Cyclooctanetetraketone, preparation method and application thereof in preparing macrocyclic polyamine compounds

Abstract

The present invention provides cyclooctanetetraketone, a preparation method, and its use in preparing macrocyclic polyamine compounds, belonging to the field of organic synthesis. The present invention creatively uses cyclooctanetetraketone compounds as starting materials, avoiding the macrocyclic ring-closure reactions used in traditional methods, thereby developing a new method for synthesizing macrocyclic polyamine compounds.

Description

[0001] This application is a divisional application of the invention patent application with the application date of January 5, 2022, application number 202210005271.0, and name "Cyclohexanetetraketone, preparation method and its application in the preparation of macrocyclic polyamine compounds". Technical Field

[0002] The present invention relates to the field of organic synthesis, and in particular to cyclooctanetetraketone, a preparation method and application thereof in the preparation of macrocyclic polyamine compounds. Background Art

[0003] As the name suggests, macrocyclic polyamines are macrocyclic compounds containing multiple amino groups. They represent a new class of macrocyclic compounds, following crown ethers and porphyrins. Macrocyclic polyamines can form stable metal complexes with transition metal ions, lanthanide metal ions, and other metals. The ring nitrogen atoms are strongly basic, allowing them to form ammonium ions with hydrogen ions. The rings are easily modified with carboxyl, hydroxyl, phosphate, and other hydrophilic or functional groups, yielding a range of water-soluble ligands. These ligands can be used to understand the structure of metalloenzymes, study catalytic mechanisms, and design and synthesize artificial nucleases.

[0004] For example, Dar-Fu Tai et al. [1] The C in the cyclic tetrapeptide represented by compound 6 was reported. α (i) With C α The distance between (i+3) is less than Therefore, it is very suitable for metal ion chelation. The above method can be used to construct some ligands that are stable and capable of transferring electrons. This enzyme simulation can be used to accelerate some specific reactions.

[0005] For example, Masoud Salavati-Niasari [2] It is reported that the product of compound 9 complexed with magnesium ions can be encapsulated in the nanopores of Y-type zeolite to form a nanocomposite material, which can be used to oxidize cyclohexene in different solvents.

[0006] In addition, macrocyclic amide compounds similar to compounds 6 and 9 can be used to obtain another important compound, cyclopentane, through a one-step reduction reaction. This compound is a very important intermediate for the synthesis of diagnostic reagents and therapeutic drugs.

[0007]

[0008] In the prior art, the synthesis methods of macrocyclic polyamine compounds mainly include direct synthesis and template synthesis. However, no matter which method involves macrocyclic annulation reaction, the raw materials of macrocyclic annulation reaction are very easy to undergo polymerization reaction with each other or themselves. If the conditions are not right, the generated product will be a polymer. Therefore, the annulation reaction in the prior art usually needs to meet the requirements of low concentration (the concentration of the reactants is usually 10 -5 mol / L or less), low feeding speed, low temperature (below 0°C), etc., which brings great difficulties to industrial production.

[0009] Such as Sulekh Chandra and others [3] The following reaction for synthesizing macrocyclic polyamine compounds by direct synthesis is reported:

[0010]

[0011] According to reports, during the above reaction, the diamine must be added dropwise to the diethyl oxalate at an extremely slow rate.

[0012] Another example is Caroline M. Reid, etc. [4] The following reaction for synthesizing macrocyclic polyamine compounds by template synthesis is reported:

[0013]

[0014] According to reports, the realization of the above reaction requires certain requirements for the chirality of the complex formed, and the route is relatively long (constructing a chiral N-Fe complex also requires multiple steps of reaction), the overall yield is relatively low, and industrial production also has certain difficulties.

[0015] References:

[0016] [1]Tai DF, LinY F. Molecularly imprinted cavities template themacrocyclization oftetrapeptides[J]. Chemical Communications, 2008, 1(43): 5598-5600.

[0017] [2]M Salavati-Niasari.Selective oxidation of cyclohexene to di-2-cyclohexenylether by host(nanocavity of zeolite-Y) / guest(manganese(II)complexes with 12-and 14-membered tetraazaz tetraone macrocyclic complexes)nanocomposite materials(HGNM)[J].Journal of Molecular Catalysis A:Chemical,2007,272:249-257.

[0018] [3]Chandra S,Gupta L K.Spectroscopic approach in characterization ofchromium(III),manganese(II),iron(III)and copper(II)complexes with anitrogendonor tetradentate,14-membered azamacrocyclic ligand[J].Spectrochimica ActaPart A Molecular&Biomolecular Spectroscopy,2005,61(9):2139-2144.

[0019] [4]Reid CM, Ebikeme C, Barrett MP, et al.Synthesis and anti-protozoalactivity ofC2-substituted polyazamacrocycles[J].Bioorganic&medicinalchemistry letters,2008,18(7):2455-2458. Summary of the Invention

[0020] The present invention is made to solve the above-mentioned problems, and its purpose is to provide cyclooctanetetraketone and a preparation method thereof, and to prepare a series of macrocyclic polyamine compounds using cyclooctanetetraketone as a starting material. This method avoids the use of macrocyclic ring-closing reactions in traditional methods that are not industrially friendly, and thus obtains a series of macrocyclic polyamine compounds through a completely new route.

[0021] The present invention provides a cyclooctane tetraketone compound, which is any one of the following compounds:

[0022]

[0023] The cyclooctane tetraketone compound provided by the present invention may also have such characteristics, and the structural formula is as follows:

[0024]

[0025] The present invention also provides a method for preparing cyclooctane tetraketone, which is used to prepare compound I, and has the following characteristics:

[0026]

[0027] The steps include:

[0028] Step 1, reacting compound 1 with an olefinic perhydroxylation reagent to obtain compound 2;

[0029] Step 2: Compound 2 is reacted with a hydroxyl oxidation reagent to obtain the target compound I.

[0030] In the preparation method of the cyclooctanetetraketone compound provided by the present invention, used for preparing compound I, it can also have the following characteristics: the olefinic bond perhydroxylation reagent is any one or more of potassium permanganate, osmium tetroxide, methyl rhenium trioxide, iodine-wet silver acetate or peroxide.

[0031] In the preparation method of the cyclooctanetetraketone compound provided by the present invention, used to prepare compound I, it can also have the following characteristics: the hydroxyl oxidation reagent is any one or more of chromic acid, peroxide, Jones reagent, Collins reagent, pyridinium chlorochromate, pyridinium dichromate, permanganate, active manganese dioxide, hypochlorite, hypobromite, DMSO or trialkoxyaluminum.

[0032] The preparation method of the cyclooctane tetraketone compound provided by the present invention, which is used to prepare Compound I, may also have the following characteristics: comprising the following steps:

[0033] Step 1: prepare a hydrogen peroxide-formic acid solution, add compound 1 to the hydrogen peroxide-formic acid solution, react for 4-24 hours, and remove formic acid by distillation under reduced pressure to obtain compound 2;

[0034] Step 2: Dissolve compound 2 and N-methylpyrrol-2-one hydrobromide (CAS: 916313-82-1) in acetonitrile, add hydrogen peroxide, react for 0.1 h-1.5 h, and post-treat to obtain compound I.

[0035] The preparation method of the cyclooctane tetraketone compound provided by the present invention, which is used to prepare Compound I, may also have the following characteristics: comprising the following steps:

[0036] Step 1: Mix 2-3 parts of hydrogen peroxide and 10-20 parts of formic acid by mole to obtain a hydrogen peroxide formic acid solution. Add 1-2 parts of compound 1 dropwise to the hydrogen peroxide formic acid solution at 0°C. After the addition is complete, heat to 30-50°C for a reaction of 4-12 hours, then cool to room temperature for a further reaction of 4-12 hours. Remove formic acid by distillation under reduced pressure to obtain compound 2.

[0037] Step 2: Dissolve 1-2 parts of compound 2 and 0.05-0.2 parts of N-methylpyrrol-2-one hydrobromide in acetonitrile, add 4-8 parts of hydrogen peroxide dropwise, and reflux for 0.1-2 hours after the addition is complete. Then, add aqueous sodium bisulfite solution to quench the reaction, filter out the solid, extract with dichloromethane, combine the organic phases, concentrate under reduced pressure, and perform flash column chromatography to obtain compound I.

[0038] The preparation method of the cyclooctane tetraketone compound provided by the present invention, which is used to prepare Compound I, may also have the following characteristics: comprising the following steps:

[0039] Step 1: 2.8 parts of hydrogen peroxide and 27.4 parts of formic acid were mixed by molar weight to obtain a hydrogen peroxide-formic acid solution. 1 part of compound 1 was added dropwise to the hydrogen peroxide-formic acid solution at 0°C. After the addition was complete, the mixture was heated to 40°C for 8 hours, then cooled to room temperature and continued to react for 8 hours. The formic acid was removed by distillation under reduced pressure to obtain compound 2.

[0040] Step 2: Dissolve 1 part of compound 2 and 0.1 parts of N-methylpyrrol-2-one hydrobromide in acetonitrile, add 5 parts of hydrogen peroxide dropwise, and reflux for 0.5 h after the addition is complete. Then, add aqueous sodium bisulfite solution to quench the reaction, filter out the solid, extract with dichloromethane, combine the organic phases, concentrate under reduced pressure, and perform flash column chromatography to obtain compound I.

[0041] The present invention also provides a method for preparing cyclooctane tetraketone, which is used to prepare compound II and has the following characteristics:

[0042]

[0043] The steps include:

[0044] Step 1, treating compound 3 with a borane reagent and hydrogen peroxide in sequence to obtain compound 4;

[0045] Step 2: react compound 4 with a hydroxyl oxidation reagent to obtain the target compound II.

[0046] In the preparation method of the cyclooctanetetraketone compound provided by the present invention, used to prepare compound II, it can also have the following characteristics: wherein the hydroxyl oxidation reagent is any one or more of chromic acid, peroxide, Jones reagent, Collins reagent, pyridinium chlorochromate, pyridinium dichromate, permanganate, active manganese dioxide, hypochlorite, hypobromite, DMSO or trialkoxyaluminum.

[0047] In the preparation method of the cyclooctanetetraketone compound provided by the present invention, which is used to prepare compound II, the method may also have the following characteristics: wherein the borane reagent is monochloroborane dimethyl sulfide complex or borane.

[0048] In the preparation method of the cyclooctane tetraketone compound provided by the present invention, for preparing compound II, the method may also have such characteristics that step 1 comprises the following operations:

[0049] 2-3 parts by mole of monochloroborane dimethyl sulfide complex (CAS No.: 63348-81-2) are dissolved in an organic solvent, and 1-1.5 parts of 1,3,5,7-cyclooctatetraene are added dropwise under the protection of inert gas. After the addition is complete, the reaction is refluxed. After the reaction is complete, distillation is performed, and a 160°C-170°C fraction is collected. The collected 160°C-170°C fraction is dissolved in an organic solvent, and an aqueous sodium hydroxide solution and hydrogen peroxide are added to react. After post-treatment, compound 4 is obtained.

[0050] In the preparation method of the cyclooctane tetraketone compound provided by the present invention, for preparing compound II, the method may also have such characteristics that step 1 comprises the following operations:

[0051] A solution containing 1-2 parts of compound 3 by mole is added dropwise to a solution containing 4-10 parts of borane, and the mixture is stirred for reaction. 10-20 parts of aqueous sodium hydroxide solution and 10-20 parts of hydrogen peroxide are then added dropwise, and the mixture is post-treated to obtain compound 4.

[0052] In the preparation method of the cyclooctane tetraketone compound provided by the present invention, for preparing compound II, the method may also have such characteristics that step 2 comprises the following operations:

[0053] Compound 4 is dissolved in an organic solvent, and an aqueous solution of TEMPO and sodium hypochlorite is added, followed by stirring for reaction and post-treatment to obtain compound II.

[0054] In the preparation method of the cyclooctane tetraketone compound provided by the present invention, for preparing compound II, the method may also have such characteristics that step 2 comprises the following operations:

[0055] Dissolve 1-2 parts of compound 4 by mole in an organic solvent, add 4-10 parts of pyridinium dichromate, stir to react, and post-treat to obtain compound II.

[0056] The present invention also provides a use of any one of the above-mentioned cyclooctane tetraketones in the preparation of macrocyclic polyamine compounds, having the following technical features:

[0057] Macrocyclic polyamine compounds are

[0058] In the application provided by the present invention, the invention may further have the following characteristics: cyclooctane tetraketone is Macrocyclic polyamine compounds are

[0059] The reaction formula for the preparation of macrocyclic polyamine compounds from cyclooctane tetraketone is as follows:

[0060]

[0061] The process comprises the following reaction steps:

[0062] Compound II is reacted with a carbonyl oximation reagent and then treated with a Lewis acid or a protonic acid to obtain compound 6.

[0063] In the application provided by the present invention, the invention may further have the following characteristics: cyclooctane tetraketone is Macrocyclic polyamine compounds are

[0064] The reaction formula for the preparation of macrocyclic polyamine compounds from cyclooctane tetraketone is as follows:

[0065]

[0066] The process comprises the following reaction steps:

[0067] Compound 9 is obtained by reacting compound I with a carbonyl oximation reagent and then treating with a Lewis acid or a protonic acid.

[0068] The application provided by the present invention may also have the following characteristics: wherein the carbonyl oximation reagent is selected from any one of hydroxylamine hydrochloride, hydroxylamine, chloramine or acetylhydroxylamine.

[0069] The application provided by the present invention may also have the following characteristics: wherein the Lewis acid is selected from any one or more of phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, boron trifluoride, boron trichloride, arylsulfonyl halide, and alkylsulfonyl halide, and the protonic acid is selected from any one or more of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, or polyphosphoric acid.

[0070] The application provided by the present invention may also have the following feature: the reaction of preparing macrocyclic polyamine compounds from cyclooctanetetraketone is a one-pot reaction.

[0071] The application provided by the present invention may also have the following characteristics: the synthesis of compound 6 from compound II comprises the following steps:

[0072] Dissolve 1-2 parts of compound II, 4-12 parts of hydroxylamine hydrochloride and 4-20 parts of sodium acetate in an alcohol solvent by molar amount, stir and react for 0.5 h-5 h, replace the solvent with a weak nucleophilic solvent, add 4-12 parts of sulfonyl chloride, 4-20 parts of a base and 0.01-0.50 parts of DMAP, stir and react for 1 h-5 h, and post-treat to obtain compound 6.

[0073] The application provided by the present invention may also have the following characteristics: the synthesis of compound 6 from compound II comprises the following steps:

[0074] Dissolve 1 part of compound II, 6 parts of hydroxylamine hydrochloride and 7.2 parts of sodium acetate in ethanol in molar amounts, stir and react for 1 hour, replace the solvent with DMF, add 10 parts of p-toluenesulfonyl chloride or p-bromobenzenesulfonyl chloride, 10 parts of triethylamine and 0.1 part of DMAP, stir and react for 3 hours, add dichloromethane to dilute, wash with water and saturated sodium chloride aqueous solution, combine the organic phases, dry and concentrate to obtain compound 6.

[0075] The application provided by the present invention may also have the following characteristics: the synthesis of compound 6 from compound II comprises the following steps:

[0076] Dissolve 1-2 parts of compound II, 4-12 parts of hydroxylamine hydrochloride and 4-20 parts of sodium acetate in an alcohol solvent by molar amount, stir and react for 0.5 h-5 h, evaporate the solvent, add protonic acid, raise the temperature to 80°C-150°C, stir and react for 0.1 h-5 h, return to room temperature after the reaction, adjust the pH value of the reaction system to 5-7, extract with dichloromethane, combine the organic phases, dry, concentrate and purify to obtain compound 9.

[0077] The application provided by the present invention may also have the following characteristics: the synthesis of compound 6 from compound II comprises the following steps:

[0078] 1 part of compound II, 6 parts of hydroxylamine hydrochloride and 7.2 parts of sodium acetate were dissolved in ethanol by molar amount, stirred and reacted for 1 hour, the solvent was evaporated, 70%-90% sulfuric acid was added, the temperature was raised to 100°C, and the reaction was stirred for 3 hours. After the reaction, the temperature was returned to room temperature, and the pH value of the reaction system was adjusted to 6 with ammonia water. The reaction was diluted with water and extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound 9.

[0079] The application provided by the present invention may also have the following characteristics: the synthesis of compound 9 from compound 1 comprises the following steps:

[0080] 1-2 parts of compound I, 4-12 parts of hydroxylamine hydrochloride, and 4-20 parts of sodium acetate, by molar amount, were dissolved in an alcohol solvent and stirred for 0.5-5 hours. The solvent was replaced with a weak nucleophilic solvent, 4-12 parts of sulfonyl chloride, 4-20 parts of a base, and 0.01-0.50 parts of DMAP were added, and the reaction was stirred for 1-5 hours. After post-treatment, compound 9 was obtained.

[0081] The application provided by the present invention may also have the following characteristics: the synthesis of compound 9 from compound 1 comprises the following steps:

[0082] Dissolve 1 part of compound I, 6 parts of hydroxylamine hydrochloride and 7.2 parts of sodium acetate in ethanol by molar amount, stir and react for 1 hour, replace the solvent with DMF, add 10 parts of p-toluenesulfonyl chloride or p-bromobenzenesulfonyl chloride, 10 parts of triethylamine and 0.1 part of DMAP, stir and react for 3 hours, add dichloromethane to dilute, wash with water and saturated sodium chloride aqueous solution, combine the organic phases, dry and concentrate to obtain compound 9.

[0083] The application provided by the present invention may also have the following characteristics: the synthesis of compound 9 from compound 1 comprises the following steps:

[0084] Dissolve 1-2 parts of compound I, 4-12 parts of hydroxylamine hydrochloride and 4-20 parts of sodium acetate in a solvent by molar amount, stir and react for 0.5 h-5 h, evaporate the solvent, add protonic acid, raise the temperature to 80°C-150°C, stir and react for 0.1 h-5 h, return to room temperature after the reaction, adjust the pH value of the reaction system to 5-7, extract with dichloromethane, combine the organic phases, dry, concentrate and purify to obtain compound 9.

[0085] The application provided by the present invention may also have the following characteristics: the synthesis of compound 9 from compound 1 comprises the following steps:

[0086] 1 part of compound I, 6 parts of hydroxylamine hydrochloride and 7.2 parts of sodium acetate by mole were dissolved in ethanol, stirred and reacted for 1 hour, the solvent was evaporated, 70%-90% sulfuric acid was added, the temperature was raised to 100°C, and the reaction was stirred for 3 hours. After the reaction, the temperature was returned to room temperature, and the pH value of the reaction system was adjusted to 6 with ammonia water. The reaction was diluted with water and extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound 9.

[0087] The application provided by the present invention may also have the following characteristics: wherein the weak nucleophilic reagent is any one or more of acetonitrile, acetone, dichloromethane, chloroform or DMF.

[0088] Functions and effects of the invention

[0089] According to the cyclooctane tetraketone involved in the present invention, a new synthesis route of macrocyclic polyamine compounds is opened up because cyclooctane tetraketone is creatively used as an intermediate for synthesizing macrocyclic polyamine compounds.

[0090] According to the preparation method of cyclooctatetraone involved in the present invention, cyclooctatetraone compounds can be synthesized in an extremely simple and efficient manner because 1,5-cyclooctadiene or 1,3,5,7-cyclooctatetraene is innovatively used as the starting material.

[0091] According to the application of cyclooctanetetraketone in the preparation of macrocyclic polyamine compounds involved in the present invention, a new method for synthesizing macrocyclic polyamine compounds is developed because cyclooctanetetraketone compounds are creatively used as starting materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Figure 1 is the hydrogen spectrum of compound II prepared in Example 2 of the present invention;

[0093] Figure 2 It is the carbon spectrum of compound II prepared in Example 2 of the present invention. DETAILED DESCRIPTION

[0094] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is described in detail below with reference to embodiments and drawings.

[0095] In the following examples, ammonia water is a commercially available aqueous ammonia solution with a concentration of 25%-28%, which is not titrated before use.

[0096] In the following examples, sulfuric acid with a mass fraction of 70%-90% was prepared by using commercially available concentrated sulfuric acid with a mass fraction of 98%.

[0097] In the following examples, hydrogen peroxide was a commercially available 30% hydrogen peroxide solution, which was not titrated before use.

[0098] In the following examples, the sodium hypochlorite aqueous solution is a commercially available 30% sodium hypochlorite aqueous solution, which was not titrated before use.

[0099] In the following examples, DMF is N,N-dimethylformamide, and DMAP is 4-dimethylaminopyridine.

[0100] In the following examples, unless otherwise specified, all raw materials are commercially available.

[0101] In Examples 5-8, the possible reaction mechanism for preparing compound 6 from compound II is as follows:

[0102]

[0103] In the above formula, E is an electrophilic reagent.

[0104] It is worth noting that the reaction mechanism described above is only theoretically deduced by the applicant based on experimental phenomena and has not been rigorously verified experimentally. During the actual reaction process, some or all of the raw materials may obtain the target product through other reaction pathways.

[0105] In Examples 3-4, the possible reaction mechanism for preparing compound 9 from compound I is similar to the possible reaction mechanism for preparing compound 6 from compound II described above, and will not be repeated here.

[0106] <Example 1>

[0107] A preparation method of 1,2,5,6-cyclooctanetetraketone

[0108] This embodiment provides a method for preparing 1,2,5,6-cyclooctanetetraketone, and the reaction equation is as follows:

[0109]

[0110] The process comprises the following reaction steps:

[0111] Step 1: 293.3 g of 30% hydrogen peroxide (2.59 mol, 2.8 eq) and 1165 g of formic acid (25.3 mol, 27.4 eq) were mixed to obtain a hydrogen peroxide-formic acid solution. 100 g of compound 1 (0.924 mol, 1 eq) was added dropwise to the hydrogen peroxide-formic acid solution at 0°C. After the addition was complete, the mixture was heated to 40°C and stirred for 8 h. The mixture was then cooled to room temperature and stirred for 8 h. The formic acid and water were removed by distillation under reduced pressure to obtain 125 g of compound 2 with a yield of 76.7%.

[0112] Step 2: 100 g of compound 2 (0.568 mol, 1 eq) and 19.4 g of N-methylpyrrole-2-one hydrobromide (0.057 mol, 0.1 eq) were dissolved in 300 mL of acetonitrile, and 322 g of 30% hydrogen peroxide (2.84 mol, 5 eq) was added dropwise. After the addition was complete, the mixture was refluxed for 0.5 h, and 200 mL of 1.5 mol / L aqueous sodium bisulfite solution was added to quench the reaction. The solid was filtered off, and the mixture was extracted with dichloromethane three times. The organic phases were combined, concentrated under reduced pressure, and subjected to flash column chromatography to obtain 68.7 g of compound I with a yield of 71.9%.

[0113] Compound I is characterized as follows:

[0114] 1 H NMR (400MHz, CDCl3) δ2.75 (s, 8H).

[0115] <Example 2>

[0116] A preparation method of 1,3,5,7-cyclooctanetetraketone

[0117] This embodiment provides a method for preparing 1,3,5,7-cyclooctanetetraketone, and the reaction equation is as follows:

[0118]

[0119] The process comprises the following reaction steps:

[0120] Step 1: 50 g of compound 3 (480 mmol, 1 eq) was dissolved in 200 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 3. The tetrahydrofuran solution of compound 3 was added dropwise to 2.88 L of a 1 mol / L borane solution in tetrahydrofuran. The mixture was stirred at room temperature for 1 h. 1.44 L of a 5 mol / L aqueous sodium hydroxide solution and 652 g of 30% hydrogen peroxide (5.76 mol, 12 eq) were added dropwise in sequence. The mixture was stirred for 6 h, allowed to stand, and separated. The organic phase was taken and washed with a saturated aqueous sodium carbonate solution (500 mL × 2). The organic phase was concentrated under reduced pressure and subjected to column chromatography to obtain 52.5 g of compound 4 with a yield of 62.1%.

[0121] Step 2: Dissolve 50 g of compound 4 (283.8 mmol, 1 eq) in 400 mL of dichloromethane, add 534 g of pyridinium dichromate (1.42 mol, 5 eq), and stir at room temperature for 4 h. Wash with water (250 mL × 3), take the organic phase, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography to obtain 40.5 g of compound II with a yield of 84.8%.

[0122] like Figure 1-2 As shown, the characterization of compound II is as follows:

[0123] 1 H NMR(400MHz,D2O)δ3.02(s,8H). 13 C NMR (101MHz, CDCl3) δ36.72, 208.34.

[0124] <Example 3>

[0125] Preparation method of compound 9

[0126] This example provides a one-pot method for preparing compound 9, and the reaction equation is as follows:

[0127]

[0128] The process comprises the following reaction steps:

[0129] 20 g of compound I (118.9 mmol, 1 eq), 49.5 g of hydroxylamine hydrochloride (713.4 mmol, 6 eq) and 70.2 g of sodium acetate (856.1 mmol, 7.2 eq) were dissolved in 150 mL of ethanol and stirred for 1 h. 100 mL of DMF was added and about 70 mL of ethanol was distilled off. 100 mL of DMF was then added and all the remaining ethanol was distilled off. 120.4 g of triethylamine (1.19 mol, 10 eq), 226.9 g of p-toluenesulfonyl chloride (1.19 mol, 10 eq) and 1.45 g of DMAP (11.9 mmol, 0.1 eq) were added in sequence and stirred for 3 h. 100 mL of dichloromethane was added to dilute the mixture and the mixture was washed with water (200 mL × 3) and saturated sodium chloride aqueous solution (200 mL × 1). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 5.8 g of compound 9 in a yield of 21.4%.

[0130] <Example 4>

[0131] This example provides a one-pot method for preparing compound 9, and the reaction equation is as follows:

[0132]

[0133] The process comprises the following reaction steps:

[0134] 20 g of compound I (118.9 mmol, 1 eq), 49.5 g of hydroxylamine hydrochloride (713.4 mmol, 6 eq) and 70.2 g of sodium acetate (856.1 mmol, 7.2 eq) were dissolved in 150 mL of ethanol and stirred for 1 h. The ethanol was distilled off and 200 mL of 80% aqueous sulfuric acid solution was added dropwise under an ice-water bath. The temperature was raised to 100 ° C. and the reaction was stirred for 3 h. After the reaction was completed, the temperature was returned to room temperature. The pH value of the reaction system was adjusted to 6 with ammonia water, diluted with 100 mL of water, and extracted with dichloromethane (250 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 4.2 g of compound 9 with a yield of 15.5%.

[0135] <Example 5>

[0136] Preparation method of compound 6

[0137] This example provides a one-pot method for preparing compound 6, and the reaction equation is as follows:

[0138]

[0139] The process comprises the following reaction steps:

[0140] 20 g of compound II (118.9 mmol, 1 eq), 49.5 g of hydroxylamine hydrochloride (713.4 mmol, 6 eq) and 70.2 g of sodium acetate (856.1 mmol, 7.2 eq) were dissolved in 150 mL of ethanol and stirred for 1 h. 100 mL of DMF was added and about 70 mL of ethanol was distilled off. 100 mL of DMF was added and all the remaining ethanol was distilled off. 120.4 g of triethylamine (1.19 mol, 10 eq), 226.9 g of p-toluenesulfonyl chloride (1.19 mol, 10 eq) and 1.45 g of DMAP (11.9 mmol, 0.1 eq) were added in sequence and stirred for 3 h. 100 mL of dichloromethane was added to dilute the mixture and the mixture was washed with water (200 mL × 3) and saturated sodium chloride aqueous solution (200 mL × 1). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 23.7 g of compound 6 in a yield of 87.3%.

[0141] Compound 6 is characterized by:

[0142] 1 H NMR (400MHz, CDCl3) δ3.97 (s, 8H), 6.92 (s, 4H).

[0143] <Example 6>

[0144] Preparation method of compound 6

[0145] This example provides a one-pot method for preparing compound 6, and the reaction equation is as follows:

[0146]

[0147] The process comprises the following reaction steps:

[0148] 20 g of compound II (118.9 mmol, 1 eq), 49.5 g of hydroxylamine hydrochloride (713.4 mmol, 6 eq) and 70.2 g of sodium acetate (856.1 mmol, 7.2 eq) were dissolved in 150 mL of ethanol and stirred for 1 h. The ethanol was distilled off and 200 mL of 80% aqueous sulfuric acid solution was added dropwise under an ice-water bath. The temperature was raised to 100° C. and the reaction was stirred for 3 h. After the reaction was completed, the temperature was returned to room temperature. The pH value of the reaction system was adjusted to 6 with ammonia water, diluted with 100 mL of water, and extracted with dichloromethane (250 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 5.1 g of compound 9 with a yield of 18.8%.

[0149] <Example 7>

[0150] Preparation method of compound 6

[0151] This example provides a one-pot method for preparing compound 6, which is basically the same as the preparation method provided in Example 5, except that the solvent replacement step is not performed. The reaction equation is as follows:

[0152]

[0153] The process comprises the following reaction steps:

[0154] 20 g of compound II (118.9 mmol, 1 eq), 49.5 g of hydroxylamine hydrochloride (713.4 mmol, 6 eq) and 70.2 g of sodium acetate (856.1 mmol, 7.2 eq) were dissolved in 150 mL of ethanol and stirred for 1 h. 120.4 g of triethylamine (1.19 mol, 10 eq), 226.9 g of p-toluenesulfonyl chloride (1.19 mol, 10 eq) and 1.45 g of DMAP (11.9 mmol, 0.1 eq) were added in sequence and stirred for 3 h. 100 mL of dichloromethane was added to dilute the mixture, washed with water (200 mL × 3), washed with saturated sodium chloride aqueous solution (200 mL × 1), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 5.5 g of compound 6 with a yield of 20.3%.

[0155] <Example 8>

[0156] Screening of reaction conditions for the preparation of compound 6

[0157] This example screens the Lewis acid or protonic acid in the preparation method provided in Example 5 or Example 6.

[0158] When Lewis acid is used, the reaction conditions are as follows (hereinafter referred to as reaction conditions A):

[0159] 20 g of compound II (118.9 mmol, 1 eq), 49.5 g of hydroxylamine hydrochloride (713.4 mmol, 6 eq) and 70.2 g of sodium acetate (856.1 mmol, 7.2 eq) were dissolved in 150 mL of ethanol and stirred for 1 h. 100 mL of DMF was added and about 70 mL of ethanol was distilled off. Then 100 mL of DMF was added and all the remaining ethanol was distilled off. 120.4 g of triethylamine (1.19 mol, 10 eq), Lewis acid, and 1.45 g of DMAP (11.9 mmol, 0.1 eq) were added in sequence and stirred for 3 h. 100 mL of dichloromethane was added to dilute the mixture, washed with water (200 mL × 3), washed with saturated sodium chloride aqueous solution (200 mL × 1), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to collect the target product.

[0160] When a protonic acid is used, the reaction conditions are as follows (hereinafter referred to as reaction conditions B):

[0161] 20 g of compound II (118.9 mmol, 1 eq), 49.5 g of hydroxylamine hydrochloride (713.4 mmol, 6 eq) and 70.2 g of sodium acetate (856.1 mmol, 7.2 eq) were dissolved in 150 mL of ethanol and stirred for 1 h. The ethanol was distilled off and protonic acid was added dropwise under an ice-water bath. The temperature was raised to 100 ° C. and stirred for 3 h. After the reaction, the temperature was returned to room temperature. The pH value of the reaction system was adjusted to 6 with ammonia water, diluted with 100 mL of water, extracted with dichloromethane (250 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to collect the target product.

[0162] The screening results are shown in Table 1:

[0163] Table 1 Reaction conditions screening table

[0164] Serial number Lewis acid or protonic acid Reaction conditions Dosage Yield 1 p-Toluenesulfonyl chloride Reaction Conditions A 1.19 mol 87.3％ 2 p-Toluenesulfonyl chloride Reaction Conditions A 0.71 mol 72.7％ 3 4-Bromobenzenesulfonyl chloride Reaction Conditions A 1.19 mol 84.4％ 4 Methanesulfonyl chloride Reaction Conditions A 1.19 mol 26.3％ 5 Thionyl chloride Reaction Conditions A 1.19 mol 20.5％ 6 Phosphorus oxychloride Reaction Conditions A 1.19 mol 23.8％ 7 80% sulfuric acid aqueous solution Reaction Conditions B 200mL 18.8％ 8 70% sulfuric acid aqueous solution Reaction Conditions B 200mL 15.7％ 9 36% hydrochloric acid aqueous solution Reaction Conditions B 300mL 16.0％ 10 Polyphosphoric acid Reaction Conditions B 200mL 23.9％

[0165] As shown in Table 1, when protonic acid and some Lewis acids are used in the reaction, the yields are low. However, when p-toluenesulfonyl chloride and p-bromobenzenesulfonyl chloride are used as the reaction partners, the yields are greatly improved.

[0166] The reason for the above phenomenon may be that in the above reaction, compound II will first form an oxime with hydroxylamine hydrochloride, and from the perspective of molecular orbital theory, the group in the trans position of the oxime hydroxyl group is the group that can migrate preferentially, but under acidic conditions, the cis and trans conversions of the oxime are very fast, so the above reaction may theoretically produce multiple isomers, which will make it difficult to obtain a single product in high yield. However, when sulfonic acid chloride is used, during the reaction, sulfonyl chloride will react with oxime to form a sulfonamide intermediate. For substrates such as compound II, if arylsulfonyl chloride represented by p-toluenesulfonyl chloride or p-bromobenzenesulfonyl chloride is used, due to the steric hindrance effect, the four sulfonamide groups of the intermediate formed will be in the trans position at the same time and difficult to convert to the cis position, so the reaction can obtain a higher yield; while the steric hindrance of the methanesulfonamide formed by methanesulfonyl chloride is not enough to prevent the cis and trans isomers of the oxime from converting to each other, so the yield is also low.

[0167] <Example 9>

[0168] Preparation of compound 10

[0169] This example provides a method for preparing compound 10 (cyclamenine) from compound 6, and the reaction equation is:

[0170]

[0171] The process comprises the following reaction steps:

[0172] 20 g of compound 6 (87.6 mmol, 1 eq) was dissolved in 120 mL of tetrahydrofuran, and 182 mL of a 2.5 mol / L solution of lithium aluminum hydride in tetrahydrofuran was added dropwise in an ice-water bath. After the addition was complete, the mixture was refluxed at 68°C for 8 h. After the reaction was complete, 200 mL of a 2 mol / L aqueous sodium hydroxide solution was added in an ice-water bath to quench the reaction. The solid was filtered off, and the mixture was extracted with 200 mL of dichloromethane. The organic phases were combined, washed once with 200 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to flash column chromatography to obtain 11.0 g of compound 10 in a yield of 72.8%.

[0173] Compound 10 was characterized by:

[0174] 1 H NMR (400MHz, CDCl3) δ2.68 (s, 16H), 2.18 (s, 4H).

[0175] Functions and Effects of the Embodiments

[0176] According to the application of cyclooctanetetraketone in the preparation of macrocyclic polyamine compounds involved in the above embodiments, a new method for synthesizing macrocyclic polyamine compounds is opened up because cyclooctanetetraketone compounds are creatively used as starting materials.

[0177] Furthermore, since 1,3,5,7-cyclooctanetetraone is used as the starting material and p-toluenesulfonyl chloride or p-bromobenzenesulfonyl chloride is used as the Lewis acid, macrocyclic polyamine compounds can be prepared in high yield, thereby avoiding the use of macrocyclic ring-closure reactions with low industrial production efficiency used in traditional preparation methods to prepare macrocyclic polyamine compounds.

[0178] Furthermore, since a one-pot method is adopted in the process of preparing macrocyclic polyamine compounds using 1,3,5,7-cyclooctanetetraketone, the reaction process is effectively shortened and the reaction efficiency is greatly improved.

[0179] Furthermore, since the one-pot method includes a solvent replacement step, the reaction yield can be further improved, making it suitable for industrial production.

[0180] The above embodiments are preferred examples of the present invention and are not intended to limit the scope of protection of the present invention.

Claims

1. The use of cyclooctane tetraketone in the preparation of macrocyclic polyamine compounds, characterized in that: Cyclooctanetetraketone Macrocyclic polyamine compounds are The reaction formula for the preparation of macrocyclic polyamine compounds from cyclooctane tetraketone is as follows: The process comprises the following reaction steps: Dissolve 1-2 parts of compound I, 4-12 parts of hydroxylamine hydrochloride and 4-20 parts of sodium acetate in an alcohol solvent by molar amount, stir and react for 0.5h-5h, replace the solvent with a weak nucleophilic solvent, add 4-12 parts of p-toluenesulfonyl chloride, 4-20 parts of a base and 0.01-0.50 parts of DMAP, stir and react for 1h-5h, and post-treat to obtain compound 9. The weak nucleophile is DMF.

2. The use according to claim 1, characterized in that The reaction of preparing macrocyclic polyamine compounds from cyclooctanetetraketone is a one-pot reaction.

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