Synthesis method of furaltadone

Abstract

The invention discloses a synthesis method of furatadone, which comprises the following steps: by taking 1-(4-morpholinyl)-2-propyne as a raw material, carrying out [3 + 2] cycloaddition reaction on the 1-(4-morpholinyl)-2-propyne and di-tert-butyl azodicarboxylate to obtain a 3, 5-disubstituted oxazolone intermediate; then under the action of a Pd / C catalyst, carrying out a hydrogenation reaction of olefin to obtain N-Boc protected AMOZ; finally, the AMOZ protected by N-Boc and 5-nitrofurfural are subjected to a condensation reaction under the action of hydrogen chloride, and the product furaltadone is obtained. The synthesis method is simple, environmentally friendly and suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing furazolidone. Background Technology

[0002] Furazolidone is an antibacterial drug with a broad antibacterial spectrum, effective against most Gram-positive and Gram-negative bacteria, such as Staphylococcus aureus, Escherichia coli, and Streptococcus pyogenes. Therefore, it is mainly used clinically to treat intestinal infectious diseases in chickens, such as Escherichia coli infection, pullorum disease, and coccidiosis; and as a growth promoter for pigs, poultry, and aquatic animals.

[0003] Current methods for synthesizing furazolidone can be summarized as follows: the epoxide intermediate 4-(2,3-epoxypropyl)morpholine, obtained through a multi-step reaction, undergoes a ring-opening reaction with hydrazine hydrate to generate a hydrazine-based compound, which is then cyclized with a carbonate to synthesize the intermediate 5-(morpholinylmethyl)-3-amino-2-oxazolidinone (AMOZ), followed by dehydration condensation with the corresponding aldehyde to obtain the final product. However, this synthetic route is relatively long (5-7 steps in total) and uses toxic hydrazine hydrate and generates hazardous epoxide intermediates [see J. Shu, L. He, H. Ding, et al.]. Analytical Methods [2014, 2306-2313; Chinese Patent Application No.: 201310226349.2; Chinese Patent Application No.: 202010315236.X]. In addition, another academic paper reported the synthesis of the key intermediate AMOZ [Y. Takeda, S. Okumura, S. Tone, et al.]. Organic Letters [2012, 14, 4874-4877.], the steps include: allylamine undergoing a carbon dioxide insertion reaction at low temperature to generate 5-(iodomethyl)oxazolidin-2-one; subsequently undergoing a nucleophilic substitution reaction with morpholine to obtain 5-(morpholinylmethyl)oxazolidin-2-one; followed by... N The amination reaction yields the AMOZ intermediate, which can then be used to synthesize furazolidone using existing methods. However, this synthetic route involves harsh reaction conditions and is not highly atom-economical. Therefore, developing a simple and novel method for the synthesis of furazolidone is of great significance. Summary of the Invention

[0004] The purpose of this invention is to provide a method for synthesizing furazolidone that is simple, environmentally friendly, and suitable for large-scale production.

[0005] To achieve the above objectives, the solution of the present invention is: The application discloses a synthesis method of furanone, which comprises the following steps: taking 1-(4-morpholinyl)-2-propyne as raw material, and carrying out [3+2] cycloaddition reaction on the 1-(4-morpholinyl)-2-propyne and di-tert-butyl azodicarboxylate to obtain 3,5-disubstituted oxazolone intermediate; then, under the action of Pd / C catalyst, olefin hydrogenation reaction is carried out to obtain N Boc-protected AMOZ; finally N Boc-protected AMOZ is subjected to condensation reaction with 5-nitrofurfural under the action of hydrogen chloride to obtain the product furanone, wherein the structural formula of the 3,5-disubstituted oxazolone intermediate is The structural formula of the Boc-protected AMOZ is N . .

[0006] The application discloses a synthesis method of furanone, which comprises the following steps: In step 1, the copper-based catalyst is one of cupric chloride and cupric bromide, the base is one of potassium carbonate, triethylamine, triethylenediamine and 1,4-diazabicyclo[2.2.2]octane, the ligand is one of 2,2'-bipyridine, 1,10-phenanthroline, 1,3-bis(diphenylphosphino)propane and 1,3-bis(diphenylphosphino)propane, and the solvent is one of toluene, chloroform, dichloromethane, dichloroethane, tetrahydrofuran and dimethylformamide. In step 2, the 3,5-disubstituted oxazolone intermediate and Pd / C catalyst are sequentially added into a reaction container, vacuum is drawn and hydrogen is replaced, a solvent is added, and stirring is carried out at room temperature overnight; after the reaction is completed, the Pd / C catalyst is filtered through diatomite, the residual organic phase is extracted with ethyl acetate for multiple times, the organic phases are combined and dried with anhydrous sodium sulfate, then rotary evaporation operation is carried out to remove the ethyl acetate, and column chromatography separation treatment is carried out to obtain N Boc-protected AMOZ. In step 3, the Boc-protected AMOZ and 5-nitrofurfural are dissolved in a solvent, and then hydrogen chloride / dioxane solution or hydrogen chloride / methanol solution is added; the reaction is carried out under stirring at 50-100 DEG C for 5-120 minutes; after the reaction system is cooled to room temperature, saturated sodium bicarbonate solution is added into the reaction mixture, and ethyl acetate is used to extract multiple times; the organic phases are combined and dried with anhydrous sodium sulfate; excess ethyl acetate is removed through vacuum distillation; and column chromatography separation treatment is carried out to obtain the final product furanone. N

[0007] In step 1, the copper-based catalyst is one of cupric chloride and cupric bromide, the base is one of potassium carbonate, triethylamine, triethylenediamine and 1,4-diazabicyclo[2.2.2]octane, the ligand is one of 2,2'-bipyridine, 1,10-phenanthroline, 1,3-bis(diphenylphosphino)propane and 1,3-bis(diphenylphosphino)propane, and the solvent is one of toluene, chloroform, dichloromethane, dichloroethane, tetrahydrofuran and dimethylformamide.​N , N , N ’ N ’-tetramethylethylenediamine and ethylenediamine.

[0008] In step 1, the molar amount ratio of 1-(4-morpholinyl)-2-propyne, di-tert-butyl azodicarboxylate, a copper-based catalyst, a ligand and a base is 100:100~200:15~30:15~30:1~10.

[0009] In step 1, the solvent is a mixture of isopropyl alcohol and acetonitrile in a volume ratio of 9~1:1, and the solvent added per millimole of alkyne is preferably 2.0 ml.

[0010] In step 2, the mass amount of the Pd / C catalyst is 5%~30% of the mass amount of the 3,5-disubstituted oxazolone intermediate, and the loading amount of Pd in the Pd / C catalyst is 10%~15%.

[0011] In step 2, the solvent is one of methanol, ethyl acetate and acetone, and the solvent added per 90 mg of the 3,5-disubstituted oxazolone intermediate is preferably 1.5~2.0 mL.

[0012] In step 3, the solvent is one of methanol, acetonitrile and dioxane, and the solvent added per 20 mg N of the Boc-protected AMOZ is preferably 0.3~1.0 mL.

[0013] In step 3, the N molar amount ratio of the Boc-protected AMOZ to 5-nitrofurfural is 1:1~2.

[0014] In step 3, the molar concentration of hydrogen chloride in the hydrogen chloride / dioxane solution is 4 mol / L, and the molar concentration of hydrogen chloride in the hydrogen chloride / methanol solution is 2 mol / L, and the hydrogen chloride / dioxane solution or the hydrogen chloride / methanol solution added per 20 mg N of the Boc-protected AMOZ is preferably 30~50 μL.

[0015] After the above technical solution, the furanone synthesis method has the following advantages: 1, the synthesis route is shortened to 3 steps, and two steps are green and sustainable catalytic reactions; 2, the use of toxic hydrazine hydrate is avoided, and there is no dangerous epoxide intermediate generated, which is green and environmentally friendly; 3, all raw materials and catalysts can be obtained by commercial purchase and are cheap, and are suitable for large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1NMR hydrogen spectrum of the product of step 1; Figure 2 NMR carbon spectrum of the product of step 1; Figure 3 NMR hydrogen spectrum of the product of step 2; Figure 4 NMR carbon spectrum of the product of step 2; Figure 5 NMR hydrogen spectrum of the product of step 3; Figure 6 NMR carbon spectrum of the product of step 3. DETAILED DESCRIPTION

[0017] In order to further explain the technical scheme of the present application, the present application will be described in detail below through specific examples.

[0018] A synthesis method of furanthenone, which is as follows: 1-(4-morpholinyl)-2-propyne is used as raw material, and [3+2] cycloaddition reaction is carried out with di-tert-butyl azodicarboxylate to obtain 3,5-disubstituted oxazolone intermediate; then, olefin hydrogenation reaction is carried out under the action of Pd / C catalyst to obtain N Boc-protected AMOZ; finally N Boc-protected AMOZ is subjected to condensation reaction with 5-nitrofurfural under the action of hydrogen chloride to obtain product furanthenone, wherein the structural formula of the 3,5-disubstituted oxazolone intermediate is , N The structural formula of Boc-protected AMOZ is .

[0019] Specifically, a synthesis method of furanthenone comprises the following steps: Step 1, first, a stirring rod is placed in a 15 mL sealed tube, and 345.4 mg (1.5 mmol) of di-tert-butyl azodicarboxylate, 26.9 mg (0.2 mmol) of copper chloride, 5.6 mg (0.05 mmol) of 1,4-diazabicyclo[2.2.2]octane are sequentially added, argon is pumped in (repeated three times), 1.6 mL of isopropyl alcohol / 0.4 mL of acetonitrile solvent is added in an argon atmosphere, and then 125.2 mg (1.0 mmol) of 1-(4-morpholinyl)-2-propyne and 23.2 mg (0.2 mmol) N , N , N N ​The reaction mixture was stirred at 30°C for 6 hours, then the temperature was raised to 50°C and the reaction was stirred for 3 hours. After the system cooled to room temperature, 4 mL of saturated sodium bicarbonate solution was added to quench the reaction, and the reaction mixture was extracted with 6 mL of ethyl acetate three times. The organic phase was combined and dried with anhydrous sodium sulfate. The excess ethyl acetate was removed by distillation under reduced pressure. The remaining organic phase was separated by silica gel column chromatography (ethyl acetate) to obtain 131.2 mg of white solid product, i.e., 3,5-disubstituted oxazolone intermediate, with a yield of 44%. 石油醚 :V 乙酸乙酯 =3:1) to obtain 33.0 mg of white solid product, i.e., 3,5-disubstituted oxazolone intermediate, with a yield of 44%. The synthetic route of step 1 is shown in the following formula: ; Spectrum data analysis: As shown in Figure 1 , 1 H NMR (400 MHz, DMSO- d 6) δ 10.11-9.57 (m, 1H, -N H CO), 7.12(s, 1H), 3.65-3.50 (m, 4H), 3.26 (s, 2H), 2.44-2.29 (m, 4H), 1.51-1.29 (m,9H); As shown in Figure 2 , 13 C{ 1 H} NMR (101 MHz, DMSO- d 6) δ 154.1, 153.4, 133.9, 117.2,81.1, 66.1, 52.5, 52.3, 27.9; HRMS (ESI) m / z: [M + Na] + Calcd for C 13 H 21 N3NaO5 + 322.1373, found322.1375; Step 2, a stirring bar was placed in a 3 mL reaction bottle, 90 mg (0.3 mmol) of 3,5-disubstituted oxazolone intermediate and 9.0 mg of 10% Pd / C catalyst were sequentially added, vacuum was replaced with hydrogen, 1.5 mL of methanol was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, the Pd / C catalyst was filtered using diatomite, extracted with 6 mL of ethyl acetate three times, the organic phase was combined and dried with anhydrous sodium sulfate, and then rotary evaporation was performed to remove the ethyl acetate. The remaining organic phase was separated by silica gel column chromatography (ethyl acetate) to obtain 33.0 mg of white solid product, i.e., NBoc-protected AMOZ, yield 37%; the synthetic route of Step 2 is shown in the following formula: ; Spectrum data analysis: As shown in Figure 3 , 1 H NMR (400 MHz, CDCl3) δ 6.86 (br s, 1H, -N H CO), 4.73-4.55(m, 1H), 3.81-3.70 (m, 1H), 3.69-3.58 (m, 4H), 3.58-3.37 (m, 1H), 2.77-2.63(m, 1H), 2.63-2.37 (m, 5H), 1.42 (s, 9H); As shown in Figure 4 , 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 154.2, 152.7, 136.0, 129.0,128.2, 127.0, 122.5, 114.2, 81.3, 27.9; HRMS (ESI) m / z: [M + Na] + Calcd for C 13 H 23 N3NaO5 + 324.1530, found324.1534; Step 3, then put a stirring bar in a 15 mL sealed tube, dissolve 20.7 mg N Boc-protected AMOZ (0.07 mmol) and 14.1 mg 5-nitrofurfural (0.1 mmol) in 0.5 mL methanol, after dissolution, add 35 μL, 4 mol / L hydrogen chloride / dioxane solution (0.14 mmol), heat to 80 ℃, react for 30 minutes under stirring, then after the reaction system is cooled to room temperature, add 4 mL saturated sodium bicarbonate solution to quench the reaction, extract with 6 mL ethyl acetate for three times, combine the organic phase and dry with anhydrous sodium sulfate, remove the excess ethyl acetate by distillation under reduced pressure, separate and process the remaining organic phase by silica gel column chromatography (V 二氯甲烷 :V 甲醇 =40:1) to obtain 19.0 mg of yellow solid product, furanone, yield 85%; the synthetic route of Step 3 is shown in the following formula:

[0020] Spectrum data analysis: As Figure 5 shown, 1 H NMR (400 MHz, DMSO- d 6) δ 7.85 (s, 1H), 7.80 (d, J = 4.0 Hz,1H), 7.15 (d, J = 4.0 Hz, 1H), 5.02-4.88 (m, 1H), 4.04 (t, J = 8.8 Hz, 1H), 3.71-3.62 (m, 1H), 3.62-3.48 (m, 4H), 2.74-2.60 (m, 2H), 2.55-2.40 (m, 4H); As Figure 6 shown, 13 C{ 1 H} NMR (100 MHz, DMSO- d 6) δ 152.8, 151.8, 132.0, 114.9,114.7, 71.3, 66.2, 60.7, 53.7, 45.9; HRMS (ESI) m / z: [M + Na] + Calcd for C 13 H 16 N4NaO6 + 347.0962, found347.0958。

[0021] The raw materials and reagents used in the present application are all known materials in the art, which can be purchased on the market.

[0022] The above examples and drawings are not limited to the product shape and style of the present application, and any appropriate changes or modifications made by those skilled in the art shall be considered as not departing from the scope of the present application.

Claims

1. A method of synthesizing furanone, characterized by: is prepared by using 1-(4-morpholinyl)-2-propyne as raw material, and carrying out [3+2] cycloaddition reaction with di-tert-butyl azodicarboxylate to obtain 3,5-disubstituted oxazolone intermediate, then carrying out olefin hydrogenation reaction under the action of Pd / C catalyst to obtain N -Boc protected AMOZ; finally N -Boc protected AMOZ is subjected to condensation reaction with 5-nitrofurfural under the action of hydrogen chloride to obtain product furanacrylonitrile, wherein, the structural formula of the 3,5-disubstituted oxazolone intermediate is , the structural formula of the N -Boc protected AMOZ is .

2. The method of claim 1, wherein: The method comprises the following steps: Step 1, first, under the protection of argon, di-tert-butyl azodicarboxylate, a copper-based catalyst and a base are dissolved in a solvent, then a ligand and 1-(4-morpholinyl)-2-propyne are added, and the reaction is stirred at 30 DEG C under a closed condition for 5-10 hours, then the temperature is increased to 40-60 DEG C and the reaction is carried out for 1-12 hours, then the reaction system is cooled to room temperature, a saturated sodium bicarbonate solution is added to the reaction mixture, the organic phase is extracted with ethyl acetate for several times, the combined organic phase is dried with anhydrous sodium sulfate, excess ethyl acetate is removed by distillation under reduced pressure, and the 3,5-disubstituted oxazolone intermediate is obtained by column chromatography separation and treatment; Step 2, then in the reaction vessel is added 3,5-disubstituted oxazolone intermediate and Pd / C catalyst in sequence, vacuum-exchanged with hydrogen, solvent is added, stirred at room temperature overnight, after the reaction is completed, the Pd / C catalyst is filtered using diatomite, the remaining organic phase is extracted with ethyl acetate multiple times, the organic phases are combined and dried with anhydrous sodium sulfate, followed by a rotary evaporation operation to remove ethyl acetate, and column chromatography separation and treatment to obtain N - Boc-protected AMOZ; Step 3: Then, under sealed conditions, N -Boc-protected AMOZ and 5-nitrofurfural are dissolved in a solvent, and then hydrogen chloride / dioxane solution or hydrogen chloride / methanol solution is added. The mixture is heated to 50-100°C and reacted with stirring for 5-120 minutes. After the reaction system is cooled to room temperature, a saturated sodium bicarbonate solution is added to the reaction mixture, and the mixture is extracted multiple times with ethyl acetate. The organic phases are combined and dried over anhydrous sodium sulfate. Excess ethyl acetate is removed by vacuum distillation, and the final product, furazolidone, is obtained by column chromatography.

3. The method of claim 2, wherein: In Step 1, the copper-based catalyst is one of copper chloride and copper bromide, the base is one of potassium carbonate, triethylamine, triethylenediamine, and 1,4-diazabicyclo[2.2.2]octane, the ligand is one of N , N , N ’ N ’-tetramethylethylenediamine and ethylenediamine.

4. The method of claim 2, wherein: In step 1, the molar ratio of 1-(4-morpholinyl)-2-propyne, di-tert-butyl azodicarboxylate, a copper-based catalyst, a ligand and a base is 100:100-200:15-30:15-30:1-10.

5. The method of claim 2, wherein: In step 1, the solvent is a mixture of isopropyl alcohol and acetonitrile in a volume ratio of 9-1:1, and the amount of solvent added per millimole of alkyne is preferably 2.0 ml.

6. The method of claim 2, wherein: In step 2, the mass amount of Pd / C catalyst is 5%-30% of the mass amount of 3,5-disubstituted oxazolone intermediate, and the loading amount of Pd in the Pd / C catalyst is 10%-15%.

7. The method of claim 2, wherein: In step 2, the solvent is one of methanol, ethyl acetate and acetone, and the amount of solvent added per 90 mg of 3,5-disubstituted oxazolone intermediate is preferably 1.5-2.0 mL.

8. The method of claim 2, wherein: In Step 3, the solvent is one of methanol, acetonitrile, and dioxane, 0.3 to 1.0 mL per 20 mg of Boc-protected AMOZ is preferable. N The solvent to be added for Boc-protected AMOZ is preferably 0.3 to 1.0 mL.

9. The method of claim 2, wherein: In step 3, the N The molar ratio of -Boc-protected AMOZ to 5-nitrofurfural is 1:1~2.

10. The method of claim 2, wherein: In Step 3, the molar concentration of hydrogen chloride in the hydrogen chloride / dioxane solution is 4 mol / L, the molar concentration of hydrogen chloride in the hydrogen chloride / methanol solution is 2 mol / L, and the amount of the hydrogen chloride / dioxane solution or the hydrogen chloride / methanol solution added per 20 mg of the Boc-protected AMOZ is preferably 30 to 50 μL. N The amount of the hydrogen chloride / dioxane solution or the hydrogen chloride / methanol solution added to the Boc-protected AMOZ is preferably 30 to 50 μL.

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