Method for preparing fenpyrazone intermediate

Abstract

The present invention relates to the preparation field of pesticide intermediates, and discloses a method for preparing a benzathine intermediate, including: (1) in the presence of a first solvent, a compound shown in formula (II) is subjected to a methylation reaction to obtain a compound shown in formula (III); (2) the compound shown in formula (III) is subjected to a diazotization reaction, and then reacted with formaldehyde oxime and chloropropionaldehyde oxime to obtain compounds shown in formula (IV-1) and formula (IV-2) respectively; (3) the compound shown in formula (IV-1) is reacted with sodium hypochlorite, and then reacted with ethylene, or, under alkaline conditions, the compound shown in formula (IV-2) is cyclized to obtain a compound shown in formula (V); (4) the compound shown in formula (V) is subjected to an oxidation reaction to obtain a benzathine intermediate shown in formula (I); wherein, in formula (I)-(V), R is an alkyl group of C1-C4. The method has mild conditions, high purity and high yield.

Description

Technical Field

[0001] The invention relates to the field of preparation of pesticide intermediates, and in particular to a method for preparing a fenpyroxetine intermediate. Background Art

[0002] Topramezone is a benzoyl pyrazolone herbicide first developed by BASF. It belongs to the class of hydroxyphenylpyruvate dioxidase (HPPD) inhibitors. Its English common name is topramezone, its Chinese name is topramezone or benpyrazoline, and its trade name is CampusR or "Baowei". It can effectively control annual grass weeds and broad-leaved weeds in corn fields. It is safe for corn, but its scope of use has gradually expanded to crops such as rice and sugarcane, and it can be safely used in combination with other pesticides. In 2018, the global topramezone market size was approximately US$109 million, and the total amount of technical application was approximately 269.35 tons, of which the corn field market accounted for 65.55% and other crops accounted for approximately 34.45%. Topramezone has excellent efficacy and broad market prospects, but its extremely difficult synthesis process makes it expensive and thus limits its widespread use.

[0003] At present, the preparation process of fenpyroxetine mainly includes the following two routes:

[0004] Route 1:

[0005]

[0006] Route 2:

[0007]

[0008] Among them, the preparation of compound (8) in route 1 (see US20026469176) requires ultra-low temperature reaction to construct the isoxazole ring. At the same time, this route also uses highly toxic carbon monoxide and expensive metal palladium catalyst, resulting in high costs.

[0009] CN103788083A discloses compound (7) in preparation route 2, and the preparation route is as follows:

[0010]

[0011] The source of the starting material is difficult, and it is also prepared by referring to the method in US20026469176. At the same time, in the process of converting to carboxyl, n-butyl lithium is used to react under ultra-low temperature conditions of -100°C to -60°C, which makes industrial production difficult.

[0012] In summary, the methods for preparing benzathine and its intermediates in the prior art have technical problems such as difficulty in sourcing starting raw materials, harsh reaction conditions, low yield and purity, and high cost; therefore, it is necessary to seek a method for preparing benzathine and its intermediates with mild conditions, low yield and purity, and low cost. Summary of the invention

[0013] The purpose of the present invention is to overcome the technical defects of the prior art, such as the difficulty in sourcing starting raw materials, harsh reaction conditions, low yield and purity, and high cost, and to provide a method for preparing a benzathine intermediate, which has the advantages of mild conditions, low yield and purity, and low cost.

[0014] In order to achieve the above object, the present invention provides a method for preparing a fenpyroxetine intermediate, the method comprising the following steps:

[0015] (1) in the presence of a first solvent, subjecting the compound represented by formula (II) to a methylation reaction with a methylating agent to obtain a compound represented by formula (III),

[0016]

[0017] (2) subjecting the compound represented by formula (III) to a diazotization reaction, and then subjecting the compound to a first reaction with formaldehyde oxime to obtain a compound represented by formula (IV-1),

[0018] or,

[0019] The compound represented by formula (III) is subjected to a diazotization reaction and then subjected to a second reaction with chloropropionaldehyde oxime to obtain a compound represented by formula (IV-2).

[0020]

[0021] (3) subjecting the compound represented by formula (IV-1) to a third reaction with sodium hypochlorite, and then subjecting the compound represented by formula (V) to a fourth reaction with ethylene to obtain a compound represented by formula (V); or

[0022] Under alkaline conditions, the compound represented by formula (IV-2) is subjected to a ring-closing reaction to obtain a compound represented by formula (V).

[0023]

[0024] (4) subjecting the compound represented by formula (V) to an oxidation reaction to obtain a fenpyroxetine intermediate represented by formula (I),

[0025]

[0026] Wherein, in formula (I)-(V), R is a C1-C6 alkyl group.

[0027] Preferably, in step (1), the compound represented by formula (III) can also be prepared by the following method:

[0028] i. In the presence of solvent-I, 3,4-dichlorotoluene and a Friedel-Crafts acylating agent are subjected to a Friedel-Crafts acylating reaction, and then subjected to a nitrating reaction with a nitrating agent to obtain a compound represented by formula (VI),

[0029]

[0030] ii. subjecting the compound represented by formula (VI) to an esterification reaction with an esterification agent to obtain a compound represented by formula (VII),

[0031]

[0032] iii. In the presence of a non-protonic polar solvent, the compound represented by formula (VII) is subjected to a fifth reaction with sodium thiomethoxide to obtain a compound represented by formula (VIII).

[0033]

[0034] iv. subjecting the compound represented by formula (VIII) to a hydrogenation reduction reaction to obtain a compound represented by formula (III).

[0035] Compared with the prior art, the present invention provides a new method (new process route) for preparing a fenpyroxetine intermediate (structure shown in formula (I)). The present invention uses a compound of structure shown in formula (II) or 3,4-dichlorotoluene as a starting material, which is relatively easy to obtain, and finally obtains the target compound by cleverly designing steps (1)-(4), avoiding the defects of harsh conditions and high cost in carbonyl insertion reaction, and has the advantages of mild conditions, high reaction yield and purity, and low cost, which is conducive to industrial production. DETAILED DESCRIPTION

[0036] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0037] In the present invention, unless otherwise specified, “first”, “second”, “third”, “fourth” and “fifth” do not indicate a sequence of precedence or a limitation on the materials or steps. They are only used to distinguish the materials or steps. For example, the “first”, “second”, “third”, “fourth” and “fifth” in “first reaction”, “second reaction”, “third reaction”, “fourth reaction” and “fifth reaction” are only used to indicate that these are not the same reaction.

[0038] The present invention provides a method for preparing a fenpyroxetine intermediate, the method comprising the following steps:

[0039] (1) in the presence of a first solvent, subjecting the compound represented by formula (II) to a methylation reaction with a methylating agent to obtain a compound represented by formula (III),

[0040]

[0041] (2) subjecting the compound represented by formula (III) to a diazotization reaction, and then subjecting the compound to a first reaction with formaldehyde oxime to obtain a compound represented by formula (IV-1),

[0042] or,

[0043] The compound represented by formula (III) is subjected to a diazotization reaction and then subjected to a second reaction with chloropropionaldehyde oxime to obtain a compound represented by formula (IV-2).

[0044]

[0045] (3) subjecting the compound represented by formula (IV-1) to a third reaction with sodium hypochlorite, and then subjecting the compound represented by formula (V) to a fourth reaction with ethylene to obtain a compound represented by formula (V); or

[0046] Under alkaline conditions, the compound represented by formula (IV-2) is subjected to a ring-closing reaction to obtain a compound represented by formula (V).

[0047]

[0048] (4) subjecting the compound represented by formula (V) to an oxidation reaction to obtain a fenpyroxetine intermediate represented by formula (I),

[0049]

[0050] Wherein, in formula (I)-(V), R is a C1-C4 alkyl group.

[0051] In some embodiments of the present invention, preferably, in step (1), relative to 1 mol of the compound represented by formula (II), the amount of the methylating agent used is 0.95-2 mol, for example, 0.95 mol, 1 mol, 1.1 mol, 1.2 mol, 1.5 mol, 2 mol, and any value in the range consisting of any two values, preferably 1-1.5 mol.

[0052] In some embodiments of the present invention, preferably, in step (1), the conditions of the methylation reaction include: temperature of 0-100° C., preferably 10-30° C.; time of 1-10 h, preferably 2-5 h.

[0053] In some embodiments of the present invention, preferably, in step (1), relative to 1 g of the compound represented by formula (II), the amount of the first solvent used is 1-15 g, for example, 2 g, 4 g, 6 g, 8 g, 10 g, 15 g, and any value in the range consisting of any two numerical values, preferably 2-8 g.

[0054] In some embodiments of the present invention, preferably, in step (1), the methylating agent is selected from at least one of dimethyl sulfate, dimethyl carbonate, methyl chloride, methyl bromide and methyl iodide, preferably selected from dimethyl sulfate and / or methyl chloride, more preferably dimethyl sulfate.

[0055] In some embodiments of the present invention, preferably, in step (1), the first solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, chlorobenzene, toluene and xylene, preferably 1,2-dichloroethane.

[0056] According to the present invention, preferably, in step (1), the compound represented by formula (III) can also be prepared by the following method:

[0057] i. In the presence of solvent-I, 3,4-dichlorotoluene and a Friedel-Crafts acylating agent are subjected to a Friedel-Crafts acylating reaction, and then subjected to a nitrating reaction with a nitrating agent to obtain a compound represented by formula (VI),

[0058]

[0059] ii. subjecting the compound represented by formula (VI) to an esterification reaction with an esterification agent to obtain a compound represented by formula (VII),

[0060]

[0061] iii. In the presence of a non-protonic polar solvent, the compound represented by formula (VII) is subjected to a fifth reaction with sodium thiomethoxide to obtain a compound represented by formula (VIII).

[0062]

[0063] iv. subjecting the compound represented by formula (VIII) to a hydrogenation reduction reaction to obtain a compound represented by formula (III).

[0064] In some embodiments of the present invention, preferably, in step i, relative to 1 mol of 3,4-dichlorotoluene, the amount of the Friedel-Crafts acylating agent is 0.95-2 mol, for example, 0.95 mol, 1 mol, 1.1 mol, 1.2 mol, 1.5 mol, 2 mol, and any value in the range consisting of any two numerical values, preferably 1-1.5 mol; the amount of the nitrating agent is 1-2 mol, for example, 1 mol, 1.1 mol, 1.2 mol, 1.5 mol, 2 mol, and any value in the range consisting of any two numerical values, preferably 1-1.5 mol.

[0065] In the present invention, the type of the Friedel-Crafts acylating agent has a wide selection range. Preferably, the Friedel-Crafts acylating agent is selected from acetyl chloride and / or oxalyl chloride, preferably acetyl chloride.

[0066] In some embodiments of the present invention, preferably, the nitrating agent is nitric acid.

[0067] In some embodiments of the present invention, preferably, the conditions of the Friedel-Crafts acylation reaction include: a temperature of 25-90° C., preferably 30-50° C.; and a time of 1-10 h, preferably 2-5 h. The use of the preferred conditions is more conducive to improving the purity and yield of the compound represented by formula (VI).

[0068] In some embodiments of the present invention, preferably, the conditions of the nitration reaction include: temperature of 0-60°C, preferably 0-30°C; time of 1-9h, preferably 2-6h. The preferred conditions are more conducive to improving the purity and yield of the compound represented by formula (VI).

[0069] In the present invention, unless otherwise specified, the Friedel-Crafts acylation reaction and the nitration reaction are carried out in solvent-I. Preferably, relative to 1 g of 3,4-dichlorotoluene, the amount of solvent-I is 1-15 g, for example, 1 g, 2 g, 3 g, 4 g, 5 g, 8 g, 10 g, and any value in the range of any two values, preferably 2-8 g.

[0070] In some embodiments of the present invention, preferably, the solvent-I is selected from at least one of 1,2-dichloroethane, chloroform and dichloromethane, preferably 1,2-dichloroethane.

[0071] In some embodiments of the present invention, preferably, in step ii, relative to 1 mol of the compound represented by formula (VI), the amount of the esterification reagent used is 1-2 mol, for example, 1 mol, 1.1 mol, 1.2 mol, 1.5 mol, 2 mol, and any value in the range consisting of any two values, preferably 1-1.5 mol.

[0072] In some embodiments of the present invention, preferably, the conditions of the esterification reaction include: temperature of 0-50°C, preferably 0-20°C; time of 1-10h, preferably 2-5h. The use of the preferred conditions is more conducive to improving the purity and yield of the compound represented by formula (VII).

[0073] In some embodiments of the present invention, preferably, the esterification agent is an alcohol, preferably selected from C1-C6 alcohols, more preferably at least one selected from methanol, ethyl acetate, isopropanol, n-butanol and tert-butanol.

[0074] In some embodiments of the present invention, preferably, the esterification reaction process comprises: in the presence of catalyst-I, subjecting the compound represented by formula (VI) to the esterification reaction with an esterification agent.

[0075] In some embodiments of the present invention, preferably, relative to 1 mol of the compound represented by formula (VI), the amount of the catalyst-I used is 0.02-0.2 mol, for example, 0.02 mol, 0.05 mol, 0.08 mol, 0.1 mol, 0.2 mol, and any value in the range consisting of any two values, preferably 0.05-0.1 mol.

[0076] In some embodiments of the present invention, preferably, the catalyst-I is selected from at least one of sulfuric acid, p-toluenesulfonic acid and solid cationic sulfonic acid resin, preferably sulfuric acid.

[0077] In some embodiments of the present invention, preferably, in step iii, relative to 1 mol of the compound represented by formula (VII), the amount of sodium methyl mercaptan is 1-2 mol, for example, 1 mol, 1.1 mol, 1.2 mol, 1.5 mol, 2 mol, and any value in the range consisting of any two numerical values, preferably 1-1.5 mol.

[0078] In some embodiments of the present invention, preferably, the conditions of the fifth reaction include: temperature of 0-50°C, preferably 0-20°C; time of 1-10h, preferably 2-5h. The use of the preferred conditions is more conducive to improving the purity and yield of the compound represented by formula (VIII).

[0079] In the present invention, unless otherwise specified, the fifth reaction is carried out in the presence of an aprotic polar solvent. Preferably, relative to 1 g of the compound represented by formula (VII), the amount of the aprotic polar solvent is 1-15 g, for example, 1 g, 2 g, 3 g, 4 g, 5 g, 8 g, 10 g, and any value in the range of any two values, preferably 2-8 g.

[0080] In some embodiments of the present invention, preferably, the aprotic polar solvent is selected from at least one of N,N-dimethylformamide (i.e., DMF), N,N-dimethylacetamide (i.e., DMAC), N-methylpyrrolidone (i.e., NMP), dimethyl sulfoxide (i.e., DMSO) and 1,3-dimethyl-2-imidazolidinone (abbreviated as DMI).

[0081] In some embodiments of the present invention, preferably, in step iv, the hydrogenation reduction process comprises: in the presence of catalyst-II, subjecting the compound represented by formula (VIII), triethylamine and hydrogen to the hydrogenation reduction reaction to obtain the compound represented by formula (III).

[0082] In some embodiments of the present invention, preferably, relative to 1 mol of the compound represented by formula (VIII), the amount of the catalyst-II is 1-5 g, for example, 1 g, 1.2 g, 1.5 g, 2 g, 3 g, 5 g, and any value in the range consisting of any two numerical values, preferably 1-2 g; the amount of triethylamine is 1-3 mol, for example, 1 mol, 1.1 mol, 1.2 mol, 1.5 mol, 2 mol and 3 mol, and any value in the range consisting of any two numerical values, preferably 1-1.2 mol.

[0083] In some embodiments of the present invention, preferably, the catalyst-II is palladium carbon.

[0084] In some embodiments of the present invention, preferably, the conditions of the hydrogenation reduction reaction include: temperature of 95-125°C, preferably 90-120°C; time of 1-15h, preferably 5-10h. The preferred conditions are more conducive to improving the purity and yield of the compound represented by formula (III).

[0085] In some embodiments of the present invention, preferably, in step (2), the conditions of the diazotization reaction include: temperature of -10°C to 5°C, preferably -5°C to 0°C; time of 1-10h, preferably 2-5h.

[0086] In some embodiments of the present invention, preferably, in step (2), the diazotization reaction process comprises: under acidic conditions, subjecting the compound represented by formula (III) and a diazotization reagent to the diazotization reaction.

[0087] In some embodiments of the present invention, preferably, in step (2), the acidic condition is provided by an inorganic acid, preferably the inorganic acid is selected from hydrochloric acid and / or sulfuric acid, preferably sulfuric acid; preferably, the diazotization agent is selected from nitrites, preferably selected from sodium nitrite and / or potassium nitrite, most preferably sodium nitrite.

[0088] In some embodiments of the present invention, preferably, in step (2), relative to 1 mol of the compound represented by formula (III), the amount of the inorganic acid used is 3-10 mol, for example, 3 mol, 4 mol, 5 mol, 10 mol, and any value in the range consisting of any two numerical values, preferably 3-5 mol; the amount of the diazotizing agent used is 1-3 mol, for example, 1 mol, 1.1 mol, 1.2 mol, 1.5 mol, 3 mol, and any value in the range consisting of any two numerical values, preferably 1-1.5 mol.

[0089] In some embodiments of the present invention, preferably, in step (2), relative to 1 mol of the compound represented by formula (III), the amount of formaldehyde oxime and chloropropionaldehyde oxime used is independently 1-5 mol, for example, 1 mol, 1.1 mol, 1.2 mol, 1.5 mol, 2 mol, 5 mol, and any value in the range consisting of any two values, preferably 1-2 mol.

[0090] In some embodiments of the present invention, preferably, the conditions of the first reaction and the second reaction each independently include: temperature of -10°C to 10°C, preferably 0-5°C; time of 1-10h, preferably 2-6h.

[0091] In the present invention, unless otherwise specified, the first reaction is carried out in the presence of a second solvent; wherein, the second solvent is not particularly limited, as long as it can meet the requirements of the present invention, for example, it can be selected from 1,2-dichloroethane; preferably, relative to 1g of the compound represented by formula (III), the amount of the second solvent is 1-10g, for example, 1g, 2g, 3g, 4g, 5g, 8g, 10g, and any value in the range composed of any two numerical values, preferably 1-5g.

[0092] In the present invention, unless otherwise specified, the second reaction is carried out in the presence of a third solvent; wherein, the third solvent is not particularly limited, as long as it can meet the requirements of the present invention, for example, it can be selected from 1,2-dichloroethane; preferably, relative to 1g of the compound represented by formula (III), the amount of the third solvent is 1-10g, for example, 1g, 2g, 3g, 4g, 5g, 8g, 10g, and any value in the range composed of any two numerical values, preferably 1-5g.

[0093] In some embodiments of the present invention, preferably, in step (2), the chloropropionaldehyde oxime is prepared by the following method: after acrolein and hydrochloric acid gas are contacted to react I, a base and hydroxylamine hydrochloride are added to carry out contact reaction II to obtain the chloropropionaldehyde oxime.

[0094] In some embodiments of the present invention, preferably, the conditions of the contact reaction-I include: temperature of -10°C to 10°C, preferably 0-5°C; time of 1-10h, preferably 2-6h; further preferably, the conditions of the contact reaction-II include: temperature of -10°C to 10°C, preferably 0-5°C; time of 1-20h, preferably 5-12h.

[0095] In some embodiments of the present invention, preferably, relative to 1 mol of acrolein, the amount of the base used is 0.5-5 mol, for example, 0.5 mol, 1 mol, 1.5 mol, 2 mol, 3 mol, 5 mol, and any value in the range consisting of any two numerical values, preferably 1-2 mol; the amount of hydroxylamine hydrochloride used is 1-5 mol, for example, 1 mol, 1.1 mol, 1.5 mol, 2 mol, 3 mol, 5 mol, and any value in the range consisting of any two numerical values, preferably 1-2 mol.

[0096] In the present invention, the type of the base has a wide selection range. Preferably, the base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate, preferably sodium carbonate and / or sodium bicarbonate, more preferably sodium bicarbonate.

[0097] In the present invention, unless otherwise specified, the contact reaction-I and the contact reaction-II are carried out in the presence of a fourth solvent; wherein, the fourth solvent is not particularly limited, as long as it can meet the requirements of the present invention, for example, it can be selected from 1,2-dichloroethane; preferably, relative to 1g of acrolein, the amount of the fourth solvent is 1-10g, for example, 1g, 2g, 3g, 4g, 5g, 8g, 10g, and any value in the range consisting of any two numerical values, preferably 1-5g.

[0098] In some embodiments of the present invention, preferably, in step (3), relative to 1 mol of the compound represented by formula (IV-1), the amount of sodium hypochlorite used is 1-5 mol, for example, 1 mol, 1.2 mol, 1.5 mol, 2 mol, 5 mol, and any value in the range consisting of any two numerical values, preferably 1-2 mol; the amount of ethylene used is 2-20 mol, for example, 2 mol, 3 mol, 4 mol, 5 mol, 10 mol, 15 mol, 20 mol, and any value in the range consisting of any two numerical values, preferably 2-5 mol.

[0099] In some embodiments of the present invention, preferably, the conditions of the third reaction include: temperature of -10°C to 10°C, preferably 0-5°C; time of 1-10h, preferably 2-6h.

[0100] In some embodiments of the present invention, preferably, the conditions of the fourth reaction include: temperature of -10°C to 10°C, preferably 0-5°C; time of 1-15h, preferably 5-10h.

[0101] In the present invention, unless otherwise specified, the third reaction and the fourth reaction are each independently carried out in the presence of a fifth solvent; wherein, the fifth solvent is not particularly limited, as long as it can meet the requirements of the present invention, for example, it can be selected from 1,2-dichloroethane; preferably, relative to 1g of the compound represented by formula (IV-1), the amount of the fifth solvent is 1-10g, for example, 1g, 2g, 3g, 4g, 5g, 8g, 10g, and any value in the range composed of any two numerical values, preferably 1-5g.

[0102] In some embodiments of the present invention, preferably, in step (3), the alkaline condition is provided by a base and / or a water-soluble alkaline salt, preferably provided by at least one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide, and more preferably, the alkaline condition is provided by potassium carbonate and / or sodium carbonate.

[0103] In some embodiments of the present invention, preferably, the amount of the base and / or water-soluble alkaline salt used is 1-5 mol, for example, 1 mol, 1.2 mol, 1.5 mol, 2 mol, 3 mol, 4 mol, 5 mol, and any value in the range consisting of any two values, preferably 1-3 mol, relative to 1 mol of the compound represented by formula (IV-2).

[0104] In some embodiments of the present invention, preferably, in step (3), the conditions for the ring-closure reaction include: temperature of 20-100°C, preferably 50-80°C; time of 1-10h, preferably 2-5h.

[0105] In the present invention, unless otherwise specified, the ring-closing reaction is carried out in the presence of a sixth solvent; wherein, the sixth solvent is not particularly limited, as long as it can meet the requirements of the present invention, for example, it can be selected from 1,2-dichloroethane; preferably, relative to 1g of the compound represented by formula (IV-2), the amount of the sixth solvent is 1-10g, for example, 1g, 2g, 3g, 4g, 5g, 8g, 10g, and any value in the range composed of any two numerical values, preferably 1-5g.

[0106] In some embodiments of the present invention, preferably, in step (4), the conditions of the oxidation reaction include: temperature of 50-100°C, preferably 70-80°C; time of 1-15h, preferably 2-8h.

[0107] In the present invention, unless otherwise specified, the oxidation reaction is carried out in the presence of a seventh solvent; wherein, the seventh solvent is not particularly limited, as long as it can meet the requirements of the present invention, for example, it can be selected from 1,2-dichloroethane; preferably, relative to 1g of the compound represented by formula (V), the amount of the seventh solvent is 1-10g, for example, 1g, 2g, 3g, 4g, 5g, 8g, 10g, and any value in the range consisting of any two numerical values, preferably 1-5g.

[0108] In some embodiments of the present invention, preferably, in step (4), the oxidation reaction is carried out in the presence of an oxidizing agent, and the oxidizing agent is hydrogen peroxide.

[0109] In some embodiments of the present invention, preferably, relative to 1 mol of the compound represented by formula (V), the amount of the oxidizing agent used is 2-8 mol, for example, 2 mol, 3 mol, 4 mol, 5 mol, 6 mol, 8 mol, and any value in the range consisting of any two values, preferably 3-6 mol.

[0110] In the present invention, there is no particular limitation on the preparation method of the compound represented by formula (II), and it can be prepared by referring to conventional methods in the art, for example, it can be prepared by referring to WO 2018 / 160891 A1.

[0111] In the present invention, room temperature refers to "25° C." unless otherwise specified.

[0112] The present invention will be described in detail below through examples.

[0113] In the following examples, unless otherwise specified, all raw materials used were commercially available.

[0114] The contents (purity) of reactants and products were measured by liquid chromatography (Agilent HPLC 1260).

[0115] The conversion and selectivity of the reaction were calculated by the following formula:

[0116] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

[0117] Selectivity = actual molar amount of target product / theoretical molar amount of target product × 100%.

[0118] In addition, the compound represented by formula (II) in the following preparation example was prepared by referring to the method disclosed in WO 2018 / 160891 A1.

[0119] The present invention will be described in detail below through examples.

[0120] Preparation Example 1

[0121] Preparation of the compound represented by the structure of formula (II)

[0122] At room temperature, 1.1 mol of 30 wt% concentrated hydrochloric acid, 1 mol of 2-methyl-3-amino-benzoic acid methyl ester and 50 g of water were added to a 1L four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, and the mixture was heated under reflux for 30 min. The mixture was cooled to 20°C, sodium thiocyanate was added, and the reaction was continued under reflux. The reaction was monitored by HPLC. When the area of ​​2-methyl-3-amino-benzoic acid methyl ester accounted for the percentage of all peak areas <0.2%, the stirring reaction was stopped, the reaction solution was cooled to room temperature, 50 g of methanol was added, the temperature was continued to be lowered to 0°C, and a large amount of Solids are precipitated, filtered, and 1,2-dichloroethane is added to the solids to reflux and separate water. When the water content is less than 500ppm, the temperature is lowered to 50-60°C, and 1 mol of sulfonyl chloride is added dropwise. After the addition is complete, the reaction is continued for 1 hour, and the reaction is monitored by HPLC. After the raw materials have reacted, 1,2-dichloroethane is removed under reduced pressure, and 10 mol of 40 wt% sodium hydroxide aqueous solution is added to the system, heated to reflux for hydrolysis, and the reaction is completed by HPLC monitoring, and the temperature is lowered to room temperature, and the pH is adjusted to 3. Solids are precipitated, filtered and dried to obtain 100 g of the compound represented by formula (II). Wherein, R is methyl.

[0123] Preparation Example 2

[0124] Preparation of chloropropionaldehyde oxime:

[0125] At room temperature, add 1 mol of acrolein and 250 g of 1,2-dichloroethane to a 1L four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, cool to 0°C, introduce dry hydrochloric acid gas, stop aeration after gas phase detection shows that the reaction of the raw materials is complete, add 1.5 mol of sodium bicarbonate and 1.1 mol of hydroxylamine hydrochloride, react at 0-5°C for 10 h, stop the reaction after gas phase detection shows that the reaction of the raw materials is complete, remove the salt, quantify the mother liquor (containing 25% product), and store at 0-5°C for later use.

[0126] Example 1

[0127] This example is used to illustrate the preparation of the compound represented by formula (I), wherein R is methyl.

[0128] (1) Preparation of the compound represented by formula (III)

[0129] In a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 1 mol of the compound represented by formula (II) and 300 g of 1,2-dichloroethane were added in sequence, and 1.2 mol of dimethyl sulfate was added dropwise under stirring at a temperature of 5-10°C. After the addition was completed for 4 hours, the reaction was continued at 5-10°C for 1 hour. The reaction was analyzed by high performance liquid chromatography (HPLC). When the percentage of the compound represented by formula (II) in the system accounted for all peak areas was less than 0.1%, the reaction was stopped to obtain a material containing the compound represented by formula (III), the material was allowed to stand for stratification, and 1,2-dichloroethane was removed under reduced pressure to obtain the compound represented by formula (III), with a purity of 95wt% and a yield of 95% (based on the compound represented by formula (II));

[0130] (2) Preparation of the compound represented by formula (IV-1)

[0131] In a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 1 mol of the compound represented by formula (III), 4 mol of a 25wt% sulfuric acid aqueous solution, cool to -5°C to 0°C, start to dropwise add 1.1 mol of a 30wt% sodium nitrite aqueous solution, add the solution after 2 hours, continue to keep warm for 1 hour, perform HPLC analysis and detection, stop the reaction when the percentage of the compound represented by formula (III) in the system accounts for less than 0.1% of all peak areas, adjust the pH to 6-6.5 with a 15wt% sodium hydroxide aqueous solution, and control the temperature to 0°C for standby use;

[0132] In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 1.1 mol of formaldehyde oxime and 250 g of 1,2-dichloroethane, cool to -5 to 0°C, start to drop the above diazonium salt aqueous solution, add it over 2 hours, keep it warm at 0-3°C for 1 hour, and perform HPLC analysis and detection. When the percentage of the diazonium salt of the compound represented by formula (III) in the system accounts for less than 0.1% of all peak areas, stop the reaction, let it stand to separate, remove 1,2-dichloroethane under reduced pressure, and obtain the compound represented by formula (IV-1) with a purity of 90wt% and a yield of 90% (based on the compound represented by formula (III));

[0133] (3) Preparation of the compound represented by formula (V)

[0134] To a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 1 mol of the compound represented by formula (IV-1) and 200 g of 1,2-dichloroethane, cool to 0-3°C, and begin to dropwise add 1.2 mol of sodium hypochlorite for 2 hours. Perform HPLC analysis and detection. When the percentage of the compound represented by formula (IV-1) in the system accounts for less than 0.5% of all peak areas, stop the reaction, transfer the mother liquor of the system to an autoclave, introduce 10 kg of ethylene gas, react at 0-5°C for 10 hours, until the pressure remains constant, stop the reaction, and remove 1,2-dichloroethane by desolventizing under reduced pressure to obtain a compound represented by formula (V) with a purity of 95wt% and a yield of 90% (based on the compound represented by formula (IV-1));

[0135] (4) Preparation of the compound represented by formula (I)

[0136] In a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 1 mol of the compound represented by formula (V) and 300 g of 1,2-dichloroethane were added in sequence, heated to reflux, and 5 mol of 30 wt% hydrogen peroxide was added dropwise at 75°C. The addition was completed within 3 hours, and the reaction was continued at this temperature for 4 hours. When the percentage of the compound represented by formula (V) in all peak areas detected by liquid phase was less than 0.1%, the heating reaction was stopped, the mixture was cooled to room temperature, allowed to stand for stratification, and 1,2-dichloroethane was removed under reduced pressure to obtain the compound represented by formula (I) with a purity of 95 wt% and a yield of 95% (based on the compound represented by formula (V));

[0137] The total yield of the above steps (1)-(4) is 73.1%.

[0138] Example 2

[0139] This example is used to illustrate the preparation of the compound represented by formula (I), wherein R is methyl.

[0140] (1) Preparation of the compound represented by formula (III)

[0141] In a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 1 mol of the compound represented by formula (II) and 300 g of 1,2-dichloroethane were added in sequence, and 1.2 mol of dimethyl sulfate was added dropwise at 5-10°C under stirring for 4 hours. After the addition was completed, the reaction was continued at 5-10°C for 1 hour. The reaction was analyzed by high performance liquid chromatography (HPLC). When the percentage of the compound represented by formula (II) in the system accounted for less than 0.1% of all peak areas, the reaction was stopped to obtain a material containing the compound represented by formula (III). The material was allowed to stand for stratification, and 1,2-dichloroethane was removed under reduced pressure to obtain the compound represented by formula (III), with a purity of 95wt% and a yield of 95% (based on the compound represented by formula (II));

[0142] (2) Preparation of the compound represented by formula (IV-2)

[0143] In a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 1 mol of the compound represented by formula (III), 4 mol of a 25wt% sulfuric acid aqueous solution, cool to -5°C to 0°C, start to drop 1.1 mol of a 30wt% sodium nitrite aqueous solution, add the solution over 2 hours, keep warm for 1 hour, and perform HPLC analysis and detection. When the percentage of the compound represented by formula (III) in the system accounts for less than 0.1% of all peak areas, stop the reaction, adjust the pH to 6-6.5 with 15wt% sodium hydroxide, and control the temperature to 0°C for standby use;

[0144] In a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 1.1mol of chloropropionaldehyde oxime, 250g of 1,2-dichloroethane, and 50g of water, cool to -5°C to 0°C, and begin to dropwise add the above-mentioned diazonium salt aqueous solution. After 2h of dropwise addition, continue to keep warm at 0-3°C for 1h, and perform HPLC analysis and detection. After the percentage of the diazonium salt of the compound represented by formula (III) in the system accounts for less than 0.1% of all peak areas, stop the reaction, let stand to separate, and remove 1,2-dichloroethane under reduced pressure to obtain the compound represented by formula (IV-2) with a purity of 88wt% and a yield of 85% (based on the compound represented by formula (III));

[0145] (3) Preparation of the compound represented by formula (V)

[0146] To a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 1 mol of the compound represented by formula (IV-2), 200 g of 1,2-dichloroethane, and 1.2 mol of potassium carbonate, heat and reflux to react for 4 hours, and perform HPLC analysis and detection. When the percentage of the compound represented by formula (IV-2) in the system accounts for less than 0.4% of all peak areas, stop the reaction, filter to remove the salt, and remove 1,2-dichloroethane under reduced pressure to obtain a compound represented by formula (V), with a purity of 90wt% and a yield of 91% (based on the compound represented by formula (IV-2));

[0147] (4) Preparation of the compound represented by formula (I)

[0148] In a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 1 mol of the compound represented by formula (V) and 300 g of 1,2-dichloroethane were added in sequence, heated to reflux, and 5 mol of 30 wt% hydrogen peroxide was added dropwise at 75°C. The addition was completed in about 3 hours, and the reaction was kept warm for 4 hours. When the percentage of the compound represented by formula (V) in all peak areas was less than 0.1% by liquid phase detection, the heating reaction was stopped, the temperature was lowered to room temperature, and the mixture was allowed to stand for stratification. 1,2-dichloroethane was removed under reduced pressure to obtain the compound represented by formula (I) with a purity of 95 wt% and a yield of 95% (based on the compound represented by formula (V));

[0149] The total yield of the above steps (1)-(4) is 69.8%.

[0150] Example 3

[0151] The method of Example 1 is followed, except that

[0152] In step (1), 1.2 mol of dimethyl sulfate is replaced by 1.2 mol of methyl chloride to obtain a compound represented by formula (III) with a purity of 91 wt % and a yield of 89%;

[0153] The total yield of the above steps (1)-(4) is 68.4%.

[0154] Example 4

[0155] The method of Example 1 is followed, except that

[0156] In step (1), the methylation reaction temperature is replaced with 90° C. to obtain a compound represented by formula (III) with a purity of 95 wt % and a yield of 80%.

[0157] The total yield of the above steps (1)-(4) is 61.6%.

[0158] It can be seen from the above Examples 1-4 that the method provided by the present invention, i.e., using the compound of the structure shown in formula (II) as the starting material, and finally obtaining the target product through steps (1)-(4), avoids the defects of harsh reaction conditions and high cost, and has the advantages of mild conditions, high reaction yield and purity, and low cost.

[0159] Compared with Example 3, Example 1 uses a preferred methylating agent to improve the purity and yield of the compound represented by formula (III), thereby facilitating improving the overall yield of the reaction.

[0160] Compared with Example 4, Example 1 adopts the preferred methylation reaction conditions, thereby improving the yield of the compound represented by formula (III), thereby facilitating improving the overall yield of the reaction.

[0161] Example 5

[0162] This example is used to illustrate the preparation of the compound represented by formula (I), wherein R is methyl.

[0163] (1) Preparation of the compound represented by formula (III)

[0164] i. At room temperature, add 300g of 1,2-dichloroethane, 1 mol of 3,4-dichlorotoluene, 1.1 mol of aluminum chloride, heated to 40°C, began to drop 1.1 mol of acetyl chloride, the addition was completed in 2 hours, the reaction was continued for 1 hour, HPLC analysis and detection, when the area of ​​3,4-dichlorotoluene accounts for less than 0.2% of the total peak area, the reaction was stopped, the reaction solution was cooled to room temperature, and added dropwise to 300 g of ice water, the temperature was controlled not to be higher than 35°C, the addition was completed, and stirring was continued for 30 minutes, and then the mixture was allowed to stand for separation, and after the organic phase was desolvated, 4 mol of sulfuric acid was added, the temperature was lowered to 0°C, and 1.1 mol of nitric acid was started to be added dropwise, the addition was completed in 4 hours, and the temperature was kept at 0°C for 1 hour, and the temperature was continued to rise to 40°C for reaction for 1 hour, HPLC analysis and detection, when the raw material reaction was completed, ethyl acetate was added for extraction, and the mixture was allowed to stand for separation, and the solid was desolvated to obtain the compound represented by formula (VI), with a purity of 95wt% and a yield of 90% (based on 3,4-dichlorotoluene);

[0165] ii. In a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 1 mol of the compound represented by formula (VI), 300 g of toluene, 1.5 mol of methanol, and 0.05 mol of sulfuric acid were added in sequence, and the mixture was heated to 10°C for reflux reaction for 8 h. HPLC analysis was performed. When the percentage of the compound represented by formula (VI) in the system accounted for less than 0.1% of all peak areas, the reaction was stopped to obtain a material containing the compound represented by formula (VII). After toluene was removed under reduced pressure, the compound represented by formula (VII) was obtained, with a purity of 98 wt % and a yield of 95% (based on the compound represented by formula (VI));

[0166] iii. Add 1 mol of the compound represented by formula (VII) and 300 g of DMF to a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, cool to 5°C, start to dropwise add 5.5 mol of a 20 wt% sodium methyl mercaptan aqueous solution, complete the dropwise addition in 2 hours, continue to keep warm for 1 hour, and perform HPLC analysis and detection. When the percentage of the compound represented by formula (VII) in the system accounts for less than <0.1% of all peak areas, stop the reaction, adjust the pH to 2.3 with 15 wt% hydrochloric acid, recover DMF under reduced pressure, evaporate as much as possible, recover general purpose, add 1,2-dichloroethane for extraction, and desolventize to obtain a compound represented by formula (VIII) with a purity of 95 wt% and a yield of 90% (based on the compound represented by formula (VII));

[0167] iv. Add 1 mol of the compound represented by formula (VIII), 200 g of methanol, 1.2 mol of triethylamine, and 2 g of palladium carbon to a 1 L autoclave equipped with a mechanical stirrer and a thermometer. Replace the mixture with nitrogen three times, fill the mixture with hydrogen to a pressure of 20 kg, and then heat the mixture to 100-120° C. for 8 h. Perform HPLC analysis and detection. When the percentage of the compound represented by formula (VIII) in the system is less than 0.5% of the total peak area, stop the reaction, filter out the catalyst, and remove the solvent by decompression to obtain the compound represented by formula (III). The purity is 95 wt % and the yield is 90% (based on the compound represented by formula (VIII)).

[0168] (2) Preparation of the compound represented by formula (IV-1)

[0169] In a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 1 mol of the compound represented by formula (III), 4 mol of a 25wt% sulfuric acid aqueous solution, cool to -5°C to 0°C, start to drop 1.1 mol of a 30wt% sodium nitrite aqueous solution, add the solution after 2 hours, keep warm for 1 hour, and perform HPLC analysis and detection. When the percentage of the compound represented by formula (III) in the system accounts for less than 0.1% of all peak areas, stop the reaction, adjust the pH to 6 with a 15wt% sodium hydroxide aqueous solution, and control the temperature to 0°C for standby use;

[0170] In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 1.1 mol of formaldehyde oxime and 250 g of 1,2-dichloroethane, cool to -5 to 0°C, start to drop the above diazonium salt aqueous solution, add it over 2 hours, keep it warm at 0-3°C for 1 hour, and perform HPLC analysis and detection. When the percentage of the diazonium salt of the compound represented by formula (III) in the system accounts for less than 0.1% of all peak areas, stop the reaction, let it stand to separate, remove 1,2-dichloroethane under reduced pressure, and obtain the compound represented by formula (IV-1) with a purity of 90wt% and a yield of 90% (based on the compound represented by formula (III));

[0171] (3) Preparation of the compound represented by formula (V)

[0172] To a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 1 mol of the compound represented by formula (IV-1) and 200 g of 1,2-dichloroethane, cool to 0-3°C, and begin to dropwise add 1.2 mol of sodium hypochlorite for 2 hours. Perform HPLC analysis and detection. When the percentage of the compound represented by formula (IV-1) in the system accounts for less than 0.5% of all peak areas, stop the reaction, transfer the mother liquor of the system to an autoclave, introduce 10 kg of ethylene gas, react at 0-5°C for 10 hours, until the pressure remains constant, stop the reaction, and remove 1,2-dichloroethane by desolventizing under reduced pressure to obtain a compound represented by formula (V) with a purity of 95wt% and a yield of 90% (based on the compound represented by formula (IV-1));

[0173] (4) Preparation of the compound represented by formula (I)

[0174] In a 1L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 1 mol of the compound represented by formula (V) and 300 g of 1,2-dichloroethane were added in sequence, heated to reflux, and 5 mol of 30 wt% hydrogen peroxide was added dropwise at 75°C. The addition was completed within 3 hours, and the reaction was continued at this temperature for 4 hours. When the percentage of the compound represented by formula (V) in all peak areas detected by liquid phase was less than 0.1%, the heating reaction was stopped, the mixture was cooled to room temperature, allowed to stand for stratification, and 1,2-dichloroethane was removed under reduced pressure to obtain the compound represented by formula (I) with a purity of 95 wt% and a yield of 95% (based on the compound represented by formula (V));

[0175] The total yield of the above steps (1)-(4) is 53.3%.

[0176] Example 6

[0177] According to the method of Example 5, the difference is that

[0178] In step i, acetyl chloride is replaced by oxalyl chloride to obtain a compound represented by formula (VI) with a purity of 91 wt % and a yield of 89%;

[0179] The total yield of the above steps (1)-(4) is 52.7%.

[0180] Example 7

[0181] According to the method of Example 5, the difference is that

[0182] In step ii, 0.05 mol of sulfuric acid is replaced by 0.05 mol of p-toluenesulfonic acid to obtain a compound represented by formula (VII) with a purity of 93 wt % and a yield of 90%;

[0183] The total yield of the above steps (1)-(4) is 50.5%.

[0184] Example 8

[0185] According to the method of Example 5, the difference is that

[0186] In step iv, the amount of triethylamine is replaced with 0.5 mol to obtain a compound represented by formula (III) with a purity of 70 wt % and a yield of 60%;

[0187] The total yield of the above steps (1)-(4) is 35.5%.

[0188] It can be seen from the above Examples 5-8 that the method provided by the present invention, i.e., using 3,4-dichlorotoluene as the starting material, obtaining the compound represented by formula (III) through steps i-iv, and then combining steps (2)-(4) to finally obtain the target product, i.e., the compound represented by formula (I), avoids the defects of harsh reaction conditions and high cost, and has the advantages of mild conditions, high reaction yield and purity, and low cost.

[0189] Compared with Example 6, Example 5 uses a preferred Friedel-Crafts acylating agent to improve the purity and yield of the compound represented by formula (VI), thereby facilitating improving the overall yield of the reaction.

[0190] Compared with Example 7, Example 5 uses the preferred type of catalyst-I to improve the purity and yield of the compound represented by formula (VII), thereby helping to improve the overall yield of the reaction.

[0191] Compared with Example 8, Example 5 uses a preferred amount of triethylamine to improve the purity and yield of the compound represented by formula (III), thereby facilitating improving the overall yield of the reaction.

[0192] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing a fenpyroxetine intermediate, characterized in that: The method comprises the following steps: (1) in the presence of a first solvent, subjecting the compound represented by formula (II) to a methylation reaction with a methylating agent to obtain a compound represented by formula (III), wherein the methylating agent is selected from dimethyl sulfate and methyl chloride; (2) subjecting the compound represented by formula (III) to a diazotization reaction with a diazotizing agent, and then subjecting the compound to a first reaction with formaldehyde oxime to obtain a compound represented by formula (IV-1), wherein the diazotizing agent is selected from nitrite; or, The compound represented by formula (III) is subjected to a diazotization reaction and then subjected to a second reaction with chloropropionaldehyde oxime to obtain a compound represented by formula (IV-2). (3) subjecting the compound represented by formula (IV-1) to a third reaction with sodium hypochlorite, and then subjecting the compound represented by formula (V) to a fourth reaction with ethylene to obtain a compound represented by formula (V); or Under alkaline conditions, the compound represented by formula (IV-2) is subjected to a ring-closing reaction to obtain a compound represented by formula (V). (4) subjecting the compound represented by formula (V) to an oxidation reaction to obtain a fenpyroxetine intermediate represented by formula (I), Wherein, in formula (I)-(V), R is a C1-C6 alkyl group.

2. The method according to claim 1, wherein: In step (1), Relative to 1 mol of the compound represented by formula (II), the amount of the methylating agent used is 0.95-2 mol; The conditions of the methylation reaction include: temperature of 0-100°C; time of 1-10h; Relative to 1 g of the compound represented by formula (II), the amount of the first solvent used is 1-15 g; The first solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, chlorobenzene, toluene and xylene.

3. The method according to claim 2, wherein: In step (1), Relative to 1 mol of the compound represented by formula (II), the amount of the methylating agent used is 1-1.5 mol; The conditions of the methylation reaction include: temperature of 10-30°C; time of 2-5h; Relative to 1 g of the compound represented by formula (II), the usage amount of the first solvent is 2-8 g.

4. The method according to claim 1, wherein: In step (1), the compound represented by formula (III) can also be prepared by the following method: i. In the presence of solvent-I, 3,4-dichlorotoluene and a Friedel-Crafts acylating agent are subjected to a Friedel-Crafts acylating reaction, and then subjected to a nitrating reaction with a nitrating agent to obtain a compound represented by formula (VI), ii. subjecting the compound represented by formula (VI) to an esterification reaction with an esterification agent to obtain a compound represented by formula (VII), iii. In the presence of a non-protonic polar solvent, the compound represented by formula (VII) is subjected to a fifth reaction with sodium thiomethoxide to obtain a compound represented by formula (VIII). iv. subjecting the compound represented by formula (VIII) to a hydrogenation reduction reaction to obtain a compound represented by formula (III).

5. The method according to claim 4, wherein: In step i, Relative to 1 mol of 3,4-dichlorotoluene, the amount of the Friedel-Crafts acylating agent is 0.95-2 mol; the amount of the nitrating agent is 1-2 mol; The conditions of the Friedel-Crafts acylation reaction include: temperature of 25-90° C.; time of 1-10 h; The conditions of the nitration reaction include: temperature of 0-60°C; time of 1-9h; Relative to 1 g of 3,4-dichlorotoluene, the amount of the solvent-I is 1-15 g; The Friedel-Crafts acylating agent is selected from acetyl chloride and / or oxalyl chloride; The nitrating agent is nitric acid; The solvent-I is selected from at least one of 1,2-dichloroethane, chloroform and dichloromethane.

6. The method according to claim 5, wherein: In step i, Relative to 1 mol of 3,4-dichlorotoluene, the amount of the Friedel-Crafts acylating agent is 1-1.5 mol; the amount of the nitrating agent is 1-1.5 mol; The conditions of the Friedel-Crafts acylation reaction include: temperature of 30-50°C; time of 2-5h; The conditions of the nitration reaction include: temperature of 0-30°C; time of 2-6h; Relative to 1 g of 3,4-dichlorotoluene, the amount of the solvent-I is 2-8 g; The Friedel-Crafts acylating agent is acetyl chloride; The solvent-I is selected from 1,2-dichloroethane.

7. The method according to claim 4, wherein: In step ii, Relative to 1 mol of the compound represented by formula (VI), the amount of the esterification agent used is 1-2 mol; The conditions of the esterification reaction include: temperature of 0-50°C; time of 1-10h; The esterification agent is selected from C1-C6 alcohols; The esterification reaction process comprises: in the presence of catalyst-I, subjecting the compound represented by formula (VI) to the esterification reaction with an esterification agent; Relative to 1 mol of the compound represented by formula (VI), the amount of the catalyst-I is 0.02-0.2 mol; The catalyst-I is selected from at least one of sulfuric acid, p-toluenesulfonic acid and solid cationic sulfonic acid resin.

8. The method according to claim 7, wherein: In step ii, The amount of the esterification agent used is 1-1.5 mol relative to 1 mol of the compound represented by formula (VI); The conditions of the esterification reaction include: temperature of 0-20°C; time of 2-5h; The esterification agent is selected from at least one of methanol, ethyl ester, isopropanol, n-butanol and tert-butanol; Relative to 1 mol of the compound represented by formula (VI), the amount of the catalyst-I is 0.05-0.1 mol; The catalyst-I is sulfuric acid.

9. The method according to claim 4, wherein: In step iii, The amount of sodium methyl mercaptan is 1-2 mol relative to 1 mol of the compound represented by formula (VII); The conditions of the fifth reaction include: temperature of 0-50°C; time of 1-10h; Relative to 1 g of the compound represented by formula (VII), the amount of the aprotic polar solvent is 1-15 g; The aprotic polar solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and 1,3-dimethyl-2-imidazolidinone; In step iv, The hydrogenation reduction process comprises: in the presence of catalyst-II, subjecting the compound represented by formula (VIII), triethylamine and hydrogen to the hydrogenation reduction reaction to obtain the compound represented by formula (III); Wherein, relative to 1 mol of the compound represented by formula (VIII), the amount of the catalyst-II is 1-5 g; the amount of triethylamine is 1-3 mol; Wherein, the catalyst-II is palladium carbon; The conditions of the hydrogenation reduction reaction include: temperature of 95-125° C.; time of 1-15 h.

10. The method according to claim 9, wherein: In step iii, The amount of sodium methyl mercaptan is 1-1.5 mol relative to 1 mol of the compound represented by formula (VII); The conditions of the fifth reaction include: temperature of 0-20°C; time of 2-5h; Relative to 1 g of the compound represented by formula (VII), the amount of the aprotic polar solvent is 2-8 g; In step iv, Relative to 1 mol of the compound represented by formula (VIII), the amount of the catalyst-II is 1-2 g; the amount of triethylamine is 1-1.2 mol; The conditions of the hydrogenation reduction reaction include: temperature of 90-120° C.; time of 5-10 h.

11. The method according to claim 1, wherein: In step (2), The conditions of the diazotization reaction include: temperature of -10°C to 5°C; time of 1-10h; The diazotization reaction process comprises: under acidic conditions, subjecting the compound represented by formula (III) and a diazotization reagent to the diazotization reaction; The acidic conditions are provided by an inorganic acid; The diazotizing agent is selected from sodium nitrite and / or potassium nitrite; Relative to 1 mol of the compound represented by formula (III), the amount of the inorganic acid used is 3-10 mol; the amount of the diazotizing agent used is 1-3 mol.

12. The method according to claim 11, wherein: In step (2), The conditions of the diazotization reaction include: temperature of -5°C to 0°C; time of 2-5h; The inorganic acid is selected from hydrochloric acid and / or sulfuric acid; Relative to 1 mol of the compound represented by formula (III), the amount of the inorganic acid used is 3-5 mol; the amount of the diazotizing agent used is 1-1.5 mol.

13. The method according to claim 1, wherein: In step (2), Relative to 1 mol of the compound represented by formula (III), the amount of formaldehyde oxime and chloropropionaldehyde oxime used is independently 1-5 mol; The conditions of the first reaction and the second reaction each independently include: temperature of -10°C to 10°C; time of 1-10h; In step (2), the chloropropionaldehyde oxime is prepared by the following method: acrolein and hydrochloric acid gas are subjected to contact reaction-I, and then a base and hydroxylamine hydrochloride are added to carry out contact reaction-II to obtain the chloropropionaldehyde oxime; Wherein, the conditions of the contact reaction-I include: temperature of -10°C to 10°C; time of 1-10h; Wherein, the conditions of the contact reaction-II include: temperature of -10°C to 10°C; time of 1-20h; Wherein, relative to 1 mol of acrolein, the amount of the base used is 0.5-5 mol; the amount of hydroxylamine hydrochloride used is 1-5 mol; Wherein, the alkali is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

14. The method according to claim 13, wherein: In step (2), Relative to 1 mol of the compound represented by formula (III), the amount of formaldehyde oxime and chloropropionaldehyde oxime used is independently 1-2 mol; The conditions of the first reaction and the second reaction independently include: temperature of 0-5°C; time of 2-6h; The conditions of the contact reaction-I include: temperature of 0-5°C; time of 2-6h; The conditions of the contact reaction-II include: temperature of 0-5°C; time of 5-12h; Relative to 1 mol of acrolein, the amount of the base used is 1-2 mol; the amount of hydroxylamine hydrochloride used is 1-2 mol; The base is selected from sodium carbonate and / or sodium bicarbonate.

15. The method according to claim 1, wherein: In step (3), Relative to 1 mol of the compound represented by formula (IV-1), the amount of sodium hypochlorite used is 1-5 mol; the amount of ethylene used is 2-20 mol; The conditions of the third reaction include: temperature of -10°C to 10°C; time of 1-10h; The conditions of the fourth reaction include: temperature of -10°C to 10°C; time of 1-15h; The alkaline conditions are provided by a base and / or a water-soluble alkaline salt; The amount of the base and / or the water-soluble alkaline salt is 1-5 mol relative to 1 mol of the compound represented by formula (IV-2); The conditions of the ring-closing reaction include: temperature of 20-100° C.; time of 1-10 h.

16. The method according to claim 15, wherein: In step (3), Relative to 1 mol of the compound represented by formula (IV-1), the amount of sodium hypochlorite used is 1-2 mol; the amount of ethylene used is 2-5 mol; The conditions of the third reaction include: temperature of 0-5°C; time of 2-6h; The conditions of the fourth reaction include: temperature of 0-5°C; time of 5-10h; The alkaline condition is provided by at least one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide; The amount of the base and / or the water-soluble alkaline salt is 1-3 mol relative to 1 mol of the compound represented by formula (IV-2); The conditions of the ring-closing reaction include: temperature of 50-80° C.; time of 2-5 h.

17. The method according to claim 16, wherein: The alkaline condition is provided by potassium carbonate and / or sodium carbonate.

18. The method according to any one of claims 1 to 17, wherein: In step (4), The conditions of the oxidation reaction include: temperature of 50-100°C; time of 1-15h; The oxidation reaction is carried out in the presence of an oxidizing agent, and the oxidizing agent is hydrogen peroxide; Relative to 1 mol of the compound represented by formula (V), the amount of the oxidizing agent used is 2-8 mol.

19. The method according to claim 18, wherein: In step (4), The conditions of the oxidation reaction include: temperature of 70-80°C; time of 2-8h; Relative to 1 mol of the compound represented by formula (V), the amount of the oxidizing agent used is 3-6 mol.

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