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

Abstract

The invention provides a preparation method and application of 3-methoxy-4-chlorobenzaldehyde, and the preparation method comprises the following steps: (1) mixing p-chlorobenzaldehyde with a bromination reagent and an additive for reaction to obtain 3-bromo-4-chlorobenzaldehyde; and (2) mixing the 3-bromo-4-chlorobenzaldehyde with methoxide and a catalyst, and carrying out a reaction so as to obtain the 3-methoxy-4-chlorobenzaldehyde. According to the preparation method provided by the invention, cheap p-chlorobenzaldehyde is taken as a raw material, and compared with the reaction process in the prior art, the preparation method has the characteristics of cheap and easily available reaction materials, high reaction yield and mild reaction conditions.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a preparation method of 3-methoxy-4-chlorobenzaldehyde and an application thereof, and in particular to a preparation method of 3-methoxy-4-chlorobenzaldehyde with low cost and an application thereof. Background Art

[0002] 3-Methoxy-4-chlorobenzaldehyde is an important synthetic intermediate in medicine and luminescent materials. It can be mainly used in the synthesis of chemiluminescent substrate CDP-Star, anticancer drug Bcl-2 inhibitor and TEAD inhibitor, and has important applications and significance in the field of medical and chemical materials. At present, there are few literature reports on the synthesis of 3-methoxy-4-chlorobenzaldehyde, and 3-methoxy-4-chlorobenzaldehyde is relatively expensive. Therefore, it is of great significance to seek a new optimized synthesis method for 3-methoxy-4-chlorobenzaldehyde.

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

[0004] Patents US6906063A1, EP2314593A1, WO2010 / 9069A1, etc. provide a method for preparing 3-methoxy-4-chlorobenzaldehyde by using 3-methoxy-4-chlorotoluene as a raw material through oxidation by ammonium cerium nitrate, or oxidation by potassium permanganate to acid and then reduction. No matter which method is used, it is difficult to avoid using expensive 3-methoxy-4-chlorotoluene as a raw material, and a strong oxidant is required, which has the disadvantages of high reaction risk, poor oxidation selectivity and high cost.

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

[0006] In view of the deficiencies in the prior art, the object of the present invention is to provide a preparation method of 3-methoxy-4-chlorobenzaldehyde and its application, in particular to provide a low-cost preparation method of 3-methoxy-4-chlorobenzaldehyde and its application. The preparation method provided by the present invention uses cheap p-chlorobenzaldehyde as a raw material, and compared with the existing process reaction process, it has the characteristics of cheap and easy to obtain reaction materials, high reaction yield, and mild reaction conditions.

[0007] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

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

[0009] (1) reacting p-chlorobenzaldehyde with a brominating agent and an additive to obtain 3-bromo-4-chlorobenzaldehyde;

[0010] (2) 3-bromo-4-chlorobenzaldehyde is mixed with methoxide and a catalyst for reaction to obtain the 3-methoxy-4-chlorobenzaldehyde.

[0011] The method uses cheap p-chlorobenzaldehyde as a raw material, and prepares 3-methoxy-4-chlorobenzaldehyde through two steps of bromination and methoxylation. Compared with the original process reaction process, the method has the characteristics of cheap and easy-to-obtain reaction materials, high reaction yield, high selectivity, mild reaction conditions, high safety, and is more suitable for industrial production.

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

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

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

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

[0016] Preferably, the molar ratio of 3-bromo-4-chlorobenzaldehyde to methoxide and catalyst in step (2) is (0.8-1.2):(2.5-3.5):(0.04-0.2), wherein the proportion of 3-bromo-4-chlorobenzaldehyde can be 0.8, 0.9, 1, 1.1 or 1.2, and the proportion of methoxide can be 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2. , 3.3, 3.4 or 3.5, etc., the number of catalysts 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, and other values ​​not listed within the above numerical 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 of cuprous iodide, cuprous bromide, cuprous chloride, bis(triphenylphosphine) cuprous iodide, bis(triphenylphosphine) cuprous bromide or bis(triphenylphosphine) cuprous chloride, or a combination of at least two thereof.

[0019] The present invention adopts copper compounds as catalysts, thereby significantly reducing production costs compared with other industrial rare earth metal catalysts such as palladium and cerium.

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

[0021] On the other hand, the present invention also provides the use of the above-mentioned preparation method 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] The invention provides a preparation method of 3-methoxy-4-chlorobenzaldehyde. Starting from cheap p-chlorobenzaldehyde as a raw material, 3-methoxy-4-chlorobenzaldehyde is prepared through two steps of bromination and methoxylation. Compared with the original process reaction process, the method has the characteristics of cheap and easy-to-obtain reaction materials, high reaction yield, high selectivity, mild reaction conditions and high safety, and is more suitable for industrial production. DETAILED DESCRIPTION

[0024] In order to further explain the technical means and effects adopted by the present invention, the technical solution of the present invention is further described below in conjunction with the preferred embodiments of the present invention, but 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, and the specific steps are as follows:

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

[0028] In a three-necked flask, first add 100 mL of acetone, then add 14.5 g of p-chlorobenzaldehyde and 10.2 g of sodium bromide, and after mixing, lower the temperature to -10°C, and under stirring, dropwise add a mixed solution of 30 g of potassium persulfate and 100 g of water within three hours. After the dropwise addition is completed, keep the reaction warm for 4 hours and monitor the reaction by TLC until the conversion of the raw materials is completed. After the reaction is completed, add 200 mL of ethyl acetate, separate the organic layer, and then wash the water layer three times with 100 mL of ethyl acetate. Remove the organic phase solvent by distillation under reduced pressure to obtain a total of 21.0 g of white solid 3-bromo-4-chlorobenzaldehyde, with a reaction yield of 92.8% (calculated as p-chlorobenzaldehyde).

[0029] The characterizations are as follows: H-NMR (400 MHz, rt, CDCl3): δ = 7.65 (d, 1H), 7.78 (dd, 1H), 8.14 (d, 1H), 9.96 (s, 1H); C-NMR (400 MHz, 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, first add 100 mL of methanol and 30 mL of N,N-dimethylformamide, then add 21.9 g of 3-bromo-4-chlorobenzaldehyde and 16.2 g of sodium methoxide, and finally add 0.99 g of cuprous iodide, mix and stir, raise the temperature to 85°C, keep the reaction for 10 hours, and monitor the reaction by TLC until the conversion of the raw materials is completed. After the reaction is completed, pour the reaction solution into 200 mL of water, add 200 mL of ethyl acetate, separate the organic layer, and then wash the water layer three times with 200 mL of ethyl acetate, and remove the organic phase solvent by vacuum distillation to obtain a total of 15.5 g of white solid 3-methoxy-4-chlorobenzaldehyde, with a reaction yield of 91%.

[0032] The characterizations are as follows: H-NMR (400 MHz, 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 (400 MHz, 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, and the specific steps are as follows:

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

[0036] In a three-necked flask, first add 100 mL of acetone, then add 14.5 g of p-chlorobenzaldehyde and 11.9 g of potassium bromide, and after mixing, lower the temperature to -10°C, and under stirring, dropwise add a mixed solution of 30 g of potassium persulfate and 100 g of water within three hours. After the dropwise addition is completed, keep the reaction warm for 4 hours and monitor the reaction by TLC until the conversion of the raw materials is completed. After the reaction is completed, add 200 mL of ethyl acetate, separate the organic layer, and then wash the water layer with 100 mL of ethyl acetate three times. Remove the organic phase solvent by distillation under reduced pressure to obtain a total of 20.3 g of white solid 3-bromo-4-chlorobenzaldehyde, with a reaction yield of 89.7% (calculated as p-chlorobenzaldehyde).

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

[0038] In a three-necked flask, first add 100 mL of methanol and 30 mL of N,N-dimethylformamide, then add 21.9 g of 3-bromo-4-chlorobenzaldehyde and 16.2 g of sodium methoxide, and finally add 0.99 g of cuprous chloride, mix and stir, raise the temperature to 85°C, keep the reaction for 10 hours, and monitor the reaction by TLC until the conversion of the raw materials is completed. After the reaction is completed, pour the reaction solution into 200 mL of water, add 200 mL of ethyl acetate, separate the organic layer, and then wash the water layer three times with 200 mL of ethyl acetate, and remove the organic phase solvent by vacuum distillation to obtain a total of 15.8 g of white solid 3-methoxy-4-chlorobenzaldehyde, with a reaction yield of 93%.

[0039] Example 3

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

[0041] Example 4

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

[0043] Example 5

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

[0045] Example 6

[0046] This embodiment provides a preparation method of 3-methoxy-4-chlorobenzaldehyde, which is basically the same as Example 1, except that NBS is selected as the bromination reagent in the first step reaction, the amount of NBS is 21.36 g, the amount of DMSO is 0.78 g, and a total of 18.3 g of white solid 3-bromo-4-chlorobenzaldehyde is obtained, and the reaction yield is 80.9% (calculated as p-chlorobenzaldehyde).

[0047] Example 7

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

[0049] Example 8

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

[0051] Example 9

[0052] This embodiment provides a preparation method of 3-methoxy-4-chlorobenzaldehyde, which is basically the same as Example 1, except that the amount of catalyst added in the second step reaction is changed, and 1.98 g of cuprous iodide is added to finally obtain 16.7 g of white solid 3-methoxy-4-chlorobenzaldehyde, and the reaction yield is 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, and the specific steps are as follows:

[0055] In a three-necked flask, first add 100 mL of acetic acid, 15.2 g of m-methoxybenzaldehyde and 15.8 g of hydrogen peroxide, and finally add 55 g of concentrated hydrochloric acid dropwise at 10 ° C. After the addition is completed, stir and raise the temperature to 50 ° C. Keep the reaction for 10 hours. Monitor the reaction by LCMS until the conversion of the raw materials is completed. It is found that a mixture of 4.2 g of 3-methoxy-4-chlorobenzaldehyde and 9.3 g of 2-chloro-5-methoxybenzaldehyde is obtained, and the selectivity is poor and difficult to control.

[0056] Comparative Example 2

[0057] The present comparative example provides a method for preparing 3-methoxy-4-chlorobenzaldehyde, and the specific steps are as follows: first, in a three-necked flask, add 150 mL of chloroform, 13.6 g of m-methoxybenzaldehyde, 26.7 g of NCS, and 1.6 g of DMSO, stir the mixture, raise the temperature to 75° C., reflux for 6 hours, and monitor the reaction by LCMS, and it is found that 14.8 g of 2-chloro-5-methoxybenzaldehyde is obtained, and the yield is 96.7%, but the products are all methoxy para-position products, not the target product 3-methoxy-4-chlorobenzaldehyde.

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

[0059] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to 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 further describe various possible combinations.

Claims

1. A method for preparing 3-methoxy-4-chlorobenzaldehyde, characterized in that: The preparation method comprises the following steps: (1) reacting p-chlorobenzaldehyde with a brominating agent and an additive to obtain 3-bromo-4-chlorobenzaldehyde; (2) 3-bromo-4-chlorobenzaldehyde is mixed with methoxide and a catalyst for reaction to obtain the 3-methoxy-4-chlorobenzaldehyde.

2. The preparation method according to claim 1, characterized in that: The molar ratio of p-chlorobenzaldehyde, bromination 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 or 2, characterized in that: The bromination reagent in step (1) comprises any one of sodium bromide, potassium bromide, bromine or NBS, or a combination of at least two of them.

4. The preparation method according to any one of claims 1 to 3, characterized in that The additive in step (1) includes any one of potassium persulfate, DMSO, acetic acid, titanium tetrachloride, aluminum chloride, sulfur or sulfonyl chloride, or a combination of at least two thereof.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The reaction temperature of step (1) is -20 to 10°C and the reaction time is 3 to 5 hours.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The molar ratio of 3-bromo-4-chlorobenzaldehyde to methoxide and catalyst in step (2) is (0.8-1.2):(2.5-3.5):(0.04-0.2).

7. The preparation method according to any one of claims 1 to 6, characterized in that: The methoxide in step (2) includes sodium methoxide and / or potassium methoxide.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The catalyst in step (2) comprises any one of cuprous iodide, cuprous bromide, cuprous chloride, bis(triphenylphosphine) cuprous iodide, bis(triphenylphosphine) cuprous bromide or bis(triphenylphosphine) cuprous chloride, or a combination of at least two thereof.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The reaction temperature in step (2) is 80-100° C. and the reaction time is 8-15 h.

10. Use of the preparation method according to any one of claims 1 to 9 in the preparation of pharmaceutical compound intermediates and / or luminescent material intermediates.