Preparation method of 2-methoxy-4-cyanobenzaldehyde

Abstract

The invention provides a preparation method of 2-methoxy-4-cyanobenzaldehyde, which comprises the following steps: m-hydroxybenzoic acid and HMTA are subjected to the action of trifluoroacetic acid to obtain a compound 1, the compound 1 and dimethyl sulfate are subjected to a reaction to obtain a compound 2, the compound 2 and ethylene glycol are subjected to a reaction to obtain a compound 3, and the compound 3 is subjected to a reaction to obtain the 2-methoxy-4-cyanobenzaldehyde. The compound 3 obtained in the step C reacts with an ammoniation reagent to obtain a compound 4, the compound 4 is subjected to a dehydration reaction firstly, then deprotection is conducted, and 2-methoxy-4-cyanobenzaldehyde is obtained. According to the preparation method, the 2-methoxy-4-cyanobenzaldehyde can be prepared with high yield, the product yield of each step can reach 80% or above, the total yield is 50% or above, and the method has low requirements on production equipment, greatly reduces the overall cost and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation and relates to a method for preparing 2-methoxy-4-cyanobenzaldehyde. Background Art

[0002] 2-Methoxy-4-cyanobenzaldehyde is a very important drug intermediate that can be used to synthesize finerenone. Finerenone is a new generation of non-steroidal mineralocorticoid receptor antagonists that has begun to emerge in the indication of diabetic nephropathy. It can effectively reduce proteinuria in short-term trials in patients with chronic diseases and type 2 diabetes. The structural formula of finerenone is as follows:

[0003]

[0004] Prior art CN 102020587 A discloses a synthetic route of 2-methoxy-4-cyanobenzaldehyde: 3-methoxy-4-methylbenzoic acid is used as a starting material, and 2-methoxy-4-cyanobenzaldehyde is obtained through multiple steps of reactions such as chlorination, amidation, dehydration, bromination and hydrolysis. Specifically:

[0005]

[0006] The disadvantage of this method is that during the bromination reaction, it is difficult to completely convert the monobrominated product into the dibrominated product, resulting in a large number of impurities in the hydrolysis reaction and the generation of toxic impurities such as tribrominated products. In addition, the carbon tetrachloride solvent used in the bromination reaction is highly toxic and is not suitable for industrial production.

[0007] CN115991661A discloses a synthetic route similar to that of CN 102020587 A, except that a free radical initiator and light conditions are used in the third step of preparing 4-dibromomethyl 3-methoxybenzonitrile, and the reaction route is:

[0008]

[0009] Although this method has a high overall yield, the dibromo product itself is a radical toxic substance and will become a radical toxic impurity when participating in the next reaction. In the process of drug production, the generation of radical toxic impurities needs to be strictly avoided.

[0010] CN 107721869 A discloses another method for synthesizing 2-methoxy-4-cyanobenzaldehyde: 4-methyl-3-methoxybenzoic acid is used as a raw material, first undergoes an acylation reaction and then an amination reaction to generate 4-methyl-3-methoxybenzamide, then undergoes a dehydration reaction to prepare 4-methyl-3-methoxybenzonitrile, then undergoes a bromine substitution reaction to obtain 4-bromomethyl-3-methoxybenzonitrile, then undergoes a hydrolysis reaction to obtain 4-hydroxymethyl-3-methoxybenzonitrile, and then undergoes oxidation to obtain 2-methoxy-4-cyanobenzaldehyde. The total yield of this route is 26.2%, which is relatively low.

[0011] The specific synthetic route is:

[0012]

[0013] In addition, in the above three prior art synthesis routes, 4-methyl-3-methoxybenzoic acid is used as a raw material, which has a high market price and a high overall production cost.

[0014] Another prior art discloses a synthetic route, the specific synthetic route is:

[0015]

[0016] This route uses red aluminum, which is flammable, and metallic palladium, which greatly increases production costs. It also uses highly toxic potassium ferrocyanide. Summary of the invention

[0017] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing 2-methoxy-4-cyanobenzaldehyde with high yield, low requirements on production equipment and low overall cost.

[0018] To achieve this object, the present invention adopts the following technical solutions:

[0019] In one aspect, the present invention provides a method for preparing 2-methoxy-4-cyanobenzaldehyde, the preparation method comprising the following steps:

[0020] A. m-Hydroxybenzoic acid reacts with HMTA (hexamethylenetetramine) under acidic conditions to obtain compound 1. The reaction formula is as follows:

[0021]

[0022] B. Compound 1 prepared in step A is reacted with a methylating agent to obtain compound 2. The reaction formula is as follows:

[0023]

[0024] C. The compound 2 obtained in step B is reacted with ethylene glycol to obtain compound 3. The reaction formula is as follows:

[0025]

[0026] D. Reacting the compound 3 obtained in step C with an aminating agent to obtain compound 4, the reaction formula is as follows:

[0027]

[0028] E. Compound 4 obtained in step D is first subjected to a dehydration reaction and then deprotected to obtain compound 5, i.e. 2-methoxy-4-cyanobenzaldehyde, and the reaction formula is as follows:

[0029]

[0030] In the present invention, the specific operation of step A is: dissolving m-hydroxybenzoic acid in an acidic substance, and then adding hexamethylenetetramine to the mixed solution in batches for reaction to obtain compound 1.

[0031] Preferably, the molar ratio of m-hydroxybenzoic acid to hexamethylenetetramine in step A is 1.0:2.0-2.5; for example, 1.0:0.2, 1.0:0.5, 1.0:0.8, 1.0:1.0, 1.0:1.3, 1.0:1.5, 1.0:1.8, 1.0:2, 1.0:2.3 or 1.0:2.5, preferably 1.0:2.1.

[0032] Preferably, the acidic condition in step A is provided by an acidic substance, and the acidic substance includes trifluoroacetic acid or methanesulfonic acid.

[0033] Preferably, relative to 1 g of the m-hydroxybenzoic acid in step A, the added volume of the acidic substance is 10-26 mL, for example 10 mL, 13 mL, 15 mL, 20 mL, 23 mL, 25 mL or 26 mL.

[0034] Preferably, the reaction temperature in step A is 70-75°C (eg, 70°C, 71°C, 72°C, 73°C, 74°C or 75°C), and the reaction time is 2-5h (eg, 2h, 3h, 4h or 5h).

[0035] Preferably, the reaction temperature in step A is 73° C. and the reaction time is 2 h.

[0036] Preferably, the methylating agent in step B is selected from dimethyl sulfate or methyl iodide, more preferably dimethyl sulfate.

[0037] Preferably, the molar ratio of compound 1 to the methylating agent in step B is 1.0:2.2-10.0, for example 1.0:2.2, 1.0:2.5, 1.0:2.8, 1.0:3.0, 1.0:4.0, 1:5.0, 1.0:6.0, 1.0:7.0, 1.0:8.0, 1.0:9.0 or 1.0:10.0, preferably 1.0:2.3-3.0, and further preferably 1.0:2.5.

[0038] Preferably, the solvent for the reaction in step B is any one of dichloromethane, dichloroethane, toluene, acetonitrile or acetone, or a combination of at least two thereof, more preferably dichloromethane or acetone, and even more preferably dichloromethane.

[0039] Preferably, the reaction in step B is carried out in the presence of a basic substance.

[0040] Preferably, the alkaline substance is selected from any one or a combination of at least two of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine and N,N-diisopropylethylamine, preferably triethylamine.

[0041] Preferably, the molar ratio of compound 1 to the alkaline substance in step B is 1.0:2.5-11.0, for example 1.0:2.5, 1.0:2.8, 1.0:3.0, 1.0:4.0, 1:5.0, 1.0:6.0, 1.0:7.0, 1.0:8.0, 1.0:9.0, 1.0:10.0 or 1.0:11.0, preferably 1.0:3.0-3.5, further preferably 1.0:3.0.

[0042] Preferably, the reaction temperature in step B is 20-30°C (e.g., 20°C, 23°C, 25°C, 28°C or 30°C), and the reaction time is 2-5h (e.g., 2h, 3h, 4h or 5h); preferably, the reaction temperature is 25°C, and the reaction time is 3h.

[0043] Preferably, step C is carried out in the presence of a catalyst;

[0044] Preferably, the catalyst is selected from any one of p-toluenesulfonic acid, dilute hydrochloric acid or dilute sulfuric acid, or a combination of at least two thereof.

[0045] The specific operation described in the above step C is: adding compound 2 obtained in step B, ethylene glycol and a catalyst into a solvent, and reacting to obtain compound 3.

[0046] Preferably, the solvent for the reaction in step C is toluene or cyclohexane, more preferably toluene.

[0047] Preferably, the molar ratio of compound 2 to ethylene glycol in step C is 1.0:4.0-20.0, for example 1.0:4.0, 1.0:5.0, 1.0:6.0, 1.0:7.0, 1.0:8.0, 1.0:10.0, 1.0:12.0, 1.0:14.0, 1.0:15.0, 1.0:18.0 or 1.0:20.0, preferably 1.0:10.0.

[0048] Preferably, the molar ratio of the compound 2 in step C to the catalyst is 1.0:0.05-0.5; for example, 1.0:0.05, 1.0:0.08, 1.0:0.1, 1.0:0.2, 1.0:0.3, 1.0:0.4, 1.0:0.5, preferably 1.0:0.1.

[0049] Preferably, the reaction temperature in step C is 100-120°C (e.g., 100°C, 105°C, 108°C, 110°C, 115°C or 120°C), and the reaction time is 4-10h (e.g., 4h, 5h, 6h, 7h, 8h, 9h, or 10h); further preferably, the reaction temperature in step C is 115°C, and the reaction time is 6h.

[0050] Preferably, the molar ratio of compound 3 described in step D to the aminating agent is 1.0:1.0-10.0; for example, 1.0:1.0, 1.0:1.3, 1.0:2.0, 1.0:2.5, 1.0:2.8, 1.0:3.0, 1.0:4.0, 1:5.0, 1.0:6.0, 1.0:7.0, 1.0:8.0, 1.0:9.0 or 1.0:10.0, preferably 1.0:2.5-5.5, and more preferably 1.0:3.5.

[0051] Preferably, the aminating agent is selected from any one of ammonia methanol, ammonia gas, ammonia water or ammonia ethanol, or a combination of at least two thereof.

[0052] Preferably, the solvent for the reaction in step D is any one of methanol, ethanol or isopropanol, or a combination of at least two of them.

[0053] Preferably, the reaction temperature in step D is 20-50°C (e.g., 20°C, 25°C, 30°C, 35°C, 40°C, 45°C or 50°C), and the reaction time is 8-48h (e.g., 8h, 10h, 15h, 18h, 20h, 24h, 28h, 30h, 33h, 36h, 38h, 42h, 46h or 48h); more preferably, the reaction temperature in step D is 30-40°C, and the reaction time is 10-30h; more preferably, the reaction temperature in step D is 35°C, and the reaction time is 16h.

[0054] Preferably, the dehydrating agent used in the dehydration reaction in step E is selected from oxalyl chloride and / or thionyl chloride.

[0055] Preferably, the molar ratio of compound 4 to the dehydrating agent in step E is 1.0:1.1-3.0, for example 1.0:1.1, 1.0:1.3, 1.0:1.5, 1.0:1.8, 1.0:2.0, 1.0:2.5, 1.0:2.8 or 1.0:3.0, preferably 1.0:1.5.

[0056] Preferably, the solvent for the dehydration reaction in step E is toluene and / or acetonitrile, more preferably toluene.

[0057] Preferably, the deprotection in step E is carried out in the presence of hydrochloric acid.

[0058] In the present invention, after the dehydration reaction in step E, hydrochloric acid is added to the reaction system for deprotection.

[0059] Preferably, the temperature of the dehydration reaction in step E is 80-120°C (e.g., 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C or 120°C), and the dehydration reaction time is 2-16h (e.g., 2h, 5h, 7h, 9h, 10h, 12h, 14h or 16h); preferably, the temperature of the dehydration reaction is 90-110°C, and the dehydration reaction time is 3-8h; more preferably, the temperature of the dehydration reaction is 100°C, and the dehydration reaction time is 3h.

[0060] Preferably, the temperature of the deprotection reaction in step E is 50-120° C., preferably 60-80° C.; and the time of the deprotection reaction is 4-16 h.

[0061] Compared with the prior art, the present invention has the following beneficial effects:

[0062] 1. In the present invention, the 2-methoxy-4-cyanobenzaldehyde can be prepared in high yield by the preparation method, the product yield of each step can reach more than 80%, the total yield is more than 50%, and the product purity is more than 99%;

[0063] 2. The method of the present invention has low requirements on production equipment, and the price of the raw material m-hydroxybenzoic acid is one-fourth of the price of 3-methoxy-4-methylbenzoic acid, which greatly reduces the overall cost and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 This is the LCMS chart of compound 5.

[0065] Figure 2 This is the H NMR spectrum of compound 5. DETAILED DESCRIPTION

[0066] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0067] Example 1-1 Synthesis of Compound 1:

[0068] The reaction equation is:

[0069]

[0070] m-Hydroxybenzoic acid (30.0 g, 1.0 eq.) was added to trifluoroacetic acid (780 mL, 26 V), and hexamethylenetetramine (64.2 g, 2.1 eq.) was added in batches at 25 ° C., and the temperature was raised to 73 ° C. and stirred for 4 h; the reaction of the raw materials was controlled to be complete by HPLC; the trifluoroacetic acid was removed by concentration, 150 mL of water was added, and 75 mL of ethyl acetate was used for extraction three times, and the organic phases were combined and concentrated to obtain 35.5 g of yellowish solid, which was pulped and filtered with 1 V acetone to obtain 31.4 g of off-white solid with a purity of 98.5% and a yield of 87.0%.

[0071] Example 1-2

[0072] Synthesis of compound 1:

[0073] m-Hydroxybenzoic acid (50.0 g, 1.0 eq.) was added to trifluoroacetic acid (1300 mL, 26 V), and hexamethylenetetramine (127.4 g, 2.5 eq.) was added in batches at 25 ° C., and the temperature was raised to 73 ° C. and stirred for 2 h; the reaction of the raw materials was controlled to be complete by HPLC; the trifluoroacetic acid was removed by concentration, 250 mL of water was added, and 125 mL of ethyl acetate was used for extraction three times, and the organic phases were combined and concentrated to obtain 55.7 g of yellowish solid, which was pulped and filtered with 1 V acetone to obtain 52.9 g of off-white solid with a purity of 97.8% and a yield of 87.9%.

[0074] Examples 1-3

[0075] Synthesis of compound 1:

[0076] m-Hydroxybenzoic acid (5.0 g, 1.0 eq.) was added to trifluoroacetic acid (130 mL, 26 V), and hexamethylenetetramine (10.2 g, 2.0 eq.) was added in batches at 25 ° C. The temperature was raised to 73 ° C. and stirred for 5 h; the reaction of the raw materials was controlled to be complete by HPLC; the trifluoroacetic acid was removed by concentration, 25 mL of water was added, and 12.5 mL of ethyl acetate was used for extraction three times, and the organic phases were combined and concentrated to obtain 5.0 g of yellowish solid, which was pulped and filtered with 1 V acetone to obtain 4.5 g of off-white solid with a purity of 98.8% and a yield of 74.8%.

[0077] Example 2-1 Synthesis of Compound 2:

[0078] The reaction equation is:

[0079]

[0080] The compound 1 (25.5 g, 1.0 eq.) prepared in Example 1-1 was dissolved in 24.0 mL of dichloromethane, and triethylamine (46.6 g, 3.0 eq.) and dimethyl sulfate (48.4 g, 2.5 eq.) were added dropwise respectively. The temperature was slowly raised to 25°C and stirred for 3 h. The reaction of compound 1 was controlled to be complete by HPLC. 76.5 mL of 5% sodium bicarbonate was added for liquid separation, and the organic phase was washed with 51.0 mL of water. The organic phase was concentrated to obtain 28.4 g of an off-white solid with a purity of 95.6% and a yield of 95.3%.

[0081] Example 2-2

[0082] Synthesis of compound 2:

[0083] The compound 1 (50.0 g, 1.0 eq.) prepared in Example 1-2 was dissolved in 10.0 mL of dichloromethane, and triethylamine (121.8 g, 4.0 eq.) and dimethyl sulfate (113.9 g, 3.0 eq.) were added dropwise respectively. The temperature was slowly raised to 20°C and stirred for 5 h. The reaction of compound 1 was controlled to be complete by HPLC. 150.0 mL of 5% sodium bicarbonate was added for liquid separation, and the organic phase was washed with 100.0 mL of water. The organic phase was concentrated to obtain 60.0 g of an off-white solid with a purity of 96.6% and a yield of 102.6%.

[0084] Example 2-3

[0085] Synthesis of compound 2:

[0086] The compound 1 (10.0 g, 1.0 eq.) prepared in Example 1-2 was dissolved in 10.0 mL of dichloromethane, and potassium carbonate (33.4 g, 4.0 eq.) and dimethyl sulfate (22.8 g, 3.0 eq.) were added respectively. The temperature was slowly raised to 30°C and stirred for 2 h. The reaction of compound 1 was controlled to be complete by HPLC. 30.0 mL of 5% sodium bicarbonate was added for liquid separation, and the organic phase was washed with 20.0 mL of water. The organic phase was concentrated to obtain 11.2 g of an off-white solid with a purity of 94.6% and a yield of 98.2%.

[0087] Example 3-1 Synthesis of Compound 3:

[0088] The reaction equation is:

[0089]

[0090] Compound 2 (25.0 g, 1.0 eq.) prepared in Example 2-1, ethylene glycol (79.9 g, 10.0 eq.) and p-toluenesulfonic acid (2.4 g, 0.1 eq.) were added to toluene (125 mL, 5 V), the temperature was raised to 105 ° C and stirred for 6 h. The reaction of compound 2 was controlled to be complete by HPLC; the temperature was adjusted to 25 ° C, 100 mL of water was added to liquidize, and the toluene layer was concentrated to dryness to obtain 25.4 g of solid. The yield was 82.8% and the purity was 95.6%.

[0091] Example 3-2

[0092] Synthesis of compound 3:

[0093] Compound 2 (50.0 g, 1.0 eq.) prepared in Example 2-2, ethylene glycol (160.0 g, 10.0 eq.) and p-toluenesulfonic acid (2.4 g, 0.05 eq.) were added to toluene (250 mL, 5 V), the temperature was raised to 120 ° C and stirred for 4 h. The reaction of compound 2 was controlled to be complete by HPLC; the temperature was adjusted to 25 ° C, 200 mL of water was added to liquidize, and the toluene layer was concentrated to dryness to obtain 52.5 g of solid. The yield was 85.6% and the purity was 96.7%.

[0094] Example 3-3

[0095] Synthesis of compound 3:

[0096] Compound 2 (10.0 g, 1.0 eq.) prepared in Example 2-3, ethylene glycol (32.0 g, 10.0 eq.) and p-toluenesulfonic acid (4.4 g, 0.5 eq.) were added to toluene (50 mL, 5 V), the temperature was raised to 100 ° C and stirred for 10 h, and the reaction of compound 2 was controlled to be complete by HPLC; the temperature was adjusted to 25 ° C, 40 mL of water was added to liquidize, and the toluene layer was concentrated to dryness to obtain 10.7 g of solid, with a yield of 87.6% and a purity of 96.5%.

[0097] Example 4-1

[0098] Synthesis of compound 4:

[0099] The reaction equation is:

[0100]

[0101] Compound 3 (25.0 g, 1.0 eq.) prepared in Example 3-1 was added to methanol (50 mL, 2V), and ammonia methanol solution (52.5 mL, 3.5 eq.) was added at 25°C, and the mixture was stirred for 16 h. The reaction of compound 3 was controlled to be complete by HPLC. The reaction solution was concentrated under reduced pressure below 40°C to obtain 20.5 g of an off-white solid with a purity of 93.4% and a yield of 87.6%.

[0102] Example 4-2

[0103] Synthesis of compound 4:

[0104] Compound 3 (25.0 g, 1.0 eq.) prepared in Example 3-2 was added to methanol (50 mL, 2V), and ammonia methanol solution (37.5 mL, 2.5 eq.) was added at 20°C, and the mixture was stirred for 30 h. The reaction of compound 3 was controlled to be complete by HPLC. The reaction solution was concentrated under reduced pressure below 40°C to obtain 19.8 g of an off-white solid with a purity of 94.2% and a yield of 84.6%.

[0105] Example 4-3

[0106] Synthesis of compound 4:

[0107] Compound 3 (25.0 g, 1.0 eq.) prepared in Example 3-2 was added to methanol (50 mL, 2 V), and ammonia methanol solution (82.5 mL, 5.5 eq.) was added at 50°C, and the mixture was stirred for 14 h. The reaction of compound 3 was controlled to be complete by HPLC. The reaction solution was concentrated under reduced pressure below 40°C to obtain 21.5 g of an off-white solid with a purity of 93.2% and a yield of 91.9%.

[0108] Example 5-1

[0109] Synthesis of compound 5:

[0110] The reaction equation is:

[0111]

[0112] Compound 4 (10.0 g, 1.0 eq.), oxalyl chloride (11.4 g, 2.0 eq.), triethylamine (13.6 g, 3.0 eq.) and triphenylphosphine (1.2 g, 0.1 eq.) prepared in Example 4-1 were added to acetonitrile (60 mL, 6 V), and the temperature was adjusted to 80 ° C and stirred for 2 h; the reaction of compound 4 was controlled by HPLC, 6 M hydrochloric acid was added to adjust the pH to neutral, and then 12.8 mL of 6 M hydrochloric acid was added at 50 ° C for deprotection for 16 h, and the mixture was concentrated to 1-2 V. 30.0 mL of isopropanol was added dropwise to crystallize and slurry for 6 h, and 6.5 g of off-white solid was obtained by filtration with a purity of 99.5% and a yield of 90.3%.

[0113] Example 5-2

[0114] Synthesis of compound 5:

[0115] Compound 4 (10.0 g, 1.0 eq.) prepared in Example 4-1 and thionyl chloride (7.99 g, 1.5 eq.) were added to toluene (45 mL, 4.5 V), the temperature was adjusted to 110 ° C and stirred for 3 h; the reaction of compound 4 was controlled by HPLC, the mixture was cooled to 45 ° C and concentrated to no distillate, 50.0 mL of isopropanol was added and the mixture was further concentrated to 1-2 V, 30.0 mL of isopropanol was added, 12.8 mL of 6 M hydrochloric acid was added dropwise, the mixture was reacted at 80 ° C for 4 h, filtered, rinsed with isopropanol (5 mL, 0.5 V), and dried in vacuo at 45 ° C to obtain 6.7 g of an off-white solid with a purity of 99.2% and a yield of 93.1%.

[0116] Example 5-3

[0117] Synthesis of compound 5:

[0118] Compound 4 (15.0 g, 1.0 eq.) prepared in Example 4-2 and thionyl chloride (24.0 g, 3.0 eq.) were added to toluene (67.5 mL, 4.5 V), the temperature was adjusted to 110 ° C and stirred for 2 h; the reaction of compound 4 was controlled by HPLC, the mixture was cooled to 45 ° C and concentrated to no distillate, 75.0 mL of isopropanol was added and the mixture was further concentrated to 1-2 V, 45.0 mL of isopropanol was added, 19.2 mL of 6 M hydrochloric acid was added dropwise, the mixture was reacted at 60 ° C for 8 h, filtered, rinsed with isopropanol (7.5 mL, 0.5 V), and dried in vacuo at 45 ° C to obtain 10.3 g of an off-white solid with a purity of 99.5% and a yield of 95.5%.

[0119] Example 5-4

[0120] Synthesis of compound 5:

[0121] Compound 4 (10.0 g, 1.0 eq.) prepared in Example 4-3 and thionyl chloride (6.4 g, 1.2 eq.) were added to toluene (4.5 mL, 4.5 V), the temperature was adjusted to 90 ° C and stirred for 16 h; the reaction of compound 4 was controlled by HPLC, the mixture was cooled to 45 ° C and concentrated to no distillate, 50.0 mL of isopropanol was added and the mixture was further concentrated to 1-2 V, 30.0 mL of isopropanol was added, 12.8 mL of 6 M hydrochloric acid was added dropwise and reacted for 16 h, filtered, rinsed with isopropanol (5.0 mL, 0.5 V), and dried in vacuo at 45 ° C to obtain 6.5 g of an off-white solid with a purity of 99.3% and a yield of 90.5%.

[0122] The LCMS chart of compound 5 prepared by the present invention (testing instrument purchased from Agilent, model: 1060+6160) is as follows Figure 1 As shown in the figure, the molecular mass of the substance is 161, which is consistent with the molecular mass of compound 5.

[0123] The NMR hydrogen spectrum of compound 5 prepared by the present invention is as follows Figure 2 As shown, its nuclear magnetic hydrogen spectrum data are as follows: 1 H-NMR (DMSO-d6, 400MHz) δppm: 10.37 (s, 1H), 7.84–7.53 (m, 3H), 3.98 (s, 3H).

[0124] The applicant declares that the present invention illustrates the process method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned process steps, that is, it does not mean that the present invention must rely on the above-mentioned process steps to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials selected by 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.

Claims

1. A method for preparing 2-methoxy-4-cyanobenzaldehyde, It is characterized in that The preparation method comprises the following steps: A. m-Hydroxybenzoic acid reacts with hexamethylenetetramine under acidic conditions to obtain compound 1. The reaction formula is as follows: B. Compound 1 prepared in step A is reacted with a methylating agent to obtain compound 2. The reaction formula is as follows: C. The compound 2 obtained in step B is reacted with ethylene glycol to obtain compound 3. The reaction formula is as follows: D. Reacting the compound 3 obtained in step C with an aminating agent to obtain compound 4, the reaction formula is as follows: E. Compound 4 obtained in step D is first subjected to a dehydration reaction and then subjected to a deprotection reaction to obtain compound 5, i.e. 2-methoxy-4-cyanobenzaldehyde, and the reaction formula is as follows:

2. The preparation method according to claim 1, It is characterized in that The molar ratio of m-hydroxybenzoic acid to hexamethylenetetramine in step A is 1.0:2.0-2.5, preferably 1.0:2.

1.

3. The preparation method according to claim 1 or 2, It is characterized in that The acidic condition in step A is provided by an acidic substance, and the acidic substance includes trifluoroacetic acid or methanesulfonic acid; Preferably, relative to 1 g of the m-hydroxybenzoic acid in step A, the added volume of the acidic substance is 10-26 mL; Preferably, the reaction temperature in step A is 70-75° C. and the reaction time is 2-5 h; Preferably, the reaction temperature in step A is 73° C. and the reaction time is 2 h.

4. The preparation method according to any one of claims 1 to 3, It is characterized in that The methylating agent in step B is selected from dimethyl sulfate or methyl iodide, more preferably dimethyl sulfate; Preferably, the molar ratio of compound 1 to the methylating agent in step B is 1.0:2.2-10.0, preferably 1.0:2.3-3.0, and more preferably 1.0:2.

5.

5. The preparation method according to any one of claims 1 to 4, It is characterized in that The solvent for the reaction in step B is any one of dichloromethane, dichloroethylene, toluene, acetonitrile or acetone, or a combination of at least two thereof, preferably dichloromethane or acetone, and more preferably dichloromethane; Preferably, the reaction in step B is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is selected from any one or a combination of at least two of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine and N,N-diisopropylethylamine, preferably triethylamine; Preferably, the molar ratio of compound 1 to the alkaline substance in step B is 1.0:2.5-11.0; preferably 1.0:3.0-3.5, and more preferably 1.0:3.

0.

6. The preparation method according to any one of claims 1 to 5, It is characterized in that The reaction temperature in step B is 20-30°C and the reaction time is 2-5h; Preferably, the reaction temperature is 25° C. and the reaction time is 3 h.

7. The preparation method according to any one of claims 1 to 6, It is characterized in that In step C, the molar ratio of compound 2 to ethylene glycol is 1.0:4.0-20.0, preferably 1.0:10.0; Preferably, step C is carried out in the presence of a catalyst; Preferably, the catalyst is selected from any one or a combination of at least two of p-toluenesulfonic acid, dilute hydrochloric acid or dilute sulfuric acid; Preferably, the molar ratio of the compound 2 to the catalyst in step C is 1.0:0.05-0.5, preferably 1.0:0.1; Preferably, the solvent for the reaction in step C is toluene or cyclohexane, preferably toluene; Preferably, the reaction temperature in step C is 100-120° C., and the reaction time is 4-10 h; Preferably, the reaction temperature in step C is 115° C. and the reaction time is 6 h.

8. The preparation method according to any one of claims 1 to 7, It is characterized in that The molar ratio of compound 3 to the aminating agent in step D is 1.0:1.0-10.0, preferably 1.0:2.5-5.5, and more preferably 1.0:3.5; Preferably, the aminating agent is selected from any one or a combination of at least two of ammonia methanol, ammonia gas, ammonia water or ammonia ethanol; Preferably, the solvent for the reaction in step D is any one of methanol, ethanol or isopropanol, or a combination of at least two thereof; Preferably, the reaction temperature in step D is 20-50°C, and the reaction time is 8-48h; Preferably, the reaction temperature in step D is 30-40°C, and the reaction time is 10-30h; further preferably, the reaction temperature in step D is 35°C, and the reaction time is 16h.

9. The preparation method according to any one of claims 1 to 8, It is characterized in that The dehydrating agent used in the dehydration reaction in step E is selected from oxalyl chloride and / or thionyl chloride; Preferably, the molar ratio of compound 4 to the dehydrating agent in step E is 1.0:1.1-3.0, preferably 1.0:1.5; Preferably, the solvent for the dehydration reaction in step E is toluene and / or acetonitrile, preferably toluene.

10. The preparation method according to any one of claims 1 to 9, It is characterized in that The deprotection in step E is carried out in the presence of hydrochloric acid; Preferably, after the dehydration reaction in step E, hydrochloric acid is added to the reaction system for deprotection; Preferably, the temperature of the dehydration reaction in step E is 80-120° C., and the dehydration reaction time is 2-16 h; Preferably, the temperature of the dehydration reaction is 90-110°C, and the dehydration reaction time is 3-8h; further preferably, the temperature of the dehydration reaction is 100°C, and the dehydration reaction time is 3h; Preferably, the temperature of the deprotection reaction in step E is 50-120° C., preferably 60-80° C.; the time of the deprotection reaction is 4-16 h.

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