Method for preparing linear amino alcohol through selective hydroamine methylation of allyl alcohol
By using a nitrogen-heterocyclic carbene metal coordination polymer catalyst for selective hydrogen amine methylation, the problems of high lipophilicity and low reaction selectivity of 4-phenylpiperazine compounds have been solved, achieving efficient and simple preparation of linear amino alcohols, which is suitable for industrial production.
Patent Information
- Application Number
- CN202511391280.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-26
- Publication Date
- 2025-11-21
AI Technical Summary
Existing technologies for preparing 4-phenylpiperazine compounds suffer from problems such as high lipid solubility, which affects in vivo metabolism and distribution, and low reaction selectivity and difficulty in product separation due to the low lipid solubility of traditional methods.
Linear amino alcohols are prepared by selective hydrogenamine methylation reaction using allyl alcohol, carbon monoxide or carbon dioxide, hydrogen and N-arylpiperazine as raw materials and nitrogen heterocyclic carbene metal coordination polymer as catalyst, avoiding the use of expensive long-chain halogenated products and simplifying the post-processing.
It achieves highly selective and efficient preparation of linear amino alcohols, simplifies product separation, reduces production costs, and is suitable for large-scale industrial applications.
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Figure CN120987876A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of fine chemical technology, specifically to a method for preparing linear amino alcohols by selective hydrogen amine methylation of allyl alcohol. Background Technology
[0002] In the past decade or so, compounds with 4-phenylpiperazine as their core skeleton and their derivatives have become a research hotspot in the field of medicinal chemistry due to their potential value in the development of selective D3 receptor ligands. From the perspective of molecular mechanism of action, the 4-phenylpiperazine moiety is both the basic core of the drug molecule and a key structural domain that ensures its efficient binding to the D3 receptor; by connecting this structure with ligand fragments such as aromatic heterocyclic rings, the compound can be further endowed with special pharmacological functions of regulating central nervous system signals, providing an important research direction for the intervention of central nervous system diseases. BP897, chemically named 4-[4-(2-methoxy-phenyl)-piperazinyl]-butyl-2-naphthylcarboxamide, is the first dopamine D3 receptor partial agonist to enter clinical trials. At the end of the last century, a research team composed of the French National Institute of Hygiene and Medical Research and the University of Cambridge in the United Kingdom discovered a substance that can inhibit drug addiction, bringing hope for a physiological solution to the problem of drug addiction. This substance that can inhibit drug addiction is BP897. Studies have shown that BP897 has good efficacy in treating drug addiction and has very important application prospects; it is currently under clinical research. Due to the good efficacy of BP897, many researchers have conducted in-depth studies on it over the past decade.
[0003] Using BP897 as a lead compound, the Gardener team constructed a novel class of tricyclic D3 receptor antagonists by directionally modifying the naphthyl fragment. To further enhance the compound's activity, the researchers optimized the key 4-phenylpiperazine domain, replacing the original methoxy group with a dichloro-substituted structure. Activity tests showed that the target compound NGB2904 and the biphenyl derivative NGB2849 exhibited high affinity and specific binding to the D3 receptor, with corresponding Ki values of 1.4 nM and 0.9 nM, respectively. In a cocaine auto-administration animal model, they inhibited drug-seeking behavior. However, due to the high lipid solubility of these compounds, their metabolism and distribution in vivo were affected. Based on this, Boecklei synthesized a 2-benzothiophene carboxamide derivative (FAUC365) as a dopamine D3 receptor antagonist. It exhibited high selectivity for the D2 / D3 receptor (a ratio of 7200, with a D3 affinity of 0.5 nm), but also showed high lipid solubility.
[0004] This invention discloses a method for preparing linear amino alcohols that features high reaction selectivity, short reaction time, readily available and relatively inexpensive raw materials, convenient product separation and purification, easy reaction control, and minimal waste generation. It provides a new, convenient, and rapid reaction pathway for the preparation and production of piperazine drugs. Summary of the Invention
[0005] The purpose of this invention is to provide an efficient and highly selective method for preparing linear amino alcohols by selective hydrogen amine methylation of allyl alcohol.
[0006] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing linear amino alcohols by selective hydrogenamine methylation of allyl alcohol, using allyl alcohol, carbon monoxide or carbon dioxide, hydrogen and... N Using arylpiperazine as a raw material and a nitrogen-containing heterocyclic carbene metal coordination polymer as a catalyst, the selective hydrogenamine methylation of allyl alcohol is catalyzed to achieve the preparation of linear amino alcohols; the specific steps are as follows: With allyl alcohol, carbon monoxide or carbon dioxide, hydrogen and N Using arylpiperazine as a raw material, ethers, alcohols, or benzene analogs as solvents, and nitrogen heterocyclic carbene coordination polymers as catalysts, the molar ratio of catalyst to amine is 1 / 10,000 to 1 / 1000, and the reaction is carried out at 80 to 200°C for 4 to 24 hours. The chemical reaction process is as follows: , in, N In arylpiperazine compounds, R is selected from C6-C, which may be substituted at the ortho, meta, or para positions or unsubstituted. 10 aryl, ortho-, meta-, para-substituted or unsubstituted hydrogen, halogen, nitro, hydroxyl, cyano, trihalomethyl, amino, C1-C 12 Alkyl, C3-C 10 cycloalkyl, C2-C 12 Alkenyl or C2-C 12 alkynyl group; Wherein, “substituted” means that one or more hydrogen atoms in a group are replaced by a substituent selected from the group consisting of: halogen, C3-C6 alkyl, C4 ester, C5 carbonyl, C5 alkyl ether, C4 hydroxy, and C1-C2 alkoxy. The general structural formula of the linear amino alcohol is shown in (I): .
[0007] Furthermore, the nitrogen-heterocyclic carbene metal coordination polymer is a nitrogen-heterocyclic carbene solid molecular catalyst of rhodium, cobalt, iridium, ruthenium, palladium, iron, nickel, or manganese.
[0008] In this invention, the N-The molar ratio of arylpiperazine to olefin is 1 to 2.5, and the solvent and N The molar ratio of -arylpiperazine is 20 to 50. Preferably, the molar ratio of solvent to amine is 20 to 35.
[0009] In this invention, nitrogen-containing heterocyclic carbene metal coordination polymers are preferred. N The molar ratio of -arylpiperazine is from 0.01% to 0.1%.
[0010] In this invention, the CO / H2 pressure ratio is preferably 1 / 1 to 1 / 20, and more preferably 1 / 5 to 1 / 10.
[0011] In this invention, the preferred reaction temperature is 120 to 150°C.
[0012] After the reaction in this invention is completed, the nitrogen-containing heterocyclic carbene metal coordination polymer is recovered by centrifugation. Centrifugation separates the catalyst from the reaction solution; after washing and drying, no further activation is required for the next catalytic reaction. The yield of the linear amino alcohol is obtained by column chromatography, and the selectivity of the linear amino alcohol is utilized. 1 The measurements were performed using HNMR.
[0013] This invention uses inexpensive and readily available allyl alcohol and N Using arylpiperazine as a raw material, carbon chain extension and olefin enrichment are achieved, yielding linear amino alcohols with high efficiency and selectivity. The electronegativity of the nitrogen-containing heterocyclic carbene ligand is significantly correlated with the catalyst activity. Among them, the nitrogen-containing heterocyclic carbene ligands in the metal coordination polymers have strong σ-electron-donating ability, and the catalytic activity is significantly improved with further enhancement of the electron-donating ability of the ligand. The conversion can be completed at a catalytic amount as low as 1%, with a reaction selectivity L / B value of 96 / 4 and an amino alcohol yield of 55-63%.
[0014] This invention uses inexpensive and readily available allyl alcohol and N Using arylpiperazine as a starting material avoids the use of long-chain halogenated compounds, which are more difficult to synthesize and more expensive. The operation is simple and high-purity linear amino alcohols can be obtained without complicated post-processing filtration, making it suitable for large-scale industrial applications.
[0015] The advantages of the method of the present invention are: (1) The reaction has high linear selectivity and can well produce linear amino alcohols; (2) The reaction does not require the use of long-chain halogenated products with complicated synthesis processes and high prices as starting materials, nor does it require the addition of bases or acids as additives, which avoids complicated post-processing. (3) Due to the insolubility of nitrogen heterocyclic carbene metal coordination polymers in common organic solvents and water, the catalyst can be recovered by simple filtration after the reaction. The catalyst can be recycled dozens of times without significant decrease in catalytic activity and selectivity, and has great industrial application value.
[0016] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, the preferred embodiments of the present invention are described in detail below with reference to the accompanying drawings. Attached Figure Description
[0017] Figure 1 The image shows the 1H NMR spectrum of the product obtained in Example 2, which is a selectively hydrogenated product of allyl alcohol and 1-(2,3-dichlorophenyl)piperazine.
[0018] Figure 2 The image shows the carbon NMR spectrum of the product obtained in Example 2, which is the product of selective hydrogen amine methylation of allyl alcohol and 1-(2,3-dichlorophenyl)piperazine. Detailed Implementation
[0019] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0020] In the description of this invention, it should be noted that the terms "center," "upper," "lower," "left," "right," "vertical," "horizontal," "inner," and "outer," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are used only for the convenience of describing the invention and for simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the invention. Furthermore, the terms "first," "second," and "third" are used for descriptive purposes only and should not be construed as indicating or implying relative importance.
[0021] Furthermore, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.
[0022] Example 1, Preparation of piperazine substrate 1 A nitrogen-containing heterocyclic carbene rhodium coordination polymer (0.005 mmol), 1-(2,3-dichlorophenyl)piperazine (0.5 mmol), tetrahydrofuran (4 mL), and allyl alcohol (1.25 mmol) were added sequentially to a reaction vessel. The system was purged with carbon monoxide three times and pressurized to 9 atm, then purged with hydrogen to 80 atm. The reaction vessel was placed in an oil bath and heated to 150°C for 18 hours. After the reaction, the reaction vessel was cooled to 0°C in an ice bath. Trimethoxybenzene was added as an internal standard, and the reaction solution was diluted with dichloromethane. The selectivity of the linear amine was determined by... 1 The solution after the reaction was analyzed by ¹H NMR, and then high-purity linear amino alcohols were obtained by column chromatography. The yield was 63%, and the selectivity was L:B = 96 / 4.
[0023] Example 2, Preparation of piperazine substrate 2 A nitrogen-containing heterocyclic carbene rhodium coordination polymer (0.005 mmol), 1-(2,3-dichlorophenyl)piperazine (0.5 mmol), tetrahydrofuran (4 mL), and allyl alcohol (1.25 mmol) were added sequentially to a reaction vessel. The system was purged with carbon monoxide three times and pressurized to 9 atm, then purged with hydrogen to 80 atm. The reaction vessel was placed in an oil bath and heated to 150°C for 18 hours. After the reaction, the reaction vessel was cooled to 0°C in an ice bath. Trimethoxybenzene was added as an internal standard, and the reaction solution was diluted with dichloromethane. The selectivity of the linear amine was determined by... 1 The solution after the reaction was analyzed by ¹H NMR, and then high-purity linear amino alcohols were obtained by column chromatography. The yield was 55%, and the selectivity was L:B = 96 / 4.
[0024] Example 3, Preparation of piperazine substrate 3 A nitrogen-containing heterocyclic carbene rhodium coordination polymer (0.005 mmol), 1-(2,3-dichlorophenyl)piperazine (0.5 mmol), tetrahydrofuran (4 mL), and allyl alcohol (1.25 mmol) were added sequentially to a reaction vessel. The system was purged with carbon monoxide three times and pressurized to 9 atm, then purged with hydrogen to 80 atm. The reaction vessel was placed in an oil bath and heated to 150°C for 18 hours. After the reaction, the reaction vessel was cooled to 0°C in an ice bath. Trimethoxybenzene was added as an internal standard, and the reaction solution was diluted with dichloromethane. The selectivity of the linear amine was determined by... 1 The solution after the reaction was analyzed by ¹H NMR, and then high-purity linear amino alcohols were obtained by column chromatography. The yield was 56%, and the selectivity was L:B = 96 / 4.
[0025] In summary, this invention provides a method for preparing linear amino alcohols by selective hydrogenamine methylation of allyl alcohol, using inexpensive and readily available allyl alcohol and... NUsing arylpiperazine as a starting material avoids the use of long-chain halogenated compounds, which are more difficult to synthesize and more expensive. The operation is simple and high-purity linear amino alcohols can be obtained without complicated post-processing filtration, making it suitable for large-scale industrial applications.
[0026] Furthermore, the method of the present invention also has the following advantages: (1) The reaction has high linear selectivity and can effectively yield linear amino alcohols; (2) The reaction does not require the use of long-chain halogenated products with complicated synthesis processes and high prices as starting materials, nor does it require the addition of bases or acids as additives, which avoids complicated post-processing. (3) Due to the insolubility of nitrogen heterocyclic carbene metal coordination polymers in common organic solvents and water, the catalyst can be recovered by simple filtration after the reaction. The catalyst can be recycled dozens of times without significant decrease in catalytic activity and selectivity, and has great industrial application value.
[0027] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0028] The embodiments described above are merely illustrative of implementation methods of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.
Claims
1. A method for preparing linear amino alcohols by selective hydrogen amine methylation of allyl alcohol, characterized in that, With allyl alcohol, carbon monoxide or carbon dioxide, hydrogen and N Using arylpiperazine as a raw material and a nitrogen-containing heterocyclic carbene metal coordination polymer as a catalyst, the selective hydrogenamine methylation of allyl alcohol is catalyzed to achieve the preparation of linear amino alcohols; the specific steps are as follows: With allyl alcohol, carbon monoxide or carbon dioxide, hydrogen and N Using arylpiperazine as a raw material, ethers, alcohols, or benzene analogs as solvents, and nitrogen heterocyclic carbene coordination polymers as catalysts, the molar ratio of catalyst to amine is 1 / 10,000 to 1 / 1000, and the reaction is carried out at 80 to 200°C for 4 to 24 hours. The chemical reaction process is as follows: , in, N In arylpiperazine compounds, R is selected from ortho-, meta-, para-substituted, or unsubstituted C6-C. 10 aryl, ortho-, meta-, para-substituted or unsubstituted hydrogen, halogen, nitro, hydroxyl, cyano, trihalomethyl, amino, C1-C 12 Alkyl, C3-C 10 cycloalkyl, C2-C 12 Alkenyl or C2-C 12 alkynyl group; Wherein, "substituted" means that one or more hydrogen atoms in the group are replaced by substituents selected from the group consisting of: halogen, C3-C6 alkyl, C4 ester, C5 carbonyl, C5 alkyl ether, C4 hydroxy, and C1-C2 alkoxy. The general structural formula of the linear amino alcohol is shown in (I): 。 2. The method for preparing linear amino alcohols by selective hydrogen amine methylation of allyl alcohol according to claim 1, characterized in that, The nitrogen-heterocyclic carbene metal coordination polymer is a nitrogen-heterocyclic carbene solid molecular catalyst of rhodium, cobalt, iridium, ruthenium, palladium, iron, nickel, or manganese.
3. The method for preparing linear amino alcohols by selective hydrogen amine methylation of allyl alcohol according to claim 1, characterized in that, The N -The molar ratio of arylpiperazine to olefin is 1 to 2.5, and the molar ratio of solvent to amine is 20 to 50.
4. The method for preparing linear amino alcohols by selective hydrogen amine methylation of allyl alcohol according to claim 1, characterized in that, The nitrogen heterocyclic carbene metal coordination polymer and N The molar ratio of -arylpiperazine is from 0.01% to 0.1%.
5. The method for preparing linear amino alcohols by selective hydrogen amine methylation of allyl alcohol according to claim 1, characterized in that, The CO / H2 pressure ratio in the reaction is 1 / 1 to 1 / 20.
6. The method for preparing linear amino alcohols by selective hydrogen amine methylation of allyl alcohol according to claim 1, characterized in that, The reaction temperature is 120 to 150°C.