Diazamacrocyclic compound intermediates and preparation methods and applications thereof
Through simplified process flow and new reaction conditions, the problems of more than three wastes and high risk in the preparation of piperazine and high piperazine are solved, and the preparation of diaza macrocyclic compounds with high purity and high yield is achieved, which is suitable for industrialization Production.
Patent Information
- Application Number
- CN202211180436.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-09-27
- Publication Date
- 2024-12-24
- Estimated Expiration
- 2042-09-27
AI Technical Summary
In the prior art, the process of preparing piperazine and high piperazine has problems such as more waste, high risk of deprotection process and poor operational safety, which is difficult to meet the needs of industrial production.
A new process method is adopted to prepare high-purity dichloride by reacting compounds in halogenated reagents and reaction solvents, followed by reaction with ethylenediamine and alkaline reagents, and finally react with hydrazine hydrochloride under the third alkaline reagent to prepare Aza macrocyclic compounds simplify the process and reduce the risk.
The high purity and high yield preparation of diaza macrocyclic compounds is achieved, the process is simple and the cost is low, suitable for industrial production, and the danger and pollution problems in traditional methods are avoided.
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Abstract
Description
Technical Field
[0001] The invention relates to the field of organic synthesis, and in particular to a diazamacrocyclic compound intermediate and a preparation method thereof, as well as application of the compound in preparing the diazamacrocyclic compound. Background Art
[0002] Diaza macrocyclic compounds, including piperazine and homopiperazine, are important pharmaceutical intermediates and fine chemical raw materials. The main use is as a pharmaceutical intermediate. Piperazine can be used to synthesize piperazine phosphate, piperazine sulfate, norfloxacin, pipemidic acid, quinolone, rifampicin, etc. The Western medicine pulepene is a new type of highly effective antihypertensive drug, whose main ingredient is prazosin; theophylline acetate piperazine can be used to treat burn shock, hypertension and other symptoms; various piperazine alcohols and their derivatives can be used for clinical anesthesia; piperazine alkylamino quinoline and pyridine have antimalarial activity; N, N-di(-2-pyrazinyl) piperazine and N-2-pyridyl piperazine have analgesic effects; organic acid salts of piperazine such as piperazine adipate and piperazine citrate are widely used anthelmintics. In addition, there are some derivatives of piperazine, such as N-methylpiperazine and N-ethylpiperazine, which are the main raw materials for the production of ofloxacin and enrofloxacin respectively. Homopiperazine is a nitrogen seven-membered ring compound. Most of its derivatives have strong biological activity and medicinal value. They can be used to synthesize drugs such as homopiperazine hydrochloride, cyclizine, carbamazepine, quinolone and chlorcyclizine. Drugs such as quinoline and isoquinoline derivatives, quinolone derivatives, and thiazolidine hydroxy acid amide derivatives modified with homopiperazine as raw materials have shown good therapeutic effects on the treatment of cardiovascular diseases, interstitial plasma cell pneumonia, especially interstitial plasma cell pneumonia in AIDS patients, asthma, central nervous system diseases including depression and anxiety. For example, 1-(5-isoquinolinesulfonyl) homopiperazine hydrochloride can effectively treat symptoms such as chronic angina, vitiligo, depression, anxiety, cerebral vasospasm, and local cerebral ischemia caused by cerebral vasospasm.
[0003] At present, the main method for producing piperazine is to use ethanolamine or ethylenediamine as raw materials and condense with ammonia to form a ring. During the reaction, ethanolamine or ethylenediamine is cracked and reacts with the generated piperazine to form dimethylpiperazine; ethanolamine or ethylenediamine reacts with the generated piperazine to form ethylpiperazine, and dimethylpiperazine and ethylpiperazine have similar boiling points and properties to piperazine, forming near-boiling products, which are difficult to separate. The traditional process for refining piperazine is mainly recrystallization, which requires the use of a large amount of solvents, and the process is complicated and the process is long.
[0004] At present, there are two main synthetic routes for preparing homopiperazine in large quantities:
[0005] (I) Using ethylenediamine as the raw material, benzenesulfonyl chloride is used as a protecting agent to protect the amino group, and then the ring is closed with 1,3-dibromopropane, and then concentrated sulfuric acid or hydrobromic acid is used to remove the protecting group, and finally homopiperazine is obtained by alkalization (J. Am. Chem. Soc., 1954, 76, 1126–1137). This method is currently the most mainstream homopiperazine production method in China. However, this method has two very obvious disadvantages: the first is that the protecting agent benzenesulfonyl chloride used cannot be recycled, and a large amount of waste will be generated. Usually, the production of one ton of homopiperazine will generate at least two tons of unrecyclable solid waste; the second is that the process of removing the protecting group must use highly corrosive and highly polluting concentrated sulfuric acid or hydrobromic acid, which is very corrosive to the equipment and will cause great harm to the health of the operators, and the operation safety is relatively poor. This synthesis process has a lot of three wastes, and the production risk is relatively high, which is not suitable for the needs of industrial production;
[0006] (ii) Using ethylenediamine as the raw material, p-toluenesulfonyl chloride is used as the protecting agent to protect the amino group, and then the ring is closed with 1,3-dibromopropane, and then the protecting group is removed with concentrated sulfuric acid or hydrobromic acid, and finally homopiperazine is obtained by alkalization. This method is currently the most commonly used homopiperazine production method in China. This method has the same disadvantages as the previous method, and the reaction temperature is even higher when removing the protecting group, which is more dangerous and is even less suitable for the needs of industrial production;
[0007]
[0008] In view of the fact that the above-mentioned processes for preparing piperazine and homopiperazine all have the problems of more three wastes, greater danger of deprotection reagents, and poor operational safety, it is of great significance to find an industrial production method for the green synthesis of diaza macrocyclic compounds. Summary of the invention
[0009] In view of the problems existing in the above-mentioned prior art, the present invention develops a diazamacrocyclic compound intermediate with simple process, high product purity and high yield and its preparation method, as well as the application of using this compound to prepare diazamacrocyclic compounds, which is more suitable for industrial production.
[0010] One of the technical problems to be solved by the present invention is to provide a diazamacrocyclic compound intermediate, the chemical structure of which is shown in 5. , wherein n is selected from 1-10.
[0011] The second technical problem to be solved by the present invention is to provide a method for preparing a diazamacrocyclic compound intermediate, comprising the following steps:
[0012]
[0013] (a) Compound 1 is reacted in a halogenating agent and a first reaction solvent at a reaction temperature of 0-200 degrees for a reaction time of 1-20 hours to obtain Compound 2, wherein the halogenating agent is one of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, chlorosulfonic acid, and sulfonyl chloride, and the first reaction solvent is one or more of 1,2-dichloroethane, dichloromethane, chlorobenzene, nitrobenzene, and o-dichlorobenzene;
[0014] (b) Compound 2 is added to a second reaction solvent with a first alkaline reagent and ethylenediamine, the reaction temperature is 0-100 degrees, the reaction time is 1-24 hours, and compound 3 is obtained, wherein the molar ratio of compound 2 to ethylenediamine is 1:1-2, wherein the second reaction solvent is one or more of acetonitrile, ethyl acetate, dichloromethane, 1,2-dichloroethane, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, xylene, o-dichlorobenzene, benzene and toluene;
[0015] (c) In a third reaction solvent, compound 3 reacts with compound 4 in a second alkaline reagent at a reaction temperature of 25-200 degrees for a reaction time of 1-24 hours to obtain compound 5, wherein the molar ratio of compound 3 to compound 4 is 1:1-2, and the third reaction solvent is one or more of acetonitrile, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, xylene, o-dichlorobenzene, N,N-dimethylformamide, N-methylpyrrolidone, ethanol, methanol, benzene and toluene, wherein n is selected from 1-10.
[0016] In a preferred embodiment of the present invention, in step (a), the molar ratio of the compound 1 to the halogenating agent is 1:2-20.
[0017] In a preferred embodiment of the present invention, in step (b), the first alkaline reagent is one or more of sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, triethylamine, and pyridine.
[0018] In a preferred embodiment of the present invention, in step (b), the temperature is 50-60°C.
[0019] In a preferred embodiment of the present invention, in step (c), the second alkaline reagent is one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, pyridine, and DBU.
[0020] In a preferred embodiment of the present invention, in step (c), the temperature is 50-80°C.
[0021] The third technical problem to be solved by the present invention is to disclose a method for preparing a diazamacrocyclic compound intermediate and its application in preparing a diazamacrocyclic compound. The above compound 5 is added with hydrazine hydrochloride in a fourth reaction solvent in the presence of a third alkaline reagent, and refluxed for 4-10 hours to obtain a compound 6. The fourth reaction solvent is one or more of acetonitrile, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethanol, and methanol. , n is selected from 1-10.
[0022] In a preferred embodiment of the present invention, the third alkaline reagent is one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.
[0023] In a preferred embodiment of the present invention, the usage ratio of the compound 5 to hydrazine hydrochloride is 1:1-2. Beneficial Effects
[0024] The preparation method of the diaza macrocyclic compound provided by the invention is simple, low in cost, mild in reaction conditions, high in yield, and the synthesized diaza macrocyclic compound has high purity and a wider application range, and can meet the requirements of industrial production. DETAILED DESCRIPTION
[0025] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention. Example 1
[0026]
[0027] Step (a): Preparation of 4-nitrophthaloyl chloride of Formula 2
[0028] Keeping nitrogen slightly positive pressure, add 473 mL 1,2-dichloroethane and 211.13 g (1.0 mol) 4-nitrophthalic acid of Formula 1 to the 2 L reaction bottle in sequence and stir well. Then add 475.88 g (4.0 mol) thionyl chloride and 5 ml DMF, stir well after adding; heat the reaction liquid to 80°C within 1 hour, keep the temperature at 80°C and continue the reaction for 6 hours, and the reaction is completed.
[0029] The reaction solution was cooled to room temperature, and a proper amount of petroleum ether was added thereto. The resulting solution was cooled to 0°C and kept warm for crystallization overnight to precipitate a large amount of yellow crystals. The filter cake was collected by filtration, and the filter cake was washed with a proper amount of cold petroleum ether and dried to obtain 228.93 g (0.923 mol) of a yellow solid product.
[0030] Yield: 92.3%, HPLC purity: 98.3%.
[0031] Step (b): Preparation of the compound of formula 3 8-nitro-2,3,4,5-tetrahydrobenzo[f][1,4]diazoxide-1,6-dione
[0032] Add 2000 mL of acetonitrile, 228.93 g (0.923 mol) of the compound of formula 2 and 255.14 g (1.85 mol) of potassium carbonate to a 5L reaction bottle, and stir well. Then add 55.48 g (0.923 mol) of ethylenediamine dropwise, and stir well after adding. Heat the reaction solution to 50°C for reaction, keep the temperature for 8 hours, and the reaction is complete.
[0033] The reaction solution was filtered while hot to remove the solid insoluble matter. The filtrate was cooled naturally, and an appropriate amount of tert-butyl methyl ether was added thereto, and the solution was cooled to 0°C for crystallization. The crystallization was kept warm overnight to precipitate a large amount of yellow solid. The filter cake was collected by filtration, and the filter cake was washed with an appropriate amount of cold tert-butyl methyl ether and dried to obtain 187.78 g (0.798 mol) of a yellow solid product.
[0034] Yield: 86.5%, HPLC purity: 98.6%, 1 H NMR (400MHz, DMSO-d6): δ 11.28 (br s, 2H), 8.73 (s, 1H), 8.64 (d, 1H), 8.21 (d, 1H), 3.54 (br s, 4H).
[0035] Step (c): Preparation of the compound of formula 5-1 9-nitro-4,5-dihydro-3H-2,6-ethane[g][1,5]diazo-1,7-dione
[0036] Add 2000 mL of tetrahydrofuran, 187.78 g (0.798 mol) of the compound of formula 3, 60.75 g (0.798 mol) of the compound of formula 4-1, 1,3-propylene glycol, and 460.70 g (1.756 mol) of triphenylphosphine to a 5 L reaction bottle, and stir well. Cool the reaction solution to 0-5°C, and then drop 339.03 g (1.677 mol) of diisopropyl azodicarboxylate into it, drop it within 30 minutes, and stir well. After adding, keep warm and stir for 2 hours, then raise the temperature to reflux reaction, keep warm and reflux reaction for 3 hours, and the reaction is finished.
[0037] The reaction solution was cooled to room temperature naturally, and a proper amount of petroleum ether was added thereto, and then cooled to 0°C to precipitate tetrahydrofuran crystals. The crystallization was kept warm overnight to precipitate a large amount of yellow solid. The filter cake was collected by filtration, and the filter cake was washed with a proper amount of cold petroleum ether and dried to obtain 193.39 g (0.703 mol) of a yellow solid product.
[0038] Yield 88%, HPLC purity 99.0%, 1 H NMR (400MHz, DMSO-d6): δ 8.75 (s, 1H), 8.63 (d, 1H), 8.22 (d, 1H), 3.55 (br s, 4H), 3.41 (t, 4H), 1.84-1.89 (m, 2H).
[0039] Step (d): Preparation of homopiperazine of compound 6-1
[0040] Keeping nitrogen slightly positive pressure, add 850 mL of anhydrous ethanol and 193.39 g (0.703 mol) of compound 5-1 to a 5 L reaction bottle, stir well, and then dropwise add 35.17 g (0.703 mol) of hydrated Hydrazine , stir well. After adding, heat to reflux reaction. During the reaction, the water-containing solvent is continuously separated through the water separator, and an equal amount of fresh solvent is added at the same time. The reflux reaction is kept at temperature for 6 hours, and the reaction is completed.
[0041] The reaction solution was cooled to 0°C for crystallization. The crystallization was kept warm overnight to precipitate a large amount of yellow solid. The filter cake was removed by filtration, and the filter cake was identified as 4-nitrophthaloyl hydrazide. The filtrate was collected and further dried to obtain an oily substance. The 92°C / 50 mmHg fraction was collected by vacuum distillation to obtain 63.41 g (0.633 mol) of a pure white low-melting solid.
[0042] The yield is 90.1%, and the total yield of the four-step reaction is 63.30%.
[0043] Product purity: 99.17% (GC); NMR data: 1H NMR (400MHz, CDCl3): δ2.90 (t, 4H), 2.87 (s, 4H), 1.70-1.75 (m, 2H), 1.62 (bs, 2H). Example 2
[0044]
[0045] Step (c): Preparation of the compound of formula 5-2 10-nitro-3,4,5,6-tetrahydro-2,7-ethanol[c][1,6]diazepine-1,8-dione
[0046] Add 2000 mL of tetrahydrofuran, 187.78 g (0.798 mol) of the compound of formula 3, 79.15 g (0.878 mol) of the compound of formula 4-2, 1,4-butanediol, and 460.70 g (1.756 mol) of triphenylphosphine to a 5 L reaction bottle, and stir well. Cool the reaction solution to 0-5°C, and then drop 339.03 g (1.677 mol) of the compound diisopropyl azodicarboxylate into it, drop it within 30 minutes, and stir well. After adding, keep warm and stir for 2 hours, then raise the temperature to reflux for reaction, keep warm and reflux for 3 hours, and the reaction is finished.
[0047] The reaction solution was cooled to room temperature naturally, and a proper amount of petroleum ether was added thereto, and then cooled to 0°C for crystallization. The crystallization was kept warm overnight, and a large amount of yellow solid was precipitated. The filter cake was collected by filtration, and the filter cake was washed with a proper amount of cold petroleum ether and dried to obtain 208.80 g (0.722 mol) of a yellow solid product.
[0048] Yield: 90.4%, HPLC purity: 98.6%, 1 H NMR (400MHz, DMSO-d6): δ 8.74 (s, 1H), 8.63 (d, 1H), 8.21 (d, 1H), 3.54 (br s, 4H), 3.28 (t, 4H), 1.57-1.62 (m, 4H).
[0049] Step (d): Preparation of 1,4-diazacyclooctane of Formula 6-2
[0050] Keeping nitrogen slightly positive pressure, add 850mL acetonitrile and 208.80g (0.722 mol) of compound 5-2 to a 5 L reaction bottle and stir well. Then add 43.36g (0.866mol) of hydrazine hydrate dropwise and stir well. After adding, heat to reflux reaction. During the reaction, the water-containing solvent is continuously separated through the water separator, and an equal amount of fresh solvent is added at the same time. Keep the temperature and reflux for 6 hours to end the reaction.
[0051] The reaction solution was cooled to 0°C for crystallization. The crystallization was kept warm overnight to precipitate a large amount of yellow solid. The filter cake was removed by filtration, and the filter cake was identified as 4-nitrophthaloyl hydrazide. The filtrate was collected and further dried to obtain an oily substance. The 92°C / 50 mmHg fraction was collected by vacuum distillation to obtain 73.76 g (0.646 mol) of a pure white low melting point solid.
[0052] The yield is 89.5%, and the total yield of the four-step reaction is 64.60%.
[0053] Product purity: 99.57% (GC); NMR data: 1H NMR (400MHz, CDCl3): δ2.86 (s, 4H), 2.75 (t, 4H), 1.66 (bs, 2H), 1.44-1.49 (m, 4H).
[0054] Comparative Example 1
[0055]
[0056] The same operation scheme as steps (b) and (c) in Example 1 was used to convert the raw material compound into an equivalent amount of phthaloyl chloride 7. During the experiment, it was found that the product obtained when compound 8 was converted into compound 9 was very impure and the pure product of compound 9 could not be isolated.
[0057] It can be seen that the 4-nitrophthaloyl chloride of the present invention is a good reactive group here, which makes the subsequent ring-closure step feasible.
[0058] The above examples are only for illustrating the technical concept and features of the present invention. Their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it accordingly. They cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.
Claims
1. A diazamacrocyclic compound intermediate, characterized in that: Its chemical structure is shown in 5. , wherein n is selected from 1-3.
2. A method for preparing a diazamacrocyclic compound intermediate, characterized in that: The preparation method comprises the following steps: (a) Compound 1 is reacted in a halogenating agent and a first reaction solvent at a reaction temperature of 0-200 degrees for a reaction time of 1-20 hours to obtain Compound 2, wherein the halogenating agent is one of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, chlorosulfonic acid, and sulfonyl chloride, and the first reaction solvent is one or more of 1,2-dichloroethane, dichloromethane, chlorobenzene, nitrobenzene, and o-dichlorobenzene; (b) Compound 2 is added to a second reaction solvent, and a first alkaline reagent and ethylenediamine are added, the reaction temperature is 0-100 degrees, and the reaction time is 1-24 hours to obtain compound 3, wherein the molar ratio of compound 2 to ethylenediamine is 1:1-2, wherein the second reaction solvent is one or more of acetonitrile, ethyl acetate, dichloromethane, 1,2-dichloroethane, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, xylene, o-dichlorobenzene, benzene and toluene; (c) In a third reaction solvent, compound 3 reacts with compound 4 in a second alkaline reagent at a reaction temperature of 25-200 degrees and a reaction time of 1-24 hours to obtain compound 5, wherein the molar ratio of compound 3 to compound 4 is 1:1-2, and the third reaction solvent is one or more of acetonitrile, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, xylene, o-dichlorobenzene, N,N-dimethylformamide, N-methylpyrrolidone, ethanol, methanol, benzene and toluene, wherein n is selected from 1-3.
3. The method for preparing a diazamacrocyclic compound intermediate according to claim 2, characterized in that: In step (a), the molar ratio of compound 1 to the halogenating agent is 1:2-20.
4. The method for preparing a diazamacrocyclic compound intermediate according to claim 2, characterized in that: In step (b), the first alkaline reagent is one or more of sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, triethylamine, and pyridine.
5. The method for preparing a diazamacrocyclic compound intermediate according to claim 2, characterized in that: In step (b), the temperature is 50-60°C.
6. The method for preparing a diazamacrocyclic compound intermediate according to claim 2, characterized in that: In step (c), the second alkaline reagent is one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, pyridine, and DBU.
7. The method for preparing a diazamacrocyclic compound intermediate according to claim 2, characterized in that: In step (c), the temperature is 50-80°C.
8. Application of a method for preparing a diazamacrocyclic compound intermediate in preparing a diazamacrocyclic compound, characterized in that: Under air-tight conditions, the compound 5 is added with hydrazine hydrochloride in a fourth reaction solvent in the presence of a third alkaline reagent, and refluxed for 4-10 hours to obtain a compound 6, wherein the fourth reaction solvent is one or more of acetonitrile, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethanol, and methanol. , n is selected from 1-3.
9. Use of the method for preparing a diaza macrocyclic compound intermediate according to claim 8 in preparing a diaza macrocyclic compound, characterized in that: The third alkaline reagent is one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.
10. Use of the method for preparing a diaza macrocyclic compound intermediate according to claim 8 in preparing a diaza macrocyclic compound, characterized in that: The dosage ratio of the compound 5 to the hydrazine hydrochloride is 1:1-2.