A 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 present invention provides an improved method for the preparation of building blocks 2- (4-chlorophenyl)-2-hydroxy-N-(3-methoxy-4-(prop-2-yn-1-yloxy)phenethyl)acetamide, a key intermediate for the synthesis of Mandipropamid. An efficient, safe, cost-effective method for the preparation of Mandipropamid is developed. The method involves simple Nitro-aldol reaction, LAH reduction and mild Amidation reaction for synthesizing key intermediate 2-(4- chlorophenyl)-2-hydroxy-N-(3-methoxy-4-(prop-2-yn-1-yloxy)phenethyl)acetamide (E). The current synthesis method of the invention has relatively simple operation, mild reaction conditions, high yield and a simple process with, a yield up to 90%. Subsequent product purification of this method uses filtration and crystallization methods and easy column chromatography separation. This approach is highly effective and scalable, contributing to both atom and step economy in the process Therefore, the research of its synthetic process has a wide range of applications from the drug development and material synthesis point of view.

Description

[0001] A process for the synthesis of 2-(4-chlorophenyl)-2-hydroxy-N-(3-methoxy-4-(prop-2- yn-l-yloxy)phenethyl)acetamide, a key intermediate of Mandipropamid

[0002] FIELD OF THE INVENTION

[0003] The present invention provides an efficient, eco-friendly, cost-effective, and safe easy to handle synthetic process to prepare a key intermediate for the synthesis of Mandipropamid.

[0004] The present invention particularly relates to the synthesis of 2-(4-chlorophenyl)-2-hydroxy- V-(3-methoxy-4-(prop-2-yn- 1 -yloxy)phenethyl)acetamide.

[0005] The present invention more particularly relates to the synthesis of Mandipropamid through a key intermediate 2-(4-chlorophenyl)-2-hydroxy-V-(3-methoxy-4-(prop-2-yn-l- yloxy )phenethy 1) acetamide .

[0006] BACKGROUND OF THE INVENTION

[0007] Mandipropamid is a chemical compound from the class of mandelic acid amides and a fungicide from the family of CAA fungicides (Carboxylic Acid Amides). Mandipropamid is an inhibitor of cellulose-synthase and is effective against downy mildew and Phytophthora infestans (Cohen, Y.; Rubin, A.; Gotlieb, D. Activity of carboxylic acid amide (CAA) fungicides against Bremia lactucae. 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, A. O.; Whisson, S. C. and Fonne-Pfister, R. Mandipropamid targets the cellulose synthase-like PiCesA3 to inhibit cell wall biosynthesis in the oomycete plant pathogen, Phytophthora infestans. MOLECULAR PLANT PATHOLOGY 2010 77(2), 227- 243).Mandipropamid is a very effective active ingredient: the EC 80 against Phythophthorainfestans is 0.1 mg I-1, that against Plasmoparaviticola is 1.2 mg 1 -1. The EU Commission approved the use of Mandipropamid as an active ingredient in plant protection products with effect from August 1, 2013. Mandipropamid is approved under the trade names Revus and Pergado in Germany, Austria and Switzerland. Contact fungicide with strong fungicidal activity against foliar Oomycetes pathogens, it has unique translaminar action which helps longer duration of control. It is found to be effective in controlling phytopathogens such as Plasmoparaviticola on grapes and potato late blight caused by Phytophthora infestans. (Du, X-J.; Bian, Q.; Wang, H-X.; Yu, S-J.; Kou, J-J.; Wang, Z-P.; Lia, Z-M. and Zhao, W-G.; Design, synthesis, and fungicidal activity of novel carboxylic acid amides represented by N-benzhydryl valinamode carbamates. 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 Chiral Fungicide Mandipropamid. 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 mandipropamid in four types of Chinese soil. Soil Sci. Soc. Am. J. 2021, 1-17). Its mode of action involves disrupting the growth and development of these fungi in several ways.

[0008] To date, various methods have been used to synthesize Mandipropamid as a 1:1 mixture (racemate) of their enantiomers. Mandipropamid compound was prepared from various synthetically designed starting materials. Mandipropamid was first synthesized by Syngenta in 2003 (W003042166) in an elaborative manner involving different starting materials. They synthesized a glyco-ester which was the key intermediate in the synthesis; the reactions were performed at elevated temperatures using high boiling hydrocarbons or chlorinated solvents. The starting materials were used in the excess amount at high temperatures, as a result too many bi-products were formed. A series of substitution reactions, condensation reactions, addition reactions were carried out to get the key glycol ester intermediate using expensive and hazardous reagents such as H2SO4, SOCh, DABCO, DBU, HCN, KCN, Br2, cyanosilanes with metal catalysts like bismuth bromide, etc. Also, the reactions were performed in a wide range of temperatures from -80DC to 150DC. On the other hand, they synthesized the corresponding 2-(3-methoxy-4-(prop-2-yn-l-yloxy)phenyl)ethan-l -amine for coupling with glyco-ester taking vanillin as starting material using cyanohydrin reaction with HCN followed by reduction. These represented difficulties if carried out on a large scale. Overall, this synthetic route was fairly labor intensive, not only required harsh conditions but also used expensive and unstable reagents. In addition, the method had a long route and was accompanied by a large amount of bi-products, not suitable for industrialization as shown in Fig i. In the year 2009, inventor C. Lamberth published a slightly improved route of synthesis of Mandipropamid (Lamberth, C. Alkyne chemistry in crop protection. Bioorg. Med. Chem. 2009, 17, 4047-4063) using 2-(3-methoxy-4-(prop-2-yn-l-yloxy)phenyl)ethan-l -amine and 2-(4-chlorophenyl)-2-hydroxyacetic acid as starting materials. The total synthesis involves Amide coupling using BOP and diethyl isopropylamine (Hunig's base), Propargylation of 2- (4-chlorophenyl)-2-hydroxy-A-(4-hydroxy-3-methoxyphenethyl)acetamide with propargyl bromide under alkaline condition. Another alternative route was proposed via N-formylation of 2-(3-methoxy-4-(prop-2-yn-l-yloxy)phenyl)ethan-l -amine and propargylation of A-(4- hydroxy-3-methoxyphenethyl)formamide under alkaline condition. This intermediate was directly converted to the corresponding amide by Seebach’s modification of the Passerini reaction followed by the introduction of a second propargyl group into the hydroxy function of the mandelic moiety under basic conditions delivers Mandipropamid. Most of the starting materials and coupling reagents used in this reaction are highly expensive as shown in Fig 2.

[0009] Another promising route to prepare Mandipropamid by Faming Zhuanli Shenqing (Faming Zhuanli Shenqing, 102584621, 18 Jul 2012 (CN 102584621 B) and (US8129560B2)4starting from 4-chlorobenzaldehyde and vanillin. In the first step Vanillin reacts with potassium cyanide or sodium cyanide and obtains 4-hydroxy 3 -methoxybenzene acetonitrile under phase-transfer catalyst, Reduction of the corresponding 2-hydroxy-2-(4-hydroxy-3- methoxyphenyl) acetonitrile was performed using fL / Pd to give key intermediate 2-(3- methoxy-4-(prop-2-yn- 1 -yloxy)phenyl)ethan- 1 -amine. The use of toxic cyanide sources like NaCN and KCN is the main disadvantage of this methodology, which greatly limits the industrial production of this drug. It is also a high-cost multistep process, use of Bromine for bromination is quite hectic and hard to handle. Elevated reaction temperature in most steps is one of the main concerns in this methodology as shown in Fig 3 A and 3B. Recently Narsaiah et al. reported another synthetic route for the preparation of Mandipropamid (Annapurna, K.; Subba Reddy, B. V. and Narsaiah A. V. Protecting group- free synthesis of the fungicide Mandipropamid. Arkivoc 2023 (viii) 202312023) using vannilin and 4-chloroacetophenone as starting material in 5 steps. Nitroalkene was prepared using MeNCh and EDA in refluxing conditions followed by LAH reduction producing the corresponding amine in moderate yield. An oxidation reaction was attempted to prepare key mandelic acid intermediate with the help of SeCh and lanthanide salt. A costly coupling reaction using EDC / HOBt was carried out to furnish the corresponding amide product which on treatment of propargyl bromide in the presence of base delivered the Mandipropamid as shown in Fig. 4.

[0010] However, it's important to note that all of these methods necessitated the presence of either an acid or a metal catalyst, as well as toxic and costly reagents, solvents, and high temperatures. While these approaches offer valuable insights, these factors pose challenges in terms of safety and scalability for industrial applications. Some methods required the use of toxic cyanide sources and molecular bromine with extended reaction times. These factors collectively pose obstacles when considering the feasibility of implementing the approach on an industrial scale.

[0011] In contrast, the present invention employs a mild, environment-friendly, cost-effective easy to handle synthesis for 2-(4-chlorophenyl)-2-hydroxy-A-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)acetamide, a key intermediate for Mandipropamid. Notably, the present method eliminates the necessity for transition metals, expensive bases, fancy coupling reagents, and sacrificial hazardous oxidants in the reaction. Furthermore, this synthesis can be comfortably conducted at ambient temperatures in a minimum no of steps from feedstock chemicals. This method is highly effective and scalable, contributing to the process's atom and step economy. This method holds promise for efficient synthesis and aligns well with potential industrial production processes.

[0012] OBJECTIVES OF THE INVENTION Main object of the present invention is to provide a process for the preparation of 2-(4- chlorophenyl)-2-hydroxy-2V-(3-methoxy-4-(prop-2-yn- 1 -yloxy)phenethyl)acetamide, a key intermediate for Mandipropamid.

[0013] Another object of the present invention is to provide a process for the preparation of 2-(4- chlorophenyl )-2-hydroxy-A-(3-methoxy-4-(prop-2-yn- 1 -yloxyjphenethyl) acetamide useful in the manufacture of Mandipropamid in high yield.

[0014] Yet another object of the present invention to provide 2-(4-chlorophenyl)-2-hydroxy-A-(3- methoxy-4-(prop-2-yn-l-yloxy)phenethyl)acetamide in high chemical yield.

[0015] Yet another object of the present invention is to provide synthetic methodology towards the synthesis of CAA fungicide 2-(4-chlorophenyl)-A-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)-2-(prop-2-yn-l-yloxy)acetamide.

[0016] Yet another object of the present invention is to provide a commercially viable process for the synthesis of 2-(4-chlorophenyl)-2-hydroxy-A-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)acetamide towards 2-(4-chlorophenyl)-A-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)-2-(prop-2-yn-l-yloxy)acetamide synthesis.

[0017] Still another object of the present invention is to provide a user-friendly and operationally benign process for the synthesis of 2-(4-chlorophenyl)-2-hydroxy-A-(3-methoxy-4-(prop-2- yn-l-yloxy)phenethyl)acetamide with a cheaper starting material under mild and ambient conditions.

[0018] Still another object of the present invention to provide a process for synthesizing 2-(4- chlorophenyl)-2-hydroxy-A-(3-methoxy-4-(prop-2-yn- 1 -yloxyjphenethyl) acetamide without any transition metal catalyst and external oxidants.

[0019] SUMMARY OF THE INVENTION

[0020] Accordingly, the current invention introduces a new, straightforward, efficient synthetic process for synthesizing a key intermediate 2-(4-chlorophenyl)-2-hydroxy-A-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)acetamide (E), especially from easy-to-prepare starting materials like vanillin. There are several problems in the existing synthetic method for the preparation of 2-(4- chlorophenyl)-2-hydroxy-A-(3-methoxy-4-(prop-2-yn- 1 -yloxy)phenethyl) acetamide, such as the requirement of an expensive transition metal catalyst, toxic reagents, toxic oxidants, multi-step operation, and elevated temperature. Notably, a significant gap exists in finding a straightforward, eco-friendly, cost-effective route for synthesizing Mandipropamid with high efficacy.

[0021] The present invention provides a process for the preparation of 2-(4-chlorophenyl)-2-hydroxy-A- (3-methoxy-4-(prop-2-yn-l-yloxy)phenethyl)acetamide (E), comprising steps of:

[0022] (i) nitro-aldol reaction of 3-methoxy-4-(prop-2-yn-l-yloxy)benzaldehyde (A) and nitromethane in presence of an organic solvent to produce (E)-

[0023] 2-methoxy-4-(2-nitro vinyl)- 1 -(prop-2-yn- 1 -yloxy)benzene

[0024] (ii) reduction of (E)-2-methoxy-4-(2-nitrovinyl)-l-(prop-2-yn-l-yloxy)benzene (B)

[0025] (prop-2-yn- 1 -yloxy )phenyl)ethan- 1 -amine (C) in presence of a reducing agent and an organic solvent; and

[0026] (iii) amide coupling between (C) prepared in step (ii) and 2-(4- .OH j T I' chlorophenyl)-2-hydroxyacetic acid (D) “Din presence of a coupling agent at room temperature to obtain 2-(4-chlorophenyl)-2-hydroxy-2V-(3-methoxy- 4-(prop-2-yn- 1 -yloxy)phenethyl)acetamide (E) In a preferred embodiment of the present invention, the nitro-aldol reaction is carried out in the presence of a base selected from ammonium acetate, ammonium formate, sodium acetate, potassium acetate and potassium carbonate, in acetic acid solvent at ambient reaction conditions.

[0027] In a preferred embodiment of the present invention, the reducing agent of step (ii) is selected from Lithium aluminium hydride, NaBIL / Indium Powder, CuCl, NaBH4 / BF3.Et2O and Raney

[0028] Ni and H2. In an aspect of the present invention, the coupling agent of step (iii) is selected from N- hydroxysuccinimide (NHS), N'-dicyclohexylcarbodiimide (DCC) and hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) .

[0029] In a preferred embodiment of the present invention, the coupling agent of step (iii) is selected from A-hydroxysuccinimide (NHS) and N'-dicyclohexylcarbodiimide (DCC).

[0030] In an embodiment of the present invention, the organic solvent of step (i) is selected from the group consisting of acetic acid, tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide, ethyl acetate and acetone.

[0031] In another embodiment of the present invention, the organic solvent of step (ii) is selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide, ethyl acetate or acetone.

[0032] In a preferred embodiment of the present invention, the organic solvent is THF.

[0033] In a preferred embodiment of the present invention, the reaction is carried out at a temperature in the range of 0 °C to 130°C. In the case of step (ii) and step (iii) the preferred working temperatures are 95 °C and 35 °C, respectively.

[0034] In an embodiment the present invention provides a process for preparing Mandipropamid, comprising the steps of:

[0035] (i) nitro-aldol reaction of 3-methoxy-4-(prop-2-yn-l-yloxy)benzaldehyde (A) 2-methoxy-4-(2-nitro vinyl)- 1 -(prop-2-yn- 1 -yloxy)benzene (B)

[0036] (ii) reduction of (£)-2-methoxy-4-(2-nitrovinyl)-l-(prop-2-yn-l-yloxy)benzene (B) prepared in step (i) to synthesize 2-(3-methoxy-4-

[0037] (prop-2-yn- 1 -yloxy)phenyl)ethan- 1 -amine (C) in presence of a reducing agent and an organic solvent; and

[0038] (iii) amide coupling between (C) prepared in step (ii) and 2-(4- chlorophenyl)-2-hydroxyacetic acid (D) in presence of a coupling agent at room temperature to obtain 2-(4-chlorophenyl)-

[0039] 2-hydroxy-A-(3-methoxy-4-(prop-2-yn- 1 -yloxy)phenethyl)acetamide (E)

[0040] (iv) reacting 2-(4-chlorophenyl)-2-hydroxy-A-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)acetamide ( obtained in step

[0041] (iii) with propargyl bromide in the presence of aqueous sodium hydroxide and tetrabutylammonium bromide (TBAB) or any other ammonium salt, to obtain

[0042] Mandipropamid The synthesis employs an environmentally friendly ambient method that doesn't require transition metals and external oxidants. This method is highly effective and scalable, contributing to both atom and step economy in the process. As a result, this methodology holds substantial significance. It presents a novel avenue for synthesizing highly demanding Mandipropamid from feedstock chemicals. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 illustrates the synthesis of Mandipropamid according to the prior art (W003042166).

[0043] Fig. 2 illustrates the synthesis of Mandipropamid according to the prior art (Lamberth, C.

[0044] Alkyne chemistry in crop protection. Bioorg. Med. Chem. 2009, 17, 4047-4063).

[0045] Fig. 3A and 3B illustrates the synthesis of Mandipropamid according to the prior arts (Faming Zhuanli Shenqing, 102584621, 18 Jul 2012 (CN 102584621 B) and (US8129560B2).

[0046] Fig. 4 illustrates the synthesis of the key intermediate (E) from vanillin derived intermediate (A) and the synthesis of Mandipropamid from the key intermediate (E) of the present invention.

[0047] DETAILED DESCRIPTION OF THE INVENTION

[0048] The present invention provides a method for the synthesis of 2-(4-chlorophenyl)-2-hydroxy- A-(3-methoxy-4-(prop-2-yn- 1 -yloxy)phenethyl)acetamide (E), which is used as a key intermediate in synthesis of 2-(4-chlorophenyl)-A-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)-2-(prop-2-yn-l-yloxy)acetamide (Mandipropamid) synthesis starting from intermediate A. Fig. 4provides the synthesis of the key intermediate (E) from vanillin derived intermediate (A) and the synthesis of Mandipropamid from the key intermediate (E).

[0049] The technical details of the present invention are further specifically described below:

[0050] 4-hydroxy-3 -methoxybenzaldehyde through propargylation with propargyl bromide under basic conditions (K2CO3) furnishes 3-methoxy-4-(prop-2-yn-l-yloxy)benzaldehyde (A);

[0051] To the mixture of 3-methoxy-4-(prop-2-yn-l-yloxy)benzaldehyde; (A) (1.0 equiv), Nitromethane 5.0 equiv) and ammonium acetate (1.1 equiv) in AcOH were taken in an oven- dried round bottom flask. The resulting mixture was refluxed at 130 °C for 8 h. After the stipulated period of time, the reaction mixture was allowed cool down at room temperature and the precipitate was then filtered using a Buchner funnel. The pure product (£’)-2-methoxy- 4-(2-nitrovinyl)-l-(prop-2-yn-l-yloxy)benzene (B) was obtained as yellow solid; yield: 90%. LAH was taken in dry THF and the two neck round bottom flask was allowed to cool at 0 °C with continuous stirring under Ar atmosphere. Substrate B was then added dropwise at inert atmosphere. After five minutes the mixture was allowed to heat at refluxing temperature (95 °C) for 8 h in a preheated oil bath. After completion of the reaction, LAH was quenched with Et2O, aq. NaOH, and H2O following the literature procedure. After evaporating the solvent crude was purified by column chromatography using 80% EA / PE or as the crude was pure it was directly used as starting material for the next step. Pure 2-(3-methoxy-4-(prop-2-yn-l- yloxy)phenyl)ethan- 1 -amine (C) was isolated as a yellow oil, yield: 65%.2-(3-methoxy-4- (prop-2-yn- 1 -yloxy )phenyl)ethan- 1 -amine.

[0052] To a stirred solution of 2-(4-chlorophenyl)-2-hydroxy acetic acid (1.0 equiv) in THF added 2- (3-methoxy-4-(prop-2-yn-l -yloxy )phenyl)ethan-l -amine (C) (1.0 equiv) via syringe followed by A-hydroxysuccinimide (NHS) (1.1 equiv). The mixture was then cooled at 0 °C and N, N'- dicyclohexylcarbodiimide (1.1 equiv) was added. After 15 min, the cooling bath was removed and the solution was stirred at room temperature for 20 h. After completion of the reaction, the crude reaction mixture was filtered through sintered glass plate and dicyclohexylurea cake was washed with THF. The solvent was removed and the residue was dissolved in EtOAc; the organic layer was washed successively with sat, Na2CC>3, H2O, 1 (M) HC1 and brine and dried over Na2SC>4. The crude was purified using silica gel column chromatography using EA and pet ether as eluent (50% EA / PE). The final product 2-(4-chlorophenyl)-2-hydroxy-A-(3- methoxy-4-(prop-2-yn- 1 -yloxy )phene thy 1) acetamide (E) was obtained as a brown oil, yield:55%.

[0053] The key intermediate E can now easily deliver Mandipropamid in a single step after propargylation.

[0054] EXAMPLES

[0055] The following examples are given by way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention.

[0056] Example 1: O-propargylation of 3-methoxy-4-hydroxybenzaldehyde:

[0057] The vanillin (1.0 equiv) and potassium carbonate ( 1.2 equiv) were taken in a oven dried round bottom flask in DMF solvent; propargyl bromide (1.2 equiv) was added dropwise into the flask under nitrogen atmosphere. The resulting reaction mixture was stirred at 60 °C for 2 h. After the stipulated period of time, the reaction mixture was cooled down to room temperature, the organic layer was extracted from EtOAc and ice-cold water; the organic layer was dried over Na2SC>4 and the solvent was evaporated in vacuum. The crude reaction mixture was then purified using column chromatography at 5% EA / PE mixture. The pure product 3-methoxy- 4-(prop-2-yn-l-yloxy)benzaldehyde (A) obtained was obtained as a light yellow solid.; yield: 90%. 'H NMR (400 MHz, CDC13) 89.87 (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, IH ’CfH} NMR (100 MHz, CDCI3) 8 190.9, 152.1, 150.0, 130.9, 126.2, 112.6, 109.5, 77.4, 76.6, 56.6, 56.0.

[0058] Example 2: Step I: Preparation of the (E')-2-methoxy-4-(2-nitrovinyl)-l-(prop-2-yn-l- yloxy)benzene: To the mixture of 3-methoxy-4-(prop-2-yn-l-yloxy)benzaldehyde; (A) (5.0 mmol, 1.0 equiv), Nitromethane 5.0 equiv) and ammonium acetate (1.1 equiv) or other acetate sources or ammonium salts in AcOH (8 mL) or other protic and aprotic solvents were taken in an oven- dried round bottom flask. The resulting mixture was refluxed at 130 °C for 8 h or refluxed at 70-130DC for 2 h to 12 h. After the stipulated period of time, the reaction mixture was allowed cool down at room temperature and the precipitate was then filtered using a Buchner funnel. The pure product (£’)-2-methoxy-4-(2-nitrovinyl)-l-(prop-2-yn-l-yloxy)benzene (B) was obtained as yellow solid; yield: 90%.1H NMR (400 MHz, CDCI3) 8 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 = 2.4 Hz, 1H); ‘’CfH} NMR (100 MHz, CDCI3) 8 150.38, 150.01, 139.05, 135.60, 123.93, 123.86, 113.71, 110.86, 77.52, 76.60, 56.60, 56.05.

[0059] Example 3: Step II: Reduction of (E')-2-methoxy-4-(2-nitrovinyl)-l-(prop-2-yn-l- yloxy)benzene:

[0060] LAH or other metal hydride sources or Metal / H2 like raney Ni / H2 was taken in tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide, ethyl acetate or acetone preferably in THF and the two neck round bottom flask was allowed to coll at 0 °C with continuous stirring under Ar atmosphere. Substrate B was then added dropwise at inert atmosphere. After five minutes the mixture was allowed to heat at refluxing temperature (95 °C) for 2 h - 8 h in a preheated oil bath. In the case of LAH, after completion of the reaction, LAH was quenched with Et2O, aq. NaOH, and H2O following the literature procedure. After evaporating the solvent crude was purified by column chromatography using 80% EA / PE or as the crude was pure it was directly used as starting material for the next step. Pure 2-(3-methoxy-4-(prop-2-yn-l-yloxy)phenyl)ethan-l -amine (C) was isolated as a yellow oil, yield: 65%.1H NMR (400 MHz, CDCh) 8 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, 7 = 2.4 Hz, 1H); ^CfH} NMR (100 MHz, CDCh) 8 149.7, 145.2, 133.9, 120.6, 114.7, 112.5, 78.7, 75.6, 56.9, 55.8, 43.4, 39.4.

[0061] Example 4: Step III: Amide coupling between 2-(4-chlorophenyl)-2-hydroxyacetic acid and 2-(3-methoxy-4-(prop-2-yn-l-yloxy)phenyl)ethan-l-amine:

[0062] To a stirred solution of 2-(4-chlorophenyl)-2-hydroxyacetic acid (D) (1.0 equiv) in tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide, ethyl acetate or acetone preferably in THF added 2-(3-methoxy- 4-(prop-2-yn-l-yloxy)phenyl)ethan-l -amine (C) (1.0 equiv) via syringe followed by N- hydroxysuccinimide (NHS) (1.1 equiv). The mixture was then cooled at 0 °C and N, N'- dicyclohexylcarbodiimide (1.1 equiv) was added. After 15 min, the cooling bath was removed and the solution was stirred at room temperature for 20 h. After completion of the reaction, the crude reaction mixture was filtered through sintered glass plate and dicyclohexylurea cake was washed with THF. The solvent was removed and the residue was dissolved in EtOAc; the organic layer was washed successively with sat, Na2CC>3, H2O, 1 (M) HC1 and brine and dried over Na2SC>4. The crude was purified using silica gel column chromatography using EA and pet ether as eluent (50% EA / PE). The final product 2-(4-chlorophenyl)-2-hydroxy-A-(3- methoxy-4-(prop-2-yn-l-yloxy)phenethyl)acetamide (E) was obtained as a brown oil, yield:55%. 'H NMR (400 MHz, CDCh) 8 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);13C{1H} NMR (100 MHZ, CDC13) 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.

[0063] Example 5: Step IV: Preparation of Mandipropamid from 2-(4-chlorophenyl)-2- hydroxy-N-(3-methoxy-4-(prop-2-yn-l-yloxy)phenethyl)acetamide (E).

[0064] To a stirred solution of 2-(4-chlorophenyl)-2-hydroxy-2V-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)acetamide (E) (1.0 equiv) in dichloromethane (DCM) added propargyl bromide (1.5 equiv) via syringe followed by 30% aq. NaOH and TBAB (cat.) and the solution was stirred at 40 °C for 20 h. After completion of the reaction, the crude reaction mixture was dissolved in EtOAc and H2O; the organic layer was washed brine and dried over Na2SC>4. The crude was purified using silica gel column chromatography using EA and pet ether as eluent (50% EA / PE). The final product 2-(4-chlorophenyl)-A-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)-2-(prop-2-yn-l-yloxy)acetamide was obtained as a brown oil, yield:55%. 'H NMR (400 MHz, CDCI3) 8 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); NMR (100 MHz, CDCI3) 8 169.5, 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.

[0065] Advantages of the invention

[0066] 1. There is an urgent need for a better environmentally friendly and industrially viable methodology. Our established method provides a simple green, hazardous reagent reagent-free strategy for synthesizing 2-(4-chlorophenyl)-2-hydroxy-A-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)acetamide (E), a key intermediate for synthesizing Mandipropamid. In our quest to enhance the efficiency and practicality of this reaction, we've uncovered a valuable technique. This newly devised method offers a straightforward and achievable alternative, boasting advantages such as low cost, high yield, and suitability for large-scale industrial production.

[0067] 2. Notably, the innovation lies in the fact that none of the traditional reagents such as acids, transition metal catalysts, cyanide sources or oxidants are utilized in this efficient transformation. Our developed reaction most of the steps carried out under atmospheric pressure and at room temperature highlighting its practicality and simplicity. This method stands out for being both operationally straightforward and economically feasible, rendering it a valuable tool for large-scale industrial preparation.

[0068] 3. The amide coupling between key intermediates C and commercially available D was achieved using relatively easily accessible and cheap (A-hydroxy-succinimide) NHS and DCC at room temperature in an easy-to-handle reaction setup. Any other coupling reagents can be used to make the intermediate E.

[0069] 4. No toxic Cyanide sources like HCN, KCN or Br2 are employed in present synthetic routes.

[0070] 5. None of the expensive Pd or Bromine sources were used in this synthetic process.

[0071] 6. Bottle-grade solvents (AcOH, ethyl acetate, water, DMF) used for the synthesis purpose worked well under the applied reaction conditions.

[0072] 7. It is a relatively straightforward, short (five steps), economically viable and operationally simple synthetic route of Mandipropamid; hence this process is effective for industrial preparation.

Claims

Claims:

1. A process for preparation of 2-(4-chlorophenyl)-2-hydroxy-A-(3-methoxy-4-(prop-2-yn-l-yloxy)phenethyl)acetamide (E) , comprising steps of:(i) reacting 3-methoxy-4-(prop-2-yn-l-yloxy)benzaldehyde (A) and nitromethane in the presence of an organic solvent under nitro-aldol reaction to produce(£)-2-methoxy-4-(2-nitrovinyl)- 1 -(prop-2-yn- 1 -yloxy)benzene(ii) reducing (£’)-2-methoxy-4-(2-nitro vinyl)- 1 -(prop-2-yn- 1 -yloxy)benzene (B)organic solvent to synthesize 2-(3-methoxy-4-(prop-2-yn-l-yloxy)phenyl)ethan-l-amine (C) ; and(iii) reacting 2-(3-methoxy-4-(prop-2-yn-l-yloxy)phenyl)ethan-l -amine (C)obtained in step (ii) and 2-(4-chlorophenyl)-2-hydroxyacetic acid (presence of a coupling agent at room temperature to obtain 2-(4-chlorophenyl)-2-hydroxy-2V-(3- methoxy-4-(prop-2-yn- 1 -yloxy )phenethyl)acetamide (E)2. The process as claimed in claim 1, wherein the nitro-aldol reaction is carried out in the presence of a base selected from the group consisting of ammonium acetate, ammonium formate, sodium acetate, potassium acetate, potassium carbonate in acetic acid solvent at ambient reaction conditions.

3. The process as claimed in claim 1, wherein the reducing agent of step (ii) is selected from Lithium aluminium hydride, NaBfL / Indium Powder, CuCl, NaBH4 / BF3.Et2O and Raney Ni and H2.

4. The process as claimed in claim 1 , wherein the coupling agent of step (iii) is selected from N-hydroxy succinimide (NHS), N' -dicyclohexylcarbodiimide (DCC) and hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU).

5. The process as claimed in claim 4, wherein the coupling agent is selected from N- hydroxysuccinimide (NHS) and N'-dicyclohexylcarbodiimide (DCC).

6. The process as claimed in claim 1 , wherein the organic solvent of step (i) and step (ii) is selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide, ethyl acetate or acetone.

7. The process as claimed in claim 1, wherein the organic solvent is THF.

8. The process as claimed in claim 1, wherein the reduction is carried out at a temperature is in the range of 0 °C to 130°C.

9. The process as claimed in claim 1, wherein the reduction is carried out at a temperature of95 °C.

10. A process for preparing Mandipropamid ' , comprising the steps of:(i) reacting 3-methoxy-4-(prop-2-yn-l-yloxy)benzaldehyde (A) and nitromethane in presence of an organic solvent under nitro aldol reaction to produce (£’)-2-methoxy-4-(2-nitrovinyl)- 1 -(prop-2-yn- 1 -yloxy)benzene (B)prepared in step (i) in presence of a reducing agent and an organic solvent to synthesize 2-(3-methoxy-4-(prop-2-yn-l-yloxy)phenyl)ethan-l-amine (C)(iii) reacting C obtained in step (ii) and 2-(4-chlorophenyl)-2-hydroxyacetic acid (D) in presence of a coupling agent at room temperature to obtain 2-(4-chlorophenyl)-2-hydroxy-2V-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)acetamide (and(iv) reacting 2-(4-chlorophenyl)-2-hydroxy-A-(3-methoxy-4-(prop-2-yn-l- yloxy)phenethyl)acetamideobtained in step(iii) with propargyl bromide in the presence of aqueous sodium hydroxide and tetrabutylammonium chloride (TBAB) to obtain Mandipropamid

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