Preparation method and application of 3-methoxy-4-chlorobenzaldehyde

Abstract

The application provides a preparation method and application of 3-methoxy-4-chlorobenzaldehyde, and the preparation method comprises the following steps: (1) mixing and reacting p-chlorobenzaldehyde with a bromination reagent and an additive to obtain 3-bromo-4-chlorobenzaldehyde; (2) mixing and reacting the 3-bromo-4-chlorobenzaldehyde with a methoxide and a catalyst to obtain the 3-methoxy-4-chlorobenzaldehyde. The preparation method provided by the application starts from inexpensive p-chlorobenzaldehyde as a raw material, compared with the existing process, the reaction material is inexpensive and easy to obtain, the reaction yield is high, and the reaction condition is gentle.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 3-methoxy-4-chlorobenzaldehyde and its application, and particularly to a low-cost method for preparing 3-methoxy-4-chlorobenzaldehyde and its application. Background Technology

[0002] 3-Methoxy-4-chlorobenzaldehyde is an important synthetic intermediate in pharmaceuticals and luminescent materials. It is primarily used in the synthesis of the chemiluminescent substrate CDP-Star, the anticancer drug Bcl-2 inhibitor, and TEAD inhibitors, holding significant applications and importance in the medical and chemical materials field. Currently, there are few literature reports on the synthesis of 3-methoxy-4-chlorobenzaldehyde, and it is relatively expensive. Therefore, seeking new and optimized synthetic methods for 3-methoxy-4-chlorobenzaldehyde is of great significance.

[0003] Patents such as WO2005 / 82890A1 and EP2314593A1 provide existing synthetic methods that mainly use 3-methoxy-4-chlorobenzyl alcohol as a raw material and oxidize it with oxidants such as manganese dioxide or pyridinium chlorochromate (PCC) to obtain 3-methoxy-4-chlorobenzaldehyde. This method requires the use of metals and strong oxidants, and has the disadvantages of poor reaction selectivity, low safety, and the expensive raw material 3-methoxy-4-chlorobenzyl alcohol.

[0004] Patents such as US6906063A1, EP2314593A1, and WO2010 / 9069A1 provide a method for preparing 3-methoxy-4-chlorobenzaldehyde from 3-methoxy-4-chlorotoluene by oxidation with cerium ammonium nitrate or oxidation with potassium permanganate to acid followed by reduction. However, both methods inevitably use expensive 3-methoxy-4-chlorotoluene as a raw material and require strong oxidants, resulting in high reaction risk, poor oxidation selectivity, and high cost.

[0005] Therefore, how to provide a simple, low-cost, and safe method for preparing 3-methoxy-4-chlorobenzaldehyde has become an urgent problem to be solved. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing 3-methoxy-4-chlorobenzaldehyde and its applications, particularly a low-cost method for preparing 3-methoxy-4-chlorobenzaldehyde and its applications. The preparation method provided by this invention uses inexpensive p-chlorobenzaldehyde as a raw material and, compared to existing processes, features readily available and inexpensive reactants, high reaction yield, and gentle reaction conditions.

[0007] To achieve this objective, the present invention adopts the following technical solution:

[0008] On one hand, the present invention provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, the method comprising the following steps:

[0009] (1) Mix p-chlorobenzaldehyde with a brominating reagent and additives to obtain 3-bromo-4-chlorobenzaldehyde;

[0010] (2) 3-bromo-4-chlorobenzaldehyde is mixed with methanol salt and catalyst to obtain 3-methoxy-4-chlorobenzaldehyde.

[0011] The above method uses inexpensive p-chlorobenzaldehyde as a raw material and prepares 3-methoxy-4-chlorobenzaldehyde through two steps of bromination and methoxylation. Compared with the original process, the reaction process has the advantages of inexpensive and readily available reactants, high reaction yield, high selectivity, mild reaction conditions, and high safety, making it more suitable for industrial production.

[0012] Preferably, the molar ratio of p-chlorobenzaldehyde, brominating reagent and additive in step (1) is (0.8-1.2):(0.8-1.2):(1.5-2), wherein the number of p-chlorobenzaldehyde parts can be 0.8, 0.9, 1, 1.1 or 1.2, the number of brominating reagent parts can be 0.8, 0.9, 1, 1.1 or 1.2, and the number of additive parts can be 1.5, 1.6, 1.7, 1.8, 1.9 or 2, but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0013] Preferably, the brominating agent in step (1) includes any one or a combination of at least two of sodium bromide, potassium bromide, bromine, or NBS (N-bromosuccinimide).

[0014] Preferably, the additive in step (1) includes any one or a combination of at least two of potassium persulfate, DMSO (dimethyl sulfoxide), acetic acid, titanium tetrachloride, aluminum chloride, sulfur, or sulfonyl chloride.

[0015] Preferably, the reaction temperature in step (1) is -20 to 10°C, and the reaction time is 3 to 5 hours. The reaction temperature can be -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, or 10°C, etc., and the reaction time can be 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0016] Preferably, the molar ratio of 3-bromo-4-chlorobenzaldehyde to methyl salt and catalyst in step (2) is (0.8-1.2):(2.5-3.5):(0.04-0.2), wherein the amount of 3-bromo-4-chlorobenzaldehyde can be 0.8, 0.9, 1, 1.1, or 1.2, and the amount of methyl salt can be 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, or 3.2. The amounts of catalyst can be 3.3, 3.4, or 3.5, etc., and the amount of catalyst can be 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.2, etc., but are not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0017] Preferably, the methoxide in step (2) comprises sodium methoxide and / or potassium methoxide.

[0018] Preferably, the catalyst in step (2) comprises any one or a combination of at least two of cuprous iodide, cuprous bromide, cuprous chloride, bis(triphenylphosphine)cuprous iodide, bis(triphenylphosphine)cuprous bromide, or bis(triphenylphosphine)cuprous chloride.

[0019] This invention significantly reduces production costs compared to other industrial rare earth metal catalysts such as palladium and cerium by using copper compounds as catalysts.

[0020] Preferably, the reaction temperature in step (2) is 80-100℃ and the time is 8-15h. The temperature can be 80℃, 85℃, 90℃, 95℃ or 100℃, etc., and the time can be 8h, 9h, 10h, 11h, 12h, 13h, 14h or 15h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0021] On the other hand, the present invention also provides the application of the preparation method described above in the preparation of pharmaceutical compound intermediates and / or luminescent material intermediates.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] This invention provides a method for preparing 3-methoxy-4-chlorobenzaldehyde. Starting from inexpensive p-chlorobenzaldehyde, 3-methoxy-4-chlorobenzaldehyde is prepared in two steps: bromination and methoxylation. Compared with the original process, this method has the advantages of inexpensive and readily available reactants, high reaction yield, high selectivity, mild reaction conditions, and high safety, making it more suitable for industrial production. Detailed Implementation

[0024] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0025] Example 1

[0026] This embodiment provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, the specific steps of which are as follows:

[0027] Preparation and purification process of 3-bromo-4-chlorobenzaldehyde

[0028] In a three-necked flask, 100 mL of acetone was first added, followed by 14.5 g of p-chlorobenzaldehyde and 10.2 g of sodium bromide. After mixing, the temperature was lowered to -10 °C, and a mixture of 30 g of potassium persulfate and 100 g of water was added dropwise over three hours with stirring. After the addition was complete, the reaction was maintained at this temperature for 4 hours, and the reaction was monitored by TLC until the conversion of the starting material was complete. After the reaction was complete, 200 mL of ethyl acetate was added, the organic layer was separated, and the aqueous layer was washed three times with 100 mL of ethyl acetate. The organic solvent was removed by vacuum distillation to obtain 21.0 g of white solid 3-bromo-4-chlorobenzaldehyde, with a reaction yield of 92.8% (based on p-chlorobenzaldehyde).

[0029] Characterization is as follows: H-NMR (400MHz, rt, CDCl3): δ=7.65(d, 1H), 7.78(dd, 1H), 8.14(d, 1H), 9.96(s, 1H); C-NMR (400MHz, rt, CDCl3): δ=123.61, 129.03, 131.13, 134.65, 135.83, 141.04, 189.55.

[0030] Preparation and purification process of 3-methoxy-4-chlorobenzaldehyde

[0031] In a three-necked flask, 100 mL of methanol and 30 mL of N,N-dimethylformamide were added first, followed by 21.9 g of 3-bromo-4-chlorobenzaldehyde and 16.2 g of sodium methoxide. Finally, 0.99 g of cuprous iodide was added. After mixing and stirring, the temperature was raised to 85 °C and maintained for 10 hours. The reaction was monitored by TLC until the conversion of the starting material was complete. After the reaction was completed, the reaction solution was poured into 200 mL of water, and 200 mL of ethyl acetate was added. The organic layer was separated, and the aqueous layer was washed three times with 200 mL of ethyl acetate. The organic solvent was removed by vacuum distillation to obtain 15.5 g of white solid 3-methoxy-4-chlorobenzaldehyde, with a reaction yield of 91%.

[0032] Characterization is as follows: H-NMR (400MHz, rt, CDCl3): δ=3.99(s, 3H), 7.42(dd, 1H), 7.45(d, 1H), 7.57(d, 1H), 9.96(s, 1H); C-NMR (400MHz, rt, CDCl3): δ=56.30, 110.15, 124.28, 129.64, 130.78, 136.06, 155.71, 190.94.

[0033] Example 2

[0034] This embodiment provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, the specific steps of which are as follows:

[0035] Preparation and purification process of 3-bromo-4-chlorobenzaldehyde

[0036] In a three-necked flask, 100 mL of acetone was first added, followed by 14.5 g of p-chlorobenzaldehyde and 11.9 g of potassium bromide. After mixing, the temperature was lowered to -10 °C, and a mixture of 30 g of potassium persulfate and 100 g of water was added dropwise over three hours with stirring. After the addition was complete, the reaction was maintained at this temperature for 4 hours, and the reaction was monitored by TLC until the conversion of the starting material was complete. After the reaction was complete, 200 mL of ethyl acetate was added, the organic layer was separated, and the aqueous layer was washed three times with 100 mL of ethyl acetate. The organic solvent was removed by vacuum distillation to obtain 20.3 g of white solid 3-bromo-4-chlorobenzaldehyde, with a reaction yield of 89.7% (based on p-chlorobenzaldehyde).

[0037] Preparation and purification process of 3-methoxy-4-chlorobenzaldehyde

[0038] In a three-necked flask, 100 mL of methanol and 30 mL of N,N-dimethylformamide were added first, followed by 21.9 g of 3-bromo-4-chlorobenzaldehyde and 16.2 g of sodium methoxide. Finally, 0.99 g of cuprous chloride was added. After mixing and stirring, the temperature was raised to 85 °C and maintained for 10 hours. The reaction was monitored by TLC until the conversion of the starting material was complete. After the reaction was completed, the reaction solution was poured into 200 mL of water, and 200 mL of ethyl acetate was added. The organic layer was separated, and the aqueous layer was washed three times with 200 mL of ethyl acetate. The organic solvent was removed by vacuum distillation to obtain 15.8 g of white solid 3-methoxy-4-chlorobenzaldehyde, with a reaction yield of 93%.

[0039] Example 3

[0040] This embodiment provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, which is basically the same as that in Example 1, except that bromine is selected as the brominating agent in the first step of the reaction, with an amount of 7.9 g of bromine. Sulfur and sulfonyl chloride are selected as additives, with an amount of 0.32 g of sulfur and 30 mL of sulfonyl chloride. A total of 19.8 g of white solid 3-bromo-4-chlorobenzaldehyde is obtained, with a reaction yield of 87.5% (calculated based on p-chlorobenzaldehyde).

[0041] Example 4

[0042] This embodiment provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, which is basically the same as that in Example 1, except that bromine is selected as the brominating agent in the first step of the reaction, with an amount of 7.9 g of bromine and titanium tetrachloride is selected as the additive, with an amount of 0.19 g of titanium tetrachloride. A total of 19.2 g of white solid 3-bromo-4-chlorobenzaldehyde is obtained, with a reaction yield of 84.8% (calculated based on p-chlorobenzaldehyde).

[0043] Example 5

[0044] This embodiment provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, which is basically the same as that in Example 1, except that bromine is selected as the brominating agent in the first step of the reaction, and the amount of bromine used is 15.8g. Acetic acid is selected as the additive, and the amount of acetic acid used is 30g. A total of 16.5g of white solid 3-bromo-4-chlorobenzaldehyde is obtained, and the reaction yield is 72.9% (calculated based on p-chlorobenzaldehyde)%.

[0045] Example 6

[0046] This embodiment provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, which is basically the same as that in Example 1, except that NBS is selected as the brominating agent in the first step of the reaction, with an amount of 21.36 g of NBS and 0.78 g of DMSO, yielding a total of 18.3 g of white solid 3-bromo-4-chlorobenzaldehyde, with a reaction yield of 80.9% (calculated based on p-chlorobenzaldehyde).

[0047] Example 7

[0048] This embodiment provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, which is basically the same as that in Example 1, except that NBS is selected as the brominating agent in the first step of the reaction, with an amount of 21.36 g of NBS and aluminum chloride as the additive, with an amount of 1.6 g of aluminum chloride. A total of 15.6 g of white solid 3-bromo-4-chlorobenzaldehyde is obtained, with a reaction yield of 68.9% (calculated based on p-chlorobenzaldehyde).

[0049] Example 8

[0050] This embodiment provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, which is basically the same as that in Example 1, except that the catalyst used in the second step is bis(triphenylphosphine)cuprous iodide (equimolar amount with that in Example 1), and 15.2 g of white solid 3-methoxy-4-chlorobenzaldehyde is obtained, with a reaction yield of 89.2% (calculated as 3-bromo-4-chlorobenzaldehyde).

[0051] Example 9

[0052] This embodiment provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, which is basically the same as that in Example 1, except that the amount of catalyst added in the second step is changed, and 1.98g of cuprous iodide is added, finally yielding 16.7g of white solid 3-methoxy-4-chlorobenzaldehyde, with a reaction yield of 98.1% (calculated as 3-bromo-4-chlorobenzaldehyde).

[0053] Comparative Example 1

[0054] This comparative example provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, the specific steps of which are as follows:

[0055] In a three-necked flask, 100 mL of acetic acid, 15.2 g of m-methoxybenzaldehyde, and 15.8 g of hydrogen peroxide were first added. Finally, 55 g of concentrated hydrochloric acid was added dropwise at 10 °C. After the addition was completed, the mixture was stirred and the temperature was raised to 50 °C. The reaction was maintained at this temperature for 10 hours. The reaction was monitored by LCMS until the conversion of the starting material was completed. It was found that a mixture of 4.2 g of 3-methoxy-4-chlorobenzaldehyde and 9.3 g of 2-chloro-5-methoxybenzaldehyde was obtained, but the selectivity was poor and difficult to control.

[0056] Comparative Example 2

[0057] This comparative example provides a method for preparing 3-methoxy-4-chlorobenzaldehyde. The specific steps are as follows: In a three-necked flask, 150 mL of chloroform, 13.6 g of m-methoxybenzaldehyde, 26.7 g of NCS, and 1.6 g of DMSO are added. The mixture is stirred and the temperature is raised to 75 °C. The reaction is refluxed for 6 hours. The reaction is monitored by LCMS. It is found that 14.8 g of 2-chloro-5-methoxybenzaldehyde is obtained, with a yield of 96.7%. However, all products are methoxy-para-methoxybenzaldehyde products, not the target product 3-methoxy-4-chlorobenzaldehyde.

[0058] The applicant declares that this invention illustrates the preparation method and application of 3-methoxy-4-chlorobenzaldehyde through the above embodiments, but this invention is not limited to the above embodiments, that is, it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials of this invention, addition of auxiliary components, and selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

[0059] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0060] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A method for preparing 3-methoxy-4-chlorobenzaldehyde, characterized in that, The preparation method includes the following steps: (1) 3-Bromo-4-chlorobenzaldehyde is obtained by mixing p-chlorobenzaldehyde with a brominating reagent and an additive and reacting the mixture. The reaction temperature is -20~0℃ and the reaction time is 3-5 h. The brominating agent is sodium bromide or potassium bromide, and the additive is potassium persulfate. or, The brominating agent is NBS, and the additive is DMSO or aluminum chloride; or, The brominating agent is bromine, and the additive is acetic acid or titanium tetrachloride. (2) 3-bromo-4-chlorobenzaldehyde is mixed with methanol salt and catalyst to obtain 3-methoxy-4-chlorobenzaldehyde.

2. The production method according to claim 1, characterized by, The molar ratio of p-chlorobenzaldehyde, brominating reagent and additive in step (1) is (0.8-1.2):(0.8-1.2):(1.5-2).

3. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of 3-bromo-4-chlorobenzaldehyde to methanol salt and catalyst is (0.8-1.2):(2.5-3.5):(0.04-0.2).

4. The method of claim 1, wherein, The methoxide in step (2) is selected from sodium methoxide and / or potassium methoxide.

5. The preparation method according to claim 1, characterized in that, The catalyst in step (2) is selected from any one or a combination of at least two of cuprous iodide, cuprous bromide, cuprous chloride, bis(triphenylphosphine)cuprous iodide, bis(triphenylphosphine)cuprous bromide or bis(triphenylphosphine)cuprous chloride.

6. The method of claim 1, wherein, The reaction in step (2) is carried out at a temperature of 80-100℃ for 8-15 hours.

7. The application of the preparation method according to any one of claims 1-6 in the preparation of pharmaceutical compound intermediates and / or luminescent material intermediates.