A process for the synthesis of N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine

Abstract

This invention discloses a synthetic process for N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine, belonging to the field of organic synthesis technology. The process uses p-aminophenylacetic acid as the starting material and proceeds in four steps: electrophilic bromination, deamination-cyanation, a one-pot condensation-deesterification reaction, and a Suzuki cross-coupling reaction to obtain the target product. The starting materials are inexpensive and readily available, significantly reducing production costs. The bromine / glyoxylic acid system achieves efficient dibromination, and the cyano group is safely introduced via the Sandmeier reaction under mild reaction conditions. The amide condensation and methyl ester removal are combined into a one-pot process, resulting in a simple synthesis procedure, high overall yield, and product HPLC purity exceeding 98%. The entire process employs simple purification methods such as pulping, recrystallization, or salt formation, eliminating the need for column chromatography. Organic solvents can be recycled, resulting in minimal wastewater discharge. The process is highly operable, easily industrialized, and meets the requirements of green chemistry.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a synthesis process of N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine. Background Technology

[0002] Crops often suffer from abiotic stresses such as drought, floods, salinity, and pests and diseases during their growth, leading to severe yield reductions and threatening global food security. Applying chemical agents that help crops resist external stresses is one effective way to alleviate this problem. Abscisic acid (ABA), one of the four major plant hormones, can effectively induce plant responses to stressful environments and has broad application value in agricultural production.

[0003] However, natural ABA suffers from problems such as easy photoisomerization inactivation and metabolic inactivation in plants, limiting its application, and there is currently no mature chemical process to support its large-scale production. Therefore, scientists worldwide are dedicated to developing structural analogs with ABA biological functions. Research shows that N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine (compound I) is an OP analog synthesized through virtual screening, using the highly active ABA analog Opabactin (OP) and iso-PhABA as lead structures. This compound exhibits excellent inhibitory activity during the germination of Arabidopsis thaliana and rice seeds, with a significant effect on the IC50 of rice seed germination. 50 Its value is significantly better than OP, its activity in promoting stomatal closure is better than ABA and iso-PhABA, and it exhibits excellent drought resistance activity, showing the potential to become a new variety of efficient and environmentally friendly plant growth regulator.

[0004] Chinese invention patent CN116239500B has disclosed the structure and bioactivity of compound I, but has not disclosed a synthetic process suitable for industrial production. The existing synthetic route has the following problems: (1) The starting material p-cyanophenylacetic acid is expensive; (2) The use of palladium catalysis to activate CH to introduce bromine atoms is inefficient and easily generates monobrominated byproducts that are difficult to remove during the scale-up reaction; (3) Both steps of the reaction require the use of palladium acetate, which significantly increases the cost of precious metal catalysts; (4) The two-step lithium hydroxide hydrolysis operation is cumbersome and economically inefficient; (5) The entire process route is difficult to scale up and is difficult to produce on a large scale.

[0005] Therefore, developing a simple, efficient, and industrially applicable synthesis process for Compound I has significant economic value and practical implications. Summary of the Invention

[0006] To address the technical problems of existing synthetic routes, such as expensive starting materials, cumbersome reaction steps, purification dependence on column chromatography, low efficiency of precious metal catalysts, and low overall yield, this invention provides a simple, efficient, and industrially applicable synthetic process for N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine (compound I). This process involves only four reaction steps, providing a completely new synthetic route.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] This invention provides a synthetic process for N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine (compound I), comprising the following synthetic steps:

[0009] (1) Starting from p-aminophenylacetic acid (compound 1), 2-(4-amino-3,5-dibromophenyl)acetic acid (intermediate 2) was obtained by electrophilic bromination reaction.

[0010] (2) Intermediate 2 undergoes deamination and cyanation reaction (Sandermeier reaction mechanism) to give 2-(3,5-dibromo-4-cyanophenyl)acetic acid (intermediate 3);

[0011] (3) Intermediate 3 and L-valine methyl ester hydrochloride condense to form an amide bond under the action of a condensing agent, and at the same time, the terminal methyl ester is removed in the same reaction system to obtain (2-(3,5-dibromo-4-cyanophenyl)acetyl)-L-valine (intermediate 4).

[0012] (4) Intermediate 4 and cyclopropylboronic acid undergo a Suzuki cross-coupling reaction under palladium catalyst to introduce a bicyclopropyl group, thereby obtaining the target product N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine (compound I).

[0013] The synthesis process described above is as follows:

[0014] .

[0015] In this invention, the electrophilic bromination reaction in step (1) specifically includes:

[0016] S1. P-aminophenylacetic acid is suspended in dichloromethane, and a catalytic amount of glyoxylic acid (50% w / w aqueous solution) is added. The amount of glyoxylic acid added is 0.05 to 0.1 times the molar amount of p-aminophenylacetic acid.

[0017] S2. The above system was kept in an ice-water bath at a temperature of -5℃ to 10℃. A dichloromethane solution of bromine was slowly added dropwise. The amount of bromine used was 2 to 5 times the molar amount of p-aminophenylacetic acid.

[0018] After S3 was added, the reaction was carried out at 10℃~40℃ until complete. The reaction endpoint was determined by the disappearance of the p-aminophenylacetic acid starting material spot by thin-layer chromatography (TLC).

[0019] After the S4 reaction is complete, a reducing agent aqueous solution is added to quench the reaction. The reducing agent is preferably an inorganic salt containing reducing sulfur atoms, such as sodium bisulfite, sodium sulfite, or sodium thiosulfate, and more preferably sodium bisulfite.

[0020] S5 was extracted with an organic solvent, evaporated under reduced pressure, and purified by pulping with an organic solvent to obtain a white solid 2-(4-amino-3,5-dibromophenyl)acetic acid (intermediate 2).

[0021] In the above reaction, the amount of dichloromethane used as solvent is usually controlled to be 0.5 M to 1.5 M for substrate concentration; the organic solvents used for pulping include, but are not limited to, petroleum ether, n-hexane, ethyl acetate, toluene, dichloromethane, etc., or can be a mixture of two or more solvents, preferably the petroleum ether / ethyl acetate system; the organic solvents used for extraction and pulping can be recycled and reused, saving costs and reducing pollution.

[0022] This invention uses bromine as the brominating agent for an electrophilic dibromination reaction. Compared to the inefficient CH activation route, it can rapidly complete the installation of dibromo atoms, resulting in a clean reaction system with few byproducts and no need for expensive reagents. The reaction is quenched and neutralized with sodium bisulfite afterward, producing no waste gas or waste acid emissions. Both the reaction solvent and the organic solvent used for extraction can be recycled, achieving a balance between high efficiency, economy, and environmental protection.

[0023] In this invention, the deamination cyanidation reaction in step (2) specifically includes:

[0024] In step S1, intermediate 2 is dissolved in acetonitrile (substrate concentration 1–2 M), and sodium bisulfite, cuprous cyanide, and ferric nitrate nonahydrate are added sequentially at room temperature (10°C–35°C). The amount of sodium bisulfite is 1–2 times the molar amount of intermediate 2, the amount of cuprous cyanide is 1.5–5 times the molar amount, and the amount of ferric nitrate nonahydrate is 2–6 times the molar amount (preferably 2–3 times the molar amount to avoid the side reaction of decyanation of the carboxymethyl group on the side chain).

[0025] After adding S2, the temperature is raised to 40℃~80℃ (preferably 50℃~60℃) and the reaction is carried out for 18~48 hours. The reaction progress is monitored by thin-layer chromatography (TLC).

[0026] After the S3 reaction is completed, the mixture is filtered through diatomaceous earth, extracted with organic solvent, and purified by acid-base treatment with alkaline solution (preferably 10%–30% potassium carbonate aqueous solution) and acid solution (preferably 1–3 M hydrochloric acid). Finally, it is pulped with organic solvent (preferably a mixture of petroleum ether and ethyl acetate) to obtain a white or yellow solid 2-(3,5-dibromo-4-cyanophenyl)acetic acid (intermediate 3).

[0027] The organic solvents used in the above extraction and pulping processes can all be recycled and reused, saving costs and reducing pollution.

[0028] This deamination cyanation reaction efficiently introduces cyano groups, avoiding the use of expensive cyanophenylacetic acid as a raw material and significantly reducing costs. During the reaction, the diazo compound immediately participates in the Sandmeier reaction after being generated, with no accumulation of diazonium salts, ensuring high safety and suitability for scale-up production. Furthermore, the organic solvents used in the post-treatment can be recycled and reused, making it environmentally friendly and economical.

[0029] In this invention, the amide bond formation-demethylation reaction in step (3) specifically includes:

[0030] In step S1, intermediate 3 is dissolved in an organic solvent (substrate concentration 0.5 M to 1.5 M), and L-valine methyl ester hydrochloride (1 to 3 molar amounts), acyl transfer catalyst (0.05 to 0.2 molar amounts), base (3 to 8 molar amounts), and condensing agent (1 to 5 molar amounts) are added sequentially. The reaction is carried out at room temperature, and the reaction is monitored by thin-layer chromatography (TLC) until the amide bond is completely formed. The organic solvent is preferably acetonitrile, the condensing agent is preferably EDCI hydrochloride, the acyl transfer catalyst is preferably 1-hydroxybenzotriazole (HOBt), and the base is preferably N,N-diisopropylethylamine (DIPEA).

[0031] After the S2 reaction is complete, quench the reaction with 0.5 M to 3 M hydrochloric acid (preferably 1 M) to pH 2 to 5, extract with organic solvent, and concentrate under reduced pressure.

[0032] S3 dissolves the obtained crude product in a mixed solvent of a polar aprotic solvent, alcohol, and water (tetrahydrofuran is preferred as the polar aprotic solvent, and methanol or ethanol is preferred as the alcohol). Under ice bath conditions (-5℃ to 5℃), a base is added, and the reaction is carried out at room temperature to remove the terminal methyl ester. The base is preferably lithium hydroxide (2 to 8 molar amounts) because of its good selectivity, which can avoid cyano hydrolysis and racemization of the chiral center.

[0033] After the S4 reaction is complete, the pH is adjusted to 2-4 with 1 M-3 M hydrochloric acid, extracted with organic solvent, concentrated under reduced pressure, and the crude product is directly purified by pulping with organic solvent (preferably a mixture of petroleum ether and ethyl acetate) to obtain a white solid (2-(3,5-dibromo-4-cyanophenyl)acetyl)-L-valine (intermediate 4).

[0034] All organic solvents used in the above extractions can be recycled and reused, saving costs and reducing pollution.

[0035] This invention combines amide condensation and methyl ester removal into a one-pot tandem reaction, reducing unit operations and post-processing steps, shortening the production cycle, and lowering the total amount of organic solvents used. The condensation reaction yield is close to quantitative, and the use of inexpensive and readily available EDCI and HOBt makes it suitable for large-scale production. The product only requires slurry purification, eliminating the need for column chromatography, making the operation simple and easy to implement industrially.

[0036] In this invention, the Suzuki cross-coupling reaction in step (4) specifically includes:

[0037] S1 dissolves intermediate 4, a cyclopropyl donor, a palladium catalyst, a ligand, and a base in an organic solvent and water (preferably 1,4-dioxane, used in an amount to achieve a substrate concentration of 1–2 M, and water used in an amount to achieve a substrate concentration of 0.2–0.4 M); wherein the cyclopropyl donor is cyclopropylboronic acid or cyclopropylpinaborate, used in an amount 2–5 times the molar amount of intermediate 4; the palladium catalyst is preferably palladium acetate, used in an amount 0.01–0.2 times the molar amount of intermediate 4; the ligand is preferably tricyclohexylphosphine, used in an amount 0.1–0.3 times the molar amount of intermediate 4; and the base is preferably tripotassium phosphate, used in an amount 3–8 times the molar amount of intermediate 4.

[0038] S2 replaces the system with an inert gas (argon or nitrogen);

[0039] S3 is heated to 90℃~120℃ (preferably 105℃~110℃) and refluxed, and monitored by thin-layer chromatography (TLC) until the reactants have basically reacted completely;

[0040] S4 was cooled to room temperature (10℃~40℃), extracted with organic solvent, concentrated under reduced pressure, then purified by salt formation, freed, extracted, and evaporated to dryness to obtain the final target product N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine (compound I).

[0041] In the salt formation step, dibenzylamine is preferred, and the amount used is 0.8 to 1.2 times the molar amount of product I (preferably 0.95 to 1.05 times the molar amount); the acid used in the free step is preferably 1 M to 3 M hydrochloric acid. All organic solvents used in the above extraction can be recycled and reused, saving costs and reducing pollution.

[0042] This invention places the sole palladium-catalyzed Suzuki reaction as the final step in the synthetic route, reducing the total amount of precious metal catalyst used and avoiding the adverse effects of subsequent reactions on product purity. The reaction exhibits high selectivity and yield, and the final product requires only a simple salt-free purification process, eliminating the need for column chromatography. The purification conditions are mild, the operation is simple, and the controllability is high, effectively solving the problems of high solvent consumption, low efficiency, and difficulty in scaling up existing column chromatography techniques. This truly achieves a process design suitable for industrial production.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] (1) The starting materials are cheap and readily available, and the cost is significantly reduced: p-aminophenylacetic acid (or p-bromophenylacetic acid) is used to replace the expensive p-cyanophenylacetic acid, which reduces the cost of raw materials by more than 80%; and the palladium-catalyzed Suzuki reaction is moved to the last step, reducing the amount of precious metals used, which is economical.

[0045] (2) The reaction steps are simple and the overall yield is good: only four steps are required for synthesis (the original route has five to six steps), in which amide condensation and deesterification are completed in one pot; the product HPLC purity is >98%, which meets the application requirements.

[0046] (3) High efficiency and safety of bromination and cyano introduction: The bromine / glyoxylic acid system is used for room temperature double bromination, with a yield of nearly 97.8% in 4 hours, without the need for precious metals or NBS reagents; Sandmeier cyanation has no diazonium salt accumulation, is highly safe, and avoids the use of expensive and highly toxic cyano raw materials.

[0047] (4) The purification process is simple and environmentally friendly: the whole process adopts pulping, recrystallization or salt formation purification, without column chromatography, greatly reducing the consumption of organic solvents and operating time; the solvent can be recovered, the wastewater is small, the operation is strong, and it is suitable for industrialization. Detailed Implementation

[0048] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of protection of this invention.

[0049] After reading the contents disclosed in this invention, those skilled in the art can make appropriate adjustments or substitutions to the process parameters of the methods and applications described in this invention without departing from the spirit and scope of this invention. Such obvious adjustments, substitutions or combinations should be included within the protection scope of this invention.

[0050] Unless otherwise specified, the materials, reagents, instruments and testing methods used in the following embodiments can be obtained commercially or prepared, operated and implemented with reference to conventional methods disclosed in the art.

[0051] It should be noted that all technical parameters described in this document as numerical ranges (such as temperature, ratio, time, content, etc.) should be understood as encompassing all possible sub-ranges and specific numerical points within that range, regardless of whether the specific numerical value or sub-range is explicitly listed. Unless otherwise specified, the technical terms used in this document have the meanings commonly understood by those skilled in the art.

[0052] Example 1: Synthesis of N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine

[0053] 1. Synthesis of 2-(4-amino-3,5-dibromophenyl)acetic acid (intermediate 2)

[0054] p-Aminophenylacetic acid (compound 1, 30 g, 198.4 mmol) was suspended in 300 mL of dichloromethane, and a catalytic amount of glyoxylic acid (50% aqueous solution, 0.5 mL) was added. The reaction system was cooled in an ice-water bath. Bromine (69.7 g, 436.6 mmol) was dissolved in 150 mL of dichloromethane and slowly added dropwise to the reaction system, controlling the dropping rate to keep the reaction temperature below 10 °C. After the addition was complete, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 4 hours.

[0055] After the reaction was monitored by TLC to be complete, the reaction solution was poured into 300 mL of 10% sodium bisulfite aqueous solution and stirred for 10 minutes, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was washed twice with water, then twice with a mixed solvent of petroleum ether and ethyl acetate in a ratio of 10:1. The filter cake was collected and dried under vacuum at 50 °C to give a white solid product, 2-(4-amino-3,5-dibromophenyl)acetic acid (intermediate 2), with a yield of 97.8%.

[0056] The product characterization data are as follows:

[0057] 1 H NMR (500 MHz, DMSO-d6) δ 12.25 (s, 1H), 7.34 (s, 2H), 5.74 (s, 2H), 3.45 (s, 2H).

[0058] 13 C NMR (126 MHz, DMSO-d6) δ 173.15, 141.86, 133.24, 125.95, 107.78, 38.91.

[0059] 2. Synthesis of 2-(3,5-dibromo-4-cyanophenyl)acetic acid (intermediate 3)

[0060] The 2-(4-amino-3,5-dibromophenyl)acetic acid (intermediate 2, 30 g, 97.1 mmol) obtained in the previous step was dissolved in 260 mL of acetonitrile. Sodium bisulfite (14.7 g, 116.5 mmol), cuprous cyanide (17.4 g, 194.2 mmol), and ferric nitrate nonahydrate (78.5 g, 194.2 mmol) were added sequentially. After the additions were complete, the reaction mixture was heated in an oil bath at 55 °C for 48 hours.

[0061] After the reaction was completed as monitored by TLC, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrates were combined and transferred to a separatory funnel, washed three times with 200 mL of 1M hydrochloric acid, and the organic phase was separated. The aqueous phase was adjusted to pH ≈ 10 with potassium carbonate aqueous solution, and then extracted twice with 200 mL of a 1:1 mixture of petroleum ether and ethyl acetate. The aqueous phase was collected, adjusted to pH ≈ 4 with 1M hydrochloric acid, and then extracted three times with 300 mL of ethyl acetate. The ethyl acetate phases were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate.

[0062] After concentration under reduced pressure, the mixture was pulped with a petroleum ether:ethyl acetate mixture and filtered to obtain a yellow solid product, 2-(3,5-dibromo-4-cyanophenyl)acetic acid (intermediate 3), with a yield of 74.4%.

[0063] The product characterization data are as follows:

[0064] 1 H NMR (500 MHz, DMSO-d6) δ 12.71 (s, 1H), 7.84 (s, 2H), 3.75 (s, 2H).

[0065] 13 C NMR (126 MHz, DMSO-d6) δ 171.63, 144.52, 133.96, 126.08, 116.64, 115.75, 39.80.

[0066] 3. Synthesis of (2-(3,5-dibromo-4-cyanophenyl)acetyl)-L-valine (intermediate 4)

[0067] In a reaction flask, 2-(3,5-dibromo-4-cyanophenyl)acetic acid (intermediate 3, 18.9 g, 59.25 mmol), L-valine methyl ester hydrochloride (15 g, 88.89 mmol), and 4-dimethylaminopyridine (723.9 mg, 5.94 mmol) obtained in the previous step were added sequentially. Then, 180 mL of acetonitrile was added to dissolve the reactants. N,N-diisopropylethylamine (60 g, 296.3 mmol) was added, followed by the slow addition of EDCI hydrochloride (22.8 g, 118.5 mmol). After the additions were complete, the reaction was allowed to proceed overnight at room temperature under argon protection.

[0068] After the reaction of the starting materials was completed as monitored by TLC, post-processing was performed. The reaction flask was cooled in an ice-water bath, and tetrahydrofuran (50 mL), methanol (50 mL), and water (150 mL) were added sequentially, followed by lithium hydroxide (4.26 g, 177.6 mmol). The ice bath was removed, and the mixture was transferred to room temperature and reacted for 6 hours. After the methyl ester disappeared as monitored by TLC, the mixture was cooled to room temperature.

[0069] Adjust the pH to approximately 4 with 1M hydrochloric acid. Transfer the reaction mixture to a separatory funnel, dilute with ethyl acetate, and separate the layers. Extract the aqueous phase twice with 240 mL of ethyl acetate. Combine the ethyl acetate phases, wash five times with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and slurry with a petroleum ether:ethyl acetate mixture to give a white solid product (2-(3,5-dibromo-4-cyanophenyl)acetyl)-L-valine (intermediate 4), in 89.2% yield.

[0070] The product characterization data are as follows:

[0071] 1 H NMR (500 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.42 (d, J = 8.5 Hz, 1H), 7.83 (s, 2H), 4.18 (dd, J = 8.4, 5.6 Hz, 1H), 3.70 (s, 2H), 2.15-2.06 (m,1H), 0.92 (d, J = 10Hz, 3H), 0.89 (d, J = 5Hz, 3H).

[0072] 13 C NMR (126 MHz, DMSO-d6) δ 173.34, 169.08, 145.90, 133.23, 126.13, 116.59, 115.55, 57.82, 41.42, 30.27, 19.54, 18.36.

[0073] 4. Synthesis of N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine (Compound I)

[0074] In a three-necked flask, the following were added sequentially: (2-(3,5-dibromo-4-cyanophenyl)acetyl)-L-valine (intermediate 4, 15 g, 35.85 mmol), cyclopropylboronic acid (7.7 g, 89.7 mmol), palladium acetate (805.5 mg, 3.59 mmol), tricyclohexylphosphine (2 g, 7.17 mmol), and potassium phosphate (27 g, 125.5 mmol). After the addition was complete, the air in the system was replaced with argon gas, and 240 mL of 1,4-dioxane and 30 mL of water were added. The reaction system was then transferred to an oil bath at 105 °C and heated under reflux for 7 hours.

[0075] After the reaction of the starting materials was basically completed as monitored by TLC, the mixture was cooled to room temperature. The reaction solution was transferred to a separatory funnel, ethyl acetate and water were added, and the mixture was separated. The aqueous phase was extracted twice with 200 mL of ethyl acetate. The ethyl acetate phases were combined, washed three times with saturated brine, and dried overnight with anhydrous sodium sulfate.

[0076] After concentration under reduced pressure, 150 mL of dichloromethane was added to dissolve the concentrate, followed by the addition of dibenzylamine (7.79 g, 39.5 mmol). A white solid gradually precipitated out. After stirring at room temperature for 6 hours, the system was filtered. The filter cake was washed three times with a mixed solvent of petroleum ether and dichloromethane (10:1), and the filter cake was collected and dried.

[0077] The dried filter cake was transferred to a reaction flask and dissolved in 250 mL of dichloromethane. 1M hydrochloric acid was slowly added to adjust the pH to approximately 4, breaking down the formed salt and releasing the product. After the solid was completely dissolved, it was transferred to a separatory funnel and separated. The aqueous phase was extracted twice more with 150 mL of dichloromethane. The dichloromethane phases were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The mixture was evaporated under reduced pressure to obtain the white solid target product N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine (compound I), in 85.5% yield.

[0078] The product characterization data are as follows:

[0079] 1H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 6.79 (s, 2H), 4.13 (dd, J = 8.5, 5.6 Hz, 1H), 3.49 (s, 2H), 2.19-2.13 (m,2H), 2.06 (dq, J = 13.4, 6.7 Hz, 1H), 1.11-1.08 (m, 4H), 0.87 (d, J = 6.8 Hz,3H), 0.84 (d, J = 6.8 Hz, 3H), 0.79-0.73 (m, 4H).

[0080] 13 C NMR (126 MHz, DMSO-d6) δ 173.49, 169.99, 147.68, 142.76, 122.51,117.87, 111.10, 57.61, 42.66, 30.30, 19.58, 18.33, 14.41, 9.76, 9.65.

[0081] Comparative Example

[0082] This comparative example refers to the method described in Example 1 of Chinese Patent Application CN116239500B (Application No.: 202310233429.4, Application Date: March 13, 2023) to prepare the target compound N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine (compound I). The specific steps are as follows:

[0083] Step 1: Synthesis of methyl p-cyanophenylacetate

[0084] p-Cyanophenylacetic acid (30 g, 186.3 mmol) was dissolved in 300 mL of dichloromethane, and oxalyl chloride (28.4 g, 223.6 mmol) was added. The mixture was heated under reflux overnight. After the reaction was complete as monitored by TLC, the solvent was removed under reduced pressure, and the residue was dissolved in anhydrous methanol (200 mL). The mixture was reacted in an ice bath for 30 min. The methanol was removed under reduced pressure, and the product was dissolved in ethyl acetate. The solution was washed with saturated sodium carbonate aqueous solution, separated, dried over dryness, and concentrated under reduced pressure to give 31.8 g of a colorless needle-like solid product, with a yield of 95%. No column chromatography purification was required.

[0085] Step 2: Synthesis of methyl (3,5-dibromo-4-cyanophenyl)acetate

[0086] The product from the previous step (20 g, 114.2 mmol) was dissolved in 200 mL of 1,2-dichloroethane, and NBS (61.0 g, 342.6 mmol), TsOH (9.8 g, 57.1 mmol), and palladium acetate (1.28 g, 5.71 mmol) were added sequentially. The reaction was carried out overnight at 70 °C. After the reaction was complete, the mixture was filtered, the filtrate was washed with saturated brine, dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give 27.8 g of a white solid product, with a yield of 70%.

[0087] Step 3: Synthesis of methyl (4-cyano-3,5-dicyclopropylphenyl)acetate

[0088] The product from the previous step (15 g, 43.1 mmol) and cyclopropylboronic acid (11.1 g, 129.3 mmol) were dissolved in 200 mL of toluene. The mixture was purged with argon, and then tricyclohexylphosphine (1.21 g, 4.31 mmol), palladium acetate (0.48 g, 2.16 mmol), and 1 mL of water were added sequentially. After another argon purging, the mixture was reacted overnight at 100 °C. After the reaction was complete, the mixture was washed with saturated brine, extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium bicarbonate solution, dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give 11.6 g of a white solid product, in 97% yield.

[0089] Step 4: Synthesis of (4-cyano-3,5-dicyclopropylphenyl)acetic acid

[0090] The product from the previous step (10 g, 35.6 mmol) was dissolved in a mixed solvent of 10 mL methanol and 10 mL water. Lithium hydroxide monohydrate (4.48 g, 106.8 mmol) was added at 0 °C, and the mixture was stirred overnight at 0 °C. After the reaction was complete, the pH was adjusted to 2-3 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give 9.0 g of a white solid product, with a yield of 94%.

[0091] Step 5: Synthesis of N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine

[0092] The product from the previous step (8 g, 29.6 mmol), L-valine methyl ester hydrochloride (5.95 g, 35.5 mmol), and DMAP (9.4 g, 77.0 mmol) were dissolved in 100 mL of dichloromethane, and DCC (7.33 g, 35.5 mmol) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, the filtrate was washed with saturated sodium carbonate aqueous solution, extracted with ethyl acetate, dried over the organic phase, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give a white solid intermediate ester in 97% yield. The above intermediate ester was dissolved in a mixed solvent of 10 mL methanol and 10 mL water, and lithium hydroxide monohydrate (3.73 g, 88.8 mmol) was added at 0 °C. The mixture was stirred overnight at 0 °C. After the reaction was complete, the pH was adjusted to 2-3 with 1M hydrochloric acid, extracted with ethyl acetate, dried over the organic phase, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the target product as a white solid with a yield of 98%.

[0093] Example of effect

[0094] This example systematically compares the four-step synthesis process described in Embodiment 1 of the present invention with the five-step synthesis process described in the comparative example (Chinese Patent Application CN116239500B, application number: 202310233429.4) to highlight the advanced nature and industrial applicability of the technical solution of the present invention.

[0095] Table 1 Comparison of Starting Raw Material Costs

[0096]

[0097] As shown in Table 1, this invention uses inexpensive and readily available p-aminophenylacetic acid instead of expensive p-cyanophenylacetic acid (which costs approximately 6-8 times more per unit) as the starting material. Although this invention requires the additional introduction of the cyano group via the Sandmeier reaction, the reaction is simple to operate, yields stable results, and the overall raw material cost is reduced by approximately 86.8% compared to the comparative example, resulting in significant economic benefits.

[0098] Table 2 Comparison of Key Steps (Bromotion Reaction)

[0099]

[0100] As shown in Table 2, the present invention has significant advantages in bromination reactions: it uses inexpensive bromine instead of expensive NBS and palladium acetate, resulting in low reagent costs; the reaction conditions are mild, and the reaction can be completed in 4 hours at room temperature (compared to overnight reaction in the prior art), resulting in low energy consumption and high efficiency; the yield is significantly increased to 97.8%, which is about 28 percentage points higher than the 70% of the prior art; the purification process only requires simple slurrying and does not require column chromatography, making it more suitable for industrial production.

[0101] Table 3 Overall Process Comparison

[0102]

[0103] In summary, this invention proposes for the first time a four-step synthetic strategy of "electrophilic bromination → Sandmeier cyanation → one-pot condensation and deesterification → Suzuki coupling," featuring a novel route design, reduced total steps, and avoidance of expensive starting materials. The bromination reaction uses a bromine / glyoxylic acid system instead of the NBS / palladium system, with a reaction time of 4 hours at room temperature and a yield of 97.8%, eliminating the need for column chromatography. The amide condensation and deesterification are combined into a one-pot process, simplifying operations. Purification methods such as pulping, recrystallization, and salt formation are used throughout the process. These improvements work synergistically to achieve a simple, efficient, environmentally friendly, and industrially suitable synthetic process.

Claims

1. A process for synthesizing N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine, characterized in that, The synthesis process includes the following steps: (1) Starting with p-aminophenylacetic acid, 2-(4-amino-3,5-dibromophenyl)acetic acid was obtained by electrophilic bromination reaction; (2) 2-(4-amino-3,5-dibromophenyl)acetic acid is given by deamination and cyanidation reaction to 2-(3,5-dibromo-4-cyanophenyl)acetic acid; (3) 2-(3,5-dibromo-4-cyanophenyl)acetic acid and L-valine methyl ester hydrochloride condense under the action of a condensing agent to form an amide bond, while removing the terminal methyl ester to obtain (2-(3,5-dibromo-4-cyanophenyl)acetyl)-L-valine; (4) (2-(3,5-dibromo-4-cyanophenyl)acetyl)-L-valine and cyclopropylboronic acid are subjected to a Suzuki cross-coupling reaction under palladium catalyst to introduce a bicyclopropyl group, yielding N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine.

2. The synthesis process according to claim 1, characterized in that, The electrophilic bromination reaction in step (1) includes: suspending p-aminophenylacetic acid in an organic solvent, adding a catalytic amount of glyoxylic acid, adding bromine dropwise at -5℃ to 10℃, reacting at 10℃ to 40℃ until complete after the addition is finished, quenching with a reducing agent aqueous solution, extracting, evaporating to dryness, recrystallizing to obtain 2-(4-amino-3,5-dibromophenyl)acetic acid.

3. The synthesis process according to claim 2, characterized in that, The organic solvent is dichloromethane; the reducing agent is sodium bisulfite, sodium sulfite, or sodium thiosulfate; and the amount of bromine used is 2 to 5 times the molar amount of p-aminophenylacetic acid.

4. The synthesis process according to claim 1, characterized in that, The deamination cyanation reaction in step (2) includes: dissolving 2-(4-amino-3,5-dibromophenyl)acetic acid in an organic solvent, adding sodium bisulfite, cuprous cyanide and ferric nitrate nonahydrate in sequence, heating to 40℃~80℃ for reaction, filtering after the reaction is completed, extracting, purifying with acid and alkali, and pulping to obtain 2-(3,5-dibromo-4-cyanophenyl)acetic acid.

5. The synthesis process according to claim 4, characterized in that, The organic solvent is acetonitrile; the amount of sodium bisulfite is 1 to 2 times the molar amount of 2-(4-amino-3,5-dibromophenyl)acetic acid; the amount of cuprous cyanide is 1.5 to 5 times the molar amount of 2-(4-amino-3,5-dibromophenyl)acetic acid; and the amount of ferric nitrate nonahydrate is 2 to 6 times the molar amount of 2-(4-amino-3,5-dibromophenyl)acetic acid.

6. The synthesis process according to claim 1, characterized in that, Step (3) includes: dissolving 2-(3,5-dibromo-4-cyanophenyl)acetic acid in an organic solvent, adding L-valine methyl ester hydrochloride, acyl transfer catalyst, base and condensing agent in sequence, and reacting to form an amide bond; after the reaction is completed, quenching, extraction and concentration are performed; dissolving the crude product in a polar aprotic solvent, alcohol and water, adding base to remove the terminal methyl ester; adjusting the pH, extraction, concentration and pulping are performed to obtain (2-(3,5-dibromo-4-cyanophenyl)acetyl)-L-valine.

7. The synthesis process according to claim 6, characterized in that, The organic solvent is acetonitrile; the condensing agent is EDCI hydrochloride; the acyl transfer catalyst is 1-hydroxybenzotriazole or 4-dimethylaminopyridine; the base is N,N-diisopropylethylamine; and the base used to remove the terminal methyl ester is lithium hydroxide.

8. The synthesis process according to claim 1, characterized in that, The Suzuki cross-coupling reaction in step (4) includes: dissolving (2-(3,5-dibromo-4-cyanophenyl)acetyl)-L-valine, cyclopropylboronic acid, palladium catalyst, ligand, and base in an organic solvent and water, replacing with an inert gas, heating to 90℃~120℃ for reaction, cooling after reaction, extracting, concentrating, and then salting, freeing, extracting, and evaporating to obtain N-[2-(4-cyano-3,5-dicyclopropylphenyl)acetyl]-L-valine.

9. The synthesis process according to claim 8, characterized in that, The palladium catalyst is palladium acetate; the ligand is tricyclohexylphosphine; the base is tripotassium phosphate; and the organic solvent is 1,4-dioxane.

10. The synthesis process according to claim 8, characterized in that, The organic amine used in the salt formation step is dibenzylamine; the acid used in the freeing step is hydrochloric acid.

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