A process for the preparation of 2-fluoro-5-formylbenzonitrile

Abstract

The application discloses a preparation method of 2-fluoro-5-formylbenzonitrile, which comprises the following steps: 3-bromo-4-fluorobenzaldehyde is reacted with potassium ferrocyanide under the catalysis of a catalytic system of palladium acetate and 1,3-bis(2,6-diisopropylphenyl)imidazole chloride salt, so as to obtain 2-fluoro-5-formylbenzonitrile; in the application, the extremely low-toxicity potassium ferrocyanide is used to replace the highly-toxic raw material cuprous cyanide as a cyanogen source, and the product is purified by means of water vapor distillation, so that the post-treatment is simple and easy to implement, the product quality is better, and the industrial production is easy to realize.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to the preparation method of 2-fluoro-5-formylbenzonitrile, a key intermediate of olaparib, a drug for treating non-small cell lung cancer, recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer. Background Technology

[0002] Olaparib is a targeted therapy that inhibits the growth, division, and metastasis of tumor cells, thereby controlling tumor progression. Clinically, it is primarily used to treat advanced or metastatic non-small cell lung cancer, recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. It is currently marketed in Europe, the United States, China, India, Japan, and South America.

[0003] The existing literature CN102485721A describes a method for preparing 2-fluoro-5-formylbenzonitrile by reacting 3-bromo-4-fluorobenzaldehyde with cuprous cyanide in N-methylpyrrolidone. The cuprous cyanide used in this method is highly toxic, posing significant safety risks during industrial production.

[0004] The existing literature CN114907234A describes a method for preparing 2-fluoro-5-formylbenzonitrile using o-fluorobenzonitrile, paraformaldehyde, concentrated sulfuric acid, sodium chloride, and anhydrous zinc chloride as raw materials. First, a benzyl chloride of o-fluorobenzonitrile is synthesized, followed by hydrolysis and oxidation, resulting in a three-step reaction to obtain 2-fluoro-5-formylbenzonitrile. This route is lengthy, and the benzyl chloride of o-fluorobenzonitrile is highly irritating, which is unfavorable for industrial production.

[0005] Both of the above routes share a common drawback: the purification and refining schemes are not ideal, resulting in poor product quality. Both products are pale yellow and have low purity, such as the HPLC purity of only 98% described in the experimental example CN114907234A. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a novel synthetic method for 2-fluoro-5-formylbenzonitrile. Compared to known literature schemes, this route avoids the use of the highly toxic raw material cuprous cyanide, and the reaction only requires one step. The post-processing is simple and efficient, making it easier to achieve industrial production.

[0007] To achieve the objectives of the invention, the present invention is implemented through the following technical solutions:

[0008] A method for preparing 2-fluoro-5-formylbenzonitrile includes reacting 3-bromo-4-fluorobenzaldehyde compound II with potassium ferrocyanide in a catalytic system of palladium acetate and 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride compound III to obtain 2-fluoro-5-formylbenzonitrile compound I.

[0009] The chemical reaction process is as follows:

[0010] .

[0011] Furthermore, the solvent for the reaction is N-methylpyrrolidone.

[0012] Furthermore, the reaction temperature is 140~150℃.

[0013] Furthermore, after the reaction is completed, the reaction solvent is evaporated under vacuum, and the product is purified by steam distillation.

[0014] Further, the purified product is recrystallized using a mixed solvent of ethyl acetate and n-heptane.

[0015] More specifically, a method for preparing 2-fluoro-5-formylbenzonitrile includes reacting 3-bromo-4-fluorobenzaldehyde compound II with potassium ferrocyanide in the presence of N-methylpyrrolidone under the catalytic system of palladium acetate and 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride compound III to obtain 2-fluoro-5-formylbenzonitrile compound I. After the reaction is complete, the solvent used in the reaction is evaporated under reduced pressure. Water is added to the residue, and the reactants are reheated to boiling. While the water is evaporated, the water vapor will carry some of the product out with it. The water vapor is cooled into liquid water and further cooled to below 50°C to precipitate a white crystalline powder. The powder is filtered, and the filtrate is added back to the reaction system to continue to carry out the remaining product. This process of recycling the filtrate continues until almost all the product in the reaction flask is carried out. The purified product is then dried.

[0016] Furthermore, the reaction temperature is 140~150℃.

[0017] Further, the product was purified by recrystallization using a mixed solvent with a volume ratio of acetic acid:n-heptane = 3:1, followed by drying to obtain the target product.

[0018] Compared with the preparation methods of 2-fluoro-5-formylbenzonitrile reported in existing literature, the main advantages of this invention are: the use of potassium ferrocyanide, which has extremely low toxicity, to replace the highly toxic raw material cuprous cyanide. Because the cyanide ions in the potassium ferrocyanide molecule are firmly bound to iron, potassium ferrocyanide has extremely low toxicity and is a food-grade anti-caking agent permitted for use in my country's GB2760-2014 standard; at the same time, the reaction only takes one step, the product is purified by steam distillation, the post-processing is simple and easy to perform, the product quality is better, and it is easier to realize industrial production. Attached Figure Description

[0019] Figure 1 Example 1: HPLC chromatogram of chemical purity of 2-fluoro-5-formylbenzonitrile --- blank.

[0020] Figure 2 Example 1: HPLC chromatogram for chemical purity determination of 2-fluoro-5-formylbenzonitrile --- System suitability.

[0021] Figure 3 Example 1: HPLC chromatogram of chemical purity of 2-fluoro-5-formylbenzonitrile --- reference standard.

[0022] Figure 4 Example 1: HPLC chromatogram for chemical purity detection of 2-fluoro-5-formylbenzonitrile --- Sample detection. Detailed Implementation

[0023] The following detailed description of the present invention, through several specific examples, further illustrates the above-described contents of the invention. However, this should not be construed as limiting the scope of the invention to the following specific embodiments. All techniques experimented with based on the above-described contents of the present invention fall within the scope of the present invention.

[0024] Example 1: Synthesis of Compound I of 2-fluoro-5-formylbenzonitrile

[0025] 203 g (1.0 mol) of 3-bromo-4-fluorobenzaldehyde was added to a three-necked flask. 2.2 g (10 mmol) of palladium acetate, 4.3 g (10 mmol) of 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride, 1000 mL of N-methylpyrrolidone, and 92.1 g (0.25 mol) of potassium ferrocyanide were added. The mixture was stirred and heated to 140-150 °C under nitrogen protection for 4 hours. After the reaction was complete, the solvent was evaporated under reduced pressure. 1000 mL of water was added to the residue in portions. The reactants were reheated to boiling. As the water evaporated, the steam carried some of the product with it. The steam was cooled into liquid water and further cooled to below 50 °C, precipitating a white crystalline powder. The white crystalline powder was filtered out, and the filtrate was added back to the reaction system to continue carrying away the remaining product in the reaction flask. This process was repeated until almost all the product in the reaction flask was carried away. The product was dried by forced air to obtain 127.5 g of crude product. The crude product obtained by steam distillation was recrystallized from 380 mL of a mixed solvent (acetic acid: n-heptane = 3:1), and dried by forced air to obtain 113.3 g of off-white powder, which is 2-fluoro-5-formylbenzonitrile. Melting point: 85.0~86.0℃, HPLC purity 99.90%, all single impurities less than 0.1%, see [link to relevant documentation]. Figures 1 to 4 .

[0026] HPLC method for determining the purity of compound I, 2-fluoro-5-formylbenzonitrile

[0027] Determined by high performance liquid chromatography (General Chapter 0512, Part IV, Chinese Pharmacopoeia 2020 Edition).

[0028] Blank solution diluent (acetonitrile)

[0029] Accurately weigh 20 mg of 2-fluoro-5-carboxybenzonitrile reference standard, 20 mg of 3-bromo-4-fluorobenzaldehyde, and 20 mg of p-fluorobenzaldehyde, dilute with diluent to 100 ml, shake well, and then dilute approximately 10 times to obtain the system suitability solution.

[0030] For the reference solution, take about 12 mg of this product, place it in a 25 ml volumetric flask, add acetonitrile to dissolve and dilute to the mark, and shake well.

[0031] For the test solution, take about 12 mg of this product, place it in a 25 ml volumetric flask, add acetonitrile to dissolve and dilute to the mark, and shake well.

[0032] Chromatographic conditions: An octadecylsilane-bonded silica gel column (C18 4.6 × 250 mm 5 μm) was used. The mobile phase was acetonitrile / aqueous phase = 40 / 60 (v / v) (the aqueous phase consisted of 1000 mL of water with 0.2 mL of 80% formic acid solution, and the pH was adjusted to 4.5 with ammonia). The flow rate was 1 mL / min, the detection wavelength was 255 nm, the retention time was 35 min, the column temperature was 30 °C, the diluent was acetonitrile, and the injection volume was 10 μL.

[0033] In the system suitability test, the theoretical plate number, based on the 2-fluoro-5-formylbenzonitrile peak, should be no less than 2000; the peak elution order is 2-fluoro-5-formylbenzonitrile, p-fluorobenzaldehyde, 3-bromo-4-fluorobenzaldehyde, and the resolution between the corresponding peaks of the two substances and the preceding peak should not be less than 1.5.

[0034]

[0035] Assay: Accurately measure blank solution, system suitability solution, reference solution, and test solution and inject them into the liquid phase, then record the chromatogram.

Claims

1. A method for preparing 2-fluoro-5-formylbenzonitrile, characterized in that... Compound II, including 3-bromo-4-fluorobenzaldehyde, reacts with potassium ferrocyanide in the presence of N-methylpyrrolidone under the catalysis of palladium acetate and 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride compound III to give compound I, 2-fluoro-5-formylbenzonitrile. The reaction temperature is 140-150°C. After the reaction is complete, the solvent used in the reaction is evaporated under reduced pressure. Water is added to the residue, and the reactants are reheated to boiling. While the water is evaporated, the water vapor will carry some of the product out with it. The water vapor is cooled into liquid water and further cooled to below 50°C, and a white crystalline powder is precipitated. The powder is filtered, and the filtrate is added back to the reaction system to continue to carry out the remaining product. The filtrate is recycled in this way until all the product in the reaction flask is carried out. The purified product is then dried. The chemical reaction process is as follows: 。

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