A method for preparing a pyridine derivative

Abstract

The present invention belongs to the field of pharmaceutical synthesis and relates to a preparation method of a pyridine derivative. Specifically, it relates to a preparation method of Formula III. In the presence of a base and a solvent, using an N-heterocyclic carbene palladium(II) (Pd(II)-NHC) complex as a catalyst, a compound of Formula I and a compound of Formula II react to obtain a compound of Formula III. The compound of Formula III, in the presence of a solvent and NBS, generates a mixture containing a compound of Formula IV, and then the compound of Formula IV is obtained by recrystallization. In addition, a preparation method of the compound of Formula I is also provided. In the presence of an inorganic base and methanol, 2,4-dichloropyridine reacts to form 2-chloro-4-methoxypyridine, which then forms a salt with an acid and is then converted into high-purity 2-chloro-4-methoxypyridine. In this application, the N-heterocyclic carbene palladium(II) complex is used as a catalyst, resulting in a significant increase in the yield and a significant reduction in the amount of the catalyst used; it overcomes the problems in the prior art such as the large amount of palladium catalyst and ligand used (2%), low atom utilization rate, high cost, high reaction temperature, long reaction time, and low yield, and is more suitable for industrial production. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical synthesis, and particularly relates to a preparation method of tert-butyl (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylate. Background Art

[0002] (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylate is an important intermediate for synthesizing an anaplastic lymphoma kinase (ALK) inhibitor.

[0003] 2-Chloro-4-methoxypyridine, as an important intermediate in pharmaceutical and chemical industry, is known in the prior art to be prepared by various methods. For example, Organic Process Research & Development Volume 15, Issue 5, Pages 1138 - 1148, 2011 discloses that using 2,4-dichloropyridine as the starting material, in the presence of toluene and sodium methoxide, the reaction temperature is 105 - 110 °C, and the reaction time is as long as 21 hours. JACS, Volume 133 Issue 5 Pages 1251 - 1253, 2011 also discloses a synthesis method of 2-chloro-4-methoxypyridine, using sodium hydride as the base and column chromatography for post-treatment.

[0004] (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylate as an intermediate, Document WO2016015676 discloses its preparation method, using Pd2(dba)3 as the catalyst and column chromatography for post-treatment. The amount of palladium catalyst and ligand used is large, the atom utilization rate is low, the cost is high, and the reaction is carried out at a relatively high temperature, with a long reaction time and low yield, which is not conducive to industrial production. Summary of the Invention

[0005] On the one hand, the present application provides a preparation method of Formula III,

[0006]

[0007] wherein one of R1, R2, R3 and R4 is a C1 - C6 alkoxy group, and the rest are hydrogen; and R5 is independently a C1 - C6 alkyl group or H, and R6 is selected from amino protecting groups, which include:

[0008] In the presence of a base and a solvent, using an N-heterocyclic carbene palladium(II) (Pd(II)-NHC) complex as the catalyst, the compound of Formula I and the compound of Formula II react to obtain the compound of Formula III, where L is a leaving group,

[0009]

[0010] Among them, the amino protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), 2-biphenyl-2-propoxycarbonyl (BPoc), trityl (Trityl, Trt), benzyl, Alloc, Teoc, PMB, Dmb, Fmoc, Tfa, Tos; in some specific embodiments, the amino protection is tert-butoxycarbonyl.

[0011]

[0012] Among them, the N-heterocyclic carbene palladium(II) (Pd(II)-NHC) complex can be prepared by methods well known in the art, including but not limited to reacting N-heterocyclic carbene (NHC) with a Pd-containing derivative, where N-heterocyclic carbene (NHC) refers to a class of heterocyclic compounds whose ring structure contains a carbene carbon and at least one N atom, and can be prepared by known methods or purchased as commercially available products. Examples of the N-heterocyclic carbene palladium(II) (Pd(II)-NHC) complex include, but are not limited to, (NHC)Pd(acac)Cl, (NHC)Pd(acac)2, Compound of Formula VI-1, Formula VI-2, Formula VI-3, Formula VI-4, Formula VI-5, Formula VI-6, Formula VI-7 and Formula VI-8; in some embodiments, the N-heterocyclic carbene palladium(II) complex is one or two of the above-listed compounds, where acac refers to acetylacetonate, and in the following structural formula represents conjugated electrons, and iPr refers to isopropyl.

[0013]

[0014]

[0015] Among them, the structures represented by the chemical groups in the above formula are shown as follows:

[0016]

[0017] In some embodiments, the N-heterocyclic carbene palladium(II) complex is selected from one or both of (NHC)Pd(acac)Cl and (NHC)Pd(acac)2; in some embodiments, the N-heterocyclic carbene palladium(II) complex is one or more of the compound of formula VII, the compound of formula VIII, and the compound of formula IX. Among them, in the compound of formula VII, R1’ is independently selected from isopropyl, methyl, tert-butyl, and hydrogen, R2’ is independently selected from methyl and hydrogen, and R1’ and R2’ are not both hydrogen at the same time; in some specific embodiments of the compound of formula VII, when R1’ is isopropyl, R2’ is hydrogen; or when R1’ is hydrogen, R2’ is methyl; or both R1’ and R2’ are methyl; or when R1’ is isopropyl, R2’ is methyl; or when R1’ is tert-butyl, R2’ is methyl. In the compound of formula VIII, R1’ is isopropyl and R2’ is hydrogen, or both R1’ and R2’ are methyl; in the compound of formula IX, R1’ is isopropyl and R2’ is hydrogen. In a specific embodiment, the N-heterocyclic carbene palladium(II) complex is acetylacetonato[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II) chloride.

[0018]

[0019] In some embodiments, the amount of the N-heterocyclic carbene palladium(II) complex is 1‰ - 1% of the amount of substance of the compound of formula I; in some specific embodiments, the amount of the N-heterocyclic carbene palladium(II) complex is 2‰ - 1% of the amount of substance of the compound of formula I; in some specific embodiments, the amount of the N-heterocyclic carbene palladium(II) complex is 1‰ - 3‰ of the amount of substance of the compound of formula I; in some specific embodiments, the amount of the N-heterocyclic carbene palladium(II) complex is 2‰ - 3‰ of the amount of substance of the compound of formula I.

[0020] In some embodiments, the leaving group L is a halogen, including but not limited to fluorine, chlorine, bromine, and iodine; in a specific embodiment, the leaving group L is Cl.

[0021] In the present application, the solvents include but are not limited to one or more of ether solvents, toluene, DMF, and their mixtures with water; in some embodiments, the solvent is one or more of ethylene glycol dimethyl ether, toluene, tetrahydrofuran, 1,4-dioxane, DMF, and methyltetrahydrofuran; in some embodiments, the solvent is ethylene glycol dimethyl ether.

[0022] In the present application, the bases include but are not limited to inorganic bases, and examples that can be cited include potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, and potassium hydroxide; in some embodiments, the base is one or more of potassium tert-butoxide, sodium tert-butoxide, and cesium carbonate; in some embodiments, the base is one or two of potassium tert-butoxide and sodium tert-butoxide.

[0023] In some embodiments, R1, R2, and R4 are H, and R3 is a C1-C6 alkoxy group; in some embodiments, R3 is methoxy, ethoxy, -OCH(CH3)2, -O-(CH2)2CH3; in some embodiments, R3 is methoxy.

[0024] In some embodiments, R5 is -CH3, -CH2CH3, -(CH2)2CH3, -(CH)(CH3)2; in some embodiments, R5 is -CH3; in a specific embodiment, R5 is a methyl group at the 2' position.

[0025]

[0026] In some embodiments, the temperature of the palladium-catalyzed reaction is 50-95 °C, preferably 60-90 °C, more preferably 75-85 °C; the reaction time is 0.5-2 hours, and in a specific embodiment, the reaction time is 1 hour.

[0027] In some embodiments, the molar ratio of the compound of formula II to the compound of formula I is 3-1:1, preferably 2-1:1, more preferably 1.18:1.

[0028] In the present application, the compounds involved may be asymmetric, for example, having one or more stereoisomers. The C atom connected to the R5 substituent in the present application may be a chiral C atom, for example, having an R or S configuration, or a mixture of R and S configurations.

[0029] On the other hand, the present application also provides a method for preparing the compound of formula I below, where L is Cl, R1, R2, and R4 are H, and R3 is methoxy; it includes: in the presence of an inorganic base and methanol, 2,4-dichloropyridine reacts to form 2-chloro-4-methoxypyridine, then forms a salt with an acid, and then is converted into high-purity 2-chloro-4-methoxypyridine;

[0030]

[0031] In some embodiments, the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium hydroxide, and potassium hydroxide; in some embodiments, the inorganic base is potassium carbonate or sodium carbonate; in some embodiments, the acid includes, but is not limited to, inorganic acids and organic acids; in some embodiments, the acid is selected from the group consisting of HCl, oxalic acid, citric acid, and sulfuric acid; in some embodiments, the acid is an aqueous hydrochloric acid solution; in some embodiments, the acid is hydrogen chloride gas; in some embodiments, when forming a salt with the acid and / or further liberating 2-chloro-4-methoxypyridine, an ester solvent such as ethyl acetate can be further added; in some embodiments, it can be converted into high-purity 2-chloro-4-methoxypyridine in the presence of a base (including, but not limited to, inorganic bases and organic bases, such as sodium hydroxide).

[0032] In another aspect, the present application also provides a method for preparing a compound of formula IV, which includes: reacting a compound of formula III-1 in a solvent in the presence of NBS to form a mixture containing the compound of formula IV, and then recrystallizing to obtain the compound of formula IV, where * indicates that the C atom has chirality and can be in the R configuration, S configuration, or a mixture of R and S.

[0033]

[0034]

[0035] Among them, the solvent used for recrystallization is selected from one or more of methanol, ethanol, n-hexane, methyl tert-butyl ether, isopropyl ether, ether, n-heptane, and toluene; preferably, the recrystallization solvent is selected from one, two, or three of methanol, n-hexane, and toluene; the preferred recrystallization solvents are methanol, n-hexane, or a mixture of methanol and toluene; during the reaction, the solvent used is an organic solvent; in some embodiments, the reaction solvent is acetonitrile.

[0036] In a specific embodiment, the present application provides the following preparation method, which includes:

[0037] 2-chloro-4-methoxypyridine (compound of formula I-1) reacts with (S)-3-methyl-1-tert-butoxycarbonylpiperazine (compound of formula II-1) in the presence of a base and a solvent, with an N-heterocyclic carbene palladium(II) complex as a catalyst to form (S)-4-(4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (compound of formula III-2).

[0038]

[0039] 2-chloro-4-methoxypyridine (Formula I-1 compound) can be prepared by the following method: 2,4-dichloropyridine reacts in the presence of an inorganic base and methanol to form 2-chloro-4-methoxypyridine (Formula I-1 compound), which is then salted with an acid and then converted into high-purity 2-chloro-4-methoxypyridine (Formula I-1 compound). In some embodiments, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium hydroxide, and potassium hydroxide; in some embodiments, it is potassium carbonate or sodium carbonate; in some embodiments, the added acid includes but is not limited to an inorganic acid and an organic acid; in some embodiments, the added acid is selected from HCl, oxalic acid, citric acid, and sulfuric acid; in some embodiments, the added acid is hydrogen chloride gas; in some embodiments, an ester solvent, such as ethyl acetate, may be further added during the acid addition to form the salt and / or convert to high-purity 2-chloro-4-methoxypyridine; in some embodiments, the conversion to high-purity 2-chloro-4-methoxypyridine is carried out in the presence of sodium hydroxide. In the present application, 2-chloro-4-methoxypyridine is salted with an acid, which can reduce the total content of the impurities 2-methoxy-4-chloropyridine and 2,4-dimethoxypyridine to below 0.5%. In the prior art, no salt is formed with an acid, and a direct one-step substitution reaction is performed. After post-treatment, the content of isomers in the obtained product 2-chloro-4-methoxypyridine can exceed 5%.

[0040] Wherein, the compound of formula III-2 can be further used to prepare the compound of formula IV-1, which comprises: the compound of formula III-2 is reacted in the presence of a solvent and NBS to generate a mixture containing the compound of formula IV-1, and then recrystallized to obtain a high-purity compound of formula IV-1.

[0041]

[0042]

[0043] The solvent for recrystallization is selected from one of methanol, ethanol, n-hexane, methyl tert-butyl ether, isopropyl ether, ethyl ether, n-heptane, and a methanol-toluene mixed solvent; preferably, the recrystallization solvent is selected from one of methanol, n-hexane, and a methanol-toluene mixed solvent. The applicant unexpectedly discovered that by selecting a specific recrystallization solvent for recrystallization, multiple impurities (e.g., compound X (e.g., n-hexane as the recrystallization solvent can remove X), compound XI (e.g., toluene-methanol mixed solvent can remove compound XI), compound XII, and / or compound III-2 (e.g., methanol or toluene-methanol mixed solvent can remove compounds XII and III-2)) can be effectively removed, overcoming the problems of prior art purification by column chromatography, such as complex operation, high cost, and unsuitability for industrial production.

[0044]

[0045] In addition, in the present application, an N-heterocyclic carbene palladium (II) complex is used as a catalyst, resulting in a significant increase in the yield and a significant reduction in the amount of the catalyst used; it overcomes the problems in the prior art such as large amounts of palladium catalyst and ligand (2%), low atom utilization rate, high cost, high reaction temperature, long reaction time, and low yield. In short, the preparation method provided by the present invention can effectively reduce the content of impurities, avoid the step of column chromatography purification, has a simpler synthesis process, a high yield of the target product, good purity, and is more suitable for industrial production. Detailed implementation manners

[0046] The following specific examples are intended to enable those skilled in the art to better understand and implement the present invention. They should not be considered as limiting the scope of the present invention, but only as exemplary illustrations and typical representatives of the present invention. All operations involving raw materials that are prone to oxidation or hydrolysis are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are directly commercially purchased and used without further purification.

[0047] Example 1 Preparation of the compound of formula I

[0048]

[0049] Step 1: Add 101.4 kg of 2,4-dichloropyridine, 305 L of methanol, and 142 kg of potassium carbonate (powder) to an enamel reaction tank, and heat to reflux for more than 20 h (monitored by HPLC until the content of 2,6-dichloropyridine is below 3%). After the reaction is completed, cool to 10 ± 3 °C, stir and crystallize for 30 min, and filter. Control the temperature of the filtrate below 35 °C, and slowly introduce 40 kg of HCl gas. After the introduction is completed, stir and react for more than 30 min, and concentrate under reduced pressure at 30 - 35 °C. Concentrate until no obvious liquid flows out, add 60 L of ethyl acetate and continue to concentrate for 1.5 h. After the concentration is completed, add 345 L of ethyl acetate, stir for 30 min, cool to 0 - 5 °C and continue to stir for 2.5 h, then filter by centrifugation. The wet weight of the hydrochloride salt of the compound of formula I-1 obtained by centrifugation and drying is 112.24 kg, and vacuum dry at 40 - 50 °C for 21 h. Sample and detect the isomer (2-methoxy-4-chloropyridine) until the content is below 0.20%, and collect the product.

[0050] Add the hydrochloride salt of the compound of formula I-1 to 220 L of ethyl acetate and stir for 2 min. Cool to 0 - 5 °C, and dropwise add 86.26 kg of 20% sodium hydroxide solution to the reaction solution while controlling the temperature within 20 °C. After the addition is completed, stir for 30 min, let it stand for liquid separation, and extract the aqueous phase with 50 L of ethyl acetate. Combine the organic phases, wash twice with 123 L of purified water successively, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain 64 kg of the compound of formula I-1. HRMS (M + H) + : 144.0212.

[0051]

[0052] Step 2: While stirring, 174 kg of ethylene glycol dimethyl ether, 60 kg of the compound of formula II-1, and 40 kg of potassium tert-butoxide are successively added to the reaction kettle. After stirring evenly, nitrogen replacement is carried out five times. Then, 500 g of acetylacetonato[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II) is added. After the addition, nitrogen replacement is carried out five times again. Under nitrogen protection, the liquid material is heated to 50 - 55 °C, and 36.6 kg of the compound of formula I-1 is added. During the addition process, the temperature of the liquid material is controlled at 50 - 80 °C. After the addition, the liquid material is heated to 75 - 85 °C and stirred for reaction for 1 hour, then about 1 ml of the sample is taken, and TLC is used to track and monitor until the reaction end point. After the reaction is completed, 200 kg of pre-cooled purified water is added, and after stirring for 30 minutes, 108 kg of ethyl acetate is added, and then stirred and allowed to stand for liquid separation. The lower aqueous phase is extracted twice on average with 72 kg of ethyl acetate. The combined organic phases are washed twice on average with 120 kg of sodium chloride solution. The organic phase is collected, and anhydrous sodium sulfate is added and stirred for dehydration for more than 2 hours. After filtration, the filtrate is concentrated under reduced pressure. After concentration until no liquid flows out, the compound of formula III-2 is obtained, which does not need to be purified and is directly used for the next reaction. HRMS(M+H)+: 308.1969.

[0053]

[0054] Step 3: The crude product of the compound of formula III-2 is added to 160 kg of acetonitrile and stirred until dissolved. The temperature is lowered to -5 - 0 °C, and 50 kg of N-bromosuccinimide is added in portions, 2.0 kg each time, with an interval of 5 minutes between each addition. Before the addition, the temperature of the liquid material is controlled below 10 °C. After the addition, the temperature of the liquid material is controlled at 10 - 30 °C and stirred for reaction for 2 hours, then about 1 ml of the sample is taken, and TLC is used to track and monitor until the reaction end point.

[0055] After the reaction is completed, the liquid material is concentrated under reduced pressure. After concentration until no liquid flows out, 130 kg of dichloromethane is added and stirred until dissolved. Then, 180 kg of sodium sulfite (20 kg) solution is added, and the mixture is stirred and allowed to stand for liquid separation. The upper aqueous phase is extracted twice on average with 130 kg of dichloromethane. The combined organic phases are added with sodium chloride solution and stirred and allowed to stand for liquid separation. Anhydrous sodium sulfate is added to the organic phase and stirred for dehydration for more than 2 hours. After filtration, the filtrate is concentrated under reduced pressure. After concentration until no liquid flows out, 18 kg of toluene and 160 kg of anhydrous methanol are added. The temperature of the liquid material is raised to 60 - 70 °C and stirred until clear. Then, it is slowly cooled, and the temperature of the liquid material is controlled at -10 - 0 °C and stirred for crystallization for 4 hours. Centrifugal filtration is carried out until no liquid flows out, and the filter cake is collected.

[0056] 20 kg of toluene, 144 kg of anhydrous methanol, and the filter cake are added to the enamel reaction kettle. The temperature of the liquid material is raised to 60 - 70 °C and stirred until clear. Then, it is slowly cooled, and the temperature of the liquid material is controlled at -10 - 0 °C and stirred for crystallization for 4 hours. Centrifugal filtration is carried out until no liquid flows out, and the filter cake is collected.

[0057] Add 160 kg of anhydrous methanol and the filter cake into an enamel reaction kettle, heat up, and stir at a temperature of 60 - 70 °C for 2 hours. Slowly cool down, and stir for crystal precipitation at a temperature of -10 - 0 °C for 4 hours. Centrifuge and filter until no liquid flows out, and collect the filter cake.

[0058] Put the obtained filter cake into the trays of a hot air circulation oven, spread it evenly, with the thickness of each tray < 2.0 cm, control the temperature at 30 ± 5 °C and dry for 12 hours, and turn the material every 4 hours. Heat up, continue to control the temperature at 45 ± 5 °C and dry for 12 hours, and turn the material every 4 hours. After drying, collect the material to obtain 71 kg of tert-butyl (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylate (Compound of Formula IV-1), and the yield is 72%.

[0059] 1HNMR (DMSO-d6) δ (ppm): 8.10 (1H, ArH), 6.03 (1H, ArH), 4.45 (1H, CH), 3.89 (1H, -CH3O), 1.49 (9H, -C(CH3)3), 1.14 - 1.12 (3H, -CH3).

[0060] HRMS (M + H)+: 386.1074.

[0061] Example 2

[0062]

[0063] Step 1: Add 1400.9 g of 2-chloro-4-methoxypyridine, 1691.8 g of (S)-3-methyl-1-tert-butoxycarbonylpiperazine, 16 L of dry toluene, and 1904.9 g of potassium tert-butoxide into the reaction kettle in sequence. After stirring evenly, add 155.5 g of Pd2(dba)3 and 212.2 g of BINAP, displace with nitrogen for 3 times, and reflux for 10 h under a nitrogen atmosphere. TLC shows that the raw materials have completely reacted. Add 10 L of purified water, separate the liquid, extract the aqueous layer with 10 L * 2 of ethyl acetate twice, combine the organic layers, wash with 20 L of saturated brine twice, dry with anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to a viscous state, which is directly used for the next step of the reaction.

[0064] Step 2: In the reaction kettle, add the acetonitrile solution of (S)-tert-butyl 4-(4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylate, cool down to 0 °C, and add 1290.9 g of N-bromosuccinimide portionwise under stirring. After addition, warm up to room temperature and react for 2 h. After TLC shows that the raw materials have completely reacted, evaporate to dryness under reduced pressure, add 10 L of dichloromethane and 20 L of saturated sodium bicarbonate solution, stir and wash, let it stand for layering. Extract the aqueous layer twice with 10 L * 2 of dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, add 5 Kg of silica gel with 100 - 200 mesh to make sand, pass through silica gel column chromatography, elute with n-hexane / ethyl acetate = 7:1, collect the part containing the product, and obtain 1982.6 g of the crude product under reduced pressure at 30 - 40 °C. Recrystallize with 8 L of n-hexane to obtain light yellow crystals, filter by suction, dry in a blast dryer at 55 °C to obtain 1667.4 g of the yellow powdery solid of Compound IV-1, with a yield of 51.1%.

Claims

1. A method for preparing a compound of formula IV-1, comprising: a. 2-Chloro-4-methoxypyridine (compound of formula I-1) reacts with (S)-3-methyl-1-tert-butoxycarbonylpiperazine (compound of formula II-1) in the presence of an inorganic base and a solvent, using acetylacetonato[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II) as a catalyst, to form (S)-4-(4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (compound of formula III-2); b. The compound of formula III-2 forms a mixture containing the compound of formula IV-1 in the presence of a solvent and NBS, and then the compound of formula IV-1 is obtained by recrystallization; wherein, in step a, the amount of acetylacetonato[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II) is 2‰ - 1% of the amount of substance of the compound of formula I, the reaction temperature for the palladium-catalyzed reaction is 50 - 95°C, and the molar ratio of the compound of formula II-1 to the compound of formula I-1 is 3 - 1:1; wherein, in step b, the recrystallization solvent is selected from methanol, n-hexane, or a mixture of methanol and toluene.

2. The preparation method according to claim 1, wherein in step a, the inorganic base is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, and cesium carbonate.

3. The preparation method according to claim 1, wherein in step a, the inorganic base is potassium tert-butoxide.

4. The preparation method according to claim 1, wherein in step a, the solvent is selected from one or more of ethylene glycol dimethyl ether, toluene, tetrahydrofuran, 1,4-dioxane, DMF, and methyltetrahydrofuran.

5. The preparation method according to claim 1, wherein in step a, the solvent is ethylene glycol dimethyl ether.

6. The preparation method according to claim 1, wherein, The molar ratio of the compound of formula II-1 to the compound of formula I-1 is 2 - 1:

1.

7. The preparation method according to claim 1, wherein the preparation of the compound of formula I-1 comprises: In the presence of an inorganic base and methanol, 2,4-dichloropyridine reacts to form 2-chloro-4-methoxypyridine, then forms a salt with an acid, and then is converted to 2-chloro-4-methoxypyridine.

8. The preparation method according to claim 7, wherein the inorganic base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium hydroxide, and potassium hydroxide.

9. The preparation method according to claim 7, wherein the acid is selected from one or more of hydrochloric acid, oxalic acid, citric acid, and sulfuric acid.

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