Process for the synthesis of 2-(4-chlorophenyl)-2-hydroxy-n-(3-methoxy-4-(prop-2-yn-1- yloxy)phenethyl)acetamide, a key intermediate of mandipropamid

Abstract

The application provides an improved process for preparing 2-(4-chlorophenyl)-2-hydroxy-N-(3-methoxy-4-(prop-2-yn-1-oxo)phenethyl)acetamide, which is a key intermediate for synthesizing dualyn acetamide. The application develops an efficient, safe and cost-effective preparation method for dualyn acetamide. The method involves a simple nitro-hydroxy aldehyde reaction, LAH reduction and mild amidation reaction to synthesize the key intermediate 2-(4-chlorophenyl)-2-hydroxy-N-(3-methoxy-4-(prop-2-yn-1-oxo)phenethyl)acetamide (E). The synthesis process of the application is simple in operation, mild in reaction condition, high in yield and simple in process flow, and the yield is as high as 90%. The subsequent product purification of the method adopts filtration and crystallization method, and simple column chromatography separation. The method is efficient and can be scaled up, which helps to realize the atomic economy and step economy of the process. Therefore, from the perspective of drug development and material synthesis, the research on the synthesis process has wide application prospect.

Description

[0001] Invention Field This invention provides an efficient, environmentally friendly, economical, safe and easy-to-operate synthesis process for preparing a key intermediate in the synthesis of diyrylamide.

[0002] This invention particularly relates to 2-(4-chlorophenyl)-2-hydroxy- N Synthesis of 3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide.

[0003] The present invention relates more specifically to the use of the key intermediate 2-(4-chlorophenyl)-2-hydroxy- N Diyrylamide was synthesized from 3-(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide. Background Technology

[0004] Mandipropamid is a compound belonging to the mandelic acid amide class and is also a member of the CAA (carboxylic acid amide) fungicide family. Mandipropamid is an inhibitor of cellulase synthase and is effective against downy mildew and the pathogenic Phytophthora infestans (Cohen, Y.; Rubin, A.; Gotlieb, D.). [The following appears to be unrelated and possibly a separate entry:] Activity of carboxylic acid amide (CAA) fungicides against Bremia lactucae. European Journal of Phytopathology (…). Eur J Plant Pathol 2008 122 , 169–183; and Blumi, M.; Boehleri, M.; Randall, E.; Young, V.; Csukai, M.; Krausi, S.; Moulini, F.; Scalliet, G.; Avrova, AO; Whisson, SC and Fonne-Pfister, R. Diyrylamide targets the cellulose synthase-like PiCesA3 to inhibit cell wall biosynthesis in *Phytophthora infestans*, a pathogenic oomycete. Molecular Plant Pathology ( MOLECULAR PLANT PATHOLOGY 2010 11(2), 227–243). Dipyridamole is a highly effective active ingredient: its EC80 value against Phytophthora wilt is 0.1 mg / L, and against grape variegated downy mildew is 1.2 mg / L. The European Commission has approved the use of dipyridamole as an active ingredient in plant protection products since August 1, 2013. In Germany, Austria, and Switzerland, dipyridamole is approved under the trade names Revus and Pergado. As a contact fungicide, it exhibits strong fungicidal activity against foliar oomycete pathogens and possesses unique translaminar translocation properties, which helps prolong the duration of control. Studies have found that dipyridamole can effectively control plant pathogens such as Plasmoparaviticola wilt of grapes and late blight of potato caused by Phytophthora wilt. (Du, XJ.; Bian, Q.; Wang, HX.; Yu, SJ.; Kou, JJ.; Wang, ZP.; Lia, ZM. and Zhao, WG, Design, synthesis and bactericidal activity of novel carboxamide compounds represented by N-diphenylmethylvaline carbamate, Organic and Biomolecular Chemistry (Org. Biomol. Chem.). 2014,) 12 , 5427;Zhang, J.; Wu, Q.; Zhong, Y.; Wang, Z.; He, Z.;Zhang, Y. and Wang, M, Enantioselective bioactivity, toxicity and degradation in vegetables and soil of the chiral fungicide dimethomorph J. Agric. Food Chem 2021, 69 , 13416 13424; and Han, J.; Chen, Y.; Liu, Z.; Chen, D.; Zhang, K.; Hu, D, Enantioselective environmental behavior of the chiral fungicide dimethomorph in four Chinese soils, Journal of the Soil Science Society (Soil Sci. Soc. Am. J. 2021, 1–17). Its mechanism of action involves disrupting the growth and development of these fungi through multiple pathways.

[0005] To date, various methods have been employed to synthesize diyrylamide, which exists as a 1:1 mixture of enantiomers (racemic). Diyrylamide compounds can be prepared from a variety of synthetically designed starting materials. Diyrylamide was first synthesized by Syngenta in 2003 using a refined approach (WO03042166), a method involving different starting materials. They synthesized a sugar ester, a key intermediate in the synthesis; the reaction was carried out at high temperatures using high-boiling hydrocarbons or chlorinated solvents. Excessive use of the starting material at high temperatures resulted in the formation of numerous byproducts. To obtain the key sugar ester intermediate, a series of substitution, condensation, and addition reactions were carried out, using expensive and hazardous reagents such as sulfuric acid (H₂SO₄), thionyl chloride (SOCl₂), 1,4-diaminobutane (DABCO), dibutylcarbamate (DBU), hydrogen cyanide (HCN), potassium cyanide (KCN), bromine (Br₂), cyanosilanes, and metal catalysts such as bismuth bromide. Furthermore, the reaction was carried out over a wide temperature range of -80°C to 150°C. On the other hand, they synthesized the corresponding 2-(3-methoxy-4-(prop-2-ynthin-1-oxy)phenyl)ethylamine from vanillin as a starting material via reaction with hydrogen cyanide (HCN) and subsequent reduction, for coupling with sugar esters. These methods present difficulties for large-scale production. Overall, the synthetic route is quite cumbersome, requiring not only harsh conditions but also expensive and unstable reagents. Moreover, the route is long and generates numerous byproducts, making it unsuitable for industrial production. Figure 1 As shown.

[0006] In 2009, inventor C. Lamberth published a slightly modified synthetic route for diyrylamide (Lamberth, C. . Alkyne Chemistry in Crop Protection Applications in bioorganic and medicinal chemistry ( Bioorg. Med. Chem. ) 2009 (17, 4047–4063), this route uses 2-(3-methoxy-4-(prop-2-ynthin-1-oxy)phenyl)ethyl-1-amine and 2-(4-chlorophenyl)-2-hydroxyacetic acid as starting materials. The entire synthetic route includes: amide coupling reaction using BOP and diethylisopropylamine (Hunigs base); under basic conditions, using propargyl bromide to react 2-(4-chlorophenyl)-2-hydroxy- N -(4-hydroxy-3-methoxyphenylethyl)acetamide undergoes propargylation. An alternative route involves first N-formylating 2-(3-methoxy-4-(prop-2-yn-1-oxy)phenyl)ethyl-1-amine, and then, under basic conditions, [further action is required]. N-(4-hydroxy-3-methoxyphenethyl)formamide undergoes propargylation. This intermediate is directly converted to the corresponding amide via a Seebach-modified Passerini reaction, followed by the introduction of a second propargyl group into the hydroxyl functional group of the mandelic acid moiety under basic conditions to yield diacetylamyramide. Most of the starting materials and coupling reagents used in this reaction are very expensive, as mentioned above. Figure 2 As shown.

[0007] Another promising method for preparing diacetylcholine is disclosed in invention patent application (CN 102584621B, July 18, 2012) and US patent (US8129560B2). This method uses 4-chlorobenzaldehyde and vanillin as starting materials. In the first step, vanillin reacts with potassium cyanide or sodium cyanide in the presence of a phase-transfer catalyst to obtain 4-hydroxy-3-methoxyphenylacetonitrile. Subsequently, the corresponding 2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetonitrile is reduced using H2 / Pd to obtain the key intermediate 2-(3-methoxy-4-(prop-2-yn-1-oxy)phenyl)ethyl-1-amine. The main drawback of this method is the use of highly toxic cyanide sources, such as NaCN and KCN, which greatly limits the industrial production of this drug. Furthermore, this method is a costly, multi-step process; the bromination process uses bromine, making the operation quite cumbersome and difficult to control. The reaction temperature is high in most steps of this method, which is also a major concern. Figure 3A and 3B As shown.

[0008] Recently, Narsaiah et al. reported another synthetic route for the preparation of diyrylamide (Annapurna, K.; Subba Reddy, BV and Narsaiah AV Synthesis of fungicide diyrylamide without protecting group). Arkivoc 2023 (viii) 202312023), this route uses vanillin and 4-chloroacetophenone as starting materials and proceeds through 5 steps. First, nitroolefins are prepared under reflux conditions using nitromethane (MeNO2) and ethylenediamine (EDA), followed by reduction with lithium aluminum hydride (LAH) to obtain the corresponding amines in moderate yields. An attempt is made to prepare the key mandelic acid intermediate via the oxidation reaction of selenium dioxide (SeO2) and lanthanide metal salts. Subsequently, an expensive coupling reaction is carried out using an EDC / HOBt coupling reagent to obtain the corresponding amide product, which reacts with propargyl bromide under alkaline conditions to finally generate diacetylamyramine. Figure 4 As shown.

[0009] However, it is worth noting that all of these methods require the use of acid or metal catalysts and involve toxic and expensive reagents, solvents, and high-temperature conditions. While these methods provide valuable insights, these factors pose challenges in terms of safety and the feasibility of industrial scale-up. Some methods require the use of toxic cyanide sources and molecular bromine, and the reaction times are lengthy. These factors all constitute obstacles when considering the feasibility of implementing these methods industrially.

[0010] In contrast, this invention employs a mild, environmentally friendly, cost-effective, and easy-to-operate synthetic method for preparing the key intermediate of diyrylamide—2-(4-chlorophenyl)-2-hydroxy- N -(3-methoxy-4-(prop-2-ynthin-1-oxy)phenethyl)acetamide. Notably, this method eliminates the need for transition metals, expensive bases, complex coupling reagents, and sacrificial hazardous oxidants in the reaction. Furthermore, this synthetic method can be easily carried out at room temperature with minimal steps from the starting chemical. The method is efficient and scalable, contributing to improved atom and step economy of the process. This method holds promise for achieving efficient synthesis and is well-suited for potential industrial production processes.

[0011] Purpose of the invention The main objective of this invention is to provide a method for preparing 2-(4-chlorophenyl)-2-hydroxy- N The method of -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide, the compound being a key intermediate of diyrylamide.

[0012] Another object of the present invention is to provide a method for preparing 2-(4-chlorophenyl)-2-hydroxy- N A method for preparing diyrylamide in high yield using 3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide.

[0013] Another object of the present invention is to provide 2-(4-chlorophenyl)-2-hydroxy- in high chemical yield. N -(3-methoxy-4-(prop-2-yne-1-oxy)phenylethyl)acetamide.

[0014] Another object of the present invention is to provide a synthetic CAA bactericide 2-(4-chlorophenyl)- N Synthetic method of 3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)-2-(prop-2-yne-1-oxy)acetamide.

[0015] Another object of the present invention is to provide a commercially viable method for synthesizing 2-(4-chlorophenyl)-2-hydroxy- N-(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide to achieve 2-(4-chlorophenyl)- N Synthesis of -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)-2-(prop-2-yne-1-oxy)acetamide.

[0016] Another object of the present invention is to provide a user-friendly and mild method for synthesizing 2-(4-chlorophenyl)-2-hydroxy- using less expensive starting materials under mild and room temperature conditions. N -(3-methoxy-4-(prop-2-yne-1-oxy)phenylethyl)acetamide.

[0017] Another object of the present invention is to provide a method for synthesizing 2-(4-chlorophenyl)-2-hydroxy- without any transition metal catalysts and external oxidants. N -(3-methoxy-4-(prop-2-yne-1-oxy)phenylethyl)acetamide. Invention Overview Therefore, this invention introduces a novel, simple, and efficient synthetic process for synthesizing the key intermediate 2-(4-chlorophenyl)- 2- Hydroxy-N-(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E), especially using readily available starting materials such as vanillin, is synthesized. Current methods for preparing 2-(4-chlorophenyl)-2-hydroxy- N The synthesis of 3-(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide faces several challenges, including the need for expensive transition metal catalysts, toxic reagents, toxic oxidants, multi-step operations, and high-temperature conditions. Notably, a direct, environmentally friendly, and cost-effective route for the efficient synthesis of diyrylamide remains lacking.

[0019] This invention provides a method for preparing 2-(4-chlorophenyl)-2-hydroxy- N The process for producing -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E) includes the following steps: (i) In the presence of an organic solvent, 3-methoxy-4-(prop-2-yne-1-oxy)benzaldehyde (A) It reacts with nitromethane to form a nitro-hydroxyl group. (E) -2-Methoxy-4-(2-nitrovinyl)-1-(prop-2-yyn-1-oxy)benzene (B) ; (ii) In the presence of a reducing agent and an organic solvent, the product prepared in step (i) is reduced. （E） -2-Methoxy-4-(2-nitrovinyl)-1-(prop-2-yyn-1-oxy)benzene (B) To synthesize 2-(3-methoxy-4-(prop-2-yn-1-oxy)phenyl)ethyl-1-amine (C) ;as well as (iii) In the presence of a coupling agent, make (C) prepared in step (ii) With 2-(4-chlorophenyl)-2-hydroxyacetic acid (D) An amide coupling reaction was carried out at room temperature to give 2-(4-chlorophenyl)-2-hydroxy- N -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E) .

[0020] In a preferred embodiment of the invention, the nitro-hydroxyl reaction is carried out in an acetic acid solvent under ambient reaction conditions in the presence of a base selected from ammonium acetate, ammonium formate, sodium acetate, potassium acetate, and potassium carbonate.

[0021] In a preferred embodiment of the present invention, the reducing agent in step (ii) is selected from lithium aluminum hydride, NaBH2O, etc. 4 / Any one of indium powder, CuCl, NaBH4 / BF3·Et2O, Raney nickel, and H2.

[0022] In one aspect of the invention, the coupling agent in step (iii) is selected from any one of N-hydroxysuccinimide (NHS), N-N'-dicyclohexylcarbodiimide (DCC), and azirmonatriazole tetramethylureonium hexafluorophosphate (HATU).

[0023] In a preferred embodiment of the present invention, the coupling agent in step (iii) is selected from... N Either 1-hydroxysuccinimide (NHS) or N-N'-dicyclohexylcarbodiimide (DCC).

[0024] In one embodiment of the present invention, the organic solvent in step (i) is selected from any one of acetic acid, tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide, ethyl acetate and acetone.

[0025] In another embodiment of the invention, the organic solvent in step (ii) is selected from tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide, ethyl acetate, or acetone.

[0026] In a preferred embodiment of the present invention, the organic solvent is tetrahydrofuran (THF).

[0027] In a preferred embodiment of the invention, the reaction is carried out in a temperature range of 0°C to 130°C. For steps (ii) and (iii), the preferred operating temperatures are 95°C and 35°C, respectively.

[0028] In one embodiment, the present invention provides a process for preparing diyrylamide, comprising the following steps: (i) In the presence of an organic solvent, 3-methoxy-4-(prop-2-yne-1-oxy)benzaldehyde (A) It reacts with nitromethane to form a nitro-hydroxyl group. (E) -2-Methoxy-4-(2-nitrovinyl)-1-(prop-2-yyn-1-oxy)benzene (B) ; (ii) In the presence of a reducing agent and an organic solvent, the reduction step ( i Prepared in ) E )-2-methoxy-4-(2-nitrovinyl)-1-(prop-2-yyn-1-oxy)benzene (B) To synthesize 2-(3-methoxy-4-(prop-2-yne-1-oxy)phenyl)ethane-1-amine (C) ;as well as (iii) In the presence of a coupling agent, make (C) prepared in step (ii) With 2-(4-chlorophenyl)-2-hydroxyacetic acid (D) An amide coupling reaction was carried out at room temperature to give 2-(4-chlorophenyl)-2-hydroxy- N -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E) ;as well as (iv) In the presence of an aqueous sodium hydroxide solution and tetrabutylammonium bromide (TBAB) or any other ammonium salt, the 2-(4-chlorophenyl)-2-hydroxy- N -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E) Reaction with propargyl bromide to obtain diyrylamide .

[0029] This synthetic process employs an environmentally friendly, room-temperature method, requiring no transition metals or external oxidants. The method is highly efficient and scalable, contributing to both atom and step economy. Therefore, this method is of great significance. It provides a new route for synthesizing high-demand diacetylcholine amides from feedstock chemicals.

[0030] Brief description of the attached figures Figure 1A route for synthesizing diyrylamide based on existing technology (WO03042166) is presented.

[0031] Figure 2 This demonstrates the application of existing technology (Lamberth, C) . Applications of Alkyne Chemistry in Crop Protection . Bioorg. Med. Chem. 2009, 17, (4047–4063) The route for synthesizing diyrylamide.

[0032] Figure 3A and 3B A route for synthesizing diyrylamide based on prior art (Chinese patent application CN 102584621 B, published July 18, 2012; and US patent US8129560B2) is presented.

[0033] Figure 4 The present invention demonstrates the route for synthesizing the key intermediate (E) using vanillin-derived intermediate (A) as the starting material, and the route for synthesizing diyrylamide from the key intermediate (E).

[0034] Detailed description of the invention This invention provides a method for synthesizing 2-(4-chlorophenyl)-2-hydroxy- N The method for synthesizing 2-(4-chlorophenyl)-(3-methoxy-4-(prop-2-yn-1-oxy)phenethyl)acetamide (E) using intermediate A as a starting material. N A key intermediate of -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)-2-(prop-2-yne-1-oxy)acetamide (diynemycin). Figure 4 The route for synthesizing the key intermediate (E) from vanillin-derived intermediate (A) and the route for synthesizing diyrylamide from key intermediate (E) are presented.

[0035] The technical details of this invention will be described in detail below: Under alkaline conditions (K2CO3), 4-hydroxy-3-methoxybenzaldehyde is subjected to propargylation reaction with propargyl bromide to generate 3-methoxy-4-(prop-2-yn-1-oxy)benzaldehyde (A). A solution of acetic acid in 3-methoxy-4-(prop-2-yne-1-oxy)benzaldehyde (A) (1.0 equivalent), nitromethane (5.0 equivalent), and ammonium acetate (1.1 equivalent) was added to a dried round-bottom flask. The resulting mixture was refluxed at 130°C for 8 hours. After the specified time, the reaction mixture was cooled to room temperature, and the precipitate was filtered through a Buchner funnel. The pure product was obtained. E2-Methoxy-4-(2-nitrovinyl)-1-(prop-2-yn-1-oxy)benzene (B) is a yellow solid; yield: 90%.

[0036] Lithium aluminum hydride (LAH) was dissolved in dry tetrahydrofuran (THF), and a two-necked round-bottom flask was placed under an argon atmosphere and continuously stirred and cooled at 0°C. Then, substrate B was added dropwise under an inert atmosphere. After five minutes, the mixture was placed in a preheated oil bath and heated at reflux temperature (95°C) for 8 hours. After the reaction was complete, LAH was quenched with diethyl ether (Et₂O), an aqueous sodium hydroxide solution, and H₂O, as described in the literature. After evaporation of the solvent, the crude product was purified by column chromatography using 80% ethyl acetate / petroleum ether (EA / PE), or, if the crude product was sufficiently pure, it was used directly as the starting material for the next step. Pure 2-(3-methoxy-4-(prop-2-yn-1-oxy)phenyl)ethylamine (C) was isolated as a yellow oil, yield: 65%.

[0037] To a THF solution of 1.0 equivalent of 2-(4-chlorophenyl)-2-hydroxyacetic acid under stirring, 1.0 equivalent of 2-(3-methoxy-4-(prop-2-yn-1-oxy)phenyl)ethylamine-1-(C) (1.0 equivalent) was added via syringe, followed by the addition of... N -Hydroxysuccinimide (NHS) (1.1 equivalents). The mixture was then cooled to 0°C, and N,N'-dicyclohexylcarbodiimide (1.1 equivalents) was added. After 15 minutes, the cooling bath was removed, and the solution was stirred at room temperature for 20 hours. After the reaction was complete, the crude reaction mixture was filtered through a sintered glass plate, and the dicyclohexylurea filter cake was washed with THF. After removing the solvent, the residue was dissolved in ethyl acetate (EtOAc); the organic layer was washed successively with saturated Na2CO3 solution, H2O, 1M HCl, and brine, and dried over Na2SO4. The crude product was purified by silica gel column chromatography using ethyl acetate (EA) and petroleum ether as eluents (50% EA / PE). The final product, 2-(4-chlorophenyl)-2-hydroxy- N -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E), yield: 55%.

[0038] The key intermediate E can be easily converted into diacetyl amide in one step via propargylation.

[0039] Example The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention.

[0040] Example 1 O-propylation of 3-methoxy-4-hydroxybenzaldehyde:

[0041] Vanillin (1.0 equivalent) and potassium carbonate (1.2 equivalent) were placed in a dried round-bottom flask, and DMF solvent was added. Under a nitrogen atmosphere, propargyl bromide (1.2 equivalent) was added dropwise to the flask. The resulting reaction mixture was stirred at 60°C for 2 hours. After the specified time, the reaction mixture was cooled to room temperature, and the organic layer was extracted from ethyl acetate (EtOAc) and ice water. The organic layer was dried with Na₂SO₄, and the solvent was removed under vacuum. The crude reaction mixture was then purified by column chromatography using a 5% EA / PE mixture as eluent. The pure product 3-methoxy-4-(prop-2-yn-1-oxy)benzaldehyde (A) was obtained as a pale yellow solid; yield: 90%.

[0042] 1 H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.46 (dd, J = 8.1, 1.9 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 4.86 (d, J = 2.4 Hz, 2H),3.94 (s, 3H), 2.56 (t, J = 2.4 Hz, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 190.9, 152.1, 150.0, 130.9, 126.2, 112.6, 109.5, 77.4, 76.6, 56.6, 56.0.

[0043] Example 2 Step I: Preparation of (E)-2-methoxy-4-(2-nitrovinyl)-1-(prop-2-yyn-1-oxy)benzene:

[0044] 3-Methoxy-4-(prop-2-yne-1-oxy)benzaldehyde (A) (5.0 mmol, 1.0 equiv), nitromethane (5.0 equiv), and ammonium acetate (1.1 equiv) or other acetate source or ammonium salt were dissolved in acetic acid (8 mL) or other protic and aprotic solvents and placed in a dried round-bottom flask. The resulting mixture was refluxed at 130 °C for 8 hours, or at 70–130 °C for 2–12 hours. After the specified time, the reaction mixture was cooled to room temperature, and the precipitate was filtered through a Buchner funnel. The pure product was obtained. E)-2-methoxy-4-(2-nitrovinyl)-1-(prop-2-yn-1-oxy)benzene (B) is a yellow solid; yield: 90%. 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 13.6 Hz, 1H), 7.53 (d, J =13.6 Hz, 1H), 7.17 (dd, J = 8.3, 1.9 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.03(d, J = 1.9 Hz, 1H), 4.83 (d, J = 2.4 Hz, 2H), 3.92 (s, 3H), 2.56 (d, J = 2.4Hz, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 150.38, 150.01, 139.05, 135.60, 123.93, 123.86, 113.71, 110.86, 77.52, 76.60, 56.60, 56.05.

[0045] Example 3 Step II: Reduction reaction of (E)-2-methoxy-4-(2-nitrovinyl)-1-(prop-2-yn-1-oxy)benzene:

[0046] Lithium aluminum hydride (LAH) or other metal hydride sources or metal / H2 (such as Raney Ni / H2) is dissolved in tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide, ethyl acetate, or acetone, preferably dissolved in THF. A double-necked round-bottom flask is placed under an argon atmosphere and stirred continuously at 0°C. Substrate B is then added dropwise under an inert atmosphere. After five minutes, the mixture is placed in a preheated oil bath and heated at reflux temperature (95°C) for 2 to 8 hours. If LAH is used, after the reaction is complete, the reaction is quenched with Et2O, NaOH aqueous solution, and H2O as described in the literature. After solvent removal, the crude product is purified by column chromatography using 80% EA / PE. If the crude product has high purity, it can be used directly as the starting material for the next step. The pure 2-(3-methoxy-4-(prop-2-yn-1-oxy)phenyl)ethyl-1-amine (C) was obtained by isolation as a yellow oil with a yield of 65%. 1H NMR (400 MHz, CDCl3) δ 6.99-6.96 (m, 1H), 6.83-6.66 (comp, 3H), 4.74 (d, J = 2.4 Hz, 2H), 3.86 (s, 3H), 2.94 (m, 2H), 2.70(m, 2H), 2.49 (t, J = 2.4 Hz, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 149.7, 145.2, 133.9, 120.6, 114.7, 112.5, 78.7, 75.6, 56.9, 55.8, 43.4, 39.4.

[0047] Example 4 Step III: Amide coupling reaction between 2-(4-chlorophenyl)-2-hydroxyacetic acid and 2-(3-methoxy-4-(prop-2-yn-1-oxy)phenyl)ethyl-1-amine:

[0048] To a stirred solution of 2-(4-chlorophenyl)-2-hydroxyacetic acid (D) (1.0 equivalent) in tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide, ethyl acetate, or acetone, preferably THF, 2-(3-methoxy-4-(prop-2-yn-1-oxy)phenyl)ethyl-1-amine (C) (1.0 equivalent) was added via syringe, followed by the addition of N-hydroxysuccinimide (NHS) (1.1 equivalent). The mixture was then cooled to 0°C, and then... N,N' -Dicyclohexylcarbodiimide (1.1 equivalents). After 15 minutes, remove the cooling bath and stir the solution at room temperature for 20 hours. After the reaction is complete, filter the crude reaction mixture through a sintered glass plate and wash the dicyclohexylurea filter cake with THF. After removing the solvent, dissolve the residue in ethyl acetate (EtOAc); wash the organic layer successively with saturated Na₂CO₃ solution, H₂O, 1M HCl, and brine, and dry with Na₂SO₄. Purify the crude product using silica gel column chromatography with EA and petroleum ether as eluents (50% EA / PE). The final product is 2-(4-chlorophenyl)-2-hydroxy- N -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E) is a brown oily substance with a yield of 55%. 1H NMR (400 MHz, CDCl3) δ 7.31-7.24 (m, 1H), 7.21 (comp, 2H), 6.90 (d, J =8.1 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 6.55 (comp, 2H), 4.90 (s, 1H), 4.72 (d, J = 2.4 Hz, 2H), 3.78 (s, 3H), 3.45 (m, 2H), 2.78-2.61 (m, 2H), 2.51 (t, J =2.4 Hz, 1H); 13 C{ 1 H} NMR(100 MHz, CDCl3) 171.9, 149.6, 145.4, 137.9, 134.1,132.4, 128.7 (X 2), 127.9 (X 2), 120.5, 114.5, 112.3, 78.6, 75.7, 73.3, 56.8,55.8, 40.4, 35.0.

[0049] Example 5 Step IV: Prepare diyrylamide from 2-(4-chlorophenyl)-2-hydroxy-N-(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E).

[0050]

[0051] To 2-(4-chlorophenyl)-2-hydroxy- N 1.0 equivalent of 3-(methoxy-4-(prop-2-yn-1-oxy)phenethyl)acetamide (E) was reacted in a stirred solution of dichloromethane (DCM) with propargyl bromide (1.5 equivalent) added via syringe, followed by the addition of 30% aqueous NaOH solution and a catalytic amount of TBAB. The solution was stirred at 40°C for 20 hours. After the reaction was complete, the crude reaction mixture was dissolved in EtOAc and H2O; the organic layer was washed with brine and dried over Na2SO4. The crude product was purified by silica gel column chromatography using EA and petroleum ether as eluents (50% EA / PE). The final product 2-(4-chlorophenyl)- N -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)-2-(prop-2-yne-1-oxy)acetamide, a brown oily substance, yield: 55%. 1HNMR(400 MHz, CDCl3) δ 7.34-7.31 (comp, 1H), 7.27-7.22 (comp, 2H), 6.94 (d, J =8.0 Hz, 1H), 6.80-6.65 (comp, 3H), 4.94 (s, 1H), 4.73 (d, J = 2.3 Hz, 2H), 4.16 (dd, J = 15.8, 2.3 Hz, 1H), 3.95 (dd, J = 15.8, 2.2 Hz, 1H), 3.81 (s, 3H), 3.60-3.43 (m, 2H), 2.86 -2.63 (m, 2H), 2.48 (dt, J = 11.4, 2.2 Hz, 2H); 13 C{ 1 H}NMR (100 MHz, CDCl3) δ 169.5, 149.7, 145.4, 134.6, 134.5, 132.6, 128.8 (X 2), 128.6 (X 2), 120.5, 114.6, 112.3, 79.6, 78.6, 75.8, 78.0, 75.7, 56.8, 56.3,55.8, 40.1, 35.1.

[0052] Advantages of the present invention 1. There is an urgent need for a more environmentally friendly and industrially feasible synthetic method. The method established in this invention provides a simple, green, and reagent-free strategy for the synthesis of 2-(4-chlorophenyl)- 2- Hydroxy-N-(3-methoxy-4-(prop-2-ynyne-1-oxy)phenethyl)acetamide (E) is a key intermediate in the synthesis of diyrylamide. In improving the efficiency and practicality of this reaction, this invention has discovered a valuable technique. This newly designed method provides a simple and feasible alternative with advantages such as low cost, high yield, and suitability for large-scale industrial production.

[0053] 2. Notably, the innovation of this invention lies in the fact that no traditional reagents, such as acids, transition metal catalysts, cyanide sources, or oxidants, are used in this highly efficient conversion process. Most of the developed reaction steps are carried out at atmospheric pressure and room temperature, highlighting its practicality and simplicity. This method stands out due to its ease of operation and economic feasibility, making it a valuable tool suitable for large-scale industrial production.

[0054] 3. The amide coupling reaction between the key intermediate C and commercially available D uses relatively readily available and inexpensive ( ) N (-hydroxysuccinimide) NHS and DCC, achieved at room temperature and in an easily operable reaction apparatus. Any other coupling agent can also be used to prepare intermediate E.

[0055] 4. In the synthetic route of this invention, toxic cyanide sources such as HCN and KCN are not used, nor is Br2.

[0056] 5. In the synthesis process of this invention, expensive palladium or bromine sources are not used.

[0057] 6. The bottle-grade solvents (AcOH, ethyl acetate, water, DMF) used in the synthesis process of this invention perform well under the applied reaction conditions.

[0058] 7. The synthetic route of diyrylamide provided by the present invention is relatively simple, has a short number of steps (five steps), is economical and feasible, and is easy to operate. Therefore, it is suitable for industrial production.

Claims

1. A method for preparing 2-(4-chlorophenyl)-2-hydroxy- N -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E) The process includes the following steps: (i) In the presence of an organic solvent, 3-methoxy-4-(prop-2-yne-1-oxy)benzaldehyde (A) It reacts with nitromethane to form a nitro-hydroxyl group. (E) -2-Methoxy-4-(2-nitrovinyl)-1-(prop-2-yyn-1-oxy)benzene (B) ; (ii) In the presence of a reducing agent and an organic solvent, the reduction step ( i Prepared in ) （E） -2-Methoxy-4-(2-nitrovinyl)-1-(prop-2-yyn-1-oxy)benzene (B) To synthesize 2-(3-methoxy-4-(prop-2-yne-1-oxy)phenyl)ethane-1-amine (C) ; as well as (iii) In the presence of a coupling agent, 2-(3-methoxy-4-(prop-2-yn-1-oxy)phenyl)ethane-1-amine (C) obtained in step (ii) is subjected to a coupling agent. With 2-(4-chlorophenyl)-2-hydroxyacetic acid (D) The reaction was carried out at room temperature to give 2-(4-chlorophenyl)-2-hydroxy- N -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E) .

2. The process according to claim 1, wherein, The nitro-hydroxyl reaction is carried out in the presence of a base, in an acetic acid solvent and under environmental reaction conditions, wherein the base is selected from the group consisting of ammonium acetate, ammonium formate, sodium acetate, potassium acetate and potassium carbonate.

3. The process according to claim 1, wherein, The reducing agent in step (ii) is selected from any one of lithium aluminum hydride, NaBH4 / indium powder, CuCl, NaBH4 / BF3·Et2O, Raney nickel, and H2.

4. The process according to claim 1, wherein, The coupling agent in step (iii) is selected from any one of N-hydroxysuccinimide (NHS), N-N'-dicyclohexylcarbodiimide (DCC), and hexafluorophosphate azobenzotriazole tetramethylureonium (HATU).

5. The process according to claim 4, wherein, The coupling agent is selected from N-hydroxysuccinimide (NHS) and N-dicyclohexylcarbodiimide (DCC).

6. The process according to claim 1, wherein, The organic solvents used in steps (i) and (ii) are selected from tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide, ethyl acetate, or acetone.

7. The process according to claim 1, wherein, The organic solvent is tetrahydrofuran (THF).

8. The process according to claim 1, wherein, The reduction reaction is carried out in a temperature range of 0°C to 130°C.

9. The process according to claim 1, wherein, The reduction reaction was carried out at 95°C.

10. A method for preparing diyrylamide The process includes the following steps: (i) In the presence of an organic solvent, 3-methoxy-4-(prop-2-yne-1-oxy)benzaldehyde (A) It reacts with nitromethane to form a nitro-hydroxyl group. (E) -2-Methoxy-4-(2-nitrovinyl)-1-(prop-2-yyn-1-oxy)benzene(B) ; (ii) In the presence of a reducing agent and an organic solvent, reduce (E)-2-methoxy-4-(2-nitrovinyl)-1-(prop-2-yn-1-oxy)benzene (B) prepared in step (i). To synthesize 2-(3-methoxy-4-(prop-2-yn-1-oxy)phenyl)ethane-1-amine (C) ; (iii) In the presence of a coupling agent, the C obtained in step (ii) is... With 2-(4-chlorophenyl)-2-hydroxyacetic acid (D) The reaction was carried out at room temperature to give 2-(4-chlorophenyl)-2-hydroxy- N -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E) ; as well as (iv) In the presence of an aqueous sodium hydroxide solution and tetrabutylammonium chloride (TBAB), the 2-(4-chlorophenyl)-2-hydroxy- N -(3-methoxy-4-(prop-2-yne-1-oxy)phenethyl)acetamide (E) The reaction with propargyl bromide yields diyrylamide. .

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