Preparation method of 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine hydrochloride

Abstract

The invention discloses a preparation method of 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine hydrochloride, which comprises the following steps: carrying out oxidation reaction on 3, 5-dimethyl pyridine to obtain 3, 5-dimethyl pyridine nitrogen oxide; the method comprises the following steps: in mixed acid of nitric acid and sulfuric acid, carrying out nitration reaction on 3, 5-dimethyl pyridine nitrogen oxide to obtain 4-nitro-3, 5-dimethyl pyridine nitrogen oxide; the method comprises the following steps: carrying out methoxy reaction on 4-nitro-3, 5-dimethyl pyridine nitrogen oxide to obtain 4-methoxy-3, 5-dimethyl pyridine nitrogen oxide, activating the 4-methoxy-3, 5-dimethyl pyridine nitrogen oxide by using an activating reagent, carrying out chlorination reaction on the 4-methoxy-3, 5-dimethyl pyridine nitrogen oxide and thionyl chloride to obtain free alkali of 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine, and carrying out reaction on the free alkali of 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine nitrogen oxide and the free alkali of 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine nitrogen oxide to obtain the 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine nitrogen oxide. And carrying out a salt forming reaction in an organic solvent of HCl to obtain the 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine hydrochloride. According to the invention, the'activation-chlorination 'yield is greater than 93.5%.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis and relates to a method for preparing 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride. Background Technology

[0002] Omeprazole is a proton pump inhibitor used to treat peptic ulcers and gastroesophageal reflux disease (GERD). It specifically targets the proton pump site on gastric parietal cells, converting into its active sulfinamide form. This sulfinamide then irreversibly binds to the sulfhydryl group of the proton pump via a disulfide bond, forming a sulfinamide-proton pump (H2O) compound. + -K + The complex of α-ATPase (-ATPase) inhibits the activity of this enzyme, thereby reducing H2 in the parietal cells. + Unable to be transported into the gastric cavity and block gastric acid secretion, this product significantly reduces the amount of gastric acid in the gastric juice. Therefore, it has a strong and sustained inhibitory effect on gastric acid secretion caused by various factors (such as basal gastric acid secretion and gastric acid secretion induced by histamine, pentagastrin, and vagal nerve stimulation, including gastric acid secretion induced by butylated cyclic adenosine monophosphate that cannot be inhibited by H2 receptor antagonists). This is related to the irreversible nature of its inhibitory effect on the proton pump; acid secretion can only be restored after a new proton pump is formed.

[0003] The structure of omeprazole is shown in Formula I:

[0004]

[0005] 2-Chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride, as a fragment of the omeprazole structure, is shown in Formula II:

[0006]

[0007] Currently, there are two main methods for synthesizing 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride.

[0008] (I) Starting with 2,3,5-trimethylpyridine, its nitrogen oxides are first obtained through oxidation, then nitrated to obtain the nitrate, followed by methoxylation, and finally chlorinated to obtain 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride. The reaction route is as follows:

[0009]

[0010] However, the 2,3,5-trimethylpyridine used in this process is expensive and, as a downstream product of the pyridine chain, is not readily available, resulting in a higher cost for the final product.

[0011] (II) Using 3,5-dimethylpyridine, which is cheaper and more readily available in the market, as the starting material, the product is obtained through oxidation, nitration, methoxylation, and chloromethylation reactions. However, the step of preparing 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine from 4-methoxy-3,5-dimethylpyridine oxynitride uses dimethyl sulfate, a highly toxic material, which makes the wastewater difficult to treat.

[0012] Patent CN114805193A discloses a process where, after methoxylation, a Vilsmeier reaction is used to obtain the intermediate 2-aldehyde-4-methoxy-3,5-dimethylpyridine, which is then reduced with a reducing agent to obtain the intermediate 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine. Finally, a chlorination reaction is carried out with a chlorinating agent to obtain the target product. This process has several shortcomings:

[0013] (1) Phosphorus oxychloride or other chlorinated reagents used in the vilsmeier reaction are prone to generating methoxy deprotected impurities, namely 2-chloromethyl-4-hydroxy-3,5-dimethylpyridine with the structure shown in Formula III.

[0014]

[0015] (2) The aldehyde group is reduced to hydroxymethyl, which uses easily explosive substances such as sodium borohydride and potassium borohydride, which is not conducive to the safety of the production process. Summary of the Invention

[0016] To address the aforementioned problems, the present invention aims to provide a method for preparing 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride, which simplifies the operation, achieves a product purity of ≥99.8%, and a yield of ≥85.0%.

[0017] A method for preparing 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride, the synthetic route is as follows:

[0018]

[0019] The process includes: starting with 3,5-dimethylpyridine, which undergoes an oxidation reaction with an oxygen source to obtain 3,5-dimethylpyridine nitrate; in a mixed acid of nitric acid and sulfuric acid, 3,5-dimethylpyridine nitrate reacts with nitric acid to obtain 4-nitro-3,5-dimethylpyridine nitrate (intermediate 1); 4-nitro-3,5-dimethylpyridine nitrate undergoes a methoxy reaction to obtain 4-methoxy-3,5-dimethylpyridine nitrate (intermediate 2); 4-methoxy-3,5-dimethylpyridine nitrate is activated in an organic solvent by an activating agent, and then undergoes a chlorination reaction with thionyl chloride to obtain a free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine, which undergoes a salt formation reaction in an organic solvent of HCl to obtain 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride.

[0020] The molar ratio of 3,5-dimethylpyridine to the oxygen source is 1:1 to 1:4, preferably 1:4.

[0021] The oxygen source is one of hydrogen peroxide, sodium hypochlorite, or m-chloroperoxybenzoic acid, preferably hydrogen peroxide.

[0022] The hydrogen peroxide has a mass fraction of 30%.

[0023] The reaction solvent for the oxidation reaction is glacial acetic acid.

[0024] The mass ratio of 3,5-dimethylpyridine to glacial acetic acid is 1:5 to 1:10, preferably 1:8. The oxidation reaction temperature is 70 to 100°C, preferably 80°C.

[0025] Specifically, the oxidation reaction is as follows: 3,5-dimethylpyridine and glacial acetic acid are mixed, heated to the reaction temperature, and an oxygen source is added dropwise. After the addition is complete, the mixture is kept at the temperature for further reaction. After the reaction is complete, the mixture is distilled under reduced pressure at a temperature of 80-90℃ and a vacuum degree of ≤-0.08MPa until no liquid drips out, to obtain 3,5-dimethylpyridine nitride.

[0026] The nitration reaction is carried out at a temperature of 80–110°C, preferably 90–100°C.

[0027] The molar ratio of 3,5-dimethylpyridine to nitric acid and sulfuric acid is 1:4:(5-7), preferably 1:4:6.

[0028] The nitric acid has a mass fraction of 65%; the sulfuric acid has a mass fraction of 98%.

[0029] Specifically, the nitration reaction is as follows: 3,5-dimethylpyridine nitride oxide is mixed with sulfuric acid, and nitric acid is added dropwise at the nitration reaction temperature. After the addition is complete, the reaction is kept at the temperature. After the reaction is complete, the reaction solution is cooled to room temperature, and the pH of the reaction system is adjusted to 3-4 with ammonia water. A solid is precipitated, filtered, and the filter cake is collected and dried to obtain 4-nitro-3,5-dimethylpyridine nitride oxide (intermediate 1).

[0030] The molar ratio of 4-nitro-3,5-dimethylpyridine nitride to sodium hydroxide is 1:1.0 to 1:1.5, preferably 1:1.2.

[0031] The mass ratio of 4-nitro-3,5-dimethylpyridine nitride to methanol is 1:3 to 1:5, preferably 1:4.

[0032] The reaction temperature for the methoxy reaction is 40–70°C, preferably 40–50°C.

[0033] Specifically, the methoxy substitution reaction is as follows: methanol and 4-nitro-3,5-dimethylpyridine nitride are mixed, and an aqueous sodium hydroxide solution is added to carry out the methylation reaction; after the reaction is completed, the reaction solution is cooled to room temperature, the pH of the reaction solution is adjusted to 7.5-9 with glacial acetic acid, the solvent is removed by vacuum distillation, dichloromethane is added to dissolve, the solution is filtered, and the filtrate is removed by vacuum distillation to obtain 4-methoxy-3,5-dimethylpyridine nitride (intermediate 2).

[0034] The sodium hydroxide aqueous solution typically has a mass fraction of 50%.

[0035] During the chlorination reaction, the mass ratio of the 4-methoxy-3,5-dimethylpyridine nitrogen oxide to the organic solvent is 1:2 to 1:12, preferably 1:3 to 1:5, and more preferably 1:4.

[0036] The organic solvent is one of dichloromethane, trichloromethane, and 1,2-dichloroethane, preferably dichloromethane.

[0037] The activating agent is an acid anhydride, which is one or a mixture of trifluoroacetic anhydride (TFAA), trifluoromethanesulfonic anhydride, and acetic anhydride, preferably trifluoroacetic anhydride.

[0038] The molar ratio of 4-methoxy-3,5-dimethylpyridine nitrogen oxide to the activating agent is 1:1.0 to 1:1.3, preferably 1:1.0 to 1:1.1, and more preferably 1:1.1.

[0039] The molar ratio of 4-methoxy-3,5-dimethylpyridine nitride to thionyl chloride is 1:1.2 to 1:1.6, preferably 1:1.5.

[0040] The chlorination reaction is carried out at a temperature of 0–10 °C.

[0041] The chlorination reaction is as follows: 4-methoxy-3,5-dimethylpyridine nitrogen oxides and an organic solvent are mixed, cooled to 0-10°C, activated with an activating reagent, and then thionyl chloride is added dropwise to carry out the chlorination reaction. After the reaction is completed, ice water is added dropwise to the reaction solution, and the liquid is separated to obtain an organic phase and an aqueous phase. The aqueous phase is extracted with the same organic solvent as the chlorination reaction. The organic phases are combined, washed with saturated brine, and the solvent is removed by distillation to obtain the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine.

[0042] The organic solvent of the HCl is one of methanol, ethanol, isopropanol (IPA) or toluene, preferably isopropanol.

[0043] During the salt formation reaction, the mass ratio of the 4-methoxy-3,5-dimethylpyridine nitrogen oxide to the organic solvent is 1:5 to 1:12, preferably 1:10.

[0044] The salt formation reaction is as follows: the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine is dissolved in an organic solvent, HCl gas is introduced into the system until the pH is 1-2, the mixture is stirred at room temperature to crystallize, filtered, and dried to obtain 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride.

[0045] The beneficial effects of this invention are:

[0046] 1. This invention uses 3,5-dimethylpyridine, which has a lower market price, as a starting material to synthesize 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride, which has a cost advantage over 2,3,5-trimethylpyridine.

[0047] 2. In this invention, an activating reagent is used to form a pyridinium salt with the O of nitrogen oxides. The strong electron-withdrawing group polarizes the carbon-hydrogen bond at the 2-position, making it easier for the sulfur atom in thionyl chloride to attack and carry out the chlorination reaction. This avoids the thionyl chloride attacking the methoxy group at the 4-position to generate the byproduct impurity 2-chloromethyl-4-hydroxy-3,5-dimethylpyridine.

[0048] 3. This invention avoids the use of highly toxic dimethyl sulfate and easily explosive reducing agents, and uses a one-step "activation-chlorination" method to replace the traditional "Vilsmeier-aldehyde-reduction-chlorination" multi-step method to synthesize the target product with a purity of over 99.8%. The one-step "activation-chlorination" method has a yield of over 93.5% and an overall yield of over 85%. Moreover, the reaction conditions are mild and simple, making it more suitable for large-scale production. Attached Figure Description

[0049] Figure 1In Example 1, 4-nitro-3,5-dimethylpyridine nitride 1 H NMR spectrum.

[0050] Figure 2 MS spectrum of 4-nitro-3,5-dimethylpyridine nitride in Example 1.

[0051] Figure 3 In Example 1, 4-methoxy-3,5-dimethylpyridine nitrogen oxides 1 H NMR spectrum.

[0052] Figure 4 2-Chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride in Example 1 1 H NMR spectrum.

[0053] Figure 5 MS spectrum of impurities in Comparative Example 1. Detailed Implementation

[0054] The technical solution of the present invention will be further illustrated by the following embodiments, but these embodiments do not constitute any limitation on the present invention.

[0055] Example 1

[0056]

[0057] Step 1: Preparation of 4-nitro-3,5-dimethylpyridine nitride (intermediate 1)

[0058] 107.1 g (1.0 mol) of 3,5-dimethylpyridine and 856.8 g (8 times the mass) of glacial acetic acid were added to a reaction flask. The temperature was raised to 80 °C, and 453.3 g (4.0 mol) of 30% hydrogen peroxide was added dropwise. After the addition was complete, the reaction was maintained at 80 °C for 5 h. After the reaction was completed by TLC monitoring, the mixture was distilled under reduced pressure (80–90 °C, vacuum -0.1–-0.08 MPa) until no liquid dripped out, yielding 3,5-dimethylpyridine oxides (pale yellow oil). 600 g of concentrated sulfuric acid (98% by mass, 6.0 mol) was added to methylpyridine oxynitride, and the mixture was heated to 90 °C. 387.7 g of nitric acid (65% by mass, 4.0 mol) was slowly added dropwise over 4 hours. After the addition was complete, the mixture was reacted at 90–100 °C for approximately 5 hours. TLC monitoring indicated the reaction was complete at this point. The reaction solution was then cooled to room temperature, and ammonia (17% by mass) was added dropwise to adjust the pH to 3–4. A solid precipitated, and the filter cake was collected. The filter cake was dried to yield 156.1 g of 4-nitro-3,5-dimethylpyridine oxynitride (intermediate 1), with a yield of 92.8% and a purity of 99.9%.

[0059] 1 H NMR (500MHz, DMSO-d6) δ8.31 (s, 2H), δ2.27 (s, 6H).

[0060] MS(ESI+)m / z:[M+H] + Calculated value of C7H8N2O3: 168.15, measured value: 169.1.

[0061] Step 2: Preparation of 4-methoxy-3,5-dimethylpyridine nitride (intermediate 2)

[0062] First, 134.5 g (0.8 mol) of 4-nitro-3,5-dimethylpyridine nitrogen oxides was added to the reaction flask, followed by 538 g (4 times the mass) of methanol. A sodium hydroxide aqueous solution (prepared by dissolving 38.4 g (0.96 mol) of sodium hydroxide in 38.4 g of water) was added dropwise. After the addition was complete, the temperature was raised to 40–50 °C and the reaction was carried out for 2 hours. After the reaction was completed by TLC monitoring, the temperature was lowered to room temperature, and the pH was adjusted to 7.5–8.5 with glacial acetic acid. The solvent was removed by vacuum distillation (temperature 40–50 °C, vacuum degree -0.1 to -0.08 MPa). Dichloromethane was added to dissolve the solvent, and the solution was filtered to remove the salt. The filtrate was then removed by vacuum distillation to obtain 121.2 g of 4-methoxy-3,5-dimethylpyridine nitrogen oxides (intermediate 2), with a yield of 98.9% and a purity of 98.6%.

[0063] 1 H NMR (500MHz, DMSO-d6) δ8.02 (d, 2H), δ3.77 (s, 3H), δ2.19 (s, 6H).

[0064] Step 3: Preparation of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride

[0065] 76.6 g (0.5 mol) of 4-methoxy-3,5-dimethylpyridine nitride and 306.4 g (4 times the mass) of dichloromethane were added to the reaction flask. The mixture was cooled to 0 °C, and 115.5 g (0.55 mol) of trifluoroacetic anhydride was added. The mixture was stirred for 1 h, and then 89.2 g (0.75 mol) of thionyl chloride was added dropwise while stirring. After the addition was complete, the mixture was stirred for another 4 h. The reaction was monitored by TLC until it was complete. 1000 mL of ice water was slowly added to the reaction mixture to quench the excess thionyl chloride. The mixture was separated into layers, and the dichloromethane phase was collected. The aqueous phase was extracted once with 150 g of dichloromethane. The dichloromethane phases were combined and backwashed three times with saturated brine (100 g × 3). The dichloromethane phase was distilled under reduced pressure (temperature 30–40 °C, vacuum degree -0.1–-0.05 MPa) until no liquid dripped, yielding the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine.

[0066] 766 g of isopropanol was added to the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine, and hydrogen chloride gas was introduced until the pH of the system was 1-2. The hydrogen chloride gas was then stopped, and the mixture was stirred at room temperature for 2 h to crystallize. The mixture was filtered, and the wet product was dried under reduced pressure at 60 °C for 8 h to obtain 106.4 g of the target product 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride, with a yield of 95.8%, a purity of 99.95%, and an overall yield of 87.9%.

[0067] 1 H NMR (500MHz, DMSO-d6) δ14.88 (s, 1H), δ8.66 (s, 1H), δ5.18 (s, 2H), δ4.06 (s, 3H), δ2.53 (s, 3H), δ2.41 (s, 3H).

[0068] Example 2

[0069] Preparation of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride

[0070] 4-Methoxy-3,5-dimethylpyridine oxide was prepared according to steps one and two of Example 1.

[0071] 15.3 g (0.1 mol) of 4-methoxy-3,5-dimethylpyridine nitrogen oxides and 61.2 g (4 times the mass) of dichloromethane were added to the reaction flask. The mixture was cooled to 0 °C, and 11.2 g (0.11 mol) of acetic anhydride was added. The mixture was stirred for 1 h, and then 17.8 g (0.15 mol) of thionyl chloride was added dropwise. The mixture was stirred for 4 h. The reaction was monitored by TLC until it was complete. 200 mL of ice water was slowly added to the reaction mixture. The mixture was separated into layers, and the dichloromethane phase was collected. The aqueous phase was extracted once with 30 g of dichloromethane. The dichloromethane phases were combined and backwashed three times with saturated brine (20 g × 3). The dichloromethane phase was distilled under reduced pressure (temperature 30–40 °C, vacuum degree -0.1–-0.05 MPa) until no liquid dripped, yielding the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine.

[0072] 153 g of isopropanol was added to the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine, and hydrogen chloride gas was introduced until the pH of the system was 1-2. The hydrogen chloride gas was then stopped, and the mixture was stirred at room temperature for 2 h to crystallize. The mixture was filtered, and the wet product was dried under reduced pressure at 60 °C for 8 h to obtain 20.9 g of the target product 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride, with a yield of 94.1% and a purity of 99.9%.

[0073] Example 3

[0074] Preparation of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride

[0075] 4-Methoxy-3,5-dimethylpyridine oxide was prepared according to steps one and two of Example 1.

[0076] Add 15.3 g (0.1 mol) of 4-methoxy-3,5-dimethylpyridine nitride and 61.2 g (4 times the mass) of dichloromethane to the reaction flask, cool to 0 °C, add 31.0 g (0.11 mol) of trifluoromethanesulfonic anhydride, stir for 1 h, then add 17.8 g (0.15 mol) of thionyl chloride dropwise, stir for 4 h, and monitor the reaction by TLC until it is complete. Slowly add 200 mL of ice water to the reaction solution, separate the layers, collect the dichloromethane phase, extract the aqueous phase once with 30 g of dichloromethane, combine the dichloromethane phases, backwash three times with saturated brine (20 g × 3), and distill the dichloromethane phase under reduced pressure (temperature 30–40 °C, vacuum degree -0.1–-0.05 MPa) until no liquid drips, to obtain the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine.

[0077] Toluene 153g was added to the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine, and hydrogen chloride gas was introduced until the pH of the system was 1-2. The introduction of hydrogen chloride was stopped, and the mixture was stirred at room temperature for 2 hours to crystallize. The mixture was filtered, and the wet product was dried under reduced pressure at 60°C for 8 hours to obtain 20.8g of the target product 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride, with a yield of 93.6% and a purity of 99.9%.

[0078] Example 4

[0079] Preparation of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride

[0080] 4-Methoxy-3,5-dimethylpyridine oxide was prepared according to steps one and two of Example 1.

[0081] 15.3 g (0.1 mol) of 4-methoxy-3,5-dimethylpyridine nitride and 61.2 g (4 times the mass) of dichloromethane were added to the reaction flask. The mixture was cooled to 0 °C, and 21.0 g (0.1 mol) of trifluoroacetic anhydride was added. The mixture was stirred for 1 h, and then 17.8 g (0.15 mol) of thionyl chloride was added dropwise. The mixture was stirred for 4 h. The reaction was monitored by TLC until it was complete. 200 mL of ice water was slowly added to the reaction mixture. The mixture was separated into layers, and the dichloromethane phase was collected. The aqueous phase was extracted once with 30 g of dichloromethane. The dichloromethane phases were combined and backwashed three times with saturated brine (20 g × 3). The dichloromethane phase was distilled under reduced pressure (temperature 30–40 °C, vacuum degree -0.1–-0.05 MPa) until no liquid dripped, yielding the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine.

[0082] 153 g of ethanol was added to the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine, and hydrogen chloride gas was introduced until the pH of the system reached 1-2. The introduction of hydrogen chloride was stopped, and the mixture was stirred at room temperature for 2 h to crystallize. The mixture was filtered, and the wet product was dried under reduced pressure at 60 °C for 8 h to obtain 20.7 g of the target product 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride, with a yield of 93.2% and a purity of 99.8%.

[0083] Example 5

[0084] Preparation of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride

[0085] 4-Methoxy-3,5-dimethylpyridine oxide was prepared according to steps one and two of Example 1.

[0086] 15.3 g (0.1 mol) of 4-methoxy-3,5-dimethylpyridine nitride and 61.2 g (4 times the mass) of dichloromethane were added to the reaction flask. The mixture was cooled to 0 °C, and 23.1 g (0.11 mol) of trifluoroacetic anhydride was added. The mixture was stirred for 1 h, and then 14.3 g (0.12 mol) of thionyl chloride was added dropwise. The mixture was stirred for 4 h. The reaction was monitored by TLC until it was complete. 200 mL of ice water was slowly added to the reaction mixture. The mixture was separated into layers, and the dichloromethane phase was collected. The aqueous phase was extracted once with 30 g of dichloromethane. The dichloromethane phases were combined and backwashed three times with saturated brine (20 g × 3). The dichloromethane phase was distilled under reduced pressure (temperature 30–40 °C, vacuum degree -0.1–-0.05 MPa) until no liquid dripped, yielding the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine.

[0087] 153 g of methanol was added to the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine, and hydrogen chloride gas was introduced until the pH of the system was 1-2. The hydrogen chloride gas was then stopped, and the mixture was stirred at room temperature for 2 h to crystallize. The mixture was filtered, and the wet product was dried under reduced pressure at 60 °C for 8 h to obtain 21.0 g of the target product 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride, with a yield of 94.5% and a purity of 99.9%.

[0088] Comparative Example 1

[0089] Preparation of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride

[0090] 4-Methoxy-3,5-dimethylpyridine oxide was prepared according to steps one and two of Example 1.

[0091] Add 15.3 g (0.1 mol) of 4-methoxy-3,5-dimethylpyridine nitrogen oxides and 61.2 g (4 times the mass) of dichloromethane to the reaction flask, cool to 0 °C, and add 17.8 g (0.15 mol) of thionyl chloride dropwise. Stir the reaction for 4 h, monitor the reaction for completion by TLC, slowly add 200 mL of ice water to the reaction solution, separate the layers, collect the dichloromethane phase, extract the aqueous phase once with 30 g of dichloromethane, combine the dichloromethane phases, and backwash three times with saturated brine (2... 0 g × 3), distilled under reduced pressure in dichloromethane phase (temperature 30~40℃, vacuum degree -0.1~-0.05Mpa) until no liquid drips; add 153 g of isopropanol, and purge with hydrogen chloride gas until the pH of the system is 1~2, then stop purging with hydrogen chloride, stir at room temperature to crystallize for 2 h, filter, and dry the wet product under reduced pressure at 60℃ for 8 h to obtain 20.1 g of the target product 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride, with a yield of 90.5% and a purity of 99.6%.

[0092] The filtered mother liquor was rotary evaporated to dryness. 100 mL of water and 100 mL of dichloromethane were added, and saturated NaHCO3 aqueous solution was added dropwise until the pH reached 6–7. The mixture was stirred for 30 min, separated, and the dichloromethane phase was obtained. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, and silica gel was added to the filtrate for mixing. The mixture was then subjected to normal-phase silica gel chromatography, eluted sequentially with petroleum ether:ethyl acetate (10:1 V / V) and dichloromethane:methanol (10:1 V / V), enriching the impurities. The impurities were sent for analysis according to MS and... 1 ¹H NMR identified the impurity as 2-chloromethyl-4-hydroxy-3,5-dimethylpyridine (structure shown in Formula III).

[0093] MS(ESI+)m / z:[M+Na] + Calculated value C8H 10 ClNO: 171.62, Measured value: 194.0.

[0094] 1 H NMR (500MHz, DMSO-d6) δ7.61 (s, 1H), δ5.02 (s, 1H), δ4.67 (s, 2H), δ1.97 (s, 3H), δ1.88 (s, 3H).

Claims

1. A process for the preparation of 2-chloromethyl-4-methoxy-3,5- dimethylpyridine hydrochloride, characterized in that: The synthetic route is as follows: ； The method comprises the following steps: taking 3,5-dimethylpyridine as a starting material, and performing an oxidation reaction with an oxygen source to obtain 3,5-dimethylpyridine N-oxide; in a mixed acid of nitric acid and sulfuric acid, 3,5-dimethylpyridine N-oxide is subjected to a nitration reaction with nitric acid to obtain 4-nitro-3,5-dimethylpyridine N-oxide; the 4-nitro-3,5-dimethylpyridine N-oxide is subjected to a methoxy reaction to obtain 4-methoxy-3,5-dimethylpyridine N-oxide, and the 4-methoxy-3,5-dimethylpyridine N-oxide is activated by an activating agent in an organic solvent, and subjected to a chlorination reaction with sulfuric chloride to obtain the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine, and a salt reaction is performed in an organic solvent of HCl to obtain 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride; The activating agent is an acid anhydride.

2. Process for the preparation of 2-chloromethyl-4-methoxy-3,5- dimethylpyridine hydrochloride according to claim 1, characterized in that: The molar ratio of 3,5-dimethylpyridine to the oxygen source is 1:1-1:4, and preferably 1:4; the oxygen source is one of hydrogen peroxide, sodium hypochlorite or meta-chloroperbenzoic acid, and preferably hydrogen peroxide; the reaction solvent of the oxidation reaction is glacial acetic acid; the mass ratio of 3,5-dimethylpyridine to glacial acetic acid is 1:5-1:10, and preferably 1:8; and the temperature of the oxidation reaction is 70-100 DEG C, and preferably 80 DEG C.

3. Process for the preparation of 2-chloromethyl-4-methoxy-3,5- dimethylpyridine hydrochloride according to claim 1, characterized in that: The molar ratio of 3,5-dimethylpyridine to nitric acid and sulfuric acid is 1:4:(5-7), and preferably 1:4:6; and the temperature of the nitration reaction is 80-110 DEG C, and preferably 90-100 DEG C.

4. Process for the preparation of 2-chloromethyl-4-methoxy-3,5- dimethylpyridine hydrochloride according to claim 1 or 3, characterized in that: The nitration reaction: 3,5-dimethylpyridine N-oxide is mixed with sulfuric acid, nitric acid is added dropwise at the temperature of the nitration reaction, after the dropwise addition is completed, the reaction is kept, after the reaction is completed, the reaction liquid is cooled to room temperature, the pH of the reaction system is adjusted to 3-4 by using ammonia water, a solid is precipitated, the solid is filtered, the filter cake is collected, and the filter cake is dried to obtain 4-nitro-3,5-dimethylpyridine N-oxide.

5. A process for the preparation of 2-chloromethyl-4-methoxy-3,5- dimethylpyridine hydrochloride according to claim 1, characterized in that: The molar ratio of 4-nitro-3,5-dimethylpyridine N-oxide to sodium hydroxide is 1:1.0-1:1.5, and preferably 1:1.2; and the reaction temperature of the methoxy reaction is 40-70 DEG C, and preferably 40-50 DEG C.

6. A process for the preparation of 2-chloromethyl-4-methoxy-3,5- dimethylpyridine hydrochloride according to claim 1, characterized by: The methoxy substitution reaction: methanol and 4-nitro-3,5-dimethylpyridine N-oxide are mixed, an aqueous sodium hydroxide solution is added, and a methylation reaction is performed; after the reaction is completed, the reaction liquid is cooled to room temperature, the pH of the reaction liquid is adjusted to 7.5-9 by using glacial acetic acid, the solvent is removed by distillation under reduced pressure, dichloromethane is added for dissolution, filtration is performed, the filtrate is distilled under reduced pressure to remove dichloromethane, and 4-methoxy-3,5-dimethylpyridine N-oxide is obtained.

7. A process for the preparation of 2-chloromethyl-4-methoxy-3,5- dimethylpyridine hydrochloride according to claim 1, characterized by: The mass ratio of the 4-methoxy-3,5-dimethylpyridine N-oxide to the organic solvent is 1:2-1:12, preferably 1:3-1:5, and more preferably 1:4; the organic solvent is one of dichloromethane, trichloromethane and 1,2-dichloroethane, and is preferably dichloromethane; the acid anhydride is one or a mixture of trifluoroacetic anhydride, triflic anhydride and acetic anhydride, and is preferably trifluoroacetic anhydride; the molar ratio of the 4-methoxy-3,5-dimethylpyridine N-oxide to the activating agent is 1:1.0-1:1.3, preferably 1:1.0-1:1.1, and more preferably 1:1.1; the molar ratio of the 4-methoxy-3,5-dimethylpyridine N-oxide to the thionyl chloride is 1:1.2-1:1.6, and is preferably 1:1.5; and the temperature of the chlorination reaction is 0-10℃.

8. A process for the preparation of 2-chloromethyl-4-methoxy-3,5- dimethylpyridine hydrochloride according to claim 1, characterized in that: The chlorination reaction is carried out as follows: the 4-methoxy-3,5-dimethylpyridine N-oxide and the organic solvent are mixed, the temperature is lowered to 0-10℃, the activating agent is added to activate, and then the thionyl chloride is added dropwise to carry out the chlorination reaction; after the reaction is completed, ice water is added dropwise to the reaction solution, the liquid is separated into an organic phase and an aqueous phase, the aqueous phase is extracted with the same organic solvent as used in the chlorination reaction, the organic phases are combined, the organic phase is washed with saturated brine, and the solvent is removed by distillation to obtain the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine.

9. A process for the preparation of 2-chloromethyl-4-methoxy-3,5- dimethylpyridine hydrochloride according to claim 1, characterized in that: The organic solvent of the HCl organic solvent is one of methanol, ethanol, isopropanol and toluene, and is preferably isopropanol; and the mass ratio of the 4-methoxy-3,5-dimethylpyridine N-oxide to the organic solvent is 1:5-1:

12.

10. Process for the preparation of 2-chloromethyl-4-methoxy-3,5- dimethylpyridine hydrochloride according to claim 1 or 9, characterized in that: The salt formation reaction is carried out as follows: the free base of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine is dissolved in the organic solvent, HCl gas is bubbled into the system until the pH is 1-2, crystallization is carried out at room temperature under stirring, filtration is carried out, and drying is carried out to obtain 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride.

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