Sulfur azacycloalkane intermediate compound and preparation method and application thereof

Abstract

The present invention discloses an intermediate compound of a thiazolyl alkane and a preparation method thereof, as well as a method for preparing a thiazolyl alkane using the intermediate compound. The preparation method is as follows: (a) in a first reaction solvent, under air-tight 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) triphenylphosphine and a coupling agent are added to a compound of formula 2 and a compound of formula 3 in a second reaction solvent, the reaction temperature is 20-100°C, the reaction time is 2-24 hours, the amount ratio of compound 2 to compound 3 is 1:1-1.5, and the coupling agent is one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate or dimethyl azodicarboxylate. The present invention has low cost, high yield, and the synthesized thiazolyl heterocycle has high purity, which is more suitable for the needs of industrialized mass production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to an intermediate compound of thiazolyl alkane and a preparation method thereof, as well as a method for preparing thiazolyl alkane by using the intermediate compound. Background Art

[0002] Heterocyclic compounds are widely present in nature, and most of the important compounds related to biology are heterocyclic compounds, such as nucleic acids, certain vitamins, antibiotics, hormones, pigments and alkaloids. In addition, heterocyclic compounds with various properties are important components of drugs, some of which can be used as drugs, pesticides, herbicides, dyes, plastics, etc.

[0003] Sulfur or nitrogen heterocyclic molecules and sulfur-nitrogen heterocyclic compounds are important heterocyclic compounds that can be used to produce various dyes, fragrances, plastics resistant to rapid cooling and heating, highly active solvents, stimulants, pesticides, brighteners, cosmetics and bioactive substances, as well as drugs such as vitamins, anesthetics and antibiotics. Among them, sulfur-nitrogen heterocyclic compounds have a variety of biological activities. In addition to various drug effects such as antibacterial, antiviral, anti-inflammatory, and hypoglycemic, anticancer activity has gradually attracted people's attention. It is precisely because of its potential application prospects in various fields that it has attracted the attention and concern of scientists, and a large number of studies have been conducted on it, and many valuable scientific research results have been achieved.

[0004] Traditional methods or processes for synthesizing sulfur-nitrogen heterocyclic compounds all have many defects to varying degrees, such as: (1) the use of expensive metal organic reagents, etc., which is costly and not conducive to industrial production; (2) high temperature and multi-step reaction conditions are required, which limits the practical application of the reaction; (3) the yield and selectivity are still not high enough and need further improvement, etc.

[0005] Therefore, developing a synthesis process for sulfur-nitrogen heterocyclic compounds with simple operation, low cost and high yield has become the goal of many scientific researchers. It not only has urgent research value, but also has good industrial application prospects. Summary of the invention

[0006] In view of the above-mentioned problems existing in the prior art, the present invention develops a simple, effective and convenient intermediate compound of thiazolyl alkane and its preparation method, as well as a method for preparing thiazolyl alkane using this intermediate compound. The method has the advantages of low cost, high yield and high purity, and is suitable for the requirements of large-scale industrial production.

[0007] One of the technical problems to be solved by the present invention is to disclose a thiazolyl alkane intermediate 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.

[0008] The second technical problem to be solved by the present invention is to disclose a method for preparing a thiazolyl alkane intermediate compound, comprising the following steps:

[0009]

[0010] (a) In a first reaction solvent, compound 1 is added to compound 6 in the presence of a condensation reagent 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 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;

[0011] (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 coupling agent is one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate or dimethyl azodicarboxylate.

[0012] In a preferred embodiment of the present invention, in step (a), the first reaction solvent is one or more of 1,2-dichloroethane, dichloromethane, tetrahydrofuran, tert-butyl methyl ether, 2-methyltetrahydrofuran, chlorobenzene, nitrobenzene, and o-dichlorobenzene.

[0013] 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.

[0014] In a preferred embodiment of the present invention, the amount of the condensing agent is 2-6 times the amount of the compound 1.

[0015] In a preferred embodiment of the present invention, the second reaction solvent is one of tetrahydrofuran, tert-butyl methyl ether, 2-methyltetrahydrofuran, acetonitrile, o-xylene, p-xylene, m-xylene, benzene and toluene.

[0016] In a preferred embodiment of the present invention, the amount of the coupling agent is 2-4 times the amount of the compound 2.

[0017] In a preferred embodiment of the present invention, the amount of the triphenylphosphine is 2-6 times the amount of the compound 2.

[0018] The third technical problem to be solved by the present invention is to disclose a method for preparing a thiazacycloalkane intermediate compound and its application in preparing thiazacycloalkane, further comprising step (c), wherein the compound 4 is stirred in a third reaction solvent under air isolation, a third alkaline reagent is added, and the temperature is raised to reflux for reaction for 4-10 hours to obtain a compound 5 ， 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.

[0019] 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

[0020] The method of the present invention has few experimental steps, low technical difficulty, mild conditions and is easy to operate. The method of the present invention avoids the process of using a multi-step reaction. In addition, a proton base such as potassium hydroxide is used in the deprotection process, and the removed protecting group can be directly recycled as a raw material. The entire reaction process is low in cost, high in yield, and the synthesized sulfur-nitrogen heterocycle has high purity, which is more suitable for the needs of large-scale industrial production. DETAILED DESCRIPTION

[0021] 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

[0022]

[0023] 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

[0024] 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 sequence and stir well. The reaction solution is cooled to 0°C, 383.4 g (2.0 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added thereto and stirred well, and then 202.38 g (2.0 mol) of triethylamine is added dropwise thereto and stirred well after the addition. The reaction solution is kept at 0°C for 1 hour, and 81.53 g (1.1 mol) of 1,3-propylenediamine is added thereto and stirred well. The reaction solution is naturally warmed to room temperature, stirred at room temperature for 6 hours, and the reaction is completed.

[0025] 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 212.34g (0.852mol) of a yellow solid product.

[0026] The yield is 85.20%, and the HPLC purity is 98.51%. 1 H NMR (400MHz, DMSO-d6): δδ11.15(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).

[0027] Step (b): Preparation of the compound of formula 4-1 11-nitro-3,4,6,7-tetrahydro-2,8-propylbenzo[f][1]thio[4,9]diazacycloundecene-1,9-dione

[0028] Add 2100 mL of tetrahydrofuran, 212.34 g (0.852 mol) of the compound of formula 2-1, 104.10 g (0.852 mol) of the compound of formula 3-1, and 491.64 g (1.874 mol) of triphenylphosphine to a 5 L reaction bottle, and stir well. Cool the reaction solution to 0-5°C, and then drop 344.57 g (1.704 mol) of diisopropyl azodicarboxylate into it, drop it within 30 minutes, and stir well. After adding, stir and react for 2 hours under heat preservation and stirring, then heat to reflux reaction, keep heat and reflux reaction for 5 hours, and the reaction is finished.

[0029] 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 500 mL of cold petroleum ether and dried to obtain 249.45 g (0.744 mol) of yellow solid product.

[0030] Yield: 87.3%, HPLC purity: 99.23%, 1 H NMR (400MHz, DMSO-d6): δ 8.75 (s, 1H), 8.64 (d, 1H), 8.22 (d, 1H), 3.35 (t, 4H), 3.21 (t, 4H), 2.77 (t, 4H), 1.83-1.87 (m, 2H).

[0031] Step (c): Preparation of the compound 1,4,8-thiadiazepine

[0032] Keeping nitrogen slightly positive pressure, add 2600 mL of anhydrous ethanol and 249.45 g (0.744 mol) of compound 4-1 to a 5 L reaction bottle and stir well. Then add 154.57 g (2.23 mol) of 90% potassium hydroxide in batches and stir well. After adding, heat to reflux reaction. Keep the temperature at reflux for 6 hours and the reaction is finished.

[0033] 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.

[0034] 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.

[0035] Add 2000 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 105.51 g (0.658 mol) of pure white solid.

[0036] The yield is 88.50%, and the total yield of the three-step reaction is 65.8%.

[0037] Product purity: 98.63% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ2.95 (t, 4H), 2.82 (t, 4H), 2.64 (t, 4H), 1.70-1.74 (m, 2H), 1.58 (br s, 2H).

[0038] 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 159.75 g (0.757 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 75.7%, and the HPLC purity was 98.65%. 1 H NMR (400MHz, DMSO-d6): δ 8.47 (s, 1H), 8.43 (d, 1H), 7.91 (d, 1H). Example 2

[0039]

[0040] 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

[0041] Keeping nitrogen slightly positive pressure, add 750mL 1,2-dichloroethane and 211.13g (1.0mol) 4-nitrophthalic acid of Formula 1 to the 5L reaction bottle in sequence and stir well. Cool the reaction solution to 0℃, add 618.99g (3.0mol) N'N-dicyclohexylcarbodiimide and stir well. Keep the reaction solution at 0℃ for 1 hour, add 105.78g (1..2mol) 1,4-butanediamine and stir well. The reaction solution rises to 80℃ naturally, keeps warm and stirs for 4 hours, and the reaction is completed.

[0042] 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 227.98 g (0.866 mol) of a yellow solid product.

[0043] The yield is 86.60%, and the HPLC purity is 98.57%. 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).

[0044] Step (b): Preparation of the compound of formula 4-2 11-nitro-3,4,6,7-tetrahydro-2,8-butylbenzo[f][1]thio[4,9]diazacycloundecene-1,9-dione

[0045] Add 2100 mL of acetonitrile, 227.98 g (0.866 mol) of the compound of formula 2-2, 105.81 g (0.866 mol) of the compound of formula 3-2, and 499.71 g (1.905 mol) of triphenylphosphine to a 5 L reaction bottle, and stir well. Cool the reaction solution to 0-5°C, and then drop 367.74 g (1.819 mol) of diisopropyl 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 4 hours, and the reaction is finished.

[0046] The reaction solution was cooled naturally to room temperature, 1500 mL of petroleum ether was added thereto, 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 270.21 g (0.773 mol) of yellow solid product.

[0047] Yield: 89.3%, HPLC purity: 98.73%, 1H NMR (400MHz, DMSO-d6): δ 8.74 (s, 1H), 8.64 (d, 1H), 8.22 (d, 1H), 3.35 (t, 4H), 3.19 (t, 4H), 2.76 (t, 4H), 1.54-1.57 (m, 4H).

[0048] Step (c): Preparation of the compound of formula 5-2 1-thia-4,9-diazacycloundecane

[0049] Keeping nitrogen slightly positive pressure, add 2700 mL of anhydrous methanol and 270.21 g (0.773 mol) of compound 4-2 to a 5 L reaction bottle and stir well. Then add 144.64 g (2.320 mol) of potassium hydroxide in batches and stir well. After adding, heat to reflux reaction. Keep the temperature at reflux reaction for 4 hours, and the reaction is finished.

[0050] 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.

[0051] 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.

[0052] Add 1500 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 121.59 g (0.698 mol) of pure white solid.

[0053] The yield is 90.2%, and the total yield of the four-step reaction is 75.2%.

[0054] Product purity: 98.63% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ2.93 (t, 4H), 2.83 (t, 4H), 2.64 (t, 4H), 1.66 (br s, 2H), 1.36-1.40 (m, 4H).

[0055] 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 162.99g (0.772 mol) of a 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%, the HPLC purity was 98.51%, and the nuclear magnetic resonance data were consistent with Example 1. Example 3

[0056]

[0057] 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

[0058] Keeping nitrogen slightly positive pressure, add 750 mL chlorobenzene 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. 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 100°C, kept warm and stirred for 2 hours, and the reaction is completed.

[0059] 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 237.35g (0.856mol) of a yellow solid product.

[0060] The yield is 85.60%, and the HPLC purity is 98.68%. 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).

[0061] Step (b): Preparation of Formula 4-3 Compound 11-nitro-3,4,6,7-tetrahydro-2,8-propylbenzo[f][1]thio[4,9]diazacycloundecene-1,9-dione

[0062] Add 2100ml 2-methyltetrahydrofuran, 237.35g (0.856mol) of formula 2-3, 156.05g (0.856mol) of formula 3-3 compound 3,6-dithia-1,8-octanediol, 493.94g (1.883 mol) of triphenylphosphine to a 5 L reaction bottle, and stir well. Cool the reaction solution to 0-5°C, then drop 447.22g (2.568mol) of diethyl azodicarboxylate into it, drop it within 30 minutes, and stir well. After adding, stir and react for 2 hours under heat preservation and stirring, then heat to reflux reaction, keep heat and reflux reaction for 6 hours, and the reaction is finished.

[0063] The reaction solution was cooled to room temperature naturally, 1200 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 320.14 g (0.756 mol) of yellow solid product.

[0064] Yield: 88.3%, HPLC purity: 98.23%, 1 H NMR (400MHz, DMSO-d6): δ8.74(s,1H), 8.64(d,1H), 8.22(d,1H), 3.35(t,4H), 3.19(t,4H), 2.82(br s,4H), 2.76(t,4H), 1.55-1.59 (m, 4H), 1.23-1.27 (m, 2H).

[0065] Step (c): Preparation of the compound 1,4-dithio-7,13-diazacyclopentadecane of formula 5-3

[0066] Keeping nitrogen slightly positive pressure, add 2700 mL of isopropanol and 320.14 g (0.756 mol) of compound 4-3 to a 5 L reaction bottle and stir well. Then add 90.70 g (2.268 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.

[0067] 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.

[0068] 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.

[0069] 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 163.75 g (0.659 mol) of pure white solid.

[0070] The yield is 87.2%, and the total yield of the four-step reaction is 65.9%.

[0071] Product purity: 98.83% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ2.93 (t, 4H), 2.86 (t, 4H), 2.80 (br s, 4H), 2.64 (t, 4H), 1.52 (br s, 2H), 1.35-1.40 (m, 4H), 1.23-1.26 (m, 2H).

[0072] 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 164.56g (0.779mol) of a light yellow solid powder. The light yellow solid powder was identified as 4-nitrophthalic acid, the protective group raw material recovery rate was 77.9%, the HPLC purity was 98.51%, and the nuclear magnetic resonance data were consistent with Example 1. Example 4

[0073]

[0074] Step (a): Preparation of the compound of formula 2-4 12-nitro-2,3,4,5,6,7,8,9-octahydrobenzo[c][1,6]diazacyclododecane-1,10-dione

[0075] Keeping nitrogen slightly positive pressure, add 750mL 2-methyltetrahydrofuran and 211.13g (1.0mol) 4-nitrophthalic acid of Formula 1 to the 5L reaction bottle in turn and stir well. The reaction solution is cooled to 0℃, and 2275.5g (6.0mol) benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate is added thereto and stirred well. The reaction solution is kept at 0℃ for 1 hour, and 195.36g (1.5 mol) 1,7-heptanediamine is added thereto and stirred well. The reaction solution is naturally raised to 79℃, stirred for 6 hours, and the reaction is completed.

[0076] 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 257.81 g (0.885 mol) of a yellow solid product.

[0077] The yield is 88.5%, and the HPLC purity is 98.61%. 1H NMR (400MHz, DMSO-d6): δ11.12 (br s, 2H), 8.73 (s, 1H), 8.62 (d, 1H), 8.21 (d, 1H), 3.18 (t, 4H), 1.54-1.58 (m, 4H), 1.22-1.26 (m, 4H). Step (b): Preparation of the compound of formula 4-4

[0078] Add 2200 mL of p-xylene, 257.81 g (0.885 mol) of compound 2-4, 267.73 g (0.885 mol) of compound 3-4 3,6,9,12-tetrathiotetradecane-1,14-diol, and 510.68 g (1.947 mol) of triphenylphosphine to a 5 L reaction bottle, and stir well. Cool the reaction solution to 0-5°C, and then drop 517.19 g (3.540 mol) of dimethyl azodicarboxylate into it, drop it within 30 minutes, and stir well. After adding, stir and react for 2 hours under heat preservation and stirring, then heat to reflux reaction, keep heat and reflux reaction for 9 hours, and the reaction is finished.

[0079] 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 300 mL of cold petroleum ether and dried to obtain 444.78 g (0.797 mol) of yellow solid product.

[0080] Yield: 90.1%, HPLC purity: 99.45%, 1 H NMR (400MHz, DMSO-d6): δ8.74(s,1H), 8.64(d,1H), 8.22(d,1H), 3.35(t,4H), 3.19(t,4H), 2.81(br s,12H), 2.76(t,4H), 1.54-1.58(m,4H), 1.23-1.28(m,4H).

[0081] Step (c): Preparation of the compound of formula 5-4

[0082] Keeping nitrogen slightly positive pressure, add 2800 mL of n-butanol and 444.78 g (0.797 mol) of compound 4-4 to a 5 L reaction bottle and stir well. Then add 57.41 g (2.392 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.

[0083] 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.

[0084] 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.

[0085] 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 269.46 g (0.704 mol) of pure white solid.

[0086] The yield is 88.3%, and the total yield of the four-step reaction is 70.4%.

[0087] Product purity: 98.30% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ2.95 (t, 4H), 2.87 (t, 4H), 2.81 (br s, 12H), 2.65 (t, 4H), 1.57 (br s, 2H), 1.35-1.42 (m, 4H), 1.23-1.28 (m, 2H).

[0088] 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 161.54g (0.765 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 76.5%, the HPLC purity was 98.51%, and the nuclear magnetic resonance data were consistent with Example 1. Example 5

[0089]

[0090] Step (a): Preparation of compound 3-3, 6-dithia-1,8-octanediol

[0091] Keeping nitrogen slightly positive pressure, add 800 mL of acetonitrile, 94.19 g (1.0 mol) of compound 7-3 ethanedithiol and 161.02 g (2.0 mol) of compound 8-3 2-chloroethanol to the 5 L reaction bottle in sequence and stir evenly. Heat the reaction solution to 60°C, add 304.06 g (2.2 mol) of potassium carbonate in 6 batches, add all within 1 hour, keep the reaction solution warm and stir for 6 hours, and the reaction is complete.

[0092] The reaction solution was cooled to room temperature naturally, and the insoluble matter was filtered out. The filtrate was evaporated to recover the solvent, and the residue was distilled under reduced pressure to collect the 100°C / 2 mmHg fraction to obtain 166.99 g (0.916 mol) of a white low melting point solid product.

[0093] The yield is 91.60%, and the HPLC purity is 98.72%. 1 H NMR (400MHz, CDCl3): δ3.76 (dd, 4H), 2.80-2.74 (m, 8H), 2.21 (s, 2H). Example 6

[0094]

[0095] Step (a): Preparation of the compound of formula 3-4: 3,6,9,12-tetrathiadecan-1,14-diol

[0096] Compound 7-4 was prepared according to the method described in ACS Nano 2017, 11, 1, 569–578

[0097] Keeping nitrogen slightly positive pressure, add 800 mL of acetonitrile, 214.42 g (1.0 mol) of compound 7-4 3,6-dithiooctane-1,8-dithiol (CAS 25423-55-6) and 249.94 g (2.0 mol) of compound 8-4 2-bromoethanol to the 5 L reaction bottle in sequence and stir evenly. Heat the reaction solution to 60°C, add 304.06 g (2.2 mol) of potassium carbonate in 6 batches, add all within 1 hour, keep the reaction solution warm and stir for 6 hours, and the reaction is complete.

[0098] The reaction solution was cooled to room temperature naturally, and the insoluble matter was filtered out. The filtrate was rotary evaporated to recover the solvent, and the residue was distilled under reduced pressure to collect the 120°C / 0.5 mmHg fraction to obtain 273.18 g (0.903 mol) of a white low melting point solid product.

[0099] The yield is 90.3%, and the HPLC purity is 98.52%. 1 H NMR (400MHz, CDCl3): δ3.74 (dd, 4H), 2.83-2.73 (m, 16H), 2.37 (s, 2H).

[0100] Comparative Example 1

[0101]

[0102] 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 10 was converted into compound 11 was very impure, and the pure product of compound 11 could not be isolated.

[0103] 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.

[0104] Comparative Example 2

[0105]

[0106] Add 2000 mL of acetonitrile, 228.93 g (0.923 mol) of the compound 4-nitrophthaloyl chloride of formula 12 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 solution to 50°C for reaction, and keep the temperature for 8 hours. A large amount of yellow solid is generated in the reaction solution. The plate is used to confirm that the reaction of 4-nitrophthaloyl chloride and 1,3-propylenediamine is complete.

[0107] 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.

[0108]

[0109] 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.

[0110] 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.

[0111] 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 thiazolyl alkane intermediate compound, characterized in that: Its chemical structure is shown in 4. , where n is equal to 1, 2, and m is equal to 1, 2, 4.

2. A method for preparing a thiazolyl alkane intermediate compound, characterized in that: The method comprises the following steps: (a) in a first reaction solvent, in the presence of a condensation reagent, compound 1 is added to compound 6 at a reaction temperature of 0-100° C. for a reaction time of 2-48 hours, wherein the molar ratio of compound 1 to compound 6 is 1:1-1.5, and 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; (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 coupling agent is one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate or dimethyl azodicarboxylate, wherein n is equal to 1, 2, and m is equal to 1, 2, 4.

3. The method for preparing the thiazolyl alkane intermediate compound according to claim 2, characterized in that: In step (a), the first reaction solvent is one or more of 1,2-dichloroethane, dichloromethane, tetrahydrofuran, tert-butyl methyl ether, 2-methyltetrahydrofuran, chlorobenzene, nitrobenzene, and o-dichlorobenzene.

4. The method for preparing the thiazolyl alkane intermediate compound according to claim 2, 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 thiazolyl alkane intermediate 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 a thiazolyl alkane intermediate compound according to claim 2, characterized in that: In step (b), the second reaction solvent is one of tetrahydrofuran, tert-butyl methyl ether, 2-methyltetrahydrofuran, acetonitrile, o-xylene, p-xylene, m-xylene, benzene and toluene.

7. The method for preparing a thiazolyl alkane intermediate 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 a thiazolyl alkane intermediate 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 thiazolyl alkane intermediate compound in preparing thiazolyl alkane, 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. ， The third reaction solvent is one or more of ethanol, methanol, isopropanol, n-butanol, and nitrobenzene, , n is equal to 1, 2, m is equal to 1, 2, 4.

10. The use of the method for preparing the thiazolyl alkane intermediate compound according to claim 9 in preparing thiazolyl alkane, characterized in that: In step (c), the third alkaline reagent is one or more of potassium hydroxide, sodium hydroxide, and lithium hydroxide.

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