4-Cyano-2-methoxybenzaldehyde and preparation method thereof
By using m-bromophenol as raw material, three steps of aldehyde, methylation and Ulmann coupling reactions were used to successfully solve the problems of large impurities, low yields and high costs in the existing 4-cyano-2-methoxybenzaldehyde synthesis process, and efficient and green industrial production was achieved.
Patent Information
- Application Number
- CN202411719928.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-28
- Publication Date
- 2025-04-04
AI Technical Summary
The existing synthesis process of 4-cyano-2-methoxybenzaldehyde has problems such as large impurities, low yields and high costs, which is difficult to meet the needs of industrial production.
Using m-bromophenol as the raw material, 4-cyano-2-methoxybenzaldehyde was successfully prepared through three steps of aldehyde, methylation and Ulmann coupling reaction. This method has few reaction steps, raw materials and reagents are cheap and easy to obtain, and there is no need to use expensive palladium catalysts and dangerous reagents, which is green and environmentally friendly.
It has achieved efficient preparation of 4-cyano-2-methoxybenzaldehyde, with high purity and high yield, suitable for industrial production, easy operation and controllable reaction conditions.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical synthesis, and in particular to 4-cyano-2-methoxybenzaldehyde and a preparation method thereof. Background Art
[0002] Finerenone is the first non-steroidal selective mineralocorticoid receptor antagonist with confirmed renal and cardiovascular benefits in patients with chronic kidney disease and type 2 diabetes. On July 9, 2021, Bayer announced that the U.S. Food and Drug Administration (FDA) approved the first non-steroidal selective mineralocorticoid receptor antagonist, finerenone, for marketing in the United States. Finerenone 10 mg or 20 mg can be used to reduce the risk of sustained decline in eGFR, end-stage renal disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease and type 2 diabetes. 4-Cyano-2-methoxybenzaldehyde is a key intermediate in the synthesis of finerenone. The synthesis process reported in the existing literature has problems such as large impurities, low yield, and high cost. It is necessary to develop a production process with high product quality and easy industrialization.
[0003] At present, the synthesis of 4-cyano-2-methoxybenzaldehyde mainly includes the following routes:
[0004] Route 1: 4-methyl-3-methoxybenzoic acid is used as the raw material, and it is sequentially subjected to amination, cyanation, bromination, and alkaline hydrolysis to produce aldehyde. The steps are long, requiring a large amount of ammonia water and thionyl chloride, resulting in highly polluted wastewater, and it is difficult to obtain dibromo products with good selectivity through bromination, and the by-product monobromo product greatly affects the atomic utilization rate of the subsequent alkaline hydrolysis.
[0005]
[0006] Route 2: Using 4-bromo-2-hydroxybenzoic acid as the raw material, red aluminum is reduced to aldehyde after esterification and etherification, and finally potassium ferrocyanide is cyanated with palladium reagent to obtain the key intermediate of phenaretin. This route uses expensive palladium reagents, which is costly, and the red aluminum post-treatment uses a large amount of acid water, which is very unfriendly to the environment. The cost of three waste treatments is too high, and it is not suitable for commercialization.
[0007]
[0008] Route 3 already exists in the market: 3-methoxy-4-iodo-bromobenzene is used as the starting material, first hydroformylation, then cyanation to obtain the key intermediate of phenaretin. This method requires expensive 3-methoxy-4-iodo-bromobenzene as the raw material, hydroformylation in an ultra-low temperature environment, the use of dangerous butyl lithium reagents and high energy consumption; cyanation uses precious metal palladium as a catalyst, which is difficult to recycle and reuse, the cost is too high and the reaction is difficult to control, and it is not suitable for industrialization.
[0009]
[0010] Route 4: 3-methoxy-4-methylbenzonitrile is condensed with DMF-DMA and then oxidized to obtain the target product. Although the route is short, high-energy sodium periodate is used as an oxidant. The oxidation process is a dangerous process in production, and its industrialization is greatly restricted.
[0011] Summary of the invention
[0012] 1. Technical issues to be resolved
[0013] In view of the deficiencies in the prior art, the present invention provides a 4-cyano-2-methoxybenzaldehyde and a preparation method thereof.
[0014] (II) Technical solution
[0015] To achieve the above objectives, the present invention is implemented through the following technical solutions:
[0016] Based on the technical problems existing in the background technology, the present invention proposes a preparation method of 4-cyano-2-methoxybenzaldehyde.
[0017] The invention discloses a method for preparing 4-cyano-2-methoxybenzaldehyde. The method takes m-bromophenol as a raw material and sequentially performs hydroformylation, methylation and Ullmann coupling reactions to obtain 4-cyano-2-methoxybenzaldehyde.
[0018] The synthetic route is:
[0019]
[0020] The present invention provides a method for preparing 4-cyano-2-methoxybenzaldehyde, comprising the following steps:
[0021] S1, dissolving the compound of formula 1 in a solvent, adding a formaldehyde reagent, a base and a catalyst, stirring and reacting at a temperature of T1, adding an acid solution to quench the reaction after the reaction is completed, extracting with an extractant, drying and concentrating to obtain a compound of formula 2;
[0022] S2, dissolving the compound of formula 2 in a solvent, adding a base, then adding a methylating agent, heating to T2 for reaction, after the reaction is completed, pouring acid water to quench the crystals, filtering and drying to obtain a compound of formula 3;
[0023] S3, dissolving the compound of formula 3 in a solvent, adding a cyanide source and a catalyst, raising the temperature to T3 and stirring for reaction, after the reaction is complete, cooling to room temperature, adding a base dropwise for quenching, extracting with an extraction solvent, washing, drying, concentrating, and crystallizing with a crystallization solvent to obtain a compound of formula 4, i.e. 4-cyano-2-methoxybenzaldehyde.
[0024] Preferably, in S1, the mass volume ratio of the compound of formula 1 to the solvent is 1:(2-10), preferably 1:(6-8).
[0025] Preferably, in said S1, the temperature T1 is 0-100°C, preferably 60-90°C.
[0026] Preferably, in S1, the formaldehyde reagent is one or more of formaldehyde and paraformaldehyde, preferably paraformaldehyde; the base is one or more of sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, pyridine, and triethylamine, preferably potassium carbonate; the catalyst is one or more of magnesium chloride, ferric chloride, zinc chloride, and boron trichloride, preferably magnesium chloride.
[0027] Preferably, in S1, the molar ratio of the compound of formula 1, the formaldehyde reagent, the base and the catalyst is 1:(1-10):(2-5)(1-3), preferably 1:(6-8):(3-4)(1.5-2.5).
[0028] Preferably, in S2, the mass volume ratio of the compound of formula 2 to the solvent is 1:(2-10), preferably 1:(6-8).
[0029] Preferably, in said S2, the temperature of T2 is 0-100°C, preferably 60-80°C.
[0030] Preferably, in S2, the base is selected from one or more of sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, pyridine, and triethylamine, preferably potassium carbonate.
[0031] Preferably, in S2, the methyl reagent is one or more of dimethyl carbonate, dimethyl sulfate, methyl iodide, and methyl p-toluenesulfonate, preferably dimethyl carbonate.
[0032] Preferably, in S2, the molar ratio of the compound of formula 2, the methylating agent and the base is 1:(1-4):(2-8), preferably 1:(2-3):(4-6).
[0033] Preferably, in S3, the mass volume ratio of the compound of formula 3 to the solvent is 1:(1-5), preferably 1:(2-3).
[0034] Preferably, in S3, the cyanide source is cuprous cyanide.
[0035] Preferably, in S3, the catalyst is one or more of cuprous iodide, potassium iodide and sodium iodide, preferably potassium iodide.
[0036] Preferably, in S3, the molar ratio of the compound of formula 3, the cyanide source and the catalyst is 1:(1-2):(0.01-0.05), preferably 1:(1.0-1.5):(0.03-0.05).
[0037] Preferably, in said S3, the temperature of T3 is 100-180°C, preferably 120-150°C.
[0038] Preferably, in S3, the crystallization solvent is one or more of methanol, ethanol and acetone, preferably methanol.
[0039] The present invention also provides a 4-cyano-2-methoxybenzaldehyde obtained by the above preparation method, and the structural formula of the 4-cyano-2-methoxybenzaldehyde is as follows:
[0040]
[0041] (III) Beneficial effects
[0042] The present invention provides a 4-cyano-2-methoxybenzaldehyde and a preparation method thereof. Compared with the prior art, the present invention has the following beneficial effects:
[0043] The present invention can obtain the final product 4-cyano-2-methoxybenzaldehyde through only three steps of chemical reaction. Compared with the prior art, the present invention has a novel synthesis route, fewer reaction steps, and the raw materials and reagents used in the reaction are cheap and easy to obtain, and no expensive palladium catalyst and dangerous reagents are needed. The present invention is green and environmentally friendly, and the reaction conditions are mild and controllable, the operation is simple, the product purity is high, the yield is high, and the product is suitable for industrial production. The present invention has broad prospects and industrial application value. DETAILED DESCRIPTION
[0044] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0045] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with specific implementation methods.
[0046] Unless otherwise specified, the materials, reagents, etc. used in the following examples and comparative examples can be obtained from commercial sources.
[0047] Example 1
[0048] A method for preparing 4-cyano-2-methoxybenzaldehyde specifically comprises the following steps:
[0049] S1. Synthesis of compound of formula 2
[0050] At room temperature, m-bromophenol (17.3 g, 0.1 mol of compound 1) was dissolved in 105 mL of acetonitrile, potassium carbonate (55.3 g, 0.4 mol), 19 g of magnesium chloride (0.2 mol), and 24 g of paraformaldehyde (0.8 eq) were added in sequence under stirring conditions, and the temperature was raised to 80°C for 6 h of heat preservation; HPLC detected that the raw material reaction was complete, 150 ml of 10% hydrochloric acid water was added, and 200 mL of EA was added for extraction, and after separation, the organic layer was washed once with 100 mL of saturated brine, and finally concentrated and dried to obtain 19.3 g of white solid compound 2 with a purity of 98.1% and a yield of 96.0%;
[0051] The reaction equation is as follows:
[0052]
[0053] S2. Synthesis of compounds of formula 3
[0054] At room temperature, the compound of formula 2 (20.1 g, 0.1 mol) and potassium carbonate (82.9 g, 0.6 mol) were dissolved in 130 mL of acetone, and 27.0 g of dimethyl carbonate (0.3 mol) was added under stirring, and the reaction was refluxed for 2 h. After the reaction was completed, the mixture was cooled to room temperature, poured into 400 ml of icy hydrochloric acid water, stirred and crystallized for 4 h, filtered, and dried at 55 ° C to obtain 21.2 g of the compound of formula 3 with a purity of 99.4% and a yield of 98.6%;
[0055] The reaction equation is as follows:
[0056]
[0057] S3. Synthesis of compounds of formula 4
[0058] At room temperature, the compound of formula 3 (21.5 g, 0.1 mol) was dissolved in 43 mL of DMF, and then cuprous cyanide (9.0 g, 0.1 mol) and potassium iodide (0.5 g, 0.003 mol) were added in sequence. After the addition, the temperature was raised to 150° C. and stirred for reaction for 6 h. After the reaction was completed by HPLC detection, 100 ml of ammonia water was added dropwise to quench, and the mixture was extracted with 200 ml of EA, washed once with saturated NaHCO3 solution, washed twice with saturated brine, and dried. Most of the solvent was concentrated, 60 ml of methanol was added, and crystallization was carried out at 0° C. for 10 h. After filtration, the mixture was dried at 55° C. to obtain 15.1 g of a solid compound of formula 4 (4-cyano-2-methoxybenzaldehyde) with a yield of 93.4%.
[0059] The reaction equation is as follows:
[0060]
[0061] Example 2
[0062] A method for preparing 4-cyano-2-methoxybenzaldehyde specifically comprises the following steps:
[0063] S1. Synthesis of compounds of formula 2
[0064] At room temperature, m-bromophenol (17.3 g, 0.1 mol of compound 1) was dissolved in 105 mL of acetonitrile, potassium carbonate (55.3 g, 0.4 mol), 32.4 g of ferric chloride (0.2 mol), and 24 g of paraformaldehyde (0.8 eq) were added in sequence under stirring conditions, and the temperature was raised to 80°C for 6 h of heat preservation; HPLC detected that the raw material reaction was complete, 150 ml of 10% hydrochloric acid water was added, and 200 mL of EA was added for extraction, and after separation, the organic layer was washed once with 100 mL of saturated brine, and finally concentrated and dried to obtain 17.7 g of brown solid compound 2 with a purity of 96.1% and a yield of 88.1%;
[0065] The reaction equation is as follows:
[0066]
[0067] S2. Synthesis of compounds of formula 3
[0068] At room temperature, the compound of formula 2 (20.1 g, 0.1 mol) and potassium carbonate (82.9 g, 0.6 mol) were dissolved in 130 mL of acetone, and 37.8 g of dimethyl sulfate (0.3 mol) was added under stirring, and the reaction was refluxed for 2 h. After the reaction was completed, the mixture was cooled to room temperature, poured into 400 ml of icy hydrochloric acid water, stirred and crystallized for 4 h, filtered, and dried at 55 ° C to obtain 20.1 g of the compound of formula 3 with a purity of 98.3% and a yield of 93.5%;
[0069] The reaction equation is as follows:
[0070]
[0071] S3. Synthesis of compounds of formula 4
[0072] At room temperature, the compound of formula 3 (21.5 g, 0.1 mol) was dissolved in 43 mL of DMF, and then cuprous cyanide (9.0 g, 0.1 mol) and potassium iodide (0.5 g, 0.003 mol) were added in sequence. After the addition, the temperature was raised to 110° C. and stirred for 6 h. After the reaction was completed by HPLC, 100 ml of ammonia water was added dropwise to quench the mixture, and the mixture was extracted with 200 ml of EA, washed once with saturated NaHCO3 solution, washed twice with saturated brine, and dried. Most of the solvent was concentrated, 60 ml of methanol was added, and crystallization was carried out at 0° C. for 10 h. After filtration, the mixture was dried at 55° C. to obtain 13.3 g of a solid compound of formula 4 (4-cyano-2-methoxybenzaldehyde) with a yield of 82.5%.
[0073] The reaction equation is as follows:
[0074]
[0075] Example 3
[0076] A method for preparing 4-cyano-2-methoxybenzaldehyde specifically comprises the following steps:
[0077] S1. Synthesis of compounds of formula 2
[0078] At room temperature, m-bromophenol (17.3 g, 0.1 mol of compound 1) was dissolved in 105 mL of acetonitrile, potassium carbonate (55.3 g, 0.4 mol), 19 g of magnesium chloride (0.2 mol), and 24 g of formaldehyde (0.8 eq) were added in sequence under stirring conditions, and the temperature was raised to 80°C for 6 h of heat preservation; HPLC detected that the raw material reaction was complete, 150 ml of 10% hydrochloric acid water was added, and 200 mL of EA was added for extraction, and after separation, the organic layer was washed once with 100 mL of saturated brine, and finally concentrated and dried to obtain 18.6 g of white solid compound 2 with a purity of 98.0% and a yield of 92.5%;
[0079] The reaction equation is as follows:
[0080]
[0081] S2. Synthesis of compounds of formula 3
[0082] At room temperature, the compound of formula 2 (20.1 g, 0.1 mol) and pyridine (47.5 g, 0.6 mol) were dissolved in 130 mL of acetone, and 27.0 g of dimethyl carbonate (0.3 mol) was added under stirring, and the reaction was refluxed for 2 h. After the reaction was completed, the mixture was cooled to room temperature, poured into 400 ml of icy hydrochloric acid water, stirred and crystallized for 4 h, filtered, and dried at 55 ° C to obtain 20.0 g of the compound of formula 3 with a purity of 99.4% and a yield of 93.0%;
[0083] The reaction equation is as follows:
[0084]
[0085] S3. Synthesis of compounds of formula 4
[0086] At room temperature, the compound of formula 3 (21.5 g, 0.1 mol) was dissolved in 43 mL of DMF, and then cuprous cyanide (9.0 g, 0.1 mol) and potassium iodide (0.5 g, 0.003 mol) were added in sequence. After the addition, the temperature was raised to 170°C and stirred for 6 h. After the reaction was complete by HPLC, 100 ml of ammonia water was added dropwise to quench the mixture, and the mixture was extracted with 200 ml of EA, washed once with saturated NaHCO3 solution, washed twice with saturated brine, and dried. Most of the solvent was concentrated, 60 ml of ethanol was added, and crystallization was carried out at 0°C for 10 h. After filtration, the mixture was dried at 55°C to obtain 14.2 g of a solid compound of formula 4 (4-cyano-2-methoxybenzaldehyde) with a yield of 88.1%.
[0087] The reaction equation is as follows:
[0088]
[0089] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.
[0090] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for preparing 4-cyano-2-methoxybenzaldehyde, characterized in that: Using m-bromophenol as the raw material, 4-cyano-2-methoxybenzaldehyde was obtained through hydroformylation, methylation and Ullmann coupling reactions. The synthetic route is: The preparation method comprises the following steps: S1, dissolving the compound of formula 1 in a solvent, adding a formaldehyde reagent, a base and a catalyst, stirring and reacting at a temperature of T1, adding an acid solution to quench the reaction after the reaction is completed, extracting with an extractant, drying and concentrating to obtain a compound of formula 2; S2, dissolving the compound of formula 2 in a solvent, adding a base, then adding a methylating agent, heating to T2 for reaction, after the reaction is completed, pouring acid water to quench the crystals, filtering and drying to obtain a compound of formula 3; S3, dissolving the compound of formula 3 in a solvent, adding a cyanide source and a catalyst, raising the temperature to T3 and stirring for reaction, after the reaction is complete, cooling to room temperature, adding a base dropwise for quenching, extracting with an extraction solvent, washing, drying, concentrating, and crystallizing with a crystallization solvent to obtain a compound of formula 4, i.e. 4-cyano-2-methoxybenzaldehyde.
2. The preparation method according to claim 1, characterized in that: S1 satisfies at least one of the following conditions: The mass volume ratio of the compound of formula 1 to the solvent is 1:2-10; T1 temperature is 0-100℃; The formaldehyde reagent is selected from one or both of formaldehyde and paraformaldehyde; The base is selected from one or more of sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, pyridine, and triethylamine; The catalyst is selected from one or more of magnesium chloride, ferric chloride, zinc chloride and boron trichloride.
3. The preparation method according to claim 1, characterized in that: In S1, the molar ratio of the compound of formula 1, the formaldehyde reagent, the base and the catalyst is 1:1-10:2-5:1-3.
4. The preparation method according to claim 1, characterized in that: S2 satisfies at least one of the following conditions: The mass volume ratio of the compound of formula 2 and the solvent is 1:2-10; T2 temperature is 0-100℃; The base is selected from one or more of sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, pyridine, and triethylamine; The methylating agent is selected from one or more of dimethyl carbonate, dimethyl sulfate, methyl iodide and methyl p-toluenesulfonate.
5. The preparation method according to claim 1, characterized in that: In S2, the molar ratio of the compound of formula 2, the methylating agent and the base is 1:1-4:2-8.
6. The preparation method according to claim 1, characterized in that: S3 satisfies at least one of the following conditions: The mass volume ratio of the compound of formula 3 and the solvent is 1:1-5; The cyanide source is cuprous cyanide; The catalyst is selected from one or more of cuprous iodide, potassium iodide and sodium iodide; T3 temperature is 100-180℃; The crystallization solvent is selected from one or more of methanol, ethanol and acetone.
7. The preparation method according to claim 1, characterized in that: In S3, the molar ratio of the compound of formula 3, the cyanide source and the catalyst is 1:1-2:0.01-0.
05.
8. 4-cyano-2-methoxybenzaldehyde obtained by the preparation method according to any one of claims 1 to 7, characterized in that: The structural formula of the 4-cyano-2-methoxybenzaldehyde is as follows: