4-Nitrophthaloyl nitrogen oxygen heterocyclic compound and its preparation method and application

Abstract

The invention discloses a 4-nitrophthaloyl nitrogen oxygen heterocyclic compound and a preparation method thereof, and a method for preparing an aza crown ether using the compound, wherein the preparation method comprises the following steps: (a) in a first reaction solvent, under air isolation conditions, compound 1 is added to compound 6 under condensation reagent conditions, the reaction temperature is 0-100°C, the reaction time is 2-48 hours, wherein the amount ratio of compound 1 to compound 6 is 1:1-1.5; (b) a compound of formula 2 and a compound of formula 3 are added to a second reaction solvent, triphenylphosphine and a coupling agent, the reaction temperature is 20-100°C, the reaction time is 2-24 hours, and the amount ratio of compound 2 to compound 3 is 1:1-1.5. The invention has low cost, high yield, and the synthesized aza crown ether has high purity, and is more suitable for the needs of industrialized mass production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound and a preparation method thereof, as well as a method for preparing an azacrown ether by using the compound. Background Art

[0002] Crown ethers, also known as "macrocyclic ethers", are macrocyclic compounds containing multiple oxygen atoms. Since Pedersen first reported crown ethers in 1967 and Pedersen, Lehn and Cram won the Nobel Prize in Chemistry in 1987, crown ether chemistry has made great progress and has become a hot research topic in modern chemistry in the following decades. At present, crown ether chemistry and application research have penetrated into many branches, such as organic synthesis, coordination chemistry, analytical chemistry, extraction chemistry, metal and isotope separation, and biochemistry. Crown ether rings of different sizes can select different metal ions and have important supramolecular recognition functions.

[0003] When the oxygen atom on the crown ether ring is replaced by a nitrogen atom, an aza crown ether is obtained. Since this type of crown ether has a strong complexing ability for transition metals and heavy metal ions, its synthesis and application have attracted people's attention. Since the hydrogen on the nitrogen atom of the aza crown ether is relatively active, it is the growth point of other substituents, and thus a side chain is introduced to generate a nitrogen-branched lasso crown ether, also called an arm-type crown ether. This functional side arm usually contains electron-donating atoms. When the metal ion binds to the atoms on the ring, it can also coordinate with the atoms of the side arm. The arm-type crown ether has a certain flexibility, and the induced three-dimensional space can be adjusted during the coordination process, which not only enhances the coordination ability, but also improves the selectivity for metal ions. It is an excellent ligand with both rigidity and flexibility.

[0004] Regarding the synthesis method of azacrown ethers, Chaves and Silvia et al. reported a synthesis method in Polyhedron (17(1), 93-104, 1998), which is as follows:

[0005]

[0006] However, this method has a series of problems such as long steps, low yield in the ring-closing step, harsh reaction conditions when removing the Ts protecting group, high corrosion to equipment, low yield, and the need for acid-base neutralization and large amount of wastewater. Therefore, there is an urgent need to develop a green synthesis, low-cost and high-yield industrial production method for nitrogen-oxygen heterocyclic compounds. Summary of the invention

[0007] In view of the problems existing in the above-mentioned prior art, the present invention develops a 4-nitrophthaloyl azacrown ether compound and a preparation method thereof, and the application of the compound in the preparation of azacrown ether compounds, which has the advantages of low cost, high yield and high purity.

[0008] One of the technical problems to be solved by the present invention is to disclose a 4-nitrophthaloyl nitrogen oxygen heterocyclic compound, the chemical structure of which is shown in 4. , where n is greater than 0 and less than or equal to 10; m is greater than 0 and less than or equal to 20.

[0009] The second technical problem to be solved by the present invention is to disclose a method for preparing a 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound, comprising the following steps:

[0010]

[0011] (a) In a first reaction solvent, compound 1 is added to compound 6 in the presence of a condensation agent under air-tight conditions, the reaction temperature is 0-100° C., the reaction time is 2-48 hours, wherein the molar ratio of compound 1 to compound 6 is 1:1-1.5, and the first reaction solvent is one or more of 1,2-dichloroethane, dichloromethane, chlorobenzene, nitrobenzene, and o-dichlorobenzene;

[0012] (b) Add triphenylphosphine and a coupling agent to the compound of formula 2 and the compound of formula 3 in a second reaction solvent, the reaction temperature is -20-100°C, the reaction time is 2-24 hours, the molar ratio of the compound of formula 2 to the compound of formula 3 is 1:1-1.5, and the second reaction solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, acetonitrile, p-xylene, o-xylene, benzene and toluene.

[0013] In a preferred embodiment of the present invention, in step (a), the condensation reagent is one of N'N-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0014] In a preferred embodiment of the present invention, in step (a), when the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, triethylamine needs to be added.

[0015] In a preferred embodiment of the present invention, in step (a), the amount of the condensing agent is 2-6 times the amount of the compound 1.

[0016] In a preferred embodiment of the present invention, in step (b), the coupling agent is one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate or dimethyl azodicarboxylate.

[0017] In a preferred embodiment of the present invention, in step (b), the amount of the coupling agent is 2-4 times the amount of the compound 2.

[0018] In a preferred embodiment of the present invention, in step (b), the amount of the triphenylphosphine is 2-6 times the amount of the compound 2.

[0019] The third technical problem to be solved by the present invention is to disclose a method for preparing a 4-nitrophthaloyl nitrogen oxygen heterocyclic compound and its application in preparing aza crown ethers, further comprising step (c) in a condition of being isolated from air, stirring the above compound 4 in a third reaction solvent, adding a third alkaline reagent, heating and refluxing for 4-10 hours to obtain compound 5 ， Wherein, the third reaction solvent is one or more of ethanol, methanol, isopropanol, n-butanol, and nitrobenzene, , n is greater than 0 and less than or equal to 10, and m is greater than 0 and less than or equal to 20.

[0020] In a preferred embodiment of the present invention, in step (c), the third alkaline reagent is one or more of potassium hydroxide, sodium hydroxide and lithium hydroxide. Beneficial Effects

[0021] The present invention uses diol to directly perform one-step cyclization reaction, and the reaction is simple; and in the protection process, a proton base such as potassium hydroxide is used, and the removed protecting group can be directly recycled as a raw material. The entire reaction process has low cost and high yield, and the synthesized azacrown ether has high purity, which is more suitable for the needs of industrial large-scale production. DETAILED DESCRIPTION

[0022] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention. Example 1

[0023]

[0024] Step (a): Preparation of the compound of formula 2-1 9-nitro-3,4,5,6-tetrahydro-1H-benzo[g][1,5]diazo-1,7(2H)-dione

[0025] Keeping nitrogen slightly positive pressure, add 750 ml of dichloromethane and 211.13 g (1.0 mol) of 4-nitrophthalic acid of Formula 1 to the 5 L reaction bottle in turn and stir well. Cool the reaction solution to 0°C, add 383.40 g (2.0 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to it, stir well, then drop 202.38 g (2.0 mol) of triethylamine to it, stir well after adding. Keep the reaction solution at 0°C for 1 hour, add 74.12 g (1.0 mol) of 1,3-propylenediamine of Formula 6-1 to it, stir well. The reaction solution rises to room temperature naturally, stirs at room temperature for 24 hours, and the reaction is complete.

[0026] The reaction solution was washed twice with 2L of water, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase obtained after drying was distilled under normal pressure to recover the solvent. The residue was recrystallized from xylene-ethyl acetate to obtain 218.33 g (0.876 mol) of a yellow solid product.

[0027] The yield is 87.60%, and the HPLC purity is 98.54%. 1 H NMR (400MHz, DMSO-d6): δ11.15(br s, 2H), 8.73(s, 1H), 8.63(d, 1H), 8.22(d, 1H), 3.19(t, 4H), 1.83-1.88(m, 2H).

[0028] Step (b): Preparation of the compound of formula 4-1 11-nitro-3,4,6,7-tetrahydro-2,8-propylbenzo[f][1]oxo[4,9]diazacycloundecene-1,9-dione

[0029] Add 2130 ml tetrahydrofuran, 218.33 g (0.876 mol) of the compound of formula 2-1, 92.96 g (0.876 mol) of the compound of formula 3-1, diethylene glycol, and 505.49 g (1.927 mol) of triphenylphosphine to a 5 L reaction bottle, and stir well. Cool the reaction solution to 0-5°C, and then drop 354.27 g (1.752 mol) of diisopropyl azodicarboxylate into it, drop it within 30 minutes, and stir well. After adding, keep warm and stir for 2 hours, then raise the temperature to reflux for reaction, keep warm and reflux for 20 hours, and the reaction is finished.

[0030] The reaction solution was cooled to room temperature naturally, 1000 mL of petroleum ether was added, and then cooled to 0°C for crystallization. The crystallization was kept warm overnight to precipitate a large amount of yellow solid. The filter cake was collected by filtration, washed with 200 mL of cold petroleum ether, and dried to obtain 250.35 g (0.784 mol) of a yellow solid product.

[0031] Yield: 89.5%, HPLC purity: 99.12%, 1 H NMR (400MHz, DMSO-d6): δ 8.75 (s, 1H), 8.64 (d, 1H), 8.22 (d, 1H), 3.67 (t, 4H), 3.39 (t, 4H), 3.21 (t, 4H), 1.83-1.88 (m, 2H).

[0032] Step (c): Preparation of the compound 1,4,8-oxadiazacyclodecane of formula 5-1

[0033] Keeping nitrogen slightly positive pressure, add 2750 mL of anhydrous methanol and 250.35 g (0.784 mol) of compound 4-1 to a 5 L reaction bottle and stir well. Then add 146.64 g (2.352 mol) of potassium hydroxide in batches and stir well. After adding, heat to reflux reaction. Keep the temperature for reflux reaction for 4 hours, and the reaction is finished.

[0034] The reaction solution was cooled to room temperature, and a large amount of dark yellow solid precipitated. The solid insoluble matter 1 was obtained by filtration and collection of the filter cake.

[0035] The filtrate was rotary evaporated to recover about two-thirds of the solvent, and 500 mL of tetrahydrofuran was added to the residue to obtain a light yellow solution. The light yellow solution was cooled to -20°C for crystallization. The crystallization was kept warm overnight to precipitate a small amount of yellow solid. The filter cake was collected by filtration to obtain a solid insoluble matter 2.

[0036] Add 200 mL of petroleum ether to the filtrate and cool to -20°C for crystallization. Keep the temperature for crystallization overnight to precipitate a large amount of white solid. Filter and collect the filter cake to obtain 101.99 g (0.707 mol) of pure white solid.

[0037] The yield is 90.2%, and the total yield of the four-step reaction is 70.7%.

[0038] Product purity: 98.25% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ3.54 (t, 4H), 3.03 (t, 4H), 2.87 (t, 4H), 1.70-1.74 (m, 2H), 1.68 (br s, 2H).

[0039] Combine the solid insoluble matter 1 and the solid insoluble matter 2, add them to 2L pure water, stir well, then add hydrochloric acid to adjust the pH to 2, filter, collect the filter cake to obtain a light yellow solid, and vacuum dry the light yellow solid to obtain 162.99g (0.772 mol) of light yellow solid powder. The light yellow solid powder was identified as 4-nitrophthalic acid, the recovery rate of the protective group raw material was 77.2%, and the HPLC purity was 98.51%. 1H NMR (400MHz, DMSO-d6): δ 8.47 (s, 1H), 8.43 (d, 1H), 7.91 (d, 1H). Example 2

[0040]

[0041] Step (a): Preparation of the compound of formula 2-2 10-nitro-2,3,4,5,6,7-hexahydrobenzo[c][1,6]diazepine-1,8-dione

[0042] Keeping nitrogen slightly positive pressure, add 600 ml chlorobenzene and 211.13 g (1.0 mol) of 4-nitrophthalic acid of Formula 1 to the 5 L reaction bottle in sequence and stir well. Cool the reaction solution to 0°C, add 618.99 g (3.0 mol) of N'N-dicyclohexylcarbodiimide, stir well after adding. Keep the reaction solution at 0°C for 1 hour, add 88.15 g (1.1 mol) of 1,4-butanediamine and stir well. Raise the reaction solution to 100°C naturally, keep it warm and stir for 2 hours, and the reaction is complete.

[0043] The reaction solution was washed twice with 2L of water, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase obtained after drying was distilled under normal pressure to recover the solvent. The residue was recrystallized from xylene-ethyl acetate to obtain 231.66 g (0.88 mol) of a yellow solid product.

[0044] Yield: 88.0%, HPLC purity: 98.91%. 1 H NMR (400MHz, DMSO-d6): δ11.21 (br s, 2H), 8.73 (s, 1H), 8.64 (d, 1H), 8.22 (d, 1H), 3.19 (t, 4H), 1.54-1.58 (m, 4H).

[0045] Step (b): Preparation of the compound of formula 4-2 11-nitro-3,4,6,7-tetrahydro-2,8-butylbenzo[f][1]oxo[4,9]diazacycloundecene-1,9-dione

[0046] Add 2140 ml acetonitrile, 231.66 g (0.88 mol) of the compound of formula 2-1, 93.39 g (0.88 mol) of the compound of formula 3-2, diethylene glycol, and 507.79 g (1.936 mol) of triphenylphosphine to a 5 L reaction bottle, and stir well. Cool the reaction solution to 0-5°C, and then drop 355.89 g (1.76 mol) of diisopropyl azodicarboxylate into it, drop it within 30 minutes, and stir well. After adding, keep warm and stir for 2 hours, then raise the temperature to reflux for reaction, keep warm and reflux for 16 hours, and the reaction is finished.

[0047] The reaction solution was cooled to room temperature naturally, 1000 ml of petroleum ether was added, and then cooled to 0°C for crystallization. The crystallization was kept warm overnight to precipitate a large amount of yellow solid. The filter cake was collected by filtration, and the filter cake was washed with 200 ml of cold petroleum ether and dried to obtain 266.06 g (0.798 mol) of yellow solid product.

[0048] Yield 90.7%, HPLC purity 99.25%, 1 H NMR (400MHz, DMSO-d6): δ 8.74 (s, 1H), 8.64 (d, 1H), 8.22 (d, 1H), 3.67 (t, 4H), 3.39 (t, 4H), 3.19 (t, 4H), 1.54-1.58 (m, 4H).

[0049] Step (c): Preparation of the compound of formula 5-2, 1-oxo-4,9-diazacycloundecane

[0050] Keeping nitrogen slightly positive pressure, add 2800ml of n-butanol and 266.06g (0.798mol) of compound 4-2 to a 5L reaction bottle and stir well. Then add 149.28g (2.394mol) of potassium hydroxide in batches and stir well. After adding, heat to reflux reaction. Keep the temperature for reflux reaction for 6 hours, and the reaction is finished.

[0051] The reaction solution was cooled to room temperature, and a large amount of dark yellow solid precipitated. The solid insoluble matter 1 was obtained by filtration and collection of the filter cake.

[0052] The filtrate was rotary evaporated to recover about two-thirds of the solvent, and 500 mL of tetrahydrofuran was added to the residue to obtain a light yellow solution. The light yellow solution was cooled to -20°C for crystallization. The crystallization was kept warm overnight to precipitate a small amount of yellow solid. The filter cake was collected by filtration to obtain a solid insoluble matter 2.

[0053] Add 1000 mL of petroleum ether to the filtrate and cool to -20°C for crystallization. Keep the temperature for crystallization overnight to precipitate a large amount of white solid. Filter and collect the filter cake to obtain 114.44 g (0.723 mol) of pure white solid.

[0054] The yield is 90.6%, and the total yield of the four-step reaction is 72.3%.

[0055] Product purity: 98.55% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ3.55 (t, 4H), 3.01 (t, 4H), 2.85 (t, 4H), 1.37-1.42 (m, 4H), 1.56 (br s, 2H).

[0056] The solid insoluble matter 1 and the solid insoluble matter 2 were combined, added to 2L of pure water, stirred, and then hydrochloric acid was added to adjust the pH to 2, filtered, and the filter cake was collected to obtain a light yellow solid, which was vacuum dried to obtain 161.35g (0.764 mol) of light yellow solid powder. The light yellow solid powder was identified as 4-nitrophthalic acid, the recovery rate of the protective group raw material was 76.4%, the HPLC purity was 98.81%, and the nuclear magnetic resonance data were consistent with Example 1. Example 3

[0057]

[0058] Step (a): Preparation of the compound of formula 2-3 11-nitro-3,4,5,6,7,8-hexahydro-1H-benzo[c][1,6]diazacycloundecene-1,9(2H)-dione

[0059] Keeping nitrogen slightly positive pressure, add 600 ml nitrobenzene and 211.13 g (1.0 mol) of 4-nitrophthalic acid, a compound of formula 1, to a 5 L reaction bottle in sequence and stir well. The reaction solution is cooled to 0°C, and 1520.92 g (4.0 mol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is added thereto. After the addition is complete, stir well. The reaction solution is kept warm at 0°C for 1 hour, and 132.83 g (1,3 mol) of 1,5-pentanediamine is added thereto and stirred well. The reaction solution is naturally raised to 80°C, kept warm and stirred for 10 hours, and the reaction is completed.

[0060] The reaction solution was washed twice with 2L of water, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase obtained after drying was distilled under normal pressure to recover the solvent. The residue was recrystallized from xylene-ethyl acetate to obtain 238.46 (0.86 mol) of a yellow solid product.

[0061] Yield: 86%, HPLC purity: 98.91%. 1 H NMR (400MHz, DMSO-d6): δ11.18(br s, 2H), 8.74(s, 1H), 8.64(d, 1H), 8.22(d, 1H), 3.19(t, 4H), 1.54-1.58(m, 4H), 1.23-1.26(m, 2H).

[0062] Step (b): Preparation of the compound of formula 4-3 11-nitro-3,4,6,7-tetrahydro-2,8-propylbenzo[f][1]oxo[4,9]diazacycloundecene-1,9-dione

[0063] Add 2100ml of tert-butyl methyl ether, 238.46 (0.86mol) of compound 2-1, 129.15g (0.86mol) of triethylene glycol, and 496.25g (1.892mol) of triphenylphosphine to a 5L reaction bottle, and stir well. Cool the reaction solution to 0-5℃, and then drop 449.31g (2.58mol) of diethyl azodicarboxylate into it, drop it within 30 minutes, and stir well. After adding, keep warm and stir for 2 hours, then raise the temperature to reflux reaction, keep warm and reflux reaction for 20 hours, and the reaction is finished.

[0064] The reaction solution was cooled to room temperature naturally, 1000 mL of petroleum ether was added, and then cooled to 0°C for crystallization. The temperature was kept for crystallization overnight, and a large amount of yellow solid was precipitated. The filter cake was collected by filtration, and the filter cake was washed with 300 mL of cold petroleum ether and dried to obtain 306.33 g (0.783 mol) of yellow solid product.

[0065] Yield 91.0%, HPLC purity 99.23%, 1 H NMR (400MHz, DMSO-d6): δ8.74(s, 1H), 8.64(d, 1H), 8.22(d, 1H), 3.71(br s, 4H), 3.67(t, 4H), 3.39(t, 4H), 3.19(t, 4H), 1.54-1.58(m,4H), 1.23-1.26(m,2H).

[0066] Step (c): Preparation of the compound 1,4-dioxa-7,13-diazacyclopentane of formula 5-3

[0067] Keeping nitrogen slightly positive pressure, add 2750 ml isopropanol and 306.33 g (0.783 mol) of compound 4-3 to a 5 L reaction bottle and stir well. Then add 104.35 g (2.348 mol) of sodium hydroxide in batches and stir well. After adding, heat to reflux reaction. Keep the temperature for reflux reaction for 8 hours, and the reaction is finished.

[0068] The reaction solution was cooled to room temperature, and a large amount of dark yellow solid precipitated. The solid insoluble matter 1 was obtained by filtration and collection of the filter cake.

[0069] The filtrate was rotary evaporated to recover about two-thirds of the solvent, and 500 ml of tetrahydrofuran was added to the residue to obtain a light yellow solution. The light yellow solution was cooled to -20°C for crystallization. The crystallization was kept warm overnight to precipitate a small amount of yellow solid. The filter cake was collected by filtration to obtain a solid insoluble matter 2.

[0070] Add 1000 mL of petroleum ether to the filtrate and cool to -20°C for crystallization. Keep the temperature for crystallization overnight to precipitate a large amount of white solid. Filter and collect the filter cake to obtain 148.98 g (0.689 mol) of pure white solid.

[0071] The yield is 88.0%, and the total yield of the four-step reaction is 68.9%.

[0072] Product purity: 98.63% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ3.67 (br s, 4H), 3.54 (t, 4H), 3.01 (t, 4H), 2.85 (t, 4H), 1.62 (br s, 2H), 1.35-1.40 (m, 4H), 1.23-1.26 (m, 2H).

[0073] The solid insoluble matter 1 and the solid insoluble matter 2 were combined, added to 2L of pure water, stirred, and then hydrochloric acid was added to adjust the pH to 2, filtered, and the filter cake was collected to obtain a light yellow solid, which was vacuum dried to obtain 164.21g (0.777 mol) of light yellow solid powder. The light yellow solid powder was identified as 4-nitrophthalic acid, the recovery rate of the protective group raw material was 77.7%, the HPLC purity was 99.12%, and the nuclear magnetic resonance data were consistent with Example 1. Example 4

[0074]

[0075] Step (a): Preparation of the compound of formula 2-4 13-nitro-3,4,5,6,7,8,9,10-octahydro-1H-benzo[c][1,6]diazocyclotridecyl-1,11(2H)-dione

[0076] Keeping nitrogen slightly positive pressure, add 600 ml o-dichlorobenzene and 211.13 g (1.0 mol) of compound 4-nitrophthalic acid of formula 1 to a 5 L reaction bottle in sequence and stir well. Cool the reaction solution to 0°C, add 2275.44 g (6.0 mol) of benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, stir well after adding. Keep the reaction solution at 0°C for 1 hour, add 195.36 g (1.5 mol) of 1,7-heptanediamine and stir well. The reaction solution rises to 60°C naturally, keeps warm and stirs for 12 hours, and the reaction is complete.

[0077] The reaction solution was washed twice with 2L of water, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase obtained after drying was distilled under normal pressure to recover the solvent. The residue was recrystallized from xylene-ethyl acetate to obtain 266.55g (0.873mol) of a yellow solid product.

[0078] The yield is 87.3%, and the HPLC purity is 98.71%. 1 H NMR (400MHz, DMSO-d6): δ11.12(br s, 2H), 8.73(s, 1H), 8.62(d, 1H), 8.21(d, 1H), 3.19(t, 4H), 1.53-1.57(m, 4H), 1.22-1.27(m, 6H).

[0079] Step (b): Preparation of the compound of formula 4-4

[0080] Add 2150 ml of p-xylene, 266.55 g (0.873 mol) of compound 2-4, 246.47 g (0.873 mol) of hexaethylene glycol, and 503.75 g (1.927 mol) of triphenylphosphine to a 5 L reaction bottle, and stir well. Cool the reaction solution to 0-5 °C, and then drop 419.56 g (3.492 mol) of dimethyl azodicarboxylate into it, drop it within 30 minutes, and stir well. After adding, keep warm and stir for 2 hours, then heat to reflux for reaction, keep warm and reflux for 2 hours, and the reaction is finished.

[0081] The reaction solution was cooled to room temperature naturally, 2000 mL of petroleum ether was added, and then cooled to 0°C for crystallization. The temperature was kept for crystallization overnight, and a large amount of yellow solid was precipitated. The filter cake was collected by filtration, and the filter cake was washed with 400 mL of cold petroleum ether and dried to obtain 426.2 g (0.773 mol) of yellow solid product.

[0082] Yield: 88.5%, HPLC purity: 99.27%, 1 H NMR (400MHz, DMSO-d6): δ8.73(s, 1H), 8.62(d, 1H), 8.21(d, 1H), 3.71(br s, 16H), 3.67(t, 4H), 3.39(t, 4H), 3.19(t, 4H), 1.53-1.57(m,4H), 1.22-1.27(m,6H).

[0083] Step (c): Preparation of the compound of formula 5-4

[0084] Keeping nitrogen slightly positive pressure, add 2700 ml of anhydrous ethanol and 426.2 g (0.773 mol) of compound 4-4 to a 5 L reaction bottle and stir well. Then add 61.81 g (2.318 mol) of lithium hydroxide in batches and stir well. After adding, heat to reflux reaction. Keep the temperature for reflux reaction for 10 hours, and the reaction is finished.

[0085] The reaction solution was cooled to room temperature, and a large amount of dark yellow solid precipitated. The solid insoluble matter 1 was obtained by filtration and collection of the filter cake.

[0086] The filtrate was rotary evaporated to recover about two-thirds of the solvent, and 500 mL of tetrahydrofuran was added to the residue to obtain a light yellow solution. The light yellow solution was cooled to -20°C for crystallization. The crystallization was kept warm overnight to precipitate a small amount of yellow solid. The filter cake was collected by filtration to obtain a solid insoluble matter 2.

[0087] Add 200 mL of petroleum ether to the filtrate and cool to -20°C for crystallization. Keep the temperature for crystallization overnight to precipitate a large amount of white solid. Filter and collect the filter cake to obtain 265.61 g (0.705 mol) of pure white solid.

[0088] The yield is 91.3%, and the total yield of the four-step reaction is 70.5%.

[0089] Product purity: 98.63% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ3.67 (br s, 16H), 3.54 (t, 4H), 3.01 (t, 4H), 2.83 (t, 4H), 1.64 (br s, 2H), 1.34-1.38 (m, 4H), 1.23-1.26 (m, 6H).

[0090] The solid insoluble matter 1 and the solid insoluble matter 2 were combined, added to 2L pure water, stirred, and then hydrochloric acid was added to adjust the pH to 2, filtered, and the filter cake was collected to obtain a light yellow solid, which was vacuum dried to obtain 162.35g (0.769mol) of light yellow solid powder. The light yellow solid powder was identified as 4-nitrophthalic acid, the recovery rate of the protective group raw material was 76.9%, and the HPLC purity was 98.51%. The nuclear magnetic resonance data were consistent with those in Example 1.

[0091] Comparative Example 1

[0092]

[0093] The same operation scheme as steps (a) and (b) in Example 1 was followed, except that the raw material compound 1 was replaced with an equivalent amount of phthalic acid. During the experiment, it was found that the product obtained when compound 8 was converted into compound 9 was very impure, and the pure product of compound 9 could not be isolated.

[0094] It can be seen that the 4-nitrophthalic acid of the present invention is a good reactive group here, which makes the subsequent ring-closure step feasible.

[0095] Comparative Example 2

[0096]

[0097] Add 2000 mL of acetonitrile, 228.93 g (0.923 mol) of the compound 4-nitrophthaloyl chloride of formula 10 and 255.14 g (1.85 mol) of potassium carbonate to a 5L reaction bottle, and stir well. Then add 68.42 g (0.923 mol) of 1,3-propylenediamine dropwise, and stir well after adding. Heat the reaction liquid to 50°C for reaction, and keep the temperature for 8 hours. A large amount of yellow solid is generated in the reaction liquid. The plate is used to confirm that the reaction of 4-nitrophthaloyl chloride and 1,3-propylenediamine is complete.

[0098] The reaction solution was filtered while hot, and the filtrate was collected. The filtrate was spin-dried and no product was found. The filter cake was poured into 2L pure water, and 10% sulfuric acid was added dropwise thereto. The pH value of the aqueous solution was adjusted to 6, and a large amount of bubbles were generated therebetween. The resulting solution was filtered under reduced pressure to obtain 225g of yellow solid. This yellow solid has a very poor solubility, and does not dissolve even in DMF and DMSO. It is often inferred according to the solubility property that it is very likely to have formed the following structure polymer.

[0099]

[0100] At the same time, we also tried to use equivalent amounts of 1,4-butanediamine and 1,5-pentanediamine to replace 1,3-propylenediamine. Again, we did not obtain the desired ring-closure product, but instead obtained a polymer with extremely poor solubility.

[0101] It can be seen that the method of preparing a ring-closed compound by directly reacting 4-nitrophthaloyl chloride with a diamine compound is not applicable to 1,3-propylenediamine and diamine compounds with longer alkane chains.

[0102] The above examples are only for illustrating the technical concept and features of the present invention. Their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it accordingly. They cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A 4-nitrophthaloyl nitrogen oxygen heterocyclic compound, characterized in that: Its chemical structure is shown in 4. , where n is equal to 1; m is equal to 1 or 6.

2. A method for preparing a 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound, characterized in that: The method comprises the following steps: (a) In the first reaction solvent, compound 1 is added to compound 6 under the condition of condensation reagent under air-tight condition, the reaction temperature is 0-100°C, the reaction time is 2-48 hours, wherein the molar ratio of compound 1 to compound 6 is 1:1-1.5, and the first reaction solvent is one or more of 1,2-dichloroethane, dichloromethane, chlorobenzene, nitrobenzene, and o-dichlorobenzene; (b) triphenylphosphine and coupling agent are added to the compound of formula 2 and the compound of formula 3 in the second reaction solvent, the reaction temperature is -20-100°C, the reaction time is 2-24 hours, the molar ratio of compound 2 to compound 3 is 1:1-1.5, and the second reaction solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, acetonitrile, p-xylene, o-xylene, benzene and toluene, wherein n is equal to 1; m is equal to 1 or 6.

3. The method for preparing the 4-nitrophthaloyl nitrogen oxygen heterocyclic compound according to claim 2, characterized in that: In step (a), the condensation reagent is one of N'N-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate.

4. The method for preparing the 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound according to claim 3, characterized in that: In step (a), when the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, triethylamine needs to be added.

5. The method for preparing the 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound according to claim 3, characterized in that: In step (a), the amount of the condensing agent is 2-6 times the amount of the compound 1.

6. The method for preparing the 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound according to claim 2, characterized in that: In step (b), the coupling agent is one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate or dimethyl azodicarboxylate.

7. The method for preparing the 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound according to claim 2, characterized in that: In step (b), the amount of the coupling agent is 2-4 times the amount of the compound 2.

8. The method for preparing the 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound according to claim 2, characterized in that: In step (b), the amount of triphenylphosphine is 2-6 times the amount of compound 2.

9. Application of a method for preparing a 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound in preparing azacrown ethers, characterized in that: The method further comprises step (c) wherein the compound 4 is stirred in a third reaction solvent under air isolation, a third alkaline reagent is added, and the mixture is heated and refluxed for 4-10 hours to obtain a compound 5, wherein the third reaction solvent is one or more of ethanol, methanol, isopropanol, n-butanol, and nitrobenzene. , where n is equal to 1; m is equal to 1 or 6.

10. The use of the method for preparing 4-nitrophthaloyl nitrogen oxygen heterocyclic compound according to claim 9 in the preparation of aza crown ethers, characterized in that: In step (c), the third alkaline reagent is one or more of potassium hydroxide, sodium hydroxide, and lithium hydroxide.

Images