Recovery method of chiral diphosphine ligand
By chemically reducing the oxidized bisphosphine ligand in the catalyst and re-reducing it to active ligand, the problem of catalyst deactivation is solved, and the reuse of catalysts and the reduction of production costs are achieved.
Patent Information
- Application Number
- CN202411864960.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-18
- Publication Date
- 2025-05-06
AI Technical Summary
The existing catalysts are inactivated after catalytic reactions, mainly because the bisphosphine ligand is oxidized, resulting in the catalyst being unable to be reused, increasing industrial production costs.
The catalyst can be reused by chemical reduction of the oxidized bisphosphine ligand and re-reducing to the active ligand. The specific method includes dissolving the oxidized bisphosphine ligand in a solvent, using diethylamine or N,N-diisopropylethylamine as the base and trichlorosilane as the reducing agent, heating the reaction, and monitoring the reaction by 31PNMR, stop heating, drain the solvent, add borane tetrahydrofuran complex, and continue stirring until the reaction is completed.
The reuse of catalysts is realized, industrial production costs are reduced, and the reaction conditions are mild, simple operation, high three-dimensional selectivity and high yields are suitable for industrial implementation.
Smart Images
Figure CN119930681A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, relates to the recovery of a catalyst used in synthesis, and specifically relates to a method for recovering a chiral diphosphine ligand. Background Art
[0002] Menthol, commonly known as menthol, is a colorless, transparent needle-shaped crystal with the advantages of refreshing coolness, low price and easy availability. From the perspective of molecular structure, menthol contains three chiral centers and has eight isomers. Among them, only the left-handed L-menthol (L-1) has a minty aroma and a cooling effect, while the right-handed D-menthol (D-1) has a pungent and irritating smell and has no cooling effect.
[0003]
[0004] Because of this, the value of L-menthol is high and it is widely used in cosmetics, toothpaste, chewing gum, refreshing drinks, medicines and other products. Naturally extracted menthol is mainly L-menthol, which is produced in India, Brazil and China. In 2009, the annual output of India's natural mint oil (L-menthol content 62% to 87%) reached about 35,000 tons. However, due to the influence of natural environmental factors and the increase in labor costs, the output of natural menthol is getting less and less, and the output is very unstable. For example, in 2010, the annual output of Indian mint oil decreased by 25%, only about 28,000 tons. Therefore, the development of an economical, efficient and green asymmetric synthesis method for L-menthol has always received extensive attention from synthetic chemists.
[0005] Citronellal is widely used in food and daily flavors because of its strong characteristic aroma. Asymmetric hydrogenation of citral is an effective method for preparing optically active citronellal, and subsequent cyclization and hydrogenation can efficiently obtain L-menthol. The key to the application of this route in industrial production is to develop efficient, cheap and highly selective chiral catalysts to obtain highly optically active (R)-citronellal.
[0006]
[0007] So far, a lot of research has been done on the asymmetric catalytic hydrogenation of citral in the literature, and a variety of catalytic systems have been developed, such as chiral diphosphine ligands, dinitrogen ligands and transition metal ruthenium, rhodium precursors as catalysts to promote the reaction [(1) Paul, AV; Laval, SG; Dang, TP; Lyon. US pat, 4237072A, 1977. (2) Jakel, C.; Paciello, R. CN pat, 101039894A, 2005. (3) Zhang Wanbin, Zhang Zhenfeng, Chen Jianzhong, Dong Jing, Bao Yuanye, Zhang Yongzhen, Li Yuan, CN pat, 105218335A, 2015. (4) Kanazawa, H.; Nishiyama, H. Conjugate Reduction of α, β-Unsaturated Aldehydes with Rhodium(Bis-Oxazolinylphenyl)Catalysts.Synlett2006,3343-3345.], and asymmetric hydrogenation and transfer hydrogenation reactions promoted by chiral organic small molecule catalysts [(1) Mayer, S.; List, B. Asymmetric Counteranion-Directed Catalysis. Angew. Chem. Int. Ed. 2006, 45, 4193-4195. (2) MacMillan, D.; Ouellet, S.; Tuttle, J. US pat, 0161024A1, 2006; 0125310A1, 2008. (3) Akagawa, K.; Akabane, H.; Sakamoto, S.; Kudo, K. Organocatalytic Asymmetric Transfer Hydrogenation in Aqueous Media Using Resin-Supported Peptide Having a Polyleucine Tether.Org.Lett.2008,10,2035-2037.(4)Maeda,H.;Yamada,S.;Itoh,H.;Hori,YA Dual Catalyst System Provides the Shortest Pathwayfor L-Menthol Synthesis.Chem.Commun.2012,48,1772-1774.]. However, these catalytic systems usually have problems such as poor reaction activity (the amount of catalyst is mostly greater than 1 mol%), complex ligand structure, difficult synthesis, poor stability, and the use of non-green solvents, which are far from meeting the requirements of industrial production.
[0008] Technicians have overcome previous shortcomings and invented a stable zero-valent rhodium chiral bisphosphine catalyst (Chinese patent CN2022115418838, a chiral bisphosphine ligand rhodium complex and its preparation method and application), which is characterized by high catalyst stability, convenient storage, and easy preparation. Using this catalyst, the asymmetric hydrogenation of citral (Z / E=8 / 92) can be achieved. Through multiple application experiments of the catalyst, a conversion number of up to 3572 (the ratio of the amount of target product to the amount of catalyst) can be obtained, and the enantioselectivity can reach up to 74% (citral Z / E=10 / 90), providing a practical route for the synthesis of (R)-citronellal.
[0009] Since the catalyst uses expensive bisphosphine ligands in addition to precious metal rhodium, the catalyst must be recycled and reused. In the relevant research on catalyst recycling, technicians found through nuclear magnetic resonance and high-resolution mass spectrometry that the main reason for catalyst deactivation is the oxidation of the bisphosphine ligands ( Figure 1 ), thus losing coordination activity and leading to catalyst deactivation.
[0010] Therefore, it is envisaged that the oxidized bisphosphine ligands can be recovered by chemical methods, thereby further reducing industrial production costs. Summary of the invention
[0011] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for recovering a chiral bisphosphine ligand, which can reduce the chiral bisphosphine ligand oxidized during the catalytic process to obtain the ligand again, so that the catalyst can be reused and the production cost can be saved.
[0012] The present invention is achieved through the following technical solutions:
[0013] A method for recovering a chiral diphosphine ligand comprises the following steps:
[0014] (1) dissolving the oxidized diphosphine ligand in a solvent, using diethylamine or N,N-diisopropylethylamine as a base and trichlorosilane as a reducing agent, and heating for reaction;
[0015] (2) 31 After the reaction is complete as monitored by PNMR, the heating is stopped, the solvent is drained under a high vacuum pump, and after cooling, a borane tetrahydrofuran complex is added, and the mixture is placed at room temperature and stirred continuously until the reaction is complete. After the reaction is completed, the crude product is purified to obtain a chiraphos borane complex, and the target product can be obtained after further deboranization.
[0016] The reaction equation is as follows:
[0017]
[0018] A further improvement of the present invention is:
[0019] The solvent is a mixed solvent of tetrahydrofuran and toluene, and the volume ratio of tetrahydrofuran to toluene is 1:0.5-1.5.
[0020] Furthermore, in step (1), the temperature of the heating reaction is 100 to 120° C., and the time is 8 to 12 hours.
[0021] Furthermore, the molar ratio of the oxidized diphosphine ligand, trichlorosilane, base and borane tetrahydrofuran complex is 1:6-20:1.5-18:5-15.
[0022] Furthermore, the purification process is as follows: after the reaction is completed, methanol is added to quench the reaction, the solvent is spin-dried, DCM is added to dilute, and if there is insoluble matter, DCM is added to dilute, and if there is insoluble matter, it is filtered with a sand core funnel (with a layer of silica gel), H2O is added to wash and extract, and the organic phase is separated and collected, dried over anhydrous sodium sulfate, and spin-dried to obtain borane-protected chiraphos.
[0023] Further, the above obtained product is added to ethanol (freezing degassing and deoxygenating), heated to reflux, and the reaction is monitored by TLC until the reaction is completed. The solvent is removed under a high vacuum pump to obtain the target product ligand.
[0024] The beneficial effects of the present invention are:
[0025] The recovery method of the present invention has the characteristics of mild reaction conditions, simple operation, high stereoselectivity, high yield, simple ligand recovery method, etc. The recovery method of the chiral bisphosphine ligand of the present invention avoids the problems of difficult catalyst recovery and harsh reaction conditions encountered in the traditional synthesis process of such compounds, and greatly reduces the production cost. The reagents used in the whole reaction are relatively easy to obtain, and the process route is of great innovation and is easy to implement in industrialization. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 This is the NMR phosphine spectrum analysis diagram of the separated phosphine oxide after the application of the chiral bisphosphine ligand catalyst;
[0027] Figure 2 is the H NMR spectrum of phosphine oxide 2;
[0028] Figure 3 is the NMR phosphine spectrum of phosphine oxide 2;
[0029] Figure 4 This is the HPLC spectrum of the racemic sample of the chiral bisphosphine ligand borane complex obtained in Example 1;
[0030] Figure 5This is the HPLC spectrum of the chiral bisphosphine ligand borane complex obtained in Example 1;
[0031] Figure 6 is the hydrogen nuclear magnetic resonance spectrum of the chiral bisphosphine ligand borane complex obtained in Example 1;
[0032] Figure 7 is the nuclear magnetic resonance phosphine spectrum of the chiral bisphosphine ligand borane complex obtained in Example 1;
[0033] Figure 8 is the hydrogen nuclear magnetic resonance spectrum of the product of Comparative Example 1;
[0034] Fig. 9 This is the hydrogen nuclear magnetic resonance spectrum of the Chiraphos ligand obtained in Example 4;
[0035] Fig.10 This is the carbon NMR spectrum of the Chiraphos ligand obtained in Example 4;
[0036] Fig.11 This is the nuclear magnetic resonance phosphine spectrum of the Chiraphos ligand obtained in Example 4. DETAILED DESCRIPTION
[0037] The present invention is described in detail below in conjunction with specific embodiments.
[0038] The catalyst 1 disclosed in Chinese patent CN2022115418838, a chiral bisphosphine ligand rhodium complex, its preparation method and application, will be deactivated and eventually become phosphine oxide 2 after participating in the asymmetric catalytic hydrogenation of citral to synthesize R-citronellal. The present invention can re-prepare catalyst 1 by reducing phosphine oxide 2 and complexing the catalyst, thereby reducing industrial production costs.
[0039]
[0040] Example 1: Acquisition of phosphine oxide 2
[0041] After the recovery and application of the catalyst, phosphine oxide 2 is separated from the deactivated catalyst, and its nuclear magnetic resonance phosphine spectrum analysis is shown in Figure 1 Since very little phosphine oxide was obtained under the experimental conditions, it was impossible to further try the recovery conditions. Therefore, phosphine oxide can be prepared by other methods for screening experimental conditions. The specific method is as follows (Ref. Tetrahedron, 2019, 75, 130733):
[0042]
[0043] The NMR spectrum of the obtained phosphine oxide 2 is as follows Figure 2 , Figure 3 shown.
[0044] Example 2
[0045] 1) Phosphine oxide 2 (0.3 mmol) was weighed into a 50 ml sealed tube. Under an argon atmosphere, the treated solvent (THF / Tol, 1 / 1, 10 mL) was added, and then placed at zero degrees Celsius, redistilled N,N-diisopropylethylamine (9 eq) was added and stirred evenly; then, trichlorosilane (10 eq) was quickly added. After completion, the mixture was placed in an oil bath, heated to 110 degrees Celsius, and reacted overnight.
[0046] 2) 31 When the reaction was complete as monitored by PNMR, heating was stopped, the solvent was drained under a high vacuum pump, and then the mixture was placed at zero degrees Celsius and borane tetrahydrofuran complex (1.0 M, 10 eq) was added. After completion, the mixture was placed at room temperature and continued to stir until the reaction was completed.
[0047] After the reaction is completed, methanol is slowly added to quench the reaction, the solvent is spin-dried, and DCM is added to dilute. If there is insoluble matter, H2O is added to extract, and the emulsion is filtered with a sand core funnel (a layer of silica gel) to separate the organic phase. This process is repeated until no insoluble matter appears. The organic phase collected at the end is dried and spin-dried to obtain the borane complex of the chiral bisphosphine ligand as a white solid with a purity of >98% (as can be seen from the nuclear magnetic hydrogen spectrum), a yield of 81% (110 mg), and an ee value of the obtained product of >99%.
[0048] Test results:
[0049] 1) Optical rotation measurement:
[0050] 2) HPLC method: ID-3, nHEX / DCM=95:5, 1 mL / min, 220 nm, t1=10.96 min, t2=11.86 min.
[0051] Example 2
[0052] 1) Phosphine oxide 2 (0.3 mmol) was weighed into a 50 ml sealed tube. Under an argon atmosphere, the treated solvent (THF / Tol, 1 / 1, 10 mL) was added, and then placed at zero degrees Celsius, redistilled diethylamine (9 eq) was added and stirred evenly; then, trichlorosilane (10 eq) was quickly added. After completion, the mixture was placed in an oil bath, heated to 110 degrees Celsius, and reacted overnight.
[0053] 2) 31 When the reaction was complete as monitored by PNMR, heating was stopped, the solvent was drained under a high vacuum pump, and then the mixture was placed at zero degrees Celsius and borane tetrahydrofuran complex (1.0 M, 10 eq) was added. After completion, the mixture was placed at room temperature and continued to stir until the reaction was completed.
[0054] After the reaction is completed, methanol is slowly added to quench the reaction, the solvent is spin-dried, and DCM is added to dilute. If there is insoluble matter, H2O is added to extract, and the emulsion is filtered with a sand core funnel (a layer of silica gel) to separate the organic phase. This is repeated until no insoluble matter appears. The organic phase collected is finally dried and spin-dried to obtain a borane complex of a chiral bisphosphine ligand with a purity of >99% and a yield of 72% (98 mg). The ee value of the obtained product is >99%.
[0055] Example 3
[0056] 1) Phosphine oxide 2 (3.74 mmol, 1.714 g) was weighed into a 50 ml sealed tube. Under an argon atmosphere, the treated solvent (THF / Tol, 1 / 1, 5 mL) was added, and then placed at zero degrees Celsius, N, N-diisopropylethylamine (9 eq) was added and stirred evenly; then, trichlorosilane (10 eq) was quickly added. After completion, the mixture was placed in an oil bath, heated to 110 degrees Celsius, and reacted overnight.
[0057] 2) 31 When the reaction was complete as monitored by PNMR, heating was stopped, the solvent was drained under a high vacuum pump, and then the mixture was placed at zero degrees Celsius and borane tetrahydrofuran complex (1.0 M, 10 eq) was added. After completion, the mixture was placed at room temperature and continued to stir until the reaction was completed.
[0058] After the reaction is completed, methanol is slowly added to quench the reaction, the solvent is spin-dried, and DCM is added to dilute. If there is insoluble matter, H2O is added to extract, and the emulsion is filtered with a sand core funnel (a layer of silica gel) to separate the organic phase. This is repeated until no insoluble matter appears. The organic phase collected is finally dried and spin-dried to obtain a borane complex of a chiral bisphosphine ligand with a purity of >99% and a yield of 86% (1.461 g). The ee value of the obtained product is >99%.
[0059] Comparative Example 1
[0060] 1) Phosphine oxide 2 (0.3 mmol) was weighed into a 50 ml sealed tube. Under an argon atmosphere, the treated solvent (THF / Tol, 1 / 1, 10 mL) was added, and then placed at zero degrees Celsius, redistilled triethylamine (9 eq) was added and stirred evenly; then, trichlorosilane (10 eq) was quickly added. After completion, the mixture was placed in an oil bath, heated to 110 degrees Celsius, and reacted overnight.
[0061] 2) 31 When the reaction was complete as monitored by PNMR, heating was stopped, the solvent was drained under a high vacuum pump, and then the mixture was placed at zero degrees Celsius and borane tetrahydrofuran complex (1.0 M, 10 eq) was added. After completion, the mixture was placed at room temperature and continued to stir until the reaction was completed.
[0062] After the reaction, methanol was slowly added to quench the reaction, the solvent was spin-dried, and DCM was added to dilute. There were insoluble substances, and H2O was added to extract. The emulsion was filtered with a sand core funnel (a layer of silica gel), and the organic phase was separated. The organic phase was concentrated and purified by column chromatography to obtain a borane complex of a chiral bisphosphine ligand. The H NMR spectrum ( Figure 8 ) can be seen in NEt 3. BH3 byproduct remained and was difficult to separate. The crude yield was 79% (107 mg). The ee value of the obtained product was >99%.
[0063] Example 4: Chiraphos ligand preparation:
[0064] Borane-protected Chiraphos (0.28 mmol, 126.1 mg) was placed in a 50 mL sealed tube, degassed ethanol (5 mL) was added under an argon atmosphere, and then heated in an oil bath at 100 degrees Celsius until the reaction was completed. After heating, the solvent was removed under vacuum to obtain the pure target product with an equivalent yield. The NMR spectrum of the obtained Chiraphos ligand is shown as follows: Figures 9 to 11 shown.
[0065] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for recovering a chiral diphosphine ligand, characterized in that: The following steps are involved: (1) dissolving the oxidized diphosphine ligand in a solvent, using diethylamine or N,N-diisopropylethylamine as a base and trichlorosilane as a reducing agent, and heating for reaction; (2) 31 After the reaction is complete as monitored by PNMR, the heating is stopped, the solvent is drained under a high vacuum pump, and after cooling, a borane tetrahydrofuran complex is added, and the mixture is placed at room temperature and stirred continuously until the reaction is complete. After the reaction is completed, the crude product is purified to obtain a chiraphos borane complex, and the target product can be obtained after further deboranization. The reaction equation is as follows:
2. A method for recovering a chiral diphosphine ligand according to claim 1, characterized in that: The solvent is a mixed solvent of tetrahydrofuran and toluene, and the volume ratio of tetrahydrofuran to toluene is 1:0.5-1.
5.
3. A method for recovering a chiral diphosphine ligand according to claim 1, characterized in that: In step (1), the heating reaction temperature is 100-120° C. and the time is 8-12 hours.
4. A method for recovering a chiral diphosphine ligand according to claim 1, characterized in that: The molar ratio of the oxidized diphosphine ligand, trichlorosilane, base and borane tetrahydrofuran complex is 1:6-20:1.5-18:5-15.
5. A method for recovering a chiral diphosphine ligand according to claim 1, characterized in that: The purification process is as follows: after the reaction is completed, methanol is added to quench the reaction, the solvent is spin-dried, DCM is added to dilute, and insoluble matter is filtered using a sand core funnel with a layer of silica gel, the filtrate is washed and extracted with H2O, the organic phase is separated and collected, dried over anhydrous sodium sulfate, and spin-dried to obtain borane-protected chiraphos.
6. A method for recovering a chiral diphosphine ligand according to claim 1, characterized in that: The deborane process is as follows: adding the chiraphos borane complex into frozen degassed and deoxygenated ethanol, heating to reflux, monitoring the reaction by TLC until the reaction is completed, and removing the solvent under a high vacuum pump to obtain the target product chiral bisphosphine ligand.