Preparation method of fenerenone intermediate

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a fenerenone intermediate 4-cyano-2-methoxybenzaldehyde. The method comprises the following steps: adding 3-methoxy-4-methylbenzonitrile into chlorobenzene, adding N, N-dimethylformamide dimethyl acetal while stirring, carrying out a heating reaction, after the reaction is finished, carrying out vacuum concentration to remove the chlorobenzene, adding an organic solvent and water, adding sodium periodate at a controlled temperature, after the heat preservation reaction is finished, carrying out centrifugal filtration to remove sodium iodate, and separating the filtrate to obtain the 3-methoxy-4-methylbenzonitrile. And concentrating and drying an organic phase, adding a saturated alkane solvent, and crystallizing to obtain the 4-cyano-2-methoxybenzaldehyde. The method has the advantages of simple synthetic route, convenience in operation, low cost, small amount of three wastes, environment friendliness, recyclable solvent and high product purity, and is more suitable for industrial mass production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a non-neliriketone intermediate 4-cyano-2-methoxybenzaldehyde. BACKGROUND

[0002] Non-neliriketone, English name: Finerenone is the first new non-steroidal, high-selective mineralocorticoid receptor antagonist (MRA) developed by Bayer Company, which can directly and accurately inhibit the overactivation of mineralocorticoid (MR) and play an anti-inflammatory and anti-fibrosis role, thereby bringing double benefits of kidney and heart. The drug was approved for marketing by the US FDA on July 9, 2021, and the trade name is Kerendia. On June 28, 2022, non-neliriketone was listed in China, and the trade name is Keshenda, which is used for the treatment of chronic kidney disease in adults caused by type II diabetes. The Chinese name of non-neliriketone is (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthalene-3-formamide.

[0003] Non-neliriketone shows unique advantages in the treatment of chronic kidney disease. It highly selectively binds to the mineralocorticoid receptor and can inhibit the pathological processes such as inflammation and fibrosis in kidney tissue caused by overactivation of the mineralocorticoid receptor. Compared with traditional steroidal MRAs (such as spironolactone and eplerenone), non-neliriketone has higher selectivity for the mineralocorticoid receptor and less effect on androgen and progesterone receptors, so it has fewer endocrine-related side effects such as male breast development. At the same time, it has a relatively low risk of causing hyperkalemia, is more suitable for long-term use, and helps to improve patient compliance.

[0004] 4-cyano-2-methoxybenzaldehyde is an important intermediate of non-neliriketone. CAS No.: 21962-45-8, molecular formula: C9H7NO2, structural formula as follows: .

[0005] Patent WO2008104306A reported that 4-hydroxy-3-methoxybenzaldehyde was used as starting material, in the presence of hydroxylamine hydrochloride and acetic acid, through the reduction reaction to prepare 4-hydroxy-3-methoxybenzonitrile. Subsequently, the intermediate was esterified with triflic anhydride in pyridine solvent to generate 4-cyano-2-methoxyphenyl triflate. Then in the reaction system consisting of N,N-dimethylformamide (DMF) and triethylamine, with bis-triphenylphosphine palladium dichloride as catalyst, the sulfonate reacted with tert-butyl acrylate. Finally, through the oxidation of sodium metaperiodate and osmium tetroxide, the target product 4-cyano-2-methoxybenzaldehyde was obtained. This synthetic route has obvious shortcomings, not only high-priced reagents such as triflic anhydride and tert-butyl acrylate are used, but also the highly toxic substance osmium tetroxide is involved, and the reaction process is accompanied by intense exothermic phenomenon, with a total molar yield of only 49.8%. The synthetic route of this scheme is as follows: . Domald. A.P et al. reported in J. Med. Chem. 2007, 50, 2468-2485 that 3-methoxy-4-methylbenzonitrile was used as starting material, in carbon tetrachloride solvent system, with benzoyl peroxide (BPO) as catalytic medium, and N-bromosuccinimide (NBS) to occur bromination reaction to prepare 3-methoxy-4-dibromomethylbenzonitrile; after the intermediate was hydrolyzed by silver nitrate as catalyst, the target product 4-cyano-2-methoxybenzaldehyde was finally obtained, and the total yield of the whole synthetic route was 76.2%. In the bromination step, double substitution at the benzyl position needs to be achieved, and the amount of NBS used is huge, while the reagent itself is relatively high in price, which increases the process cost. At the same time, silver nitrate is used in the catalytic hydrolysis step, which has four types of hazards of corrosion, explosion, poisoning and environmental hazards in industrial production, and is not suitable for large-scale production. The synthetic route of this scheme is as follows: .

[0006] The original research patent CN106795155A of Bayer Company uses 4-bromo-2-hydroxybenzoic acid as starting material, uses potassium carbonate as acid binding agent in acetone, uses dimethyl sulfate to esterify and methylate to obtain 4-bromo-2-methoxybenzoic acid methyl ester, then uses 1-methylpiperazine and toluene system to reduce with red aluminum to obtain 4-bromo-2-methoxybenzaldehyde, and finally generates 4-cyano-2-methoxybenzaldehyde by substitution with potassium hexacyanoferrate. The synthetic route of this scheme is as follows: The use of dimethyl sulfate in this route is a highly toxic methylating agent with strong corrosion and carcinogenicity. Red aluminum is a flammable strong reducing agent, which reacts violently with water and air and even burns. Palladium acetate is expensive, and the noble metal cannot be recovered, with a total molar yield of only 79%, which is not suitable for large-scale industrial production. SUMMARY

[0007] To solve the above technical problems, the present application provides a preparation method of a non-nalixone intermediate 4-cyano-2-methoxybenzaldehyde. The method has the advantages of simple synthesis route, convenient operation, low cost, less waste, green environmental protection, recyclable solvent, and high product purity, and is more suitable for industrialized mass production.

[0008] The present application is realized by the following technical solutions: A preparation method of a non-nalixone intermediate 4-cyano-2-methoxybenzaldehyde, comprising the following steps: 3-methoxy-4-methylbenzonitrile is added to chlorobenzene, N,N-dimethylformamide dimethyl acetal is added under stirring, and the reaction is carried out at elevated temperature. After the reaction is completed, chlorobenzene is removed by concentration under reduced pressure. Then, an organic solvent and water are added, sodium periodate is added under temperature control, and the reaction is carried out under heat preservation. After the reaction is completed, sodium iodate salt is removed by centrifugal filtration, the filtrate is separated, and the organic phase is concentrated to dryness. Then, saturated alkane solvent is added for crystallization to obtain 4-cyano-2-methoxybenzaldehyde.

[0009] The synthesis route of the method is as follows:

[0010] According to the route, the steps include: (1) Preparation of compound 1: 3-methoxy-4-methylbenzonitrile is added to chlorobenzene, N,N-dimethylformamide dimethyl acetal is added under stirring, and the reaction is carried out at elevated temperature. After the reaction is completed, chlorobenzene is removed by concentration under reduced pressure. Then, an organic solvent and water are added, sodium periodate is added under temperature control, and the reaction is carried out under heat preservation. After the reaction is completed, sodium iodate salt is removed by centrifugal filtration, the filtrate is separated, and the organic phase is concentrated to dryness. Then, saturated alkane solvent is added for crystallization to obtain 4-cyano-2-methoxybenzaldehyde. (2) Preparation of 4-cyano-2-methoxybenzaldehyde: To compound 1, an organic solvent and water are added, sodium periodate is added under temperature control, and the reaction is carried out under heat preservation. After the reaction is completed, sodium iodate salt is removed by centrifugal filtration, the filtrate is separated, and the organic phase is concentrated to dryness. Then, saturated alkane solvent is added for crystallization to obtain 4-cyano-2-methoxybenzaldehyde.

[0011] In the above preparation method of 4-cyano-2-methoxybenzaldehyde, the mass ratio of chlorobenzene to 3-methoxy-4-methylbenzonitrile is 0.8-30.0:1, and preferably 1.0-5.0:1.

[0012] In the above preparation method of 4-cyano-2-methoxybenzaldehyde, the mass ratio of N,N-dimethylformamide dimethyl acetal to 3-methoxy-4-methylbenzonitrile is 0.8-7.0:1, and preferably 1.5-3.0:1.

[0013] In the above preparation method of 4-cyano-2-methoxybenzaldehyde, the elevated temperature reaction temperature is 60-140℃, and preferably 110-130℃.

[0014] In the method for preparing 4-cyano-2-methoxybenzaldehyde, the organic solvent is one or more of acetonitrile, tetrahydrofuran and isopropanol.

[0015] In the method for preparing 4-cyano-2-methoxybenzaldehyde, the mass ratio of the organic solvent to 3-methoxy-4-methylbenzonitrile is 2.0-20.0:1, preferably 4.0-12.0:1.

[0016] In the method for preparing 4-cyano-2-methoxybenzaldehyde, the mass ratio of the water to 3-methoxy-4-methylbenzonitrile is 1.0-15.0:1, preferably 4.0-8.0:1.

[0017] In the method for preparing 4-cyano-2-methoxybenzaldehyde, the mass ratio of the sodium periodate to 3-methoxy-4-methylbenzonitrile is 1.4-20.0:1, preferably 3.0-8.0:1.

[0018] In the method for preparing 4-cyano-2-methoxybenzaldehyde, the reaction temperature is 10-60°C, preferably 20-30°C.

[0019] In the method for preparing 4-cyano-2-methoxybenzaldehyde, the saturated alkane solvent is one or more of n-pentane, isopentane, n-hexane, cyclohexane and n-heptane.

[0020] In the method for preparing 4-cyano-2-methoxybenzaldehyde, the mass ratio of the saturated alkane solvent to 3-methoxy-4-methylbenzonitrile is 1.0-30.0:1, preferably 3.0-8.0:1. Advantages

[0021] The method has the advantages of simple synthesis route, convenient operation, easy availability of raw materials, no need of expensive catalyst, simple post-treatment and purification, low cost of raw materials and production, recyclable solvent, green and environmentally friendly production, liquid purity of the obtained 4-cyano-2-methoxybenzaldehyde of more than 99.5%, total reaction yield of more than 83.6%, and more suitability for industrial large-scale production.

[0022] 1. The method for preparing 4-cyano-2-methoxybenzaldehyde according to the present application, the raw materials and reagents are more economical, which greatly reduces the cost of raw materials, and the specific performance is: the starting material is 3-methoxy-4-methylbenzonitrile, which is a higher commercialized pharmaceutical intermediate, and the raw material source is stable. At the same time, the use of expensive trifluoromethanesulfonic anhydride, tert-butyl acrylate, palladium acetate, and NBS with large amount and high price in the existing route is avoided, thereby reducing the production cost. The core reagents are N,N-dimethylformamide dimethyl acetal and sodium periodate, N,N-dimethylformamide dimethyl acetal is a conventional chemical raw material, which is cheap and easy to obtain; compared with reagents such as osmium tetroxide and silver nitrate, the purchasing cost of sodium periodate is lower, and no noble metal catalyst is needed.

[0023] 2. The method for preparing 4-cyano-2-methoxybenzaldehyde according to the present application has higher safety, and the use of highly toxic or toxic reagents in the existing route is avoided. The use of highly toxic osmium tetroxide, the highly toxic carcinogenic reagent dimethyl sulfate, the strong reducing agent red aluminum which is easy to burn in water and air, and the high-risk silver nitrate is avoided, thereby reducing the health hazards of reagents to operators. In the present application, sodium periodate is used as an oxidizing agent, there is no risk of corrosion of equipment, explosion, poisoning and the like, and the risk of storage, transportation and use of the reagent is greatly reduced.

[0024] 3. The method for preparing 4-cyano-2-methoxybenzaldehyde according to the present application has simplified process steps, convenient operation process, and greatly shortened reaction steps: the existing route is mostly 3-4 step reactions (such as oximation reduction-esterification-substitution-oxidation, bromination-hydrolysis, methylation-reduction-substitution), and through the research and selection of suitable starting materials and new route design, the target product can be obtained through condensation and oxidation of two steps, which reduces the separation and purification steps of intermediate products and shortens the production cycle. The operation link is more simplified, after the condensation reaction, only chlorobenzene needs to be removed by reduced pressure concentration, after the oxidation reaction, sodium iodate by-product is removed by filtration, and then the finished product can be obtained by liquid separation, concentration, beating and crystallization, without harsh reaction conditions such as complex noble metal catalytic substitution and high-temperature oxidation of mixed reagents, the operation threshold is lower, and the scale-up production is easier to realize.

[0025] 4. The method for preparing 4-cyano-2-methoxybenzaldehyde according to the present application has mild reaction conditions, high process safety and controllability, the condensation reaction is a conventional reaction with heat preservation, and the oxidation reaction is a temperature-controlled batch feeding, without the problem of “severe heat release during the reaction process” in the WO2008104306A route, thereby avoiding safety accidents such as temperature out of control and material overflow, and the stability and controllability of the reaction process are higher, which is more suitable for industrialized scale-up production.

[0026] 5、The method for preparing 4-cyano-2-methoxybenzaldehyde of the present application uses a safer solvent: chlorobenzene is used as the solvent for the condensation reaction, compared with carbon tetrachloride (toxic) in the literature J. Med. Chem. 2007, and DMF, pyridine in patents WO2008104306A and CN106795155A. The use of the solvent in the present application is more environmentally friendly. After distillation of chlorobenzene, the byproduct methanol and a small amount of DMF are removed by water washing, and then the water is removed by refluxing, and the solvent can be recycled. Acetonitrile, tetrahydrofuran, and isopropanol used in the oxidation reaction step can be separated from most of the water by liquid-liquid separation because they can be layered with high-density brine, and then treated by supergravity distillation equipment, and can also be recycled, greatly reducing the cost of the solvent, reducing the pressure of environmental protection treatment, and the process is more economical and environmentally friendly.

[0027] 6、The method for preparing 4-cyano-2-methoxybenzaldehyde of the present application has stronger industrial adaptability, and gives consideration to environmental protection and production efficiency, and the byproduct is easy to handle: the byproduct of the oxidation reaction is sodium iodate, which can be removed by simple filtration, and the byproduct sodium iodate can be repeatedly used after being treated by an oxidation process. No complex three-waste treatment process is needed, which reduces the cost of environmental protection treatment; and the problems of residual noble metal catalyst and treatment of waste liquid of toxic reagent in the existing route are avoided in the present application.

[0028] 7、The method for preparing 4-cyano-2-methoxybenzaldehyde of the present application has good crystallization and purification effect: the product is purified by crystallization from a saturated alkane solvent, which is more suitable for product separation in large-scale production than column chromatography and multiple extraction in the existing route, can realize high-yield industrial purification, and improves production efficiency. DETAILED DESCRIPTION

[0029] The present application will be further described in conjunction with specific embodiments, so that those skilled in the art can better understand the present application, but the present application is not limited thereto.

[0030] The experimental materials and reagents used in the embodiments of the present application are commercially available consumables and reagents if not otherwise specified.

[0031] The experimental methods in the following examples are generally carried out under conventional conditions or under the conditions recommended by the manufacturer unless otherwise specified. Percentages and parts are calculated by weight unless otherwise specified.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by those skilled in the art. In addition, any method and material similar or equivalent to those described can be used in the present application. The preferred embodiments described herein are only for demonstration. EMBODIMENTS

[0033] Into a 2000L reactor, charged chlorobenzene 100kg, stirred and added 3-methoxy-4-methylbenzonitrile 100kg, N,N-dimethylformamide dimethyl acetal 163.3kg, heated to 120-125℃ for 12h, TLC (ethyl acetate: petroleum ether = 1:1) detection no raw material left, concentrated under reduced pressure to remove chlorobenzene, concentrated dry, added tetrahydrofuran 400kg, purified water 400kg to the system, temperature control below 25℃, added sodium periodate solid 305.2kg in batches, after adding, heated to 20-25℃ for 2h, TLC (ethyl acetate: petroleum ether = 3:1) detection no raw material left, filtered to remove sodium periodate salt, the filtrate was allowed to stand and separated, the organic phase was concentrated, then added n-hexane 300kg to crystallize, centrifuged, and dried to obtain 4-cyano-2-methoxybenzaldehyde 94.50kg, purity 99.5%, two-step reaction molar yield 86.3%.

[0034] Solvent recovery and reuse: 1. The concentrated chlorobenzene was washed with water twice, then refluxed and separated to obtain recovered chlorobenzene: gas phase purity 99.1%, water content 0.004%, recovery rate 82.6%, which can be directly reused in the next batch.

[0035] 2. The concentrated tetrahydrofuran was separated and recovered by supergravity rectification equipment to obtain recovered tetrahydrofuran with purity 99.4% and water content 0.5%, recovery rate 81.6%, which can be directly reused in the next batch.

[0036] 3. The sodium periodate salt by-product was oxidized by sodium hypochlorite to prepare sodium periodate again for reuse, recovery rate 76.5%. Example

[0037] Into a 5000L reactor, charged chlorobenzene 300kg, stirred and added 3-methoxy-4-methylbenzonitrile 300kg, N,N-dimethylformamide dimethyl acetal 489.9kg, heated to 120-125℃ for 12h, TLC (ethyl acetate: petroleum ether = 1:1) detection no raw material left, concentrated under reduced pressure to remove chlorobenzene, concentrated dry, added tetrahydrofuran 1200kg, purified water 1200kg to the system, temperature control below 25℃, added sodium periodate solid 915.6kg in batches, after adding, heated to 20-25℃ for 2h, TLC (ethyl acetate: petroleum ether = 3:1) detection no raw material left, filtered to remove sodium periodate salt, the filtrate was allowed to stand and separated, the organic phase was concentrated, then added n-hexane 900kg to crystallize, centrifuged, and dried to obtain 4-cyano-2-methoxybenzaldehyde 276.6kg, purity 99.6%, two-step reaction molar yield 84.2%.

[0038] Solvent recovery and reuse: 1. The concentrated chlorobenzene is washed with water twice, and then refluxed to separate water to obtain recovered chlorobenzene: gas phase purity 99.4%, moisture 0.002%, recovery rate 84.3%, which can be directly used for the next batch.

[0039] 2. The concentrated tetrahydrofuran is separated and recovered by the supergravity rectification equipment to obtain recovered tetrahydrofuran with purity 99.4% and moisture 0.4%, and the recovery rate is 84.3%, which can be directly used for the next batch.

[0040] 3. The sodium periodate salt by-product is oxidized by sodium hypochlorite to prepare sodium periodate again for reuse, and the recovery rate is 72.5%. Example

[0041] Into a 5000L reactor, 300kg of chlorobenzene was added, and 300kg of 3-methoxy-4-methylbenzonitrile, 489.9kg of N,N-dimethylformamide dimethyl acetal were added under stirring, and the temperature was raised to 120-125°C for 12h. TLC (ethyl acetate: petroleum ether = 1:1) detection showed that no raw material remained. Chlorobenzene was concentrated under reduced pressure, and then 1200kg of acetonitrile and 1200kg of purified water were added to the system, and the temperature was controlled below 25°C. After the addition of 915.6kg of sodium periodate solid, the temperature was raised to 20-25°C for 2h. TLC (ethyl acetate: petroleum ether = 3:1) detection showed that no raw material remained. The sodium periodate salt was removed by filtration, and the filtrate was separated by centrifugation. After the organic phase was concentrated, 900kg of n-hexane was added for crystallization, and 274.6kg of 4-cyano-2-methoxybenzaldehyde was obtained after drying, with purity 99.6%, and the two-step reaction molar yield was 83.6%.

[0042] Solvent recovery and reuse: 1. The concentrated chlorobenzene is washed with water twice, and then refluxed to separate water to obtain recovered chlorobenzene: gas phase purity 99.0%, moisture 0.003%, recovery rate 80.7%, which can be directly used for the next batch.

[0043] 2. The concentrated acetonitrile is separated and recovered by the supergravity rectification equipment to obtain recovered acetonitrile with purity 98.3% and moisture 0.6%, and the recovery rate is 78.4%, which can be directly used for the next batch.

[0044] 3. The sodium periodate salt by-product is oxidized by sodium hypochlorite to prepare sodium periodate again for reuse, and the recovery rate is 77.7%.

[0045] Example 4 (solvent reuse): Into a 1000 L reactor, 100 kg of recovered chlorobenzene (gas phase purity 99.1%, moisture 0.003%) was charged, and 100 kg of 3-methoxy-4-methylbenzonitrile, 163.3 kg of N,N-dimethylformamide dimethyl acetal were added under stirring, and the temperature was raised to 120-125 °C for 12 h. TLC (ethyl acetate: petroleum ether = 1:1) detection showed that no raw material was left. Chlorobenzene was concentrated under reduced pressure, and after drying, 400 kg of recovered tetrahydrofuran (gas phase purity 99.4%, moisture 0.5%) was added to the system, 400 kg of purified water was added, and the temperature was controlled below 25 °C. 305.2 kg of recovered sodium periodate solid was added in batches, and after the addition was completed, the temperature was raised to 20-25 °C for 2 h. TLC (ethyl acetate: petroleum ether = 3:1) detection showed that no raw material was left. The sodium periodate salt was removed by filtration, and the filtrate was allowed to stand and separate. After the organic phase was concentrated, 300 kg of n-hexane was added to crystallize and centrifuge, and after drying, 91.8 kg of 4-cyano-2-methoxybenzaldehyde was obtained, with a purity of 99.5%, and the two-step reaction molar yield was 83.8%.

[0046] The above examples are intended to illustrate the embodiments disclosed in the present application and should not be understood to limit the present application. In addition, various modifications listed herein and changes in the method and composition of the application will be apparent to those skilled in the art, without departing from the scope and spirit of the present application. Although the present application has been described in detail with reference to various specific preferred embodiments, it should be understood that the present application should not be limited to these specific embodiments. In fact, various modifications such as those described above to those skilled in the art to obtain the application should be included within the scope of the present application.

Claims

1. A method for preparing the phenelzine intermediate 4-cyano-2-methoxybenzaldehyde, comprising the following steps: 3-Methoxy-4-methylbenzonitrile was added to chlorobenzene, and N,N-dimethylformamide dimethyl acetal was added under stirring. The mixture was heated to react, and after the reaction was completed, the chlorobenzene was removed by concentration under reduced pressure. An organic solvent and water were added, and sodium periodate was added under controlled temperature. After the reaction was completed, the sodium periodate salt was removed by centrifugation. The filtrate was separated, and the organic phase was concentrated to dryness. After crystallization by adding a saturated alkane solvent, 4-cyano-2-methoxybenzaldehyde was obtained.

2. The method for preparing the non-nelitone intermediate 4-cyano-2-methoxybenzaldehyde according to claim 1, characterized in that, The mass ratio of chlorobenzene to 3-methoxy-4-methylbenzonitrile is 0.8~30.0:1, preferably 1.0~5.0:

1.

3. The method for preparing the non-nelitone intermediate 4-cyano-2-methoxybenzaldehyde according to claim 1, characterized in that, The mass ratio of N,N-dimethylformamide dimethyl acetal to 3-methoxy-4-methylbenzonitrile is 0.8~7.0:1, preferably 1.5~3.0:

1.

4. The method for preparing the non-nelitone intermediate 4-cyano-2-methoxybenzaldehyde according to claim 1, characterized in that, The heating reaction temperature is 60~140℃, preferably 110~130℃.

5. The method for preparing the non-nelitone intermediate 4-cyano-2-methoxybenzaldehyde according to claim 1, characterized in that, The organic solvent is one or more of acetonitrile, tetrahydrofuran, and isopropanol.

6. The method for preparing the non-nelitone intermediate 4-cyano-2-methoxybenzaldehyde according to claim 1, characterized in that, The mass ratio of the organic solvent to 3-methoxy-4-methylbenzonitrile is 2.0~20.0:1, preferably 4.0~12.0:

1.

7. The method for preparing the phenelzine intermediate 4-cyano-2-methoxybenzaldehyde according to claim 1, characterized in that, The mass ratio of water to 3-methoxy-4-methylbenzonitrile is 1.0~15.0:1, preferably 4.0~8.0:

1.

8. The method for preparing the non-nelitone intermediate 4-cyano-2-methoxybenzaldehyde according to claim 1, characterized in that, The mass ratio of sodium periodate to 3-methoxy-4-methylbenzonitrile is 1.4~20.0:1, preferably 3.0~8.0:

1.

9. The method for preparing the phenelzine intermediate 4-cyano-2-methoxybenzaldehyde according to claim 1, characterized in that, The heat preservation reaction temperature is 10~60℃, preferably 20~30℃.

10. The method for preparing the non-nelitone intermediate 4-cyano-2-methoxybenzaldehyde according to claim 1, characterized in that, The saturated alkane solvent is one or more of n-pentane, isopentane, n-hexane, cyclohexane, and n-heptane.

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