Chiral ruthenium catalyst as well as preparation method and application thereof

Abstract

The invention discloses a chiral ruthenium catalyst as well as a preparation method and application thereof, and belongs to the technical field of catalysts. The ruthenium catalyst provided by the invention has two ligands of diphosphine and dinitrogen for common coordination, has higher catalytic effect and chiral principle compared with the traditional ruthenium catalyst, can realize asymmetric hydrogenation of some carbonyl compounds with lower ruthenium loading capacity to obtain chiral secondary alcohol, and can be used for preparing the chiral secondary alcohol. And the cost of the catalyst is reduced for industrial asymmetric catalytic hydrogenation.

Description

Technical Field

[0001] The present invention belongs to the technical field of catalysts, and particularly relates to a chiral ruthenium catalyst, a preparation method thereof, and an application thereof. Background Art

[0002] Asymmetric hydrogenation is a commonly used method for constructing chiral molecules in the industry at present. Japanese chemist Noyori won the Nobel Prize in Chemistry in 2001 for inventing the first-generation ruthenium catalyst for asymmetric catalytic hydrogenation. The ruthenium catalyst developed by Noyori has a milestone significance in the field of asymmetric hydrogenation, providing strong technical support for the synthesis of chiral molecules and promoting the development of related industries.

[0003] However, there are still some technical problems to be solved in the existing ruthenium catalysts. On the one hand, in some cases, its catalytic efficiency still needs to be further improved. Especially when facing some carbonyl compounds with special structures or complex reaction conditions, the ideal reaction rate and conversion rate may not be achieved. On the other hand, there are also limitations in chiral selectivity. For some substrates or reaction systems, the generation of chiral centers may not be precisely controlled, resulting in an unsatisfactory enantiomeric excess (ee value), thus affecting the optical purity of products such as chiral secondary alcohols. In addition, from the perspective of cost, the application cost of traditional ruthenium catalysts in some large-scale industrial productions is relatively high, mainly because the catalyst loading is large, which to a certain extent limits its wider application. Summary of the Invention

[0004] The purpose of this part is to outline some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this part, as well as in the abstract and title of the specification of this application, to avoid obscuring the purpose of this part, the abstract, and the title. However, such simplifications or omissions cannot be used to limit the scope of the present invention.

[0005] In view of the above and / or problems existing in the prior art, the present invention is proposed.

[0006] One of the purposes of the present invention is to provide a chiral ruthenium catalyst. The ruthenium catalyst provided by the present invention has two ligands of bisphosphine and bisnitrogen coordinated together, and can achieve the asymmetric hydrogenation of some carbonyl compounds with a lower ruthenium loading.

[0007] To solve the above technical problems, the present invention provides the following technical solution: a chiral ruthenium catalyst, and the chiral ruthenium catalyst has a structural formula shown in Formula I;

[0008]

[0009] Another object of the present invention is to provide a method for preparing the chiral ruthenium catalyst as described above, including,

[0010] (1) React pyridine-2-carboxaldehyde with (R)-(+)-tert-butanesulfinamide in a solvent in the presence of cesium carbonate to obtain the compound shown in Formula II;

[0011]

[0012] (2) React the compound shown in Formula II with o-dibromobenzene in a solvent in the presence of magnesium chips to obtain the compound shown in Formula III;

[0013]

[0014] (3) React the compound shown in Formula III with hydrochloric acid to obtain the target product shown in Formula I.

[0015] As a preferred embodiment of the method for preparing the chiral ruthenium catalyst of the present invention, wherein: in step (1), the molar ratio of pyridine-2-carboxaldehyde to (R)-(+)-tert-butanesulfinamide is 1:1 to 2;

[0016] The molar ratio of pyridine-2-carboxaldehyde to cesium carbonate is 1:1 to 2.

[0017] As a preferred embodiment of the method for preparing the chiral ruthenium catalyst of the present invention, wherein: in step (1), the solvent includes one of methanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, DMF or 1,4-dioxane;

[0018] For the reaction in step (1), the temperature is 30 to 60 °C and the time is 12 hours.

[0019] As a preferred embodiment of the method for preparing the chiral ruthenium catalyst of the present invention, wherein: in step (2), the molar ratio of the compound shown in Formula II to o-dibromobenzene is 1:1 to 2;

[0020] The molar ratio of the compound shown in Formula II to magnesium chips is 1:1.05.

[0021] As a preferred embodiment of the method for preparing the chiral ruthenium catalyst of the present invention, wherein: in step (2), the solvent includes one of tetrahydrofuran, methyl tert-butyl ether or diethyl ether;

[0022] For the reaction in step (2), the temperature is 60 to 100 °C and the time is 8 to 20 h.

[0023] As a preferred embodiment of the method for preparing the chiral ruthenium catalyst of the present invention, wherein: in step (3), the molar ratio of the compound shown in Formula III to hydrochloric acid is 1:2 to 6.

[0024] As a preferred embodiment of the preparation method of the chiral ruthenium catalyst of the present invention, in which: for the reaction in step (3), the temperature is 60-100 °C and the time is 2-4 hours.

[0025] Another object of the present invention is to provide a method for preparing aryl ketone compounds by asymmetric catalytic hydrogenation. Under a hydrogen atmosphere, the compound shown in formula IV is mixed and reacted with the compound shown in formula I, a base, and a solvent to obtain the compound shown in formula V;

[0026]

[0027] Wherein, Ar is a benzene ring, a naphthalene ring, or a pyridine ring substituted with various different substituents such as methyl, ethyl, methoxy, or halogen.

[0028] As a preferred embodiment of the method for preparing aryl ketone compounds by asymmetric catalytic hydrogenation of the present invention, in which: the molar ratio of the compound shown in formula I to the compound shown in formula IV is 0.01-0.0001:1;

[0029] The molar ratio of the base to the compound shown in formula IV is 0.001-0.1:1;

[0030] The base includes one of potassium hydroxide, potassium tert-butoxide, sodium hydroxide, and sodium carbonate;

[0031] The solvent includes one of methanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran, DMF, 1,4-dioxane, and acetonitrile;

[0032] Under the hydrogen atmosphere, the hydrogen pressure is 10-20 atm;

[0033] For the reaction, the reaction temperature is 10-60 °C and the reaction time is 8-20 h.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The ruthenium catalyst provided by the present invention has two ligands of bisphosphine and bisnitrogen coordinated together. Compared with traditional ruthenium catalysts, it has higher catalytic effect and chirality principle, and can achieve asymmetric hydrogenation of some carbonyl compounds with a lower ruthenium loading to obtain chiral secondary alcohols, reducing the cost of the catalyst for industrial asymmetric catalytic hydrogenation. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings. Among them:

[0037] Figure 1 1H NMR spectrum of the target product in Example 4 of the present invention;

[0038] Figure 2 Single crystal diffraction pattern of the target product in Example 4 of the present invention. Detailed implementation manners

[0039] To make the above objects, features and advantages of the present invention more obvious and understandable, the following describes the detailed implementation manners of the present invention in conjunction with the embodiments of the specification.

[0040] In the following description, many specific details are set forth to facilitate a thorough understanding of the present invention. However, the present invention may be implemented in other ways different from those described herein. Those skilled in the art can make similar extensions without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0041] Secondly, the so-called "one embodiment" or "embodiment" herein refers to a specific feature, structure or characteristic that may be included in at least one implementation manner of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a separate or alternative embodiment that excludes other embodiments.

[0042] Unless otherwise specified, the raw materials used in the embodiments are all commercially purchased.

[0043] Example 1

[0044] Synthesis and characterization of Compound I: Take pyridine-2-carboxaldehyde (12.9 g, 120 mmol), (R)-(+)-tert-butanesulfinamide (14.5 g, 120 mmol) and 400 ml of dichloromethane in a 1 L reaction flask, add cesium carbonate (46.9 g, 144 mmol) thereto, and stir the reaction solution at room temperature overnight. After the reaction is completed, quench with water, separate the layers, extract three times with 30 ml of dichloromethane, combine the organic phases, wash with saturated brine, separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Separate by silica gel column chromatography (PE:EA = 3:1) to obtain 26 g of an oily product (yield 96%).

[0045] Characterize the above target product, 1H NMR spectrum:

[0046] 1 H NMR(500MHz,CDCl3)δppm 8.73(d,J=4.15Hz,1H),8.69(s,1H),8.01(d,J=7.81Hz,1H),7.80(m,1H),7.39(m,1H),1.27(s,9H).13 13C NMR (125 MHz, CDCl3) δ ppm 163.9, 152.7, 150.4, 136.9, 126.1, 123.2, 58.2, 22.9. HRMS (ESI-TOF) calcd for C 10 H 15 N2OS [M+H] + 211.0900, found 211.0900. [α] D 20 = -165.2 (c 1.0, CHCl3).

[0047] According to the characterization data, the structural formula of the prepared reaction product is:

[0048]

[0049] The reaction formula is:

[0050]

[0051] Example 2

[0052] Synthesis and characterization of Compound II: Take o-dibromobenzene (29.8 g, 127 mmol) and place it in a 1 L three-necked flask. Add 400 ml of anhydrous tetrahydrofuran and magnesium chips (2.9 g, 121 mmol). Heat under reflux to initiate the reaction, and then maintain the reaction temperature until the magnesium chips disappear. Cool the newly prepared Grignard reagent to 0 °C, and add Compound I (24.2 g, 115 mmol) to the newly prepared Grignard reagent. Keep the reaction at 0 °C overnight. After the reaction is completed, quench with water, separate the layers, extract three times with 50 ml of ethyl acetate, combine the organic phases, wash with saturated brine, separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain the crude product. Separate by silica gel column chromatography (PE:EA = 3:1) to obtain 34.5 g of an oily product (yield 82%).

[0053] Characterize the above target product, 1H NMR:

[0054] 11H NMR (500 MHz, CDCl3) δ ppm 8.55 - 8.54 (m, 1H), 7.61 (td, J = 7.7, 1.7 Hz, 1H), 7.56 (dd, J = 7.8, 1.5 Hz, 1H), 7.54 - 7.51 (m, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.17 - 7.14 (m, 1H), 7.12 - 7.08 (m, 1H), 6.17 (d, J = 6.3 Hz, 1H), 5.46 (d, J = 6.2 Hz, 1H), 1.19 (s, 9H). 13 13C NMR (100.61 MHz, CDCl3) δ 159.11, 149.1, 141.2, 136.8, 132.8, 130.3, 129.1, 127.9, 123.3, 122.7, 122.6, 59.1, 56.6, 22.6.

[0055] According to the characterization data, the structural formula of the obtained reaction product is:

[0056]

[0057] The reaction equation is:

[0058]

[0059] Example 3

[0060] Synthesis and characterization of compound III: Take compound II (34.5 g, 94 mmol) in a 500 ml reaction flask, add 200 ml of 3N hydrochloric acid while stirring, stir at room temperature for 1 hour. After the reaction is completed, crystallize the reaction solution at 0 °C, filter to obtain the product, 26.1 g of colorless solid (yield 93%).

[0061] Characterize the above target product, nuclear magnetic resonance hydrogen spectrum:

[0062] 1 1H NMR (500 MHz, DMSO-d6) δ ppm 9.48 (br, 3H), 8.69 (d, J = 4.7 Hz, 1H), 7.92 (t, J = 7.7 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.53 - 7.46 (m, 3H), 7.36 (t, J = 7.7 Hz, 1H), 5.93 (br, 1H).

[0063] According to the characterization data, the structural formula of the obtained reaction product is:

[0064]

[0065] The reaction formula is as follows:

[0066]

[0067] Example 4

[0068] Synthesis and characterization of compound Cat.A: Take tris(triphenylphosphine)ruthenium(II) dichloride (959 mg, 1 mmol) and 1,4-bis(diphenylphosphino)butane (469 mg, 1.1 mmol) in a 50 ml reaction flask, add 10 ml of methanol, heat under reflux for 2 hours, cool to room temperature, add compound III (358 mg, 1.2 mmol) and triethylamine (1.7 ml, 12 mmol) to the reaction flask, continue to heat under reflux overnight. After the reaction is completed, quench with water, separate the layers, extract three times with 5 ml of ethyl acetate, combine the organic phases, wash with saturated brine, separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Separate by silica gel column chromatography (PE:EA = 1:1) to obtain 640 mg of yellow solid (yield 74%).

[0069] Characterize the above target product, and the 1H NMR is as follows Figure 1 shown:

[0070] 1 H NMR (500 MHz, CDCl3) δ ppm 9.47 - 9.45 (m, 1H), 8.29 - 8.24 (m, 2H), 7.94 - 7.90 (m, 2H), 7.56 - 7.52 (m, 1H), 7.49 - 7.46 (m, 1H), 7.44 - 7.40 (m, 2H), 7.37 - 7.21 (m, 10H), 7.18 - 7.13 (m, 2H), 7.11 - 7.07 (m, 3H), 6.92 - 6.83 (m, 4H), 5.99 (d, J = 7.8 Hz, 1H), 4.90 (dd, J = 12.6, 4.3 Hz, 1H), 4.45 (t, J = 11.7 Hz, 1H), 4.24–4.07 (m, 1H), 2.87 (q, J = 13.8 Hz, 1H), 2.38–2.24 (m, 1H), 2.22–1.76 (m, 4H), 1.68–1.56 (m, 1H).

[0071] According to the characterization data, the structural formula of the prepared reaction product is:

[0072]

[0073] The reaction formula is as follows:

[0074]

[0075] The single crystal diffraction pattern of compound Cat.A is as follows Figure 2 as shown

[0076] Example 6

[0077] Under an inert gas atmosphere, aryl ketone derivative IV (186 mg, 0.5 mmol) was added to a hydrogenation bottle, followed by the addition of Cat.A (0.04 mg, 0.00005 mmol), potassium hydroxide (5.5 mg, 0.005 mmol), and methanol (1 mL). Then, it was transferred to an autoclave, the hydrogen pressure was set (20 atm), and the reaction was carried out at 25 °C for 12 h. The solvent was evaporated to dryness to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain the pure target product V.

[0078] The reaction equation is as follows:

[0079]

[0080] The specific aryl ketone derivatives, target products, and their yields are shown in Table 2.

[0081] Table 2

[0082]

[0083]

[0084] Among them, product V-1 is a yellow oil; [α] D 20 +45.5 (c 1.0, CHCl3, 99% ee), the ee value was measured by HPLC analysis, Chiralpak IB column (0.46 x 25 cm), hexane / i-PrOH 95:5, 1.0 mL / min, λ = 215 nm, t R : 7.38 min (R), 8.04 min (S).

[0085] Product V-2 is a yellow oil; [α] D 20 +52.5 (c 1.0, CHCl3, 99% ee), the ee value was measured by HPLC analysis, Chiralpak ID column (0.46 x 25 cm), hexane / i-PrOH 97:3, 1.0 mL / min, λ = 215 nm, t R : 18.77 min (R), 19.97 min (S).

[0086] Product V-11 is a yellow oil; [α] D 20+35.5 (c 1.1, CHCl3, 99% ee), ee value was determined by HPLC analysis, using a Dacron IB column (0.46 x 25 cm), hexane / i-PrOH 95:5, 1.0 mL / min, λ = 215 nm, t R :15.09min(S),15.83min(R).

[0087] The present invention synthesizes a novel chiral ruthenium catalyst, which can be used as an asymmetric catalytic hydrogenation of simple aryl ketone compounds. Its high catalytic turnover number (TON=10000), excellent yield and diastereoselectivity (ee=99%) are the highlights of the catalyst.

[0088] Example 7

[0089] In Example 7, based on the reaction of the aromatic ketone derivative IV-1 to produce the target product V-1 in Example 6, the reaction solvent was adjusted, and the other steps were consistent with Example 6. The experimental results are shown in Table 3.

[0090] Table 3

[0091]

[0092]

[0093] As can be seen from Table 3, under the above solvent conditions, the chiral ruthenium catalysts synthesized in the present invention can be used as asymmetric catalytic hydrogenation of simple aryl ketone compounds with excellent yield and diastereoselectivity.

[0094] Comparative Example 1

[0095] The same test method as in Example 6 was used to test the reaction of aryl ketone derivative IV-1 to produce target product V-1 using the existing ruthenium catalyst Cat. B. Cat. B was purchased from Shanghai Haohong Biopharmaceutical Technology Co., Ltd., product number: 1025773, CAS: 212210-87-2. The experimental results are shown in Table 4.

[0096]

[0097] Table 4

[0098]

[0099] The ruthenium catalyst provided by the present invention has two ligands, diphosphine and dinitrogen, co-coordinated. Compared with traditional ruthenium catalysts, it has higher catalytic effect and chiral principle. It can achieve asymmetric hydrogenation of some carbonyl compounds with a lower ruthenium loading to obtain chiral secondary alcohols, thereby reducing the cost of catalysts for industrial asymmetric catalytic hydrogenation.

[0100] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered by the scope of the claims of the present invention.

Claims

1. A chiral ruthenium catalyst, characterized in that: The chiral ruthenium catalyst has a structural formula shown in Formula I; 2. The method for preparing a chiral ruthenium catalyst according to claim 1, wherein: including, (1) React pyridine-2-carboxaldehyde with (R)-(+)-tert-butanesulfinamide in a solvent, add cesium carbonate to react, and obtain a compound shown in Formula II; (2) React the compound shown in Formula II with o-dibromobenzene in a solvent and magnesium chips to obtain a compound shown in Formula III; (3) React the compound shown in Formula III with hydrochloric acid to obtain the target product shown in Formula I.

3. The method for preparing a chiral ruthenium catalyst according to claim 2, wherein: In step (1), the molar ratio of pyridine-2-carboxaldehyde to (R)-(+)-tert-butanesulfinamide is 1:1 to 2; The molar ratio of pyridine-2-carboxaldehyde to cesium carbonate is 1:1 to 2.

4. The preparation method of the chiral ruthenium catalyst according to claim 3, characterized in that: In step (1), the solvent includes one of methanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, DMF or 1,4-dioxane; For the reaction in step (1), the temperature is 30 to 60 °C and the time is 12 hours.

5. The preparation method of the chiral ruthenium catalyst according to claim 2, characterized in that: In step (2), the molar ratio of the compound shown in Formula II to o-dibromobenzene is 1:1 to 2; The molar ratio of the compound shown in Formula II to magnesium chips is 1:1.

05.

6. The method for preparing a chiral ruthenium catalyst according to claim 5, wherein: In step (2), the solvent includes one of tetrahydrofuran, methyl tert-butyl ether or diethyl ether; For the reaction in step (2), the temperature is 60 to 100 °C and the time is 8 to 20 h.

7. The method for preparing a chiral ruthenium catalyst according to claim 2, wherein: In step (3), the molar ratio of the compound shown in Formula III to hydrochloric acid is 1:2 to 6.

8. The method for preparing a chiral ruthenium catalyst according to claim 7, wherein: For the reaction in step (3), the temperature is 60 to 100 °C and the time is 2 to 4 hours.

9. A method for preparing aryl ketone compounds by asymmetric catalytic hydrogenation, characterized in that: Under a hydrogen atmosphere, mix and react the compound shown in Formula IV with the compound shown in Formula I, a base, and a solvent to obtain a compound shown in Formula V; Among them, Ar is a benzene ring, naphthalene ring, or pyridine ring substituted with various different substituents such as methyl, ethyl, methoxy, and halogen.

10. The use of the chiral ruthenium catalyst according to claim 9, characterized in that: The molar ratio of the compound shown in Formula I to the compound shown in Formula IV is 0.0001 to 0.01:1; The molar ratio of the base to the compound shown in Formula IV is 0.001 to 0.1:1; The base includes one of potassium hydroxide, potassium tert-butoxide, sodium hydroxide, and sodium carbonate; The solvent includes one of methanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran, DMF, 1,4-dioxane, and acetonitrile; Under the hydrogen atmosphere, the hydrogen pressure is 10 to 20 atm; For the reaction, the reaction temperature is 10 to 60 °C and the reaction time is 8 to 20 h.

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