Preparation method of cycleanine

Abstract

The invention discloses a preparation method of cycleanine. The preparation method specifically comprises the following steps: step 1, in the presence of an ether solvent, reacting an intermediate 1 with butanedione to prepare an intermediate 2; step 2, reacting the intermediate 2 with glyoxal in the presence of a solvent, a reducing agent and benzotriazole to prepare an intermediate 3; step 3, reacting the intermediate 3 with hydrochloric acid in the presence of a solvent to prepare an intermediate 4; step 4, reacting the intermediate 4 with alkali in the presence of a solvent to prepare an intermediate 5; and step 5, dewatering the intermediate 5 in a solvent to prepare cycleanine. The preparation method disclosed by the invention is simple to operate, high in productivity, simple in equipment, good in safety, low in cost and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically, to a method for preparing cyclotinocyanine. Background Technology

[0002] Cyclin (also known as 1,4,7,10-tetraazacyclododecane) is a crucial intermediate in the synthesis of diagnostic reagent kits and therapeutic drugs. Cyclin can be used to remove stones from the body and inhibit myocardial ischemia-reperfusion injury. It is particularly valuable in the manufacture of contrast agents for medical imaging technologies such as MRI, CT, and ultrasound, as well as in radiotherapy for malignant tumors. Cyclin and its derivatives demonstrate significant application value. Furthermore, as a precursor for synthesizing macrocyclic chelating agents for metal ions, cyclin can form highly stable complexes with ions. In particular, the complexes formed with paramagnetic metal ions (such as gadolinium ions) can be used in medical diagnostics without the high toxicity caused by free ions, exhibiting extremely high safety characteristics.

[0003] Currently, the main methods for synthesizing cyclooxaline include the Stetter method, the Richman-Atkins method, the Weisman method, the diethyl oxalate condensation method (Wuhan University, Wei Junfa et al., 1997), the glyoxal condensation method (Beracol International AG), and the amide acetal method (reported by Zhang Juan et al., Department of Chemical Engineering, Northwestern Polytechnical University, 2005, and Liu Yan, East China Normal University, 2012). Among these, the Stetter method is a pioneering method for synthesizing cyclooxaline, but the raw materials are difficult to obtain and it requires highly diluted conditions, so it is rarely used now. The improved Richman-Atkins method is a classic method for synthesizing cyclooxaline, but it involves many steps, consumes a lot of reagents, and requires highly skilled operators, making it difficult to achieve industrial production. The Weisman method utilizes the salt formation of dithiooxalamide followed by reaction with triethylenetetramine, and then hydrolysis to obtain the target product; although this method only involves three steps and has a relatively high yield, the raw material dithiooxalamide is expensive, which is also unfavorable for industrial production. The diethyl oxalate condensation method has a low yield, resulting in a low overall yield. The process reported in Tetrahedron Letters 39 (1998) 6861-6864, using triethylenetetramine and 2,3-butanedione as raw materials, is time-consuming and requires column purification of intermediates, making the process cumbersome and unsuitable for industrialization. J. Org. Chem. 2002, 67, 4081-4085 reports a method involving the reaction of triethylenetetramine and N,N-dimethylformamide dimethyl acetal, followed by reaction with 1,2-dibromoethane to generate a quaternary ammonium salt, which is then hydrolyzed under alkaline conditions to generate cyclotrenin. However, this synthetic route suffers from difficulties in detecting the intermediate quaternary ammonium salt and the inability to track the reaction progress in real time, also hindering industrial production. Therefore, developing a low-cost, efficient, and green method for the synthesis of cyclotrenin is of significant importance and promise. Summary of the Invention

[0004] The technical problem this invention aims to solve is to overcome the lack of existing methods for preparing ring-shaped ginseng, and to provide a method for preparing ring-shaped ginseng. The preparation method of this invention is simple to operate, has high production capacity, requires simple equipment, is safe, and has low cost, making it suitable for industrial production.

[0005] The present invention provides a method for preparing intermediate 2, which includes the following steps: in the presence of an ether solvent, intermediate 1 is reacted with butanedione to prepare intermediate 2;

[0006]

[0007] In one embodiment, the ether solvent is tetrahydrofuran.

[0008] In one embodiment, the molar ratio of intermediate 1 to dimethyl butylene is 1:(1.0 to 2.0), preferably 1:(1.0 to 1.1); more preferably 1:1.

[0009] In one embodiment, the mass-to-volume ratio of intermediate 1 to solvent is (0.06-1.0) g / mL; preferably 0.08 g / mL.

[0010] In one embodiment, the reaction time is 1 to 10 hours; preferably 1 to 4 hours; more preferably 2 hours.

[0011] In one approach, the reaction proceeds directly to the next step without separating the reaction solution.

[0012] In one embodiment, the reaction is performed as follows: a mixture of dimethyl ethyl ketone and solvent is added dropwise to a mixture of intermediate 1 and solvent at -15℃ to -10℃, and the mixture is kept at this low temperature for 2 hours.

[0013] In one embodiment, the reaction is carried out in the presence of nitrogen.

[0014] In one embodiment, the reaction does not require the addition of a dehydrating agent.

[0015] In one embodiment, the reaction raw materials are the solvent, intermediate 1, and dimethylglyoxal.

[0016] This invention also provides a method for preparing ring-shaped ginseng; it includes the following steps:

[0017] Step 1, preparation method of intermediate 2, wherein the preparation method of intermediate 2 is as described in any embodiment of the present invention;

[0018] Step 2: In the presence of solvent, reducing agent and benzotriazole, intermediate 2 reacts with glyoxal to prepare intermediate 3;

[0019]

[0020] Step 3: In the presence of a solvent, intermediate 3 reacts with hydrochloric acid to prepare intermediate 4;

[0021]

[0022] Step 4: In the presence of a solvent, intermediate 4 reacts with a base to prepare intermediate 5;

[0023]

[0024] Step 5: After removing water from intermediate 5 in a solvent, cyclohexane is prepared.

[0025]

[0026] In one embodiment, the solvent in step 2 is the ether solvent from step 1; more preferably, it is tetrahydrofuran.

[0027] In one embodiment, the reducing agent in step 2 is lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, calcium borohydride, or sodium triacetoxyborohydride; preferably sodium borohydride.

[0028] In one embodiment, in step 2, the glyoxal is a 40% glyoxal aqueous solution.

[0029] In one embodiment, the molar ratio of intermediate 1 in step 1 to benzotriazole in step 2 is 1:(1.8-2.5); preferably 1:(2.1-2.3); and more preferably 1:2.3.

[0030] In one embodiment, the mass-to-volume ratio of intermediate 1 in step 1 to solvent in step 2 is (0.25-0.40) g / mL; preferably 0.33 g / mL.

[0031] In one embodiment, the molar ratio of intermediate 1 in step 1 to reducing agent in step 2 is 1:(1.5-2.0); preferably 1:(1.7-1.9); and more preferably 1:1.8.

[0032] In one embodiment, the molar ratio of intermediate 1 in step 1 to glyoxal in step 2 is 1:(1.0-2.0); preferably 1:(1.0-1.1), and more preferably 1:1.0.

[0033] In one embodiment, the reaction temperature in step 2 is -20 to 0°C; preferably -15 to 10°C or -10 to 0°C.

[0034] In one embodiment, the reaction time in step 2 is 20-30 hours; preferably 25 hours.

[0035] In one embodiment, step 2 of the reaction further includes the following post-treatment steps: quenching with hydrochloric acid (e.g., 36% hydrochloric acid) to pH 5-6, and concentrating the solvent (e.g., tetrahydrofuran).

[0036] In one embodiment, step 2 involves the following reaction steps: adding a solution of benzotriazole and tetrahydrofuran dropwise to the reaction solution from step 1 at -15 to -10°C, followed by stirring at low temperature for 30 minutes after the addition is complete; then adding a 40% glyoxal aqueous solution, followed by maintaining the temperature at low temperature for 15 hours after the addition is complete; finally, adding NaBH4 at -10 to 0°C, followed by maintaining the temperature at low temperature for 10 hours after the addition is complete.

[0037] In one embodiment, in step 3, the solvent is an alcohol solvent, a nitrile solvent, or an ether solvent; the alcohol solvent may be methanol or ethanol; the nitrile solvent may be acetonitrile; the ether solvent may be tetrahydrofuran; preferably, methanol.

[0038] In one embodiment, the hydrochloric acid in step 3 is 36% hydrochloric acid.

[0039] In one embodiment, the mass-to-volume ratio of intermediate 1 in step 1 to solvent in step 3 is (0.4-0.6) g / mL; preferably 0.5 g / mL.

[0040] In one embodiment, the molar ratio of intermediate 1 in step 1 to hydrochloric acid in step 3 is 1:(8-12); preferably 1:10.

[0041] In one embodiment, step 3 involves the following steps: adding a solvent to the reactants from step 2, adding 36% hydrochloric acid dropwise at 40°C–60°C, raising the temperature to 60°C–70°C after the addition is complete, reacting for 5 hours, and then cooling to 40°C–50°C to obtain intermediate 4.

[0042] In one embodiment, step 3 of the reaction further includes the following post-processing step: filtrate recovery of benzotriazole.

[0043] In one embodiment, the solvent in step 4 is water.

[0044] In one embodiment, the alkali in step 4 is sodium hydroxide; preferably, it is a 48% sodium hydroxide aqueous solution.

[0045] In one embodiment, the mass-to-volume ratio of intermediate 1 in step 1 to solvent in step 4 is (0.25-0.4) g / mL; preferably 0.33 g / mL.

[0046] In one embodiment, the molar ratio of intermediate 1 in step 1 to the alkali in step 4 is 1:(2-4); preferably 1:3.1.

[0047] In one embodiment, step 4 involves adding the reaction product from step 3 to water, adding 48% sodium hydroxide aqueous solution dropwise until the pH reaches 14, cooling to 0°C, and then filtering.

[0048] In one embodiment, the solvent in step 5 is a benzene-based solvent; preferably toluene.

[0049] In one embodiment, the mass-to-volume ratio of intermediate 1 in step 1 to solvent in step 5 is (0.15-0.25) g / mL; preferably 0.2 g / mL.

[0050] In one embodiment, step 5 involves the following steps: mixing the reaction product from step 4 with toluene, heating to 100–150°C and refluxing to separate water, filtering while hot at 80–90°C after water separation, concentrating the filtrate under reduced pressure to remove most of the toluene, cooling to 0°C to crystallize, and filtering and drying to obtain cyclohexanetin.

[0051] In one embodiment, the preparation method of the ring-shaped tinylamine further includes a purification method for crude triethylenetetramine; preferably, the purification method includes the following steps:

[0052] ① In toluene and water, crude triethylenetetramine is dissolved, kept at a warm temperature, and crystals precipitate in the presence of triethylenetetramine hydrate seed crystals;

[0053] ② In the presence of toluene, triethylenetetramine hydrate was dehydrated to prepare triethylenetetramine (i.e., intermediate 1).

[0054] In one embodiment, the volume ratio of toluene to water in the purification method ① can be (12-14):1; preferably 13.3:1.

[0055] In one embodiment, in the purification method ①, the mass-to-volume ratio of the crude triethylenetetramine to the solvent is (0.4-0.6) g / mL; preferably 0.5 g / mL.

[0056] In one embodiment, in the refining method ①, the molar ratio of the crude triethylenetetramine to the triethylenetetramine hydrate seed crystal is 1:(0.01-0.02); preferably 1:0.014.

[0057] In one embodiment, the reaction time of the refining method ① is 1-4 hours; preferably 2 hours.

[0058] In one embodiment, the temperature of the refining method ① is 30–50°C; preferably 35–45°C.

[0059] In one embodiment, the refining method ① further includes the following post-processing steps: cooling (e.g., cooling to 0°C) and filtration to obtain triethylenetetramine hydrate solid.

[0060] In one embodiment, the mass-to-volume ratio of crude triethylenetetramine in purification method ① to toluene in purification method ② is (0.4-0.52) g / mL; preferably 0.49 g / mL.

[0061] In one embodiment, the temperature of the refining method ② is 90-150℃; preferably 100-150℃.

[0062] This invention provides a method for preparing intermediate 3; it includes the following steps:

[0063] (1) Intermediate 1 was reacted with butanedione in the presence of an ether solvent to prepare intermediate 2;

[0064]

[0065] (2) Intermediate 2 and glyoxal were reacted in the presence of solvent, reducing agent and benzotriazole to prepare intermediate 3;

[0066]

[0067] The reaction conditions for steps (1) and (2) are as described in any embodiment of the present invention.

[0068] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0069] The reagents and raw materials used in this invention are all commercially available.

[0070] The positive and progressive effects of this invention are as follows: This invention provides a method for preparing cyclohexane; it has one or more of the following advantages: 1. The reaction raw materials are simple and readily available, and the steps are very concise;

[0071] 2. Mild conditions, low equipment requirements, and easy to scale up production;

[0072] 3. It generates little waste and is environmentally friendly. Attached Figure Description

[0073] Figure 1 This is the purity spectrum of the ring vine. Detailed Implementation

[0074] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0075] Instruments and equipment

[0076] Gas chromatograph: Agilent; GC-7890A

[0077] Chromatographic column: Gas chromatography column

[0078] Heating rate (°C / min) Temperature (°C) Isothermal time (min) - 220 35

[0079] Inlet temperature: 280℃;

[0080] Detector temperature: 300℃;

[0081] Injection volume: 1 μL;

[0082] Flow split ratio: 20:1;

[0083] Column flow rate: 2.2 mL / min;

[0084] Carrier gas: H2 (or H e )

[0085] Hydrogen flow rate: 40 mL / min;

[0086] Air flow rate: 400 mL / min;

[0087] Tail-blown flow rate: 25 mL / min.

[0088] Gas phase external standard test operation procedure

[0089] 1. Solution preparation

[0090] Standard solution: Weigh 40 mg of standard into a 10 mL volumetric flask, dissolve and dilute to the mark with methanol, and mix well.

[0091] Sample solution: Transfer the sample to be tested into the sample vial.

[0092] Blank solution: methanol

[0093] 2. Measurement sequence

[0094] After the instrument stabilizes, add 1 μL of blank solution, standard solution and sample solution, and record the chromatogram.

[0095] solution Number of injections index blank solution ≥1 Do not interfere with the detection peak standard solutions 2 <![CDATA[Δ area ≤20%]]> Sample solution 1 Content: Reported value

[0096] Δ = (maximum value - minimum value) / average value * 100%

[0097] 3 Result Calculation

[0098] The content of the target substance is calculated using the following formula:

[0099]

[0100] In the formula:

[0101] A SPL ---------------------------Peak area of ​​the target analyte in the sample solution;

[0102] A STD---------------------------Average peak area of ​​the target analyte in the standard solution;

[0103] C STD ---------------------------Concentration of target analyte in standard solution, mg / mL;

[0104] ρ------------------------------Density of the solution to be tested.

[0105] Gas phase area normalization method test operation procedure

[0106] 1. Solution preparation

[0107] Sample solution: Weigh 300 mg of sample (accurate to 0.1 mg) into a 10 mL volumetric flask, dissolve and dilute to the mark with methanol, and mix well.

[0108] Blank solution: methanol

[0109] 2. Measurement sequence

[0110] After the instrument stabilizes, add 1 μL of blank solution and sample solution, and record the chromatogram.

[0111] solution Number of injections index blank solution ≥1 Do not interfere with the detection peak Sample solution 1 See expected value

[0112] 3. Result Calculation

[0113] Unknown single impurities and target products are calculated using the area normalization method. Chromatographic peaks caused by blank solutions are disregarded. Peaks less than 0.05% are disregarded.

[0114] Purity testing in the following examples: When the product is a solution, the product purity is determined by the above-described gas phase area normalization method; when the product is a solid, it is first dissolved in a conventional solvent in the art and then the product purity is determined by the above-described gas phase area normalization method.

[0115] Example 1: Preparation of Intermediate 1

[0116] In a four-necked flask, crude triethylenetetramine (50.0 g, 342.1 mmol) and toluene (87.00 g, 99.8 ml) were added, followed by the dropwise addition of water (7.50 g). After the addition was complete, the temperature was raised to 35–45 °C to dissolve the solution, and the mixture was kept at this temperature for 2 hours. The temperature was then lowered to 30–40 °C, and triethylenetetramine dihydrate seed crystals (0.90 g, 4.9 mmol) (prepared using the same method as in Example 1, except that no seed crystals were added during the reaction) were added. The mixture was slowly cooled to 0 °C and filtered to obtain solid triethylenetetramine hydrate. In another four-necked flask, toluene (89.0 g, 102.1 ml) was added, followed by the triethylenetetramine hydrate. The mixture was refluxed at 100–150 °C under normal pressure to separate the water. After the water separation was complete, the toluene was concentrated to obtain intermediate 1 with a purity of 99% and a yield of 71%.

[0117] Example 2: Preparation of Intermediate 2

[0118]

[0119] Intermediate 1 (30.0 g, 205.3 mmol) and tetrahydrofuran (106.4 g, 119.6 ml) were added to a four-necked flask, purged with nitrogen, stirred, and cooled to -15°C to -10°C. A mixture of butanedione (17.7 g, 205.3 mmol) and tetrahydrofuran (226.6 g, 254.6 ml) was added dropwise at -15°C to -10°C, and the mixture was kept at this temperature for 2 hours. This yielded intermediate 2 solution with a purity of 91% and a yield of 88%. The yield was determined by gas chromatography with an external standard, and the yield data were obtained by combining the concentrations of the reaction solution.

[0120] Example 3: Preparation of Intermediate 3

[0121]

[0122] A solution of benzotriazole (56.2 g, 471.8 mmol) and tetrahydrofuran (79.88 g, 89.8 ml) was added dropwise to the reaction solution obtained in Example 2 above at -15 to -10 °C. After the addition was complete, the mixture was stirred at low temperature for 30 min. Then, a 40% glyoxal aqueous solution (30.1 g, 207.6 mmol) was added. After the addition was complete, the mixture was kept at low temperature for 15 h. Then, NaBH4 (13.9 g, 367.4 mmol) was slowly added in portions at -10 to 0 °C. After the addition was complete, the reaction was kept at this temperature for 10 h. Finally, 36% hydrochloric acid (52.0 g) was added to quench the reaction until the pH reached 5-6, and the tetrahydrofuran was concentrated. Intermediate 3 solution was obtained with a purity of 87% and a yield of 78%. (The yield was determined by gas chromatography with an external standard, and the yield data was obtained by combining the content with the weight of the reaction solution.)

[0123] Example 4: Preparation of Intermediate 4

[0124]

[0125] Methanol (47.4 g, 60 ml) was added to the above concentrated solution, and 36% hydrochloric acid (208.0 g, 2.05 mol) was added dropwise at 40℃~60℃. After the addition was completed, the temperature was raised to 60℃~70℃ and reacted for 5 h. The temperature was then lowered to 40℃~50℃ and filtered to obtain intermediate 4 with a purity of 99.2% and a yield of 83%. Benzotriazole was recovered from the mother liquor.

[0126] Example 5: Preparation of Intermediate 5

[0127]

[0128] After adding water (90.0 g) to intermediate 4, 48% sodium hydroxide aqueous solution (53.8 g, 645.6 mmol) was added dropwise to pH 14. After slowly cooling to 0 °C, the mixture was filtered to obtain intermediate 5 with a purity of 100.0% and a yield of 94%.

[0129] Example 6: Preparation of Ring Ring Tennin

[0130]

[0131] Intermediate 5 was added to a single-necked flask, followed by toluene (130.5 g, 150 ml). The mixture was heated to 100–150 °C and refluxed to separate the water. After separation, the mixture was filtered while hot at 80–90 °C. The filtrate was concentrated under reduced pressure to remove most of the toluene. The solution was then cooled to 0 °C to crystallize, filtered, and dried to obtain cyclotenafil with a purity of 100.0% and a yield of 93%. The total yield from intermediate 1 to cyclotenafil was 50%. The purity chromatogram is shown below. Figure 1 The data is shown in Table 1 below.

[0132] Table 1

[0133]

[0134]

[0135] Comparative Example 1

[0136] The same operating steps as in the above embodiments are used, except that the solvent tetrahydrofuran in Example 2 is replaced with methanol, anhydrous ethanol, isopropanol, dichloromethane, or acetonitrile.

[0137] Results: When methanol and anhydrous ethanol were used as solvents, the feeding process of sodium borohydride produced a lot of gas, which was not suitable for large-scale production; when isopropanol was used as solvent, the proportion of impurities increased and the yield decreased; when dichloromethane was used as solvent, the reaction conversion rate decreased significantly; when acetonitrile was used as solvent, benzotriazole had low solubility in acetonitrile, which also affected the conversion rate.

[0138] Comparative Example 2

[0139] Referring to CN110698419A, after reacting acetone aldehyde with intermediate 1, it reacts with glyoxal. The acid hydrolysis process is carried out at a higher temperature, which increases the amount of impurities.

Claims

1. A method for preparing cyclohexane; characterized in that, It includes the following steps: Step 1: In the presence of an ether solvent, intermediate 1 reacts with butanedione to prepare intermediate 2; Step 2: In the presence of solvent, reducing agent and benzotriazole, intermediate 2 reacts with glyoxal to prepare intermediate 3; Step 3: In the presence of a solvent, intermediate 3 reacts with hydrochloric acid to prepare intermediate 4; Step 4: In the presence of a solvent, intermediate 4 reacts with a base to prepare intermediate 5; Step 5: After removing water from intermediate 5 in a solvent, cyclohexane is prepared.

2. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In step 1, the ether solvent is tetrahydrofuran; (2) In step 1, the molar ratio of intermediate 1 to dimethyl butyl ketone is 1:(1.0-2.0); (3) In step 1, the mass-to-volume ratio of intermediate 1 to solvent is (0.06-1.0) g / mL; and (4) In step 1, the reaction is carried out in the presence of nitrogen.

3. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In step 1, the molar ratio of intermediate 1 to dimethyl butyl ketone is 1:(1.0-1.1); (2) In step 1, the mass-to-volume ratio of intermediate 1 to solvent is 0.08 g / mL; (3) In step 1, the reaction is performed as follows: a mixture of dimethyl ethyl ketone and solvent is added dropwise to the mixture of intermediate 1 and solvent at -15℃ to -10℃, and the mixture is kept at this low temperature for 2 hours; and (4) In step 1, the reaction does not require the addition of a dehydrating agent.

4. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In step 2, the solvent is the ether solvent in step 1; (2) In step 2, the reducing agent is lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, calcium borohydride or sodium triacetoxyborohydride; (3) In step 2, the glyoxal is a 40% glyoxal aqueous solution; (4) The molar ratio of intermediate 1 in step 1 to benzotriazole in step 2 is 1:(1.8-2.5); (5) The mass-to-volume ratio of intermediate 1 in step 1 to solvent in step 2 is (0.25-0.40) g / mL; (6) The molar ratio of intermediate 1 in step 1 to reducing agent in step 2 is 1:(1.5~2.0); (7) The molar ratio of intermediate 1 in step 1 to glyoxal in step 2 is 1:(1.0~2.0); (8) In step 2, the reaction further includes the following post-treatment steps: quenching with hydrochloric acid to pH 5-6, concentrating the solvent; and (9) In step 2, the reaction operation is as follows: add a solution of benzotriazole and tetrahydrofuran dropwise to the reaction solution in step 1 at -15 to -10℃, and stir at low temperature for 30 min after the addition is completed; continue to add 40% glyoxal aqueous solution, keep warm at low temperature for 15 h after the addition is completed, add NaBH4 at -10 to 0℃, and continue to keep warm for 10 h after the addition is completed; Preferably, it satisfies one or more of the following conditions: (1) In step 2, the solvent is tetrahydrofuran; (2) In step 2, the reducing agent is sodium borohydride; (3) The molar ratio of intermediate 1 in step 1 to benzotriazole in step 2 is 1:(2.1-2.3), preferably 1:2.3; (4) The mass-to-volume ratio of intermediate 1 in step 1 to solvent in step 2 is 0.33 g / mL; (5) The molar ratio of intermediate 1 in step 1 to reducing agent in step 2 is 1:(1.7-1.9), preferably 1:1.8; (6) The molar ratio of intermediate 1 in step 1 to glyoxal in step 2 is 1:(1.0-1.1), preferably 1:1.0; and (7) In step 2, the reaction further includes the following post-treatment steps: quenching with 36% hydrochloric acid to pH 5-6 and concentrating the solvent tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In step 3, the solvent is an alcohol solvent, a nitrile solvent, or an ether solvent; The alcohol solvents described above can be Methanol or ethanol; the nitrile solvent may be acetonitrile; the ether solvent It can be tetrahydrofuran; preferably methanol; (2) In step 3, the hydrochloric acid is 36% hydrochloric acid; (3) The mass-to-volume ratio of intermediate 1 in step 1 to solvent in step 3 is (0.4-0.6) g / mL; preferably 0.5 g / mL; (4) The molar ratio of intermediate 1 in step 1 to hydrochloric acid in step 3 is 1:(8-12); preferably 1:10; (5) In step 3, the reaction is performed as follows: a solvent is added to the reaction product in step 2, 36% hydrochloric acid is added dropwise at 40℃~60℃, and after the addition is completed, the temperature is raised to 60℃~70℃ for 5 hours, and the mixture is cooled to 40℃~50℃ and filtered to obtain intermediate 4; and (6) In step 3, the reaction further includes the following post-processing step: filtrate recovery of benzotriazole.

6. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In step 4, the solvent is water; (2) In step 4, the alkali is sodium hydroxide; preferably a 48% sodium hydroxide aqueous solution; (3) The mass-to-volume ratio of intermediate 1 in step 1 to solvent in step 4 is (0.25-0.4) g / mL; preferably 0.33 g / mL; (4) The molar ratio of intermediate 1 in step 1 to the alkali in step 4 is 1:(2-4); preferably 1:3.1; and (5) In step 4, the reaction operation is as follows: add the reaction product in step 3 to water, add 48% sodium hydroxide aqueous solution dropwise to pH=14, cool to 0℃ and then filter.

7. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In step 5, the solvent is a benzene-based solvent; preferably toluene; (2) The mass-to-volume ratio of intermediate 1 in step 1 to solvent in step 5 is (0.15-0.25) g / mL; preferably 0.2 g / mL; and (3) In step 5, the reaction is performed as follows: the reaction product of step 4 is mixed with toluene, heated to 100-150°C and refluxed to separate water. After water separation is completed, the mixture is filtered while hot at 80-90°C. The filtrate is concentrated under reduced pressure to remove most of the toluene. The mixture is cooled to 0°C to crystallize, filtered and dried to obtain cyclohexane.

8. The preparation method according to claim 1, characterized in that, The preparation method also includes a purification method for crude triethylenetetramine; Preferably, the refining method includes the following steps: ① In toluene and water, crude triethylenetetramine is dissolved, kept at a warm temperature, and crystals precipitate in the presence of triethylenetetramine hydrate seed crystals; ② In the presence of toluene, triethylenetetramine hydrate was dehydrated to prepare triethylenetetramine.

9. A method for preparing intermediate 3; comprising the following steps: (1) Intermediate 1 was reacted with butanedione in the presence of an ether solvent to prepare intermediate 2; (2) Intermediate 2 and glyoxal were reacted in the presence of solvent, reducing agent and benzotriazole to prepare intermediate 3; The reaction conditions for steps (1) and (2) are as described in any one of claims 1-4.

10. A method for preparing intermediate 2; comprising the following steps: reacting intermediate 1 with butanedione in the presence of an ether solvent to prepare intermediate 2; in, The reaction conditions described in any one of claims 1-3.

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