Method for preparing 2-(trimethylsilyl)ethoxymethyl chloride

Abstract

This invention provides a method for preparing 2-(trimethylsilyl)ethoxymethyl chloride, comprising the following steps: S1, reacting chloromethyltrimethylsilane with metallic magnesium in an anhydrous and oxygen-free environment to obtain trimethylsilylmethylmagnesium chloride; S2, reacting the trimethylsilylmethylmagnesium chloride with paraformaldehyde to obtain 2-(trimethylsilyl)ethoxymagnesium chloride; S3, subjecting the 2-(trimethylsilyl)ethoxymagnesium chloride to a chloromethylating agent for chloromethylation to obtain 2-(trimethylsilyl)ethoxymethyl chloride. According to the method of this invention, the synthetic route is short, the overall yield is high, and it is applicable to a one-pot process, generating less waste, making the route more feasible and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of compound preparation technology, and specifically to a method for preparing 2-(trimethylsilyl)ethoxymethyl chloride. Background Technology

[0002] 2-(trimethylsilyl)ethoxymethyl chloride, abbreviated as SEM-Cl, is an important protecting reagent, often used for the protection of active nitrogen atoms on hydroxyl groups or heterocycles.

[0003] The chlorine atom in SEM-Cl is highly reactive; under weakly alkaline conditions such as diisopropylethylamine, it can react with the hydroxyl groups of alcohols, thus it can be used to protect hydroxyl groups. SEM protecting groups are relatively stable and difficult to remove under weakly acidic conditions, but they can be removed under strongly acidic conditions (such as trifluoroacetic acid). The most common way to remove SEM protecting groups is through reaction with fluoride ion reagents such as TBAF, resulting in elimination reactions.

[0004] Besides protecting alcohol hydroxyl groups, SEM-Cl is also a commonly used protecting agent for protecting active nitrogen atoms on heterocycles. For example, in the synthesis of the antirheumatic drug baricitinib, SEM is used to protect the active nitrogen atoms on the pyrimidine-pyrrole heterocycle (as shown in equations (1) and (2) below).

[0005]

[0006] There are existing literature reports on the synthesis of 2-(trimethylsilyl)ethoxymethyl chloride. The main synthetic routes all use trimethylsilylethanol as a raw material and react it with paraformaldehyde in the presence of hydrogen chloride or trimethylchlorosilane to obtain the product (Reference: Tetrahedron Letters, 1980, vol. 21, #35, pp. 3343-3346).

[0007] The synthetic route for preparing 2-(trimethylsilyl)ethoxymethyl chloride, the core raw material trimethylsilylethanol, is as follows: using ethyl bromoacetate as a raw material, it undergoes a Reformatsky reaction with trimethylchlorosilane, followed by reduction.

[0008] In other words, the existing synthetic route is shown in equation (3):

[0009]

[0010] The above synthetic route first synthesizes trimethylsilylethanol, which then undergoes a chloromethylation reaction with paraformaldehyde. The reaction to prepare trimethylsilylethanol is in an alkaline environment, while the subsequent chloromethylation reaction is in an acidic environment. The solvents required for the two processes differ, and the reaction conditions vary significantly. Therefore, trimethylsilylethanol must undergo cumbersome post-processing steps such as quenching, extraction, and distillation purification to be separated before proceeding to the next reaction step. Consequently, the entire process for preparing SEM-Cl is quite complex and has high production costs. Summary of the Invention

[0011] In view of this, the present invention provides a method for preparing 2-(trimethylsilyl)ethoxymethyl chloride that is simple to operate, has a short route, and is suitable for industrial production.

[0012] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0013] The method for preparing 2-(trimethylsilyl)ethoxymethyl chloride according to an embodiment of the present invention includes the following steps:

[0014] S1, Chloromethyltrimethylsilane reacts with metallic magnesium in an anhydrous and oxygen-free environment to give trimethylsilylmethylmagnesium chloride;

[0015] S2, reacts the trimethylsilylmethyl magnesium chloride with paraformaldehyde to obtain 2-(trimethylsilyl)ethoxymagnesium chloride;

[0016] S3, the 2-(trimethylsilyl)ethoxymagnesium chloride undergoes a chloromethylation reaction with a chloromethylating agent to obtain 2-(trimethylsilyl)ethoxymethyl chloride.

[0017] Furthermore, the reaction in step S1 is carried out in a solvent, which includes any one or more of diethyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0018] Furthermore, the molar ratio of chloromethyltrimethylsilane to metallic magnesium is 1:(1.1-1.5), the reaction temperature is 30-60℃, and the reaction time is 5-10h.

[0019] Further, step S2 includes:

[0020] After the reaction in step S1 is completed, paraformaldehyde is added to the reaction system to react the trimethylsilylmethyl magnesium chloride with the paraformaldehyde to obtain the 2-(trimethylsilyl)ethoxymagnesium chloride.

[0021] Furthermore, the molar ratio of the chloromethyltrimethylsilane to the paraformaldehyde is 1:(0.9-1.2), the reaction temperature is 30-60℃, and the reaction time is 5-10h.

[0022] Furthermore, the chloromethylating agent includes dichloromethane, bromochloromethane, or mixtures thereof.

[0023] Further, step S3 includes:

[0024] After the reaction in step S2 is completed, the chloromethylating agent is added to the reaction system to allow the chloromethylation reaction to occur, yielding the 2-(trimethylsilyl)ethoxymethyl chloride.

[0025] Furthermore, the molar ratio of the chloromethyltrimethylsilane to the chloromethylating agent is 1:(2-4), the reaction temperature is 30-70℃, and the reaction time is 6-10h.

[0026] Furthermore, the method also includes the following steps:

[0027] S4. After the reaction in step S3 is completed, the solid insoluble matter is removed by filtration and the solvent is evaporated to obtain the primary product. Then, the primary product is purified by distillation to obtain the purified 2-(trimethylsilyl)ethoxymethyl chloride.

[0028] The above-described technical solution of the present invention has at least one of the following beneficial effects:

[0029] According to the method of the present invention, the synthesis route is short, the overall yield is high, and the "one-pot process" is applicable, resulting in less waste and stronger feasibility of the route, making it suitable for industrial production. Detailed Implementation

[0030] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.

[0031] The preparation method according to an embodiment of the present invention will be described first below.

[0032] The method for preparing 2-(trimethylsilyl)ethoxymethyl chloride according to an embodiment of the present invention has the following synthetic route as shown in formula (4):

[0033]

[0034] Specifically, it includes the following steps:

[0035] S1, chloromethyltrimethylsilane (hereinafter, sometimes referred to as compound I) reacts with metallic magnesium in an anhydrous and oxygen-free environment to give trimethylsilylmethylmagnesium chloride (hereinafter, sometimes referred to as compound II).

[0036] In other words, the preparation method of this application uses "chloromethyltrimethylsilane" and "metallic magnesium" as starting materials for the first step reaction.

[0037] A reaction occurs in an anhydrous or oxygen-free environment, such as in an organic solvent, under an inert gas atmosphere, or under vacuum conditions.

[0038] Furthermore, the reaction in step S1 is carried out in a solvent, which includes any one or more of diethyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran. The starting materials are readily soluble in these solvents, are less prone to unnecessary side reactions, and are easily evaporated to remove impurities after the reaction, thus these solvents are preferred.

[0039] Furthermore, the molar ratio of chloromethyltrimethylsilane to metallic magnesium is 1:(1.1-1.5), the reaction temperature is 30-60℃, and the reaction time is 5-10h.

[0040] In other words, using a slightly excess of Mg can help increase the yield and accelerate the reaction rate.

[0041] Among these methods, magnesium, for example, can be used as a metallic magnesium, which helps to increase the reaction contact area and improve the reaction rate.

[0042] S2, reacts the trimethylsilylmethyl magnesium chloride with paraformaldehyde to give 2-(trimethylsilyl)ethoxymagnesium chloride (hereinafter, sometimes referred to as compound III).

[0043] In other words, after obtaining compound II, it is further reacted with paraformaldehyde to obtain compound III.

[0044] Further, step S2 may include, for example:

[0045] After the reaction in step S1 is completed, paraformaldehyde is added to the reaction system to react the trimethylsilylmethyl magnesium chloride with the paraformaldehyde to obtain the 2-(trimethylsilyl)ethoxymagnesium chloride.

[0046] In other words, after the first step of the reaction is completed and compound II is obtained, no further processing is required; paraformaldehyde can be directly added to the reaction system to initiate the second step of the reaction. The operation is simple and controllable, involves fewer pieces of equipment, has a shorter route, and produces less waste, making it more suitable for industrial production.

[0047] Furthermore, the molar ratio of the chloromethyltrimethylsilane to the paraformaldehyde is 1:(0.9-1.2), the reaction temperature is 30-60℃, and the reaction time is 5-10h. In other words, the reaction temperature conditions can be the same as the first step reaction, further simplifying the operation and reducing equipment requirements.

[0048] S3, the 2-(trimethylsilyl)ethoxymagnesium chloride is subjected to a chloromethylation reaction with a chloromethylating agent to obtain 2-(trimethylsilyl)ethoxymethyl chloride (hereinafter referred to as compound IV).

[0049] In other words, this application eliminates the need for prior alcoholysis followed by chloromethylation; instead, 2-(trimethylsilyl)ethoxymagnesium chloride is directly reacted with a chloromethylating agent to yield compound IV. Furthermore, in this application, the reaction environments for the first, second, and third steps are identical—all alkaline—making a one-pot reaction possible.

[0050] Further, step S3 may include:

[0051] After the reaction in step S2 is completed, the chloromethylating agent is added to the reaction system to allow the chloromethylation reaction to occur, yielding the 2-(trimethylsilyl)ethoxymethyl chloride.

[0052] Furthermore, the chloromethylating agent includes dichloromethane, bromochloromethane, or mixtures thereof. These two chloromethylating agents are preferred due to their advantages of high reactivity, low cost, and ease of storage.

[0053] Furthermore, the molar ratio of the chloromethyltrimethylsilane to the chloromethylating agent is 1:(2-4), the reaction temperature is 30-70℃, and the reaction time is 6-10h.

[0054] As can be seen from the above records, the reaction temperature can remain constant from beginning to end, thus requiring low equipment specifications, simple operation, short reaction route, short reaction time, and high reaction efficiency.

[0055] Furthermore, the method may also include the following steps:

[0056] S4. After the reaction in step S3 is completed, the solid insoluble matter is removed by filtration and the solvent is evaporated to obtain the primary product. Then, the primary product is purified by distillation to obtain the purified 2-(trimethylsilyl)ethoxymethyl chloride.

[0057] In other words, after the reaction is complete, the product can be purified by filtration, evaporation of the solvent, and distillation.

[0058] As can be seen from the above, the preparation method according to the present invention can be applied using a "one-pot method," meaning that intermediate products do not require further treatment and can be directly continued in the reaction system for the next step of the reaction until all reactions are completed, at which point purification can be performed all at once. Therefore, the method according to the embodiments of the present invention has a short synthetic route, high overall yield, and is applicable to the "one-pot method," resulting in less waste, stronger route feasibility, and suitability for industrial production.

[0059] The preparation method according to the present invention will be further described below with reference to specific embodiments.

[0060] Example 1

[0061] In a 2L round-bottom flask under nitrogen protection, 26.7g (1.1 eq.) of magnesium shavings were added to 1.0L of anhydrous tetrahydrofuran, and the temperature was raised to 40°C. A mixed solution of 122.7g (1.0 eq.) of compound I and 100mL of anhydrous tetrahydrofuran was slowly added dropwise. After the reaction was initiated, the dropping rate was controlled, and the internal temperature was maintained at 35-45°C. The entire reaction took 5 hours, yielding a tetrahydrofuran solution of Grignard reagent compound II. No further processing was required, and the reaction proceeded directly to the next step.

[0062] Under nitrogen protection, 27.0 g (0.9 eq.) of paraformaldehyde was added to the above Grignard reagent solution, and the reaction was carried out at an internal temperature of 40 °C for 5 h to obtain a tetrahydrofuran solution of compound III. No post-treatment was required and the next step was performed directly.

[0063] Under nitrogen protection, 170 g (2.0 eq.) of dichloromethane was added to the above reaction solution. The reaction system was sealed and heated to 70 °C for 10 h. The insoluble matter was removed by filtration, the solvent was evaporated to dryness, and then distilled under reduced pressure to obtain 103.3 g of compound IV, with a yield of 62%.

[0064] Example 2

[0065] In a 2L round-bottom flask under nitrogen protection, 24.3g (1.2 eq.) of magnesium shavings were added to 1.0L of anhydrous tetrahydrofuran, and the temperature was raised to 40°C. A mixed solution of 122.7g (1.0 eq.) of compound I and 100mL of anhydrous tetrahydrofuran was slowly added dropwise. After the reaction was initiated, the dropping rate was controlled, and the internal temperature was maintained at 35-45°C. The entire reaction took 5 hours, yielding a tetrahydrofuran solution of compound II, which could be directly proceeded to the next step without further processing.

[0066] Under nitrogen protection, 33.0 g (1.1 eq.) of paraformaldehyde was added to the above Grignard reagent solution, and the reaction was carried out at an internal temperature of 40 °C for 5 h to obtain a tetrahydrofuran solution of compound III. No post-treatment was required and the next step was performed directly.

[0067] Under nitrogen protection, 339.6 g (4.0 eq.) of dichloromethane was added to the above reaction solution. The reaction system was sealed and heated to 70 °C for 10 h. The insoluble matter was removed by filtration, the solvent was evaporated to dryness, and then the mixture was distilled under reduced pressure to obtain 108.3 g of compound (IV), with a yield of 65%.

[0068] Example 3

[0069] In a 2L round-bottom flask under nitrogen protection, 26.7g (1.1 eq.) of magnesium shavings were added to 1.0L of anhydrous tetrahydrofuran, and the temperature was raised to 30°C. A mixed solution of 122.7g (1.0 eq.) of compound I and 100mL of anhydrous tetrahydrofuran was slowly added dropwise. After the reaction was initiated, the dropping rate was controlled, and the internal temperature was maintained at 35-45°C. The entire reaction took 5 hours, yielding a tetrahydrofuran solution of compound II, which could be directly proceeded to the next step without further processing.

[0070] Under nitrogen protection, 30.0 g (1.0 eq.) of paraformaldehyde was added to the above Grignard reagent solution, and the reaction was carried out at an internal temperature of 30 °C for 5 h to obtain a tetrahydrofuran solution of compound III. No post-treatment was required to proceed directly to the next step.

[0071] Under nitrogen protection, 258.8 g (2.0 eq.) of bromochloromethane was added to the above reaction solution. The reaction system was sealed and heated to 30 °C for 10 h. The insoluble matter was removed by filtration, the solvent was evaporated to dryness, and then distilled under reduced pressure to obtain 133.4 g of compound IV, with a yield of 80%.

[0072] Example 4

[0073] In a 2L round-bottom flask under nitrogen protection, 36.5 g (1.5 eq.) of magnesium shavings were added to 1.0 L of anhydrous diethyl ether, and the temperature was raised to 30°C. A mixture of 122.7 g (1.0 eq.) of compound I and 100 mL of anhydrous diethyl ether was slowly added dropwise. After the reaction was initiated, the dropping rate was controlled, and the internal temperature was maintained at 30°C. The entire reaction took 10 h, yielding an ether solution of compound II, which could be directly proceeded to the next step without further processing.

[0074] Under nitrogen protection, 30.0 g (1.0 eq.) of paraformaldehyde was added to the above Grignard reagent solution, and the reaction was carried out at an internal temperature of 30 °C for 6 h to obtain an ether solution of compound II. No post-treatment was required and the next step was performed directly.

[0075] Under nitrogen protection, 258.8 g (2.0 eq.) of bromochloromethane was added to the above reaction solution. The reaction system was sealed and reacted at 30 °C for 10 h. The insoluble matter was removed by filtration, the solvent was evaporated to dryness, and then distilled under reduced pressure to obtain compound IV118.3 g, with a yield of 71%.

[0076] Example 5

[0077] In a 2L round-bottom flask under nitrogen protection, 36.5g (1.5 eq.) of magnesium shavings were added to 1.0L of anhydrous 2-methyltetrahydrofuran, and the temperature was raised to 60°C. A mixed solution of 122.7g (1.0 eq.) of compound I and 100mL of anhydrous 2-methyltetrahydrofuran was slowly added dropwise. After the reaction was initiated, the dropping rate was controlled, and the internal temperature was maintained at 30°C. The entire reaction took 5 hours, yielding a 2-methyltetrahydrofuran solution of compound (II), which could be directly proceeded to the next step without further processing.

[0078] Under nitrogen protection, 36.0 g (1.2 eq.) of paraformaldehyde was added to the above Grignard reagent solution, and the reaction was carried out at an internal temperature of 60 °C for 2 h to obtain a 2-methyltetrahydrofuran solution of compound (III). No post-treatment was required and the next step was performed directly.

[0079] Under nitrogen protection, 388.2 g (3.0 eq.) of bromochloromethane was added to the above reaction solution, the reaction system was sealed, and the reaction was carried out at 60 °C for 10 h.

[0080] The insoluble matter was removed by filtration, the solvent was evaporated to dryness, and then the mixture was distilled under reduced pressure to obtain 138.4 g of compound (IV), with a yield of 83%.

[0081] In summary, the method for preparing 2-(trimethylsilyl)ethoxymethyl chloride of the present invention has the advantages of a short synthetic route, simple operation, low cost, and high yield.

[0082] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing 2-(trimethylsilyl)ethoxymethyl chloride, characterized in that, Includes the following steps: S1, Chloromethyltrimethylsilane reacts with metallic magnesium in an anhydrous and oxygen-free environment to give trimethylsilylmethylmagnesium chloride; S2, reacts the trimethylsilylmethyl magnesium chloride with paraformaldehyde to obtain 2-(trimethylsilyl)ethoxymagnesium chloride; S3, the 2-(trimethylsilyl)ethoxymagnesium chloride undergoes a chloromethylation reaction with a chloromethylating agent to yield 2-(trimethylsilyl)ethoxymethyl chloride, wherein the chloromethylating agent is bromochloromethane. Step S2 includes: After the reaction in step S1 is completed, paraformaldehyde is added to the reaction system to react the trimethylsilylmethyl magnesium chloride with the paraformaldehyde to obtain the 2-(trimethylsilyl)ethoxy magnesium chloride. Step S3 includes: After the reaction in step S2 is completed, the chloromethylating reagent is added to the reaction system to allow the chloromethylation reaction to occur, yielding the 2-(trimethylsilyl)ethoxymethyl chloride. In steps S1 to S3, the reaction temperature remains constant at 30-60℃.

2. The method according to claim 1, characterized in that, The reaction in step S1 is carried out in a solvent, which includes any one or more of diethyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran.

3. The method according to claim 1, characterized in that, The molar ratio of chloromethyltrimethylsilane to metallic magnesium is 1:(1.1-1.5), and the reaction time is 5-10 h.

4. The method according to claim 1, characterized in that, The molar ratio of the chloromethyltrimethylsilane to the paraformaldehyde is 1:(0.9-1.2), and the reaction time is 5-10 h.

5. The method according to claim 1, characterized in that, The molar ratio of the chloromethyltrimethylsilane to the chloromethylating agent is 1:(2-4); the reaction time is 6-10 h.

6. The method according to claim 1, characterized in that, The method further includes the following steps: S4. After the reaction in step S3 is completed, the solid insoluble matter is removed by filtration and the solvent is evaporated to obtain the primary product. Then, the primary product is purified by distillation to obtain the purified 2-(trimethylsilyl)ethoxymethyl chloride.

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