A method for the synthesis of rotigaptide
Loteilanar was synthesized via an eight-step reaction route, using inexpensive raw materials and a mild process. This approach solved the problems of high operational risks and production difficulties in existing technologies, achieving efficient and safe production of loteilanar.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ANHUI CHENGLIAN MEDICAL TECH CO LTD
- Filing Date
- 2026-02-12
- Publication Date
- 2026-05-29
Smart Images
Figure CN122103085A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of loteranal synthesis technology, and more particularly to a method for synthesizing loteranal and its production process. Background Technology
[0002] Loteranal is a gamma-aminobutyric acid (GABA)-gated chloride channel inhibitor. It was approved by the U.S. Food and Drug Administration (FDA) on July 25, 2023, under the brand name Xdemvy. It is the only FDA-approved drug that directly targets the root cause of blepharitis—Demodex mites. At the same time, loteranal is also a novel isoxazoline insecticide that can be used for the prevention and treatment of parasites in domestic animals such as cats and dogs. After oral administration, it can quickly kill internal parasites, and its effects can last for 35 days. It also has low toxicity to humans and livestock, and has the advantages of high efficiency and low toxicity.
[0003] Currently, the main synthetic methods for loteranar use 3-methylthiophene as the starting material, but existing synthetic routes all have obvious drawbacks: Scheme 1 involves bromination, Friedel-Crafts acylation, nucleophilic addition, dehydration, condensation cyclization, Grignard reaction, and condensation to obtain loteranar. The Grignard reaction is dangerous and not conducive to large-scale industrial production. Scheme 2 involves bromination, Friedel-Crafts acylation, carbonyl protection, Grignard reaction, deprotection, condensation dehydration, condensation cyclization with hydroxylamine hydrochloride, and condensation to obtain the product. It also uses the Grignard reaction, making production difficult. Scheme 3 involves bromination, formylation, condensation, Witting reaction, cycloaddition, Grignard reaction, and condensation to obtain the product. It involves butyllithium, Witting reaction, and Grignard reaction, which is cumbersome and dangerous, and not suitable for industrial production.
[0004] Therefore, developing a new method for synthesizing loteranar with inexpensive raw materials, a safe process, simple operation, and high yield has become an urgent technical problem to be solved in this field. Summary of the Invention
[0005] In view of this, the purpose of this invention is to provide a method for synthesizing loteranar to solve the problems in the prior art.
[0006] To achieve the above objectives, this invention provides a method for synthesizing loteranal, comprising: using 3-methylthiophene as a starting material, and obtaining loteranal through an eight-step reaction, the specific steps of which are as follows: Step 1: 3-methylthiophene was subjected to Blanc chloromethylation to obtain the intermediate 2-chloromethyl-3-methylthiophene; Step 2: 2-Chloromethyl-3-methylthiophene is reacted with acetyl chloride via Friedel-Crafts acylation to obtain intermediate 1-(5-(chloromethyl)-4-methylthiophene-2-yl)acetone; Step 3: 1-(5-(chloromethyl)-4-methylthiophen-2-yl) ethyl ketone was hydrolyzed with sodium carbonate to obtain the intermediate 2-hydroxymethyl-3-methyl-5-acetylthiophene; Step 4: 2-Hydroxymethyl-3-methyl-5-acetylthiophene and 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethyl ketone were condensed under alkaline conditions to obtain the intermediate 4,4,4-trifluoro-1-(5-(hydroxymethyl)-4-methylthiophen-2-yl)-3-(3,4,5-trichlorophenyl)but-2-en-1-one; Step 5: 4,4,4-trifluoro-1-(5-(hydroxymethyl)-4-methylthiophen-2-yl)-3-(3,4,5-trichlorophenyl)but-2-en-1-one was condensed with hydroxylamine hydrochloride, and then intramolecularly cyclized under alkaline conditions to obtain the intermediate 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophen-2-yl)methanol; Step 6: 3-Methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)methanol is oxidized to obtain the intermediate 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)formaldehyde; Step 7: 3-Methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)formaldehyde is condensed with hydroxylamine hydrochloride, and then dehydrated to cyanide by a dehydrating agent to obtain the intermediate 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)formonitrile; Step 8: Loteranar is prepared by reacting 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)formonitrile with 2-chloro-N-(2,2,2-trifluoroethyl)acetamide via a Ritter reaction.
[0007] The conditions for the Blanc chloromethylation reaction in the first step are as follows: zinc chloride is used as a catalyst, 3-methylthiophene, paraformaldehyde and concentrated hydrochloric acid are used as reactants, and hydrogen chloride gas is introduced and the reaction is carried out at low temperature; wherein the mass ratio of 3-methylthiophene to paraformaldehyde is 2:1, the amount of zinc chloride added is 5% molar of 3-methylthiophene, the amount of concentrated hydrochloric acid is 2 times the molar amount of 3-methylthiophene, and the time for introducing hydrogen chloride gas is 1.5 hours.
[0008] The conditions for the Friedel-Crafts acylation reaction in the second step are: a solvent-free system, ZnO as a Lewis acid catalyst, and a reaction yield of 96%.
[0009] The conditions for the hydrolysis reaction in the third step are: methanol as a polar solvent, 1% molar of phase transfer catalyst tetrabutylammonium bromide added, and the reaction yield is 99%.
[0010] The conditions for the condensation reaction in the fourth step are: pyridine as solvent, piperidine as base, and the amount of piperidine added is 10% of the reactants. The intermediate is prepared by one-pot reaction with a yield of 95%.
[0011] In the fifth step, the base for the condensation and cyclization reactions is sodium methoxide, and the reaction yield is 95%.
[0012] In step six, the oxidation reaction uses iodine as a catalyst and hydrogen peroxide as an oxidant to oxidize hydroxyl groups to aldehyde groups, with a reaction yield of 92%.
[0013] In step seven, the dehydrating agent for the dehydration to cyanide formation is thionyl chloride. The condensation reaction uses ethanol as the solvent and sodium carbonate as the base, with an overall reaction yield of 96%.
[0014] In step 8, the Ritter reaction was carried out with ferrous chloride as a catalyst and N,N-dimethylformamide as a solvent, and the reaction was carried out under reflux with a yield of 92%.
[0015] The beneficial effects of the present invention are: (1) High atom economy: the synthesis of amides by the Ritter reaction avoids the problem of too many byproducts in the traditional synthesis route and greatly improves the atom utilization rate.
[0016] (2) Raw materials are cheap and readily available: 3-methylthiophene is used as the starting material, and the reaction raw materials such as paraformaldehyde, acetyl chloride, and hydroxylamine hydrochloride are all commonly used chemical raw materials, which are inexpensive and easy to purchase.
[0017] (3) No dangerous process: The process eliminates the dangerous Grignard reaction and butyllithium-involved reaction in the existing methods. The entire synthesis process is mild and reduces the production safety risk. Attached Figure Description
[0018] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only for this invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0019] Figure 1 Lotelanar of the present invention 1 HNMR spectrum; Figure 2 This is the HPLC chromatogram of loteranil in this invention. Detailed Implementation
[0020] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.
[0021] It should be noted that, unless otherwise defined, the technical or scientific terms used in this invention should have the ordinary meaning understood by one of ordinary skill in the art to which this invention pertains. The terms "first," "second," and similar terms used in this invention do not indicate any order, quantity, or importance, but are merely used to distinguish different components. Terms such as "comprising" or "including" mean that the element or object preceding the word encompasses the elements or objects listed following the word and their equivalents, without excluding other elements or objects. Terms such as "connected" or "linked" are not limited to physical or mechanical connections, but can include electrical connections, whether direct or indirect. Terms such as "upper," "lower," "left," and "right" are used only to indicate relative positional relationships; when the absolute position of the described object changes, the relative positional relationship may also change accordingly.
[0022] The present invention will be further described in detail below with reference to specific embodiments. The scope of protection of the present invention is not limited to the following embodiments. All equivalent transformations made based on the technical solutions of the present invention fall within the scope of protection of the present invention.
[0023] All reagents used in this embodiment are commercially available industrial-grade or chemically pure reagents, and the equipment used is conventional chemical reaction equipment.
[0024] Example 1: Synthesis of intermediate 2-chloromethyl-3-methylthiophene: Weigh 98g of 3-methylthiophene and 49g of paraformaldehyde (mass ratio 2:1), add 200mL of concentrated hydrochloric acid (2 molar amounts), cool to 0℃ in an ice bath, add 6.7g of zinc chloride (5% molar), and purge with HCl gas, controlling the bubbles to overflow at a rate of about 5 seconds, for 1.5 hours. After the reaction is complete, turn off the HCl gas supply, slowly pour the reaction system into 500mL of ice water, add 300mL of dichloromethane for extraction twice, combine the organic phases, wash with water until neutral, dry the organic phase with anhydrous sodium sulfate, filter, recover the solvent from the filtrate, and distill the residue under reduced pressure to obtain 140.16g of colorless liquid 2-chloromethyl-3-methylthiophene, yield 96%. 1 HNMR(CDCl3): 2.31(s,3H),4.62(s,2H),6.81(d,J=7.2,1H),7.41(d,J=7.2,1H).
[0025]
[0026] The specific reactions are as follows:
[0027] Example 2: Synthesis of intermediate 1-(5-(chloromethyl)-4-methylthiophen-2-yl)acetone: 146 g of 2-chloromethyl-3-methylthiophene was weighed and 4 g of ZnO catalyst was added. The mixture was cooled to 0 °C in a solvent-free system, and 80 g of acetyl chloride was added dropwise over 30 minutes. The mixture was kept at this temperature for 30 minutes. After the reaction was completed, 500 mL of ethyl acetate was added and stirred to dissolve the mixture. The mixture was filtered, and the solvent was recovered from the filtrate under reduced pressure. The residue was recrystallized from petroleum ether:ethyl acetate in a 1:1 ratio to obtain 180.48 g of 1-(5-(chloromethyl)-4-methylthiophene-2-yl)acetone, a white solid powder, with a yield of 96%. 1 HNMR(CDCl3):2.43(s,3H),2.55(s,3H),4.65(s,2H),7.21(s,1H).
[0028] The specific reactions are as follows:
[0029] Example 3: Synthesis of intermediate 2-hydroxymethyl-3-methyl-5-acetylthiophene Weigh 188 g of 1-(5-(chloromethyl)-4-methylthiophene-2-yl)acetone, dissolve it in 300 mL of methanol, add 200 mL of water and 210 g of sodium carbonate, then add 3.2 g of tetrabutylammonium bromide (1% mol), and heat to reflux for 10 h. After the reaction is complete, cool to room temperature, recover most of the solvent under reduced pressure, cool to below 10 °C in an ice bath, add 5% dilute hydrochloric acid dropwise to pH 2-3, stir and collect the white solid, filter, wash the filter cake with water until neutral, recrystallize with 95% ethanol to obtain 168.3 g of white solid 2-hydroxymethyl-3-methyl-5-acetylthiophene, yield 99%. 1 HNMR(CDCl3):2.41(s,3H),2.52(s,3H),4.82(s,2H),7.23(s,1H).
[0030] The specific reactions are as follows:
[0031] Example 4: Synthesis of intermediate 4,4,4-trifluoro-1-(5-(hydroxymethyl)-4-methylthiophen-2-yl)-3-(3,4,5-trichlorophenyl)but-2-en-1-one Weigh 34 g of 2-hydroxymethyl-3-methyl-5-acetylthiophene and 55 g of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethyl ketone. Add 150 mL of pyridine as solvent and 17 g of piperidine (10% mol) as base. Heat to reflux and react for 24 h. After the reaction is complete, cool to room temperature, recover the solvent under reduced pressure, add 300 mL of ethyl acetate to dissolve completely, slowly add 1 mol / L dilute hydrochloric acid until pH=2~3, separate the layers, wash the organic layer with water until neutral, dry with anhydrous sodium sulfate, filter, recover the solvent from the filtrate, and recrystallize the residue with isopropanol to give 81.13 g of pale yellow solid 4,4,4-trifluoro-1-(5-(hydroxymethyl)-4-methylthiophen-2-yl)-3-(3,4,5-trichlorophenyl)but-2-en-1-one, yield 95%. 1HNMR (CDCl3): 2.39 (s, 3H), 4.76 (s, 2H), 7.02 (s, 1H), 7.28 (s, 1H), 7.43 (s, 2H).
[0032] The specific reactions are as follows:
[0033] Example 5: Synthesis of intermediate 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)methanol Weigh 42.8 g of 4,4,4-trifluoro-1-(5-(hydroxymethyl)-4-methylthiophen-2-yl)-3-(3,4,5-trichlorophenyl)but-2-en-1-one and 7 g of hydroxylamine hydrochloride, add 100 mL of methanol and 13.5 g of sodium methoxide as a base, and heat to reflux for 8 h. After the reaction is complete, cool to room temperature, slowly pour the system into 150 mL of ice water, stir thoroughly to precipitate a pale yellow solid, filter, wash the filter cake with water until neutral, recrystallize with 95% ethanol to give 41.99 g of white solid 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophen-2-yl)methanol, yield 95%. 1 HNMR(CDCl3): 2.38(s,3H),3.61(m,1H),4.02(m,1H),4.81(s,2H),6.88(s,1H),7.59(s,2H).
[0034] The specific reactions are as follows:
[0035] Example 6: Synthesis of intermediate 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)formaldehyde Weigh 44.3 g of 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophen-2-yl)methanol, dissolve it in 100 mL of acetone, add 1.27 g of iodine as a catalyst, heat to 50 °C, slowly add 200 mL of hydrogen peroxide dropwise over 30 minutes, and maintain the temperature for 2 h. After the reaction is complete, cool to room temperature, slowly pour the system into 200 mL of ice water, add sodium thiosulfate until the purple color completely disappears, stir thoroughly to precipitate a large amount of white solid, filter, wash the filter cake with water, recrystallize with isopropanol to obtain 40.48 g of white solid 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophen-2-yl)formaldehyde, yield 92%. 1 HNMR(CDCl3): 2.41(s,3H),3.12(m,1H),3.64(m,1H),7.13(s,1H),7.68(s,2H),10.02(s,1H).
[0036] The specific reactions are as follows:
[0037] Example 7: Synthesis of intermediate 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)formonitrile Weigh 44 g of 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophen-2-yl)formaldehyde and 7 g of hydroxylamine hydrochloride, add 100 mL of ethanol and 15 g of sodium carbonate, and heat under reflux for 5 h. After the reaction is complete, cool to room temperature, recover the solvent under reduced pressure, add ethyl acetate to dissolve, filter, add 100 mL of water to the filtrate, dry the organic phase with anhydrous sodium sulfate, filter, and recover the solvent from the filtrate under reduced pressure. Add 120 mL of thionyl chloride to the above residue and heat under reflux for 5 h. After the reaction is complete, cool to room temperature, recover unreacted thionyl chloride under reduced pressure, add 150 mL of ethyl acetate to dissolve completely, slowly pour the solution into ice water, adjust the pH to 8-9 with 1 mol / L sodium carbonate solution, separate the layers, wash the organic layer with water until neutral, dry with anhydrous sodium sulfate, filter, recover the solvent from the filtrate under reduced pressure, recrystallize the residue with petroleum ether:ethyl acetate = 2:1 to give 42 g of pale yellow solid 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophen-2-yl)formonitrile, yield 96%. 1 HNMR(CDCl3):2.22(s,3H),3.22(m,1H),3.71(m,1H),7.12(s,1H),7.72(s,2H).
[0038] The specific reactions are as follows:
[0039] Example 8: Synthesis of Lotelanar Weigh 43.8 g of 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophen-2-yl)formonitrile and 18 g of 2-chloro-N-(2,2,2-trifluoroethyl)acetamide. Add 100 mL of LDM as solvent and 0.63 g of FeCl2 as catalyst. Heat under reflux for 6 h. After the reaction is complete, add 100 mL of water and stir for 10 minutes. Evaporate most of the solvent under reduced pressure. Dissolve the residue in 200 mL of ethyl acetate. Add 200 mL of water to the solution. Dry the organic phase with anhydrous magnesium sulfate. Filter. Recover the solvent from the filtrate under reduced pressure. Recrystallize the residue from methyl ether to give 53.27 g of white solid loteranar, yield 92%.
[0040] The specific reactions are as follows:
[0041] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention (including the claims) is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in the details for the sake of brevity.
[0042] This invention is intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the scope of protection of this invention.
Claims
1. A method for synthesizing loteranal, comprising, characterized in that, Loteranar was prepared from 3-methylthiophene via an eight-step reaction. The specific steps are as follows: Step 1: 3-methylthiophene was subjected to Blanc chloromethylation to obtain the intermediate 2-chloromethyl-3-methylthiophene; Step 2: 2-Chloromethyl-3-methylthiophene is reacted with acetyl chloride via Friedel-Crafts acylation to obtain intermediate 1-(5-(chloromethyl)-4-methylthiophene-2-yl)acetone; Step 3: 1-(5-(chloromethyl)-4-methylthiophen-2-yl) ethyl ketone was hydrolyzed with sodium carbonate to obtain the intermediate 2-hydroxymethyl-3-methyl-5-acetylthiophene; Step 4: 2-Hydroxymethyl-3-methyl-5-acetylthiophene and 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethyl ketone were condensed under alkaline conditions to obtain the intermediate 4,4,4-trifluoro-1-(5-(hydroxymethyl)-4-methylthiophen-2-yl)-3-(3,4,5-trichlorophenyl)but-2-en-1-one; Step 5: 4,4,4-trifluoro-1-(5-(hydroxymethyl)-4-methylthiophen-2-yl)-3-(3,4,5-trichlorophenyl)but-2-en-1-one was condensed with hydroxylamine hydrochloride, and then intramolecularly cyclized under alkaline conditions to obtain the intermediate 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophen-2-yl)methanol; Step 6: 3-Methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)methanol is oxidized to obtain the intermediate 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)formaldehyde; Step 7: 3-Methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)formaldehyde is condensed with hydroxylamine hydrochloride, and then dehydrated to cyanide by a dehydrating agent to obtain the intermediate 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)formonitrile; Step 8: Loteranar is prepared by reacting 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)thiophen-2-yl)formonitrile with 2-chloro-N-(2,2,2-trifluoroethyl)acetamide via a Ritter reaction.
2. The method for synthesizing loteranar according to claim 1, characterized in that, The conditions for the Blanc chloromethylation reaction in the first step are as follows: zinc chloride is used as a catalyst, 3-methylthiophene, paraformaldehyde and concentrated hydrochloric acid are used as reactants, and hydrogen chloride gas is introduced and the reaction is carried out at low temperature; wherein the mass ratio of 3-methylthiophene to paraformaldehyde is 2:1, the amount of zinc chloride added is 5% molar of 3-methylthiophene, the amount of concentrated hydrochloric acid is 2 times the molar amount of 3-methylthiophene, and the time for introducing hydrogen chloride gas is 1.5 hours.
3. The method for synthesizing loteranal according to claim 1, characterized in that, The conditions for the Friedel-Crafts acylation reaction in the second step are: a solvent-free system, ZnO as a Lewis acid catalyst, and a reaction yield of 96%.
4. The method for synthesizing loteranal according to claim 1, characterized in that, The conditions for the hydrolysis reaction in the third step are: methanol as a polar solvent, 1% molar of phase transfer catalyst tetrabutylammonium bromide added, and the reaction yield is 99%.
5. The method for synthesizing loteranar according to claim 1, characterized in that, The conditions for the condensation reaction in the fourth step are: pyridine as solvent, piperidine as base, and the amount of piperidine added is 10% of the reactants. The intermediate is prepared by one-pot reaction with a yield of 95%.
6. The method for synthesizing loteranar according to claim 1, characterized in that, In the fifth step, the base for the condensation and cyclization reactions is sodium methoxide, and the reaction yield is 95%.
7. The method for synthesizing loteranar according to claim 1, characterized in that, In step six, the oxidation reaction uses iodine as a catalyst and hydrogen peroxide as an oxidant to oxidize hydroxyl groups to aldehyde groups, with a reaction yield of 92%.
8. The method for synthesizing loteranal according to claim 1, characterized in that, In step seven, the dehydrating agent for the dehydration to cyanide formation is thionyl chloride. The condensation reaction uses ethanol as the solvent and sodium carbonate as the base, with an overall reaction yield of 96%.
9. The method for synthesizing loteranar according to claim 1, characterized in that, In step 8, the Ritter reaction was carried out with ferrous chloride as a catalyst and N,N-dimethylformamide as a solvent, and the reaction was carried out under reflux with a yield of 92%.