Preparation method of polyamine compound
By performing the substitution reaction of the compound of formula II and ethylenediamine at 0-15°C, the polyamine compound of formula I was prepared, which solved the problems of low yield and high reaction temperature in the prior art, and achieved efficient and gentle Preparation method, suitable for industrial applications.
Patent Information
- Application Number
- CN202411525629.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-30
- Publication Date
- 2025-02-07
AI Technical Summary
The existing polyamine compounds are not yielded and have high reaction temperatures, making it difficult to meet the needs of industrial applications.
A new preparation method is adopted to prepare the compound of formula I by substitution reaction of the compound of formula II and ethylenediamine, and the reaction temperature is controlled at 0-15°C, the single-step reaction yield is nearly 80%, and the reaction conditions are mild.
The preparation yield of polyamine compounds is improved, the reaction temperature is reduced, and it is suitable for large-scale industrial applications, and high-purity polyamine compounds are obtained through simple concentration steps.
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Figure CN119390580A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of organic synthesis, and in particular to a method for preparing a polyamine compound. Background Art
[0002] Polyamine compounds are a class of compounds containing more than two amino groups. They are widely present in the biological world and play an important role in regulating plant growth and development, controlling morphological construction, improving plant stress resistance, and delaying aging. Polyamine compounds can interfere with cell growth and cell death and have great application prospects in controlling cancer.
[0003] According to literature reports, N 1 -{4-[(2-aminoethylamino)-methyl]-cyclohexylmethyl}-ethane-1,2-diamine (N 1 -{4-[(2-Amino-ethylamino)-methyl]-cyclohexylmethyl}-ethane-1,2-diamine, hereinafter referred to as polyamine compounds) can be used to prepare platinum (II) complexes to reduce cytotoxicity for better cancer treatment (Synthesis of Polyamines from Ethylenediamine and Their Platinum (II) Complexes, Potential Antitumor Agents, M. Couriet.al, Eur. J. Inorg. Chem. 2006, 1868-1874).
[0004]
[0005] The preparation method of the polyamine compound described in the above document is: C6H 10 (CH2OH)2 is refluxed in the presence of toluene, triphenylphosphine, iodine and imidazole to generate the intermediate C6H 10 (CH2I)2, the intermediate is then refluxed in the presence of ethanol and ethylenediamine, and the two-step reaction is performed to obtain a polyamine compound with a yield of 55.2% (92%*60%).
[0006]
[0007] However, the total yield of the above two-step reaction is not high, but the reaction temperatures are relatively high, 110°C and 78°C respectively. Relevant researchers are looking forward to finding a preparation route with higher yield and milder reaction conditions to produce polyamine compounds.
[0008] Instruction Manual
[0009] In order to overcome the technical problems of low yield and high reaction temperature in the prior art, a method for preparing polyamine compounds is proposed, which can prepare N with higher yield and safer reaction conditions. 1 -{4-[(2-aminoethylamino)-methyl]-cyclohexylmethyl}-ethane-1,2-diamine is conducive to industrial utilization.
[0010] The present invention provides a method for preparing a compound of formula I, the steps of which are as follows: a compound of formula II undergoes a substitution reaction with ethylenediamine to prepare a compound of formula I;
[0011]
[0012] In one embodiment, the volume mass ratio of the ethylenediamine to the compound of formula II may be (0.3-10) mL:1 g, preferably (3-5) mL:1 g, for example 4 mL:1 g.
[0013] In one embodiment, the reaction temperature of the substitution reaction may be 0-15°C, preferably 0-10°C.
[0014] In one embodiment, the preparation method further comprises the following post-processing steps after the reaction is completed:
[0015] (1) mixing the reaction solution with a base, concentrating, adding a first organic solvent, filtering, and concentrating the filtrate;
[0016] (2) adding a second organic solvent and water, raising the temperature until the solid is dissolved, and lowering the temperature for crystallization to obtain a hydrate of the compound of formula I;
[0017] (3) Concentrate under reduced pressure under protective gas atmosphere.
[0018] Wherein, the base can be RO - M + Any one or more of M + is an alkali metal ion, R is H or C 1-6 Alkyl; preferably, the base is any one or more of sodium alkoxides; for example, sodium methoxide and / or sodium ethoxide.
[0019] The base is added in the form of an alcohol solution, preferably in the form of RO - M + The ROH solution was added.
[0020] The molar ratio of the base to the compound of formula II may be (2-3):1; preferably 2.5:1.
[0021] The first organic solvent may be a non-polar solvent, preferably toluene and / or benzene, such as toluene.
[0022] The second organic solvent is isopropyl acetate (iPrOAc).
[0023] The volume molar ratio of the second organic solvent to the compound of formula II may be (0.2-3) L:1 mol, preferably (0.8-1.7) L:1 mol, for example 1.27 L:1 mol.
[0024] The molar ratio of the water to the compound of formula II may be (1.8-2.2):1, preferably (1.9-2.1):1, for example 2.0:1.
[0025] The cooling and crystallization comprises the following steps: cooling from 55-65°C to 40-50°C, adding seed crystals, and cooling at a gradient of 5-10°C / h to 20-30°C; preferably, the cooling and crystallization comprises cooling from 60°C to 45°C, adding seed crystals, and cooling at a gradient of 5-10°C / h to 20-30°C.
[0026] In one embodiment, the preparation method of the compound of formula I also includes the preparation method of the compound of formula II, and the steps are as follows:
[0027] In the presence of a third organic solvent and an acid-binding agent, the compound of formula III and a sulfonylating agent undergo a substitution reaction to obtain a compound of formula II;
[0028]
[0029] In one embodiment, the third organic solvent may be selected from any one or more of dichloromethane, 1,2-dichloroethane and toluene; preferably dichloromethane and / or 1,2-dichloroethane.
[0030] In one embodiment, the molar volume ratio of the compound of formula III to the third organic solvent may be (0.1-2.0) mol:1L, preferably (0.3-1.0) mol:1L, for example 0.68 mol:1L.
[0031] In one embodiment, the acid binding agent may be an organic amine compound, preferably triethylamine and / or pyridine.
[0032] In one embodiment, the molar ratio of the acid binding agent to the compound of formula III can be (2-4):1, preferably 2.5:1.
[0033] In one embodiment, the sulfonylating agent is p-toluenesulfonyl chloride and / or p-toluenesulfonic anhydride.
[0034] In one embodiment, the molar ratio of the sulfonylating agent to the compound of formula III can be (2-2.5):1, for example 2.2:1.
[0035] In one embodiment, the reaction is carried out in the presence of a catalyst, and the catalyst is preferably DMAP.
[0036] In one embodiment, the molar ratio of the catalyst to the compound of formula III may be (0.01-0.2):1, for example (0.02-0.1):1.
[0037] In one embodiment, the reaction temperature of the substitution reaction can be 5-25°C, preferably 10-20°C.
[0038] In one embodiment, after the substitution reaction is completed, the following post-treatment steps are further included: filtering the reaction liquid after the reaction is completed, taking the filter cake, slurrying with water, filtering, and drying the filter cake.
[0039] In one embodiment, the compound of formula I is The compound of formula II is The compound of formula III is
[0040] The present invention also provides a method for preparing a compound of formula II, the steps of which are as follows: in the presence of a third organic solvent and an acid binding agent, a compound of formula III and a sulfonylating agent undergo a substitution reaction to prepare a compound of formula II;
[0041]
[0042] In one embodiment, the reaction conditions of the preparation method of the compound of formula II are as described above.
[0043] The present invention also provides a process for preparing the compound of formula I:
[0044] (1) in the presence of a third organic solvent and an acid binding agent, the compound of formula III and a sulfonylating agent undergo a substitution reaction to obtain a compound of formula II;
[0045]
[0046] (2) the compound of formula II undergoes a substitution reaction with ethylenediamine to obtain a compound of formula I;
[0047]
[0048] In one embodiment, the reaction conditions of the process route of compound I are as described above.
[0049] Beneficial effects of the present invention
[0050] The present invention provides a new preparation method for preparing a polyamine compound of formula I. The preparation method of the compound of formula I using the compound of formula II as a raw material has a high yield, a single-step reaction yield of nearly 80%, and mild reaction conditions, which is conducive to large-scale industrial application.
[0051] The present invention also provides a new route for preparing polyamine compounds, using the compound of formula II as an intermediate, the two-step reaction yield can reach more than 70%, and the reaction conditions are milder, which is also conducive to the industrial application of this route. DETAILED DESCRIPTION
[0052] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.
[0053] The reagents and raw materials used in the following examples are all commercially available.
[0054] In the following examples, TsCl refers to p-toluenesulfonyl chloride. DMAP refers to 4-dimethylaminopyridine. HPLC-ELSD method refers to the detection method of high performance liquid chromatography combined with evaporative light scattering detector. MTBE refers to tert-butyl methyl ether.
[0055] In the following examples, the moisture content is detected by LOD (loss on drying), which is a method for calculating the moisture content by measuring the change in weight of the sample before and after drying. This method records the initial weight of the sample, then weighs and records the data during the drying process. When the sample no longer loses weight, the heating is stopped and the moisture content is calculated. The specific detection method is as follows:
[0056] Weigh 1 g of the sample into a weighing bottle with constant weight, place it in a vacuum oven at 60°C for 4 hours, take it out and let it stand at room temperature for 30 minutes, and weigh it; then vacuum dry it at 60°C for 1 hour, take it out and let it stand at room temperature for 30 minutes, and weigh it; repeat the above steps several times until constant weight is achieved.
[0057] Example 1
[0058]
[0059] 80g trans-1,4-cyclohexanedimethanol (0.55mol, 1.0eq) and 800mL dichloromethane were added to the reaction bottle, and nitrogen was replaced for protection. The temperature was controlled at 0-10°C, and 139.14g triethylamine (1.38mol, 2.5eq), 6.72g DMAP (0.055mol, 0.1eq) and 230.69g TsCl (1.21mol, 2.2eq) were added in sequence, and the reaction was carried out at 10-20°C. The reaction was monitored by HPLC-ELSD method. After 16h of reaction, the content of raw material trans-1,4-cyclohexanedimethanol was less than 0.5%, and the reaction was basically completed. The reaction liquid was filtered, and the filter cake was taken. The filter cake was slurried with 800mL water, filtered, and the filter cake was taken and dried to obtain 229g solid, with a yield of 92.0% and a purity of 99.2%.
[0060] Example 2
[0061]
[0062] The temperature was controlled at 10-20°C, 100 g of trans-1,4-cyclohexanedimethanol ditoluenesulfonate (221 mmol, 1.0 eq) and 400 mL of ethylenediamine were replaced with nitrogen for protection, the temperature was raised to 40-45°C for overnight reaction, and the conversion of the raw materials was completely monitored by HPLC.
[0063] The temperature was lowered to 0-10°C, 110.5 mL of sodium methoxide methanol solution (5 mol / L, 0.55 mol, 2.5 eq) was added dropwise, and the reaction solution was concentrated under reduced pressure at 50-60°C. At room temperature, toluene was added to 1 L, filtered, and the filtrate was concentrated and evaporated to dryness to obtain a crude product, 42.2 g of a yellow oil with a purity of 98.1%.
[0064] Add 280 mL of isopropyl acetate and 7.2 mL of water (398 mmol, 1.8 eq). Raise the temperature to 60°C, the product is completely dissolved, cool to 45°C, add seed crystals, and gradually cool by 5-10°C / h. Cool to 20-30°C, filter, and the obtained white solid is the two molecules of hydrate of the product. The water content of the white solid measured by the LOD method (loss on drying method) is 13.6%.
[0065] Under nitrogen protection, the mixture was concentrated under reduced pressure at 55-60°C to a water content of about 0.5%, and then cooled to 20-30°C to obtain 39.4 g of a yellow oily substance, which was the free product, with a yield of 78.1% and a purity of 99.58%.
[0066] Comparative Example 1
[0067]
[0068] Control the temperature at 10-20℃, add 75g trans-1,4-cyclohexanedimethanol ditoluene sulfonate (166mmol, 1.0eq) and 300mL ethylenediamine, and replace with nitrogen for protection. Heat to 40-45℃ and react overnight. HPLC monitors the complete conversion of raw materials. Cool to 0-10℃, add 84mL sodium methoxide methanol solution (5mol / L, 0.415mol, 2.5eq), and concentrate the reaction solution at 50-60℃ under reduced pressure. At room temperature, add toluene to 1L, filter, and concentrate the filtrate to dryness to obtain the crude product, 30.1g of yellow oil, purity 98.5%.
[0069] 1 g of the crude product was placed in a test tube, and 9 mL of 2 mol / L hydrochloric acid or 9 mL of 2 mol / L sulfuric acid was added dropwise. No solid was precipitated in the test tube. The organic solvent was added dropwise to 10 mL in each test tube. There was still no solid precipitation. The mixed solution was placed in a separating funnel for separation. The organic phase was collected, and the aqueous phase was continuously extracted with the organic solvent for 3 times. All organic phases were combined and concentrated to dryness. The results are shown in Table 1.
[0070] Table 1 Post-processing condition screening
[0071] Serial number Crude product quality Type of acid Organic solvents Product Quality 1 1g 9mL 2mol / L hydrochloric acid Chloroform 20mg 2 1g 9mL 2mol / L hydrochloric acid Chloroform / methanol (1:1) 26mg 3 1g 9mL 2mol / L hydrochloric acid Dichloromethane 16mg 4 1g 9mL 2mol / L hydrochloric acid Dichloromethane / methanol (1:1) 24mg 5 1g 9mL 2mol / L hydrochloric acid n-Butanol 22mg 6 1g 9mL 2mol / L hydrochloric acid 2-Methyltetrahydrofuran 18mg 7 1g 9mL2mol / L sulfuric acid Chloroform 30mg 8 1g 9mL2mol / L sulfuric acid Chloroform / methanol (1:1) 36mg 9 1g 9mL2mol / L sulfuric acid Dichloromethane 26mg 10 1g 9mL2mol / L sulfuric acid Dichloromethane / methanol (1:1) 34mg 11 1g 9mL2mol / L sulfuric acid n-Butanol 28mg 12 1g 9mL2mol / L sulfuric acid 2-Methyltetrahydrofuran 24mg
[0072] As shown in the above table, after the crude polyamine compound is reacted with an acid to form a salt, it cannot be precipitated from an aqueous solution or an organic solvent, and only a small amount of the product can be obtained by extraction.
[0073] Comparative Example 2
[0074] Take 10 g of the crude product in Comparative Example 1 and purify it by distillation.
[0075] Distillation conditions: negative pressure 0.17 mbar, external temperature: 220°C, top temperature 150°C.
[0076] The purity of the crude product before distillation is 98.5%. Under the above conditions, the purity of the distilled fraction is 98.6%. The purity of the product is not significantly improved, and negative pressure and high temperature must be maintained at the same time, which is not conducive to industrial application.
[0077] Comparative Example 3
[0078] Take 2g of the crude product obtained in Comparative Example 1, add 50mL MTBE, heat to 50°C to dissolve completely, add seed crystals at 42°C for crystallization, cool to 20-30°C, and filter. The solid purity is 93.8%, and the purity of the filtrate after concentration is 93.8%. The purpose of purification cannot be achieved.
[0079] Comparative Example 4
[0080] 2 g of the crude product obtained in Comparative Example 1 was taken, 50 mL of acetonitrile was added and recrystallized, but no solid was precipitated.
[0081] Advantageous Effects of Embodiments
[0082] The above embodiment provides a new preparation method for preparing a polyamine compound of formula I. The preparation method of the compound of formula I using the compound of formula II as a raw material has a high yield, a single-step reaction yield of nearly 80%, and mild reaction conditions, which is conducive to large-scale industrial application.
[0083] The above embodiment also provides a new route for preparing polyamine compounds. With the compound of formula II as the intermediate, the two-step reaction yield can reach more than 70%, and the reaction conditions are milder, which is also conducive to the industrial application of this route.
[0084] Furthermore, the above embodiment also provides a new method for purifying polyamine compounds. In the prior art, the purification of polyamine compounds is usually to convert the polyamine compounds into salts by combining with acids, purify the salts and then add alkali to obtain the free state; or purify by distillation, recrystallization and other methods. However, in the present application, the salts of the polyamine compounds combined with acids are difficult to precipitate in water or a mixture of water and organic solvents, and are also difficult to extract from aqueous solutions by organic solvents; distillation and recrystallization are also difficult to achieve purity improvement. However, the applicant unexpectedly discovered that its hydrate can be directly precipitated from an organic solvent, and the precipitated hydrate has a high purity. The bound water can be removed by simple concentration to obtain a high-purity free-state polyamine compound.
Claims
1. A method for preparing a compound of formula I, comprising the following steps: a compound of formula II undergoes a substitution reaction with ethylenediamine to obtain a compound of formula I; 2. The method for preparing the compound of formula (I) according to claim 1, characterized in that: The preparation method of the compound of formula I satisfies any one or more of the following conditions: (1) The volume mass ratio of the ethylenediamine to the compound of formula II is (0.3-10) mL:1 g; (2) The reaction temperature of the substitution reaction is 0-15°C; (3) The method for preparing the compound of formula I comprises the following post-treatment steps after the reaction is completed: (a) mixing the reaction solution with a base, concentrating it, adding a first organic solvent, filtering it, and concentrating the filtrate; (b) adding a second organic solvent and water, heating it until the solid dissolves, cooling it for crystallization, and preparing a hydrate of the compound of formula I; and (c) concentrating it under reduced pressure under a protective gas atmosphere.
3. The method for preparing the compound of formula (I) as claimed in claim 2, characterized in that: The preparation method of the compound of formula I satisfies any one or more of the following conditions: (1) The volume mass ratio of the ethylenediamine to the compound of formula II is (3-5) mL:1 g; (2) The reaction temperature of the substitution reaction is 0-10°C; (3) The base is RO - M + Any one or more of M + is an alkali metal ion, R is H or C 1-6 alkyl; (4) the base is mixed with the reaction solution in the form of an alcohol solution; (5) The molar ratio of the base to the compound of formula II is (2-3):1; (6) The first organic solvent is a non-polar solvent; (7) The second organic solvent is isopropyl acetate; (8) The volume molar ratio of the second organic solvent to the compound of formula II is (0.2-3) L:1 mol; (9) The molar ratio of water to the compound represented by formula II is (1.8-2.2):1; (10) The cooling and crystallization comprises the following steps: cooling from 55-65°C to 40-50°C, adding seed crystals, and cooling at a gradient rate of 5-10°C / h to 20-30°C.
4. The method for preparing the compound of formula (I) as claimed in claim 3, characterized in that: The preparation method of the compound of formula I satisfies any one or more of the following conditions: (1) The volume mass ratio of the ethylenediamine to the compound of formula II is 4 mL:1 g; (2) The base is any one or more of sodium alcoholates; (3) The alkali is RO - M + Mixing the reaction solution in the form of a ROH solution; (4) the molar ratio of the base to the compound of formula II is 2.5:1; (5) The first organic solvent is toluene and / or benzene; (6) The molar ratio of water to the compound of formula II is 2.0:1; (7) The volume molar ratio of the second organic solvent to the compound of formula II is (0.8-1.7) L:1 mol.
5. A method for preparing a compound of formula I according to any one of claims 1 to 4, characterized in that: The preparation method of the compound of formula II comprises the following steps: In the presence of a third organic solvent and an acid-binding agent, the compound of formula III and a sulfonylating agent undergo a substitution reaction to obtain a compound of formula II; 6. The method for preparing the compound of formula (I) according to claim 5, characterized in that: The preparation method of the compound of formula II satisfies any one or more of the following conditions: (1) The third organic solvent is selected from any one or more of dichloromethane, 1,2-dichloroethane, and toluene; (2) The molar volume ratio of the compound of formula III to the third organic solvent is (0.1-2.0) mol:1L; (3) The acid binding agent is an organic amine compound; (4) The molar ratio of the acid binding agent to the compound of formula III is (2-4):1; (5) The sulfonylating agent is p-toluenesulfonyl chloride and / or p-toluenesulfonic anhydride; (6) A catalyst is also added to the reaction, wherein the catalyst is DMAP; (7) The reaction temperature of the substitution reaction is 5-25°C; (8) After the substitution reaction is completed, the following post-treatment steps are further included: filtering the reaction liquid after the reaction is completed, taking the filter cake, beating it with water, filtering it, and drying the filter cake.
7. The method for preparing the compound of formula (I) according to claim 6, characterized in that: The preparation method of the compound of formula II satisfies any one or more of the following conditions: (1) The third organic solvent is dichloromethane and / or 1,2-dichloroethane; (2) The molar volume ratio of the compound of formula III to the third organic solvent is (0.3-1.0) mol:1L; (3) The acid binding agent is triethylamine and / or pyridine; (4) The molar ratio of the acid binding agent to the compound of formula III is 2.5:1; (5) The molar ratio of the catalyst to the compound of formula III is (0.01-0.2):1; (6) The reaction temperature of the substitution reaction is 10-20°C.
8. The method for preparing the compound of formula (I) according to claim 7, characterized in that: The preparation method of the compound of formula II satisfies any one or more of the following conditions: (1) the molar volume ratio of the compound of formula III to the third organic solvent is 0.68 mol / L; (2) The molar ratio of the catalyst to the compound of formula III is (0.02-0.1):1; (3) The compound of formula I is The compound of formula II is The compound of formula III is 9. A method for preparing a compound of formula II, characterized in that: The steps are as follows: in the presence of a third organic solvent and an acid binding agent, a compound of formula III and a sulfonylating agent undergo a substitution reaction to obtain a compound of formula II; 10. A method for preparing a compound of formula II as claimed in claim 9, wherein the reaction conditions are as described in any one of claims 6 to 8.