[0085]

[0086] Most preferably, the compound II is selected from one of the following structures:

[0087]

[0088] Due to the adoption of the above technical solutions, the application has the following advantages and beneficial effects:

[0089] The preparation method of the polysubstituted benzyl ether of the application has the advantages of mild reaction conditions, environmental protection, recyclable alcohol, low cost, less reaction steps, high yield, reduced waste discharge, no metal residues, and suitability for industrial production.

[0090] When 2,6-dimethoxy-4-methylphenol is used as a raw material, the method can realize efficient and green synthesis of syringaldehyde by adding an oxidizing agent to the system after methoxylation.

[0091] The reaction system of the method is simple, and the source is extensive; the method is green and environment-friendly, the polar protic solvent used can be recycled, the expensive catalyst is avoided, the reaction is economical, the cost is low, and the atom efficiency is high. DETAILED DESCRIPTION

[0092] In order to more clearly illustrate the present application, the present application will be further described below in combination with preferred embodiments. It should be understood by those skilled in the art that the specific description below is illustrative rather than limiting, and should not limit the protection scope of the present application.

[0093] The present application is the result of extensive and in-depth research, and it is accidentally found that the efficient conversion of the multi-alkyl substituted p-methyl phenol methane to the multi-alkyl substituted benzyl ether and the lilac aldehyde can be realized simply and efficiently under the condition of the oxidizing agent in the polar protic solvent by using the base, especially the inorganic base, as the additive.

[0094] The structure of the compound of the present application is determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0095] The NMR is detected by using the Bruker AVANCE-400 nuclear magnetic instrument, the determination solvent includes deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD) and the like, the internal standard uses tetramethylsilane (TMS), and the chemical shift is measured in units of millionths (ppm).

[0096] The liquid chromatography-mass spectrometry (LC-MS) is detected by using the Waters SQD2 mass spectrometer. The determination of HPLC uses the Agilent 1100 high-pressure chromatograph (Microsorb 5 micron C18 100x3.0 mm chromatographic column).

[0097] The thin layer chromatography silica gel plate uses the Qingdao GF254 silica gel plate, the TLC uses 0.15-0.20 mm, and the preparation thin layer chromatography uses 0.4 mm-0.5 mm. The column chromatography generally uses the Qingdao silica gel 200-300 mesh silica gel as the carrier.

[0098] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized by using or according to the reported literature in the art.

[0099] Example 1

[0100] Preparation of 2,6-dimethoxy-4-(methoxymethyl)phenol (compound of formula I-1):

[0101]

[0102] Into a 25 mL flask was placed 2,6-dimethoxy-4-methylphenol (50 mg, 0.3 mmol), a rotor and methanol (1.58 g, 49 mmol, 2 mL), potassium t-butoxide (10 mg, 0.09 mmol), and stirred at 60 °C under an oxygen atmosphere. After 24 hours, the reaction was cooled to room temperature and the methanol was recovered by vacuum concentration. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give 2,6-dimethoxy-4-(methoxymethyl)phenol (compound of Formula I-1) 46 mg in 78% yield. 1 HNMR (400 MHz, CDC13): δ 6.57 (s, 2H), 5.57 (s, 1H), 4.37 (s, 2H), 3.88 (s, 6H), 3.37 (s, 3H). 13 CNMR (150 MHz, CDC13): δ 147.0, 134.2, 129.2, 104.6, 75.0, 57.9, 56.3.

[0103] Example 2

[0104]

[0105] Using 2,6-diethoxy-4-methylphenol instead of 2,6-dimethoxy-4-methylphenol in Example 1, and following the same procedure as in Example 1, the yield was 83%. 1 HNMR (400 MHz, CDC13): δ 6.54 (s, 2H), 5.56 (s, 1H), 4.34 (s, 2H), 4.11 (q, J = 7.2 Hz, 4H), 3.35 (s, 3H), 1.43 (t, J = 6.8 Hz, 6H). 13 CNMR (150 MHz, CDC13): δ 146.3, 134.8, 129.0, 105.8, 75.0, 64.8, 57.8, 15.0.

[0106] Example 3

[0107]

[0108] Using 4-methyl-2,6-dipropoxyphenol instead of 2,6-dimethoxy-4-methylphenol in Example 1, and following the same procedure as in Example 1, the yield was 68%. 1 HNMR (400 MHz, CDC13): δ 6.55 (s, 2H), 5.53 (s, 1H), 4.34 (s, 2H), 4.00 (t, J = 6.8 Hz, 4H), 3.36 (s, 3H), 1.88-1.79 (m, 4H), 1.03 (t, J = 7.6 Hz, 6H).13 CNMR (150 MHz, CDC13) δ 146.5, 134.9, 129.0, 105.9, 75.0, 70.9, 57.9, 22.6, 10.5.

[0109] Example 4

[0110]

[0111] Example 1 was repeated except that 2,6-diisobutoxy-4-methylphenol was used instead of 2,6-dimethoxy-4-methylphenol. The yield was 65%. 1 HNMR (400 MHz, CDC13): δ 6.48 (s, 2H), 5.46 (s, IH), 4.28 (s, 2H), 3.97 (t, J = 6.8 Hz, 4H), 3.29 (s, 3H), 1.76-1.69 (m, 4H), 1.46-1.37 (m, 4H), 0.90 (t, J = 7.2 Hz, 6H). 13 CNMR (150 MHz, CDC13): δ 145.4, 133.8, 128.0, 104.8, 74.0, 68.0, 56.8, 30.3, 18.2, 12.8.

[0112] Example 5

[0113]

[0114] Example 1 was repeated except that 2,6-diisobutoxy-4-methylphenol was used instead of 2,6-dimethoxy-4-methylphenol. The yield was 65%. 1 HNMR (400 MHz, CDC13): δ 6.48 (s, 2H), 5.46 (s, IH), 4.28 (s, 2H), 3.97 (t, J = 6.8 Hz, 4H), 3.29 (s, 3H), 1.76-1.69 (m, 4H), 1.46-1.37 (m, 4H), 0.90 (t, J = 7.2 Hz, 6H). 13 CNMR (150 MHz, CDC13): δ 145.4, 133.8, 128.0, 104.8, 74.0, 68.0, 56.8, 30.3, 18.2, 12.8.

[0115] Example 6

[0116]

[0117] Example 1 was repeated except that 2-ethoxy-6-methoxy-4-methylphenol was used instead of 2,6-dimethoxy-4-methylphenol. The yield was 73%.1 HNMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 6.56 (s, 1H), 6.55 (s, 1H), 4.28 (s, 2H), 3.99 (q, J = 6.8 Hz, 2H), 3.75 (s, 3H), 3.25 (s, 3H), 1.31 (t, J = 6.8 Hz, 3H). 13 CNMR (150 MHz, DMSO-d6): δ 148.0, 147.0, 135.3, 128.2, 106.8, 105.3, 74.1, 64.3, 57.2, 56.0, 15.0.

[0118] Example 7

[0119]

[0120] Example 1, except that 2-ethoxy-4,6-dimethylphenol was used instead of 2,6-dimethoxy-4-methylphenol, and the yield was 55%. 1 HNMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 6.56 (s, 1H), 6.55 (s, 1H), 4.28 (s, 2H), 3.99 (q, J = 6.8 Hz, 2H), 3.75 (s, 3H), 3.25 (s, 3H), 1.31 (t, J = 6.8 Hz, 3H). 13 CNMR (150 MHz, DMSO-d6): δ 148.0, 147.0, 135.3, 128.2, 106.8, 105.3, 74.1, 64.3, 57.2, 56.0, 15.0.

[0121] Example 8

[0122]

[0123] Example 1, except that 2-ethoxy-4,6-dimethylphenol was used instead of 2,6-dimethoxy-4-methylphenol, and the yield was 55%. 1 HNMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 6.56 (s, 1H), 6.55 (s, 1H), 4.28 (s, 2H), 3.99 (q, J = 6.8 Hz, 2H), 3.75 (s, 3H), 3.25 (s, 3H), 1.31 (t, J = 6.8 Hz, 3H). 13CNMR (150 MHz, CDC13): δ 145.4, 143.4, 128.9, 123.5, 122.9, 109.0, 74.9, 64.6, 57.8, 15.4, 15.0.

[0124] Example 9

[0125]

[0126] Example 1 using 2-ethoxy-4,6-dimethylphenol instead of 2,6-dimethoxy-4- methylphenol, and the other conditions and steps are the same as those of Example 1, the yield is 62%. 1 HNMR (400 MHz, CDC13): δ 6.72 (s, 1H), 6.70 (s, 1H), 5.75 (s, 1H), 4.33 (s, 2H), 4.03 (t, J = 6.8 Hz, 2H), 3.35 (s, 3H), 2.24 (s, 3H), 1.82-1.75 (m, 2H), 1.53-1.44 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H). 13 CNMR (150 MHz, CDC13): δ 145.6, 143.4, 128.9, 123.4, 122.8, 108.9, 74.9, 68.7, 57.8, 31.3, 19.2, 15.4, 13.8.

[0127] Example 10

[0128]

[0129] Example 1 using 2-ethoxy-4,6-dimethylphenol instead of 2,6-dimethoxy-4- methylphenol, and the other conditions and steps are the same as those of Example 1, the yield is 62%. 1 HNMR (400 MHz, CDC13): δ 6.72 (s, 1H), 6.70 (s, 1H), 5.75 (s, 1H), 4.33 (s, 2H), 4.03 (t, J = 6.8 Hz, 2H), 3.35 (s, 3H), 2.24 (s, 3H), 1.82-1.75 (m, 2H), 1.53-1.44 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H). 13 CNMR (150 MHz, CDC13): δ 145.6, 143.4, 128.9, 123.4, 122.8, 108.9, 74.9, 68.7, 57.8, 31.3, 19.2, 15.4, 13.8.

[0130] Example 11

[0131]

[0132] Example 1 using 4-ethyl-2,6-dimethoxyphenol instead of 2,6-dimethoxy-4- methylphenol, and the other conditions and steps are the same as those of Example 1, and the yield is 62%. 1 HNMR (400 MHz, CDC13): δ 6.53 (s, 2H), 5.52 (s, 1H), 4.19 (q, J = 6.4 Hz, 1H), 3.88 (s, 6H), 3.21 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H). 13 CNMR (150 MHz, CDC13): δ 147.1, 134.7, 133.9, 102.7, 79.9, 56.4, 56.3, 24.0.

[0133] Example 12

[0134]

[0135] Example 1 using 2,6-diethoxy-4-ethylphenol instead of 2,6-dimethoxy-4- methylphenol, and the other conditions and steps are the same as those of Example 1, and the yield is 70%. 1 HNMR (400 MHz, CDC13): δ 6.51 (s, 2H), 5.53 (s, 1H), 4.18-4.08 (m, 5H), 3.19 (s, 3H), 1.44-1.38 (m, 9H). 13 CNMR (150 MHz, CDC13): δ 145.3, 133.5, 133.4, 102.8, 78.8, 63.7, 55.3, 23.0, 14.0.

[0136] Example 13

[0137]

[0138] Example 1 using 4-ethyl-2,6-dimethoxyphenol instead of 2,6-dimethoxy-4- methylphenol, and the other conditions and steps are the same as those of Example 1, and the yield is 62%. 1 HNMR (600 MHz, CDC13): δ 6.52 (s, 2H), 5.47 (s, 1H), 4.17 (q, J = 6.6 Hz, 1H), 4.01 (t, J = 6.6 Hz, 4H), 3.21 (s, 3H), 1.88-1.82 (m, 4H), 1.41 (d, J = 6.6 Hz, 3H), 1.04 (t, J = 7.8 Hz, 6H). 13CNMR (150 MHz, CDC13): δ 146.5, 134.5, 134.4, 103.9, 79.9, 70.8, 56.3, 24.1, 22.6, 10.5.

[0139] Example 14

[0140]

[0141] Example 1 using 2,6-dimethoxy-4-propylphenol instead of 2,6-dimethoxy-4- methylphenol, and the other conditions and steps are the same as those of Example 1, the yield is 61%. 1 HNMR (600 MHz, CDC13): δ 6.51 (s, 2H), 5.47 (s, 1H), 4.17 (q, J = 6.0 Hz, 1H), 4.04 (t, J = 7.2 Hz, 4H), 3.20 (s, 3H), 1.82 - 1.77 (m, 4H), 1.52 - 1.47 (m, 4H), 1.40 (d, J = 6.6 Hz, 3H), 0.97 (t, J = 7.8 Hz, 6H). 13 CNMR (150 MHz, CDC13): δ 146.5, 134.5, 134.4, 103.9, 79.9, 69.1, 56.3, 31.4, 24.1, 19.2, 13.9.

[0142] Example 15

[0143]

[0144] Example 1 using 2,6-dimethoxy-4-propylphenol instead of 2,6-dimethoxy-4- methylphenol, and the other conditions and steps are the same as those of Example 1, the yield is 61%. 1 HNMR (600 MHz, CDC13): δ 6.50 (s, 2H), 5.50 (s, 1H), 3.90 (t, J = 7.2 Hz, 1H), 3.88 (s, 6H), 3.20 (s, 3H), 1.84 - 1.77 (m, 1H), 1.66 - 1.60 (m, 1H), 0.86 (t, J = 7.2 Hz, 3H). 13 CNMR (150 MHz, CDC13): δ 147.0, 133.9, 133.4, 103.2, 85.8, 56.6, 56.3, 31.0, 10.4.

[0145] Example 16

[0146]

[0147] The same as example 1 except that 2,6-dimethoxy-4-methylphenol in example 1 was replaced by 4-butyl-2,6-dimethoxyphenol, and the yield was 76%. 1 HNMR (600 MHz, CDC13): δ 6.44 (s, 2H), 5.46 (s, 1H), 3.91 (t, J = 6.0 Hz, 1H), 3.81 (s, 6H), 3.12 (s, 3H), 1.73 - 1.67 (m, 1H), 1.52 - 1.46 (m, 1H), 1.37 - 1.28 (m, 1H), 1.23 - 1.14 (m, 1H), 0.82 (t, J = 7.2 Hz, 3H). 13 CNMR (150 MHz, CDC13): δ 146.0, 132.8, 132.7, 102.1, 83.1, 55.5, 55.2, 39.4, 18.1, 13.0.

[0148] Example 17

[0149]

[0150] The same as example 1 except that 2,6-dimethoxy-4-methylphenol in example 1 was replaced by 4-butyl-2,6-dimethoxyphenol, and the yield was 76%. 1 HNMR (600 MHz, CDC13): δ 6.44 (s, 2H), 5.46 (s, 1H), 3.91 (t, J = 6.0 Hz, 1H), 3.81 (s, 6H), 3.12 (s, 3H), 1.73 - 1.67 (m, 1H), 1.52 - 1.46 (m, 1H), 1.37 - 1.28 (m, 1H), 1.23 - 1.14 (m, 1H), 0.82 (t, J = 7.2 Hz, 3H). 13 CNMR (150 MHz, CDC13): δ 146.0, 132.8, 132.7, 102.1, 83.1, 55.5, 55.2, 39.4, 18.1, 13.0.

[0151] Example 18

[0152]

[0153] The same as example 1 except that 2,6-dimethoxy-4-methylphenol in example 1 was replaced by 4-butyl-2,6-dimethoxyphenol, and the yield was 76%. 1 HNMR (600 MHz, CDC13): δ 6.44 (s, 2H), 5.46 (s, 1H), 3.91 (t, J = 6.0 Hz, 1H), 3.81 (s, 6H), 3.12 (s, 3H), 1.73 - 1.67 (m, 1H), 1.52 - 1.46 (m, 1H), 1.37 - 1.28 (m, 1H), 1.23 - 1.14 (m, 1H), 0.82 (t, J = 7.2 Hz, 3H).13 CNMR (150 MHz, CDC13): δ 147.0, 142.1, 134.1, 133.1, 128.4, 127.5, 126.9, 103.8, 85.5, 57.0, 56.3.

[0154] Example 19

[0155]

[0156] Example 1 using 2,6-dimethoxy-4-(4-methylbenzyl)phenol instead of 2,6-dimethoxy-4-methylphenol, and the other conditions and steps are the same as in Example 1, the yield is 62%. 1 HNMR (400 MHz, CDC13): δ 7.21 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.57 (s, 2H), 5.46 (s, IH), 5.13 (s, IH), 3.86 (s, 6H), 3.37 (s, 3H), 2.33 (s, 3H). 13 CNMR (100 MHz, CDC13): δ 147.0, 139.1, 137.2, 133.9, 133.4, 129.1, 126.8, 103.6, 85.3, 57.0, 56.3, 21.1.

[0157] Example 20

[0158]

[0159] Example 1 using 4-(4-chlorobenzyl)-2,6-dimethoxyphenol instead of 2,6-dimethoxy-4-methylphenol, and the other conditions and steps are the same as in Example 1, the yield is 57%. 1 HNMR (600 MHz, CDC13): δ 7.30 - 7.25 (m, 4H), 6.53 (s, 2H), 5.50 (s, IH), 5.12 (s, IH), 3.86 (s, 6H), 3.37 (s, 3H). 13 CNMR (150 MHz, CDC13): δ 147.1, 140.7, 134.2, 133.2, 132.6, 128.5, 128.2, 103.7, 84.7, 57.0, 56.3.

[0160] Example 21

[0161] Preparation of 2,6-dimethoxy-4-(propoxymethyl)phenol (compound of formula I-21):

[0162]

[0163] 2,6-Dimethoxy-4-methylphenol (50 mg, 0.3 mmol) was placed in a 25 mL flask, a rotor and n-propanol (1.62 g, 27 mmol, 2 mL) were added, potassium hydroxide (8 mg, 0.15 mmol) was added, and the reaction was stirred at 95 °C under an oxygen atmosphere. After 48 hours, the reaction was cooled to room temperature, and the propanol was recovered by vacuum concentration. Column chromatography of the crude product gave 2,6-dimethoxy-4-(propoxymethyl)phenol (compound of formula I-21) in a yield of 34 mg, 50%. 1 HNMR (400 MHz, CDC13): δ 6.58 (s, 2H), 5.49 (s, 1H), 4.42 (s, 2H), 3.89 (s, 6H), 3.42 (t, J = 6.4 Hz, 2H), 1.68 - 1.59 (m, 2H), 0.94 (t, J = 7.6 Hz, 3H). 13 CNMR (150 MHz, CDC13): δ 147.0, 134.1, 129.8, 104.5, 73.1, 72.0, 56.3, 23.0, 10.7.

[0164] Example 22

[0165]

[0166] Ethanol (1.58 g, 34 mmol, 2 mL) was used instead of propanol in Example 21, 65 °C was used instead of 95 °C in Example 21, and the other conditions and steps were the same as in Example 21, with a yield of 53%. 1 HNMR (400 MHz, CDC13): δ 6.58 (s, 2H), 5.54 (br s, 1H), 4.41 (s, 2H), 3.88 (s, 6H), 3.52 (q, J = 7.2 Hz, 2H), 1.24 (t, J = 6.8 Hz, 3H). 13 CNMR (150 MHz, CDC13): δ 146.9, 134.1, 129.5, 104.5, 73.0, 65.5, 56.2, 15.2.

[0167] Example 23

[0168]

[0169] n-Butanol (2 mL) was used instead of propanol in Example 21, and the other conditions and steps were the same as in Example 21, with a yield of 46%. 1HNMR (400 MHz, CDC13): δ 6.58 (s, 2H), 5.51 (s, 1H), 4.41 (s, 2H), 3.88 (s, 6H), 3.45 (t, J = 6.4 Hz, 2H), 1.63 - 1.56 (m, 2H), 1.44 - 1.35 (m, 2H), 0.92 (t, J = 7.6 Hz, 3H). 13 CNMR (150 MHz, CDC13): δ 147.0, 134.1, 129.8, 104.5, 73.2, 70.1, 56.23, 31.8, 19.4, 14.0.

[0170] Example 24

[0171]

[0172] Example 21, except that ethylene glycol monomethyl ether (2 mL) was used instead of propanol. Yield: 51%. 1 HNMR (400 MHz, CDC13): δ 6.60 (s, 2H), 5.52 (s, 1H), 4.49 (s, 2H), 3.89 (s, 6H), 3.63 - 3.56 (m, 4H), 3.40 (s, 3H). 13 CNMR (150 MHz, CDC13): δ 147.0, 134.2, 129.2, 104.7, 73.6, 72.0, 69.0, 59.1, 56.3.

[0173] Example 25

[0174]

[0175] Example 21, except that 3-buten-1-ol (2 mL) was used instead of propanol. Yield: 47%. 1 HNMR (400 MHz, CDC13): δ 6.58 (s, 2H), 5.87 - 5.79 (m, 1H), 5.51 (s, 1H), 5.13 - 5.04 (m, 2H), 4.43 (s, 2H), 3.89 (s, 6H), 3.51 (t, J = 6.8 Hz, 2H), 2.41 - 2.35 (m, 2H). 13 CNMR (150 MHz, CDC13): δ 146.9, 135.2, 134.1, 129.4, 116.4, 104.5, 73.1, 69.4, 56.2, 34.2.

[0176] Example 26

[0177]

[0178] Example 21, except that cyclopropylmethanol (2 mL) was used instead of propanol, and the other conditions and procedures were the same as in Example 21, to give a yield of 53%. 1 HNMR (400 MHz, CDC13): δ 6.58 (s, 2H), 5.51 (s, 1H), 4.45 (s, 2H), 3.88 (s, 6H), 3.28 (d, J = 7.2 Hz, 2H), 1.13 - 1.05 (m, 1H), 0.56 - 0.52 (m, 2H), 0.21 - 0.18 (m, 2H). 13 CNMR (150 MHz, CDC13): δ 146.0, 133.1, 128.6, 103.5, 73.8, 71.8, 55.2, 9.6, 2.1.

[0179] Example 27

[0180]

[0181] Example 21, except that benzyl alcohol (2 mL) was used instead of propanol, and the other conditions and procedures were the same as in Example 21, to give a yield of 42%. 1 HNMR (400 MHz, CDC13): δ 7.37 (d, J = 4.4 Hz, 4H), 7.33 - 7.29 (m, 1H), 6.60 (s, 2H), 5.52 (s, 1H), 4.55 (s, 2H), 4.48 (s, 2H), 3.89 (s, 6H). 13 CNMR (150 MHz, CDC13): δ 147.0, 138.2, 134.2, 129.3, 128.4, 127.9, 127.7, 104.7, 72.4, 71.9, 56.3.

[0182] Example 28

[0183]

[0184] Example 21, except that phenethyl alcohol (2 mL) was used instead of propanol, and the other conditions and procedures were the same as in Example 21, to give a yield of 43%. 1 HNMR (400 MHz, CDC13): δ 7.32 - 7.19 (m, 5H), 6.52 (s, 2H), 5.48 (s, 1H), 4.44 (s, 2H), 3.85 (s, 6H), 3.69 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H). 13HNMR (400 MHz, CDC13): δ 7.31-7.27 (m, 2H), 7.21-7.16 (m, 3H), 6.59 (s, 2H), 5.52 (s, IH), 4.43 (s, 2H), 3.89 (s, 6H), 3.48 (t, J = 6.4 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.98-1.91 (m, 2H).

[0185] Example 29

[0186]

[0187] Example 21 using 4-methoxybenzyl alcohol (2 mL) instead of propanol, other conditions and procedures were the same as Example 21, the yield was 42%. 1 HNMR (400 MHz, CDC13): δ 7.31-7.27 (m, 2H), 7.21-7.16 (m, 3H), 6.59 (s, 2H), 5.52 (s, IH), 4.43 (s, 2H), 3.89 (s, 6H), 3.48 (t, J = 6.4 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.98-1.91 (m, 2H). 13 CNMR (150 MHz, CDC13): δ 147.0, 141.9, 134.1, 129.6, 128.5, 128.3, 125.8, 104.6, 73.2, 69.4, 56.3, 32.4, 31.3.

[0188] Example 30

[0189]

[0190] Example 21 using 4-methoxybenzyl alcohol (2 mL) instead of propanol, other conditions and procedures were the same as Example 21, the yield was 42%. 1 HNMR (400 MHz, CDC13): δ 7.31-7.27 (m, 2H), 7.21-7.16 (m, 3H), 6.59 (s, 2H), 5.52 (s, IH), 4.43 (s, 2H), 3.89 (s, 6H), 3.48 (t, J = 6.4 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.98-1.91 (m, 2H). 13 CNMR (150 MHz, CDC13): δ 159.2, 147.0, 134.2, 130.3, 129.5, 129.4, 113.8, 104.7, 72.1, 71.6, 56.3, 55.3.

[0191] Example 31

[0192]

[0193] Example 21 was repeated, except that acetonitrile was used instead of propanol, and 4-chlorobenzyl alcohol (426 mg, 3 mmol) was added. The yield was 49%. 1 HNMR (400 MHz, CDC13): δ 7.34 - 7.28 (m, 4H), 6.58 (s, 2H), 5.53 (s, 1H), 4.50 (s, 2H), 4.46 (s, 2H), 3.89 (s, 6H). 13 CNMR (150 MHz, CDC13): δ 147.0, 136.7, 134.3, 133.4, 129.2, 129.0, 128.6, 104.7, 72.5, 71.1, 56.3.

[0194] Example 32

[0195]

[0196] Example 21 was repeated, except that 2-bromobenzyl alcohol (2 mL) was used instead of propanol. The yield was 47%. 1 HNMR (400 MHz, CDC13): δ 7.55 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.64 (s, 2H), 5.52 (s, 1H), 4.61 (s, 2H), 4.55 (s, 2H), 3.90 (s, 6H). 13 CNMR (100 MHz, CDC13): δ 147.0, 137.6, 134.3, 132.6, 129.4, 129.1, 129.0, 127.4, 123.0, 104.8, 73.0, 71.4, 56.3.

[0197] Example 33

[0198]

[0199] Example 21 was repeated, except that 3-bromobenzyl alcohol (2 mL) was used instead of propanol. The yield was 50%. 1 HNMR (400 MHz, CDC13): δ 7.53 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.28 - 7.20 (m, 2H), 6.59 (s, 2H), 5.54 (s, 1H), 4.50 (s, 2H), 4.47 (s, 2H), 3.90 (s, 6H). 13CNMR (150 MHz, CDC13): δ 147.1, 140.7, 134.4, 130.8, 130.7, 130.0, 128.9, 126.3, 122.6, 104.8, 72.7, 71.0, 56.3.

[0200] Example 34

[0201]

[0202] Example 21 using 2-methoxybenzene methanol (2 mL) instead of propanol, and the other conditions and steps were the same as those of Example 21, and the yield was 46%. 1 HNMR (400 MHz, CDC13): δ 7.40 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.62 (s, 2H), 5.49 (s, 1H), 4.59 (s, 2H), 4.52 (s, 2H), 3.89 (s, 6H), 3.83 (s, 3H). 13 CNMR (150 MHz, CDC13): δ 156.2, 145.9, 133.1, 128.7, 128.1, 127.7, 125.6, 119.4, 109.2, 103.6, 71.6, 65.8, 55.3, 54.3.

[0203] Example 35

[0204]

[0205] Example 21 using 2-bromophenyl ethanol (2 mL) instead of propanol, and the other conditions and steps were the same as those of Example 21, and the yield was 45%. 1 HNMR (400 MHz, CDC13): δ 7.53 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.10 - 7.06 (m, 1H), 6.53 (s, 2H), 5.48 (s, 1H), 4.46 (s, 2H), 3.87 (s, 6H), 3.70 (t, J = 7.2 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H). 13 CNMR (150 MHz, CDC13): δ 147.0, 138.2, 134.1, 132.8, 131.2, 129.4, 128.0, 127.3, 124.7, 104.3, 73.1, 69.1, 56.3, 36.5.

[0206] Example 36

[0207]

[0208] The procedure of Example 21 was repeated except that 2-naphthalenemethanol (2 mL) was used instead of propanol. The yield was 44%. 1 HNMR (400 MHz, CDC13): δ 8.05 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.52 - 7.45 (m, 2 H), 7.42 - 7.38 (m, 2 H), 6.51 (s, 2 H), 5.47 (s, 1 H), 4.46 (s, 2 H), 3.85 - 3.81 (m, 8 H), 3.42 (t, J = 7.2 Hz, 2 H). 13 CNMR (150 MHz, CDC13): δ 147.0, 134.9, 134.1, 133.8, 132.1, 129.4, 128.8, 127.1, 126.9, 125.9, 125.6, 125.5, 123.7, 104.4, 73.3, 70.4, 56.2, 33.5.

[0209] Example 37

[0210]

[0211] The procedure of Example 21 was repeated except that deuterated methanol (2 mL) was used instead of propanol. The yield was 75%. 1 HNMR (400 MHz, CDC13): δ 7.21 (d, J = 8.1 Hz, 2 H), 7.13 (d, J = 7.9 Hz, 2 H), 6.57 (s, 2 H), 5.46 (s, 1 H), 5.13 (s, 1 H), 3.86 (s, 6 H), 2.33 (s, 3 H). 13 CNMR (150 MHz, CDC13): δ 147.0, 139.1, 137.1, 133.9, 133.4, 129.1, 126.8, 103.6, 85.2, 56.3, 56.0 (m), 21.1.

[0212] Example 38

[0213] Preparation of Syringaldehyde (Compound of Formula II):

[0214]

[0215] Into a 25 mL flask was placed 2,6-dimethoxy-4-methylphenol (50 mg, 0.3 mmol), a rotor and methanol (2 mL), potassium tert-butoxide (10 mg, 0.09 mmol) was added, and stirred at 60 °C under an oxygen atmosphere. After 24 h, 2,3-dichloro-5,6-dicyano-p-benzoquinone (68 mg, 0.3 mmol) was added and the reaction was continued for 12 h at 60 °C. The reaction was cooled to room temperature and the methanol was recovered by vacuum concentration. The crude product was purified by column chromatography to give syringaldehyde (compound of formula II-1) 44 mg in 80% yield. 1 HNMR (400 MHz, CDC13): δ 9.83 (s, 1H), 7.16 (s, 2H), 6.07 (s, 1H), 3.98 (s, 6H). 13 CNMR (150 MHz, CDC13): δ 190.8, 147.4, 140.8, 128.4, 106.7, 56.5.

[0216] The above description is only the preferred embodiment of the present application, and is not intended to limit the present application in any form. Although the present application has been disclosed as above with the preferred embodiment, it is not intended to limit the present application, and any person skilled in the art can make some changes or modifications to the above-mentioned technical content with equivalent embodiments without departing from the technical solution of the present application. Any simple modification, equivalent change and modification made according to the technical essence of the present application to the above embodiments, as long as it does not depart from the technical solution of the present application, shall still belong to the scope of the present application.

Claims

1. A method for preparing a multi-substituted benzyl ether, characterized in that, Includes the following steps: Compound III was dissolved in an excess of a polar protic solvent, a base was added, and the mixture was reacted for 1–48 h at 15–100 °C under the action of an oxidant to obtain compound I. The molar ratio of compound III to the base is 1:0.05–1; The polar protic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, ethylene glycol, 3-buten-1-ol, cyclopropanol, benzyl alcohol, ethylene glycol monomethyl ether, phenethyl alcohol, phenylpropanol, 4-methoxybenzyl alcohol, 4-chlorobenzyl alcohol, 2-bromobenzyl alcohol, 3-bromobenzyl alcohol, 2-methoxybenzyl alcohol, 2-bromophenylethanol, 2-naphthylethanol, and deuterated methanol; The alkali is selected from at least one of potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, potassium methoxide, potassium carbonate, potassium bicarbonate, and sodium bicarbonate. The oxidant is selected from oxygen; In compound III, R1 is selected from C1-C20 alkyl and C1-C20 alkoxy groups; R2 is selected from C1-C20 alkyl and C1-C20 alkoxy groups; R3 is selected from hydrogen, C1-C20 alkyl groups, R6 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R7 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R8 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R9 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R 10 Selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; In compound I, R1 is selected from C1-C20 alkyl and C1-C20 alkoxy groups; R2 is selected from C1-C20 alkyl and C1-C20 alkoxy groups; R3 is selected from hydrogen, C1-C20 alkyl groups, R6 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R7 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R8 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R9 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R 10 Selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R4 is selected from C1-C20 alkyl groups, -(CH2)n1OR 11 Deuterated C1-C20 alkyl groups n1 is selected from positive integers from 1 to 10; R 11 Selected from hydrogen and C1-C10 alkyl groups; n2 is selected from positive integers from 0 to 10; n3 is selected from positive integers from 0 to 10; n4 is selected from positive integers from 0 to 10; n5 is selected from positive integers from 0 to 10; R 12 Selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R 13 Selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R 14 Selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R 15 Selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen; R 16 Selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen.

2. The method for preparing the multi-substituted benzyl ether according to claim 1, characterized in that, In compound III, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and n-hexoxy. R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and n-hexoxy. R3 is selected from hydrogen, hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl.

3. The method for preparing the multi-substituted benzyl ether according to claim 1, characterized in that, In compound I, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and n-hexoxy. R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and n-hexoxy. R3 is selected from hydrogen, hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl. R4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CD3, -CH2CD3, -CH2CH2OCD3.

4. The method for preparing the multi-substituted benzyl ether according to claim 2, characterized in that, Compound III is selected from one of the following structures:

5. The method for preparing the multi-substituted benzyl ether according to claim 3, characterized in that, Compound I is selected from one of the following structures:

6. A method for preparing a multi-substituted benzaldehyde, characterized in that, Includes the following steps: Compound IV was dissolved in an excess of a polar protic solvent, a base was added, and the mixture was reacted for 1 to 48 hours at 15–100 °C under the action of a first oxidant. A second oxidant was then added, and the mixture was reacted for 1 to 48 hours at 15–100 °C to obtain the compound shown in Formula II. The molar ratio of compound IV to the base is 1:0.05–1; The molar ratio of compound IV to the second oxidant is 1:0.05 to 1.5; The polar protic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, ethylene glycol, 3-buten-1-ol, cyclopropanol, benzyl alcohol, ethylene glycol monomethyl ether, phenethyl alcohol, phenylpropanol, 4-methoxybenzyl alcohol, 4-chlorobenzyl alcohol, 2-bromobenzyl alcohol, 3-bromobenzyl alcohol, 2-methoxybenzyl alcohol, 2-bromophenylethanol, 2-naphthylethanol, and deuterated methanol; The alkali is selected from at least one of potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, potassium methoxide, potassium carbonate, potassium bicarbonate, and sodium bicarbonate. The first oxidant is selected from oxygen; The second oxidant is selected from 2,3-dichloro-5,6-dicyanobenzoquinone; In compound IV, R1 is selected from C1-C20 alkyl and C1-C20 alkoxy groups; R2 is selected from C1-C20 alkyl and C1-C20 alkoxy groups; In compound II, R1 is selected from C1-C20 alkyl and C1-C20 alkoxy groups; R2 is selected from C1-C20 alkyl and C1-C20 alkoxy groups.

7. The method for preparing polysubstituted benzaldehyde according to claim 6, characterized in that, In compound IV: R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and n-hexoxy. R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

8. The method for preparing polysubstituted benzaldehyde according to claim 6, characterized in that, In compound II, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and n-hexoxy. R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

9. The method for preparing polysubstituted benzaldehyde according to claim 7, characterized in that, Compound IV is selected from one of the following structures:

10. The method for preparing polysubstituted benzaldehyde according to claim 8, characterized in that, Compound II is selected from one of the following structures:

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