Asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol

Abstract

The invention relates to the technical field of synthesis of organic compounds, in particular to an asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol. The method comprises the following steps: at a preset temperature, in a hydrogen atmosphere, in a solvent and in the presence of alkali, carrying out asymmetric catalytic hydrogenation reaction on a compound as shown in a formula I by taking a complex formed by a planar chiral metallocene ligand and ruthenium salt as a catalyst to form a compound as shown in a formula II. The method has the advantages of convenient raw material reagent source, high substrate conversion rate, good stereoselectivity, economy, high efficiency, simple and reliable operation, and suitableness for industrial amplification.

Description

Technical Field

[0001] This invention relates to the field of organic compound synthesis technology, specifically to an asymmetric catalytic hydrogenation synthesis method for chiral aryl (pyrrolidine-2-yl) methanol. Background Technology

[0002] The structure of chiral aryl (pyrrolidin-2-yl)methanol is as follows:

[0003] , Chiral aryl (pyrrolidine-2-yl) methanol, as a core structural unit derived from the natural chiral amino acid proline, occupies a pivotal position in the fields of medicinal chemistry and asymmetric synthesis due to its unique rigid pyrrolidine skeleton and flexibly modifiable functional groups.

[0004] First, chiral aryl (pyrrolidine-2-yl)methanol is a key pharmacophore in many bioactive molecules, widely embedded in the backbones of natural products and drug molecules with important physiological functions. For example, the highly cytotoxic antitumor drug Dolastanin 10, quinoline-prolyl derivatives that disrupt Vibrio cholerae biofilm formation, and phenanthrene-indole alkaloids (such as tylophoridine E) all exhibit activities inextricably linked to this core structure. Second, chiral aryl (pyrrolidine-2-yl)methanol is an efficient synthetic tool for constructing more complex drug molecules. In synthetic chemistry, proline-derived chiral prolyl and its aryl-substituted analogs are high-performance chiral ligands or small organic molecule catalysts, enabling the efficient and selective synthesis of various chiral-enriched molecules. More importantly, ring-expansion reactions via its nitrogen-center ion intermediate provide an elegant strategy for the rapid construction of another important class of drug backbones—functionalized chiral piperidines (such as 2-arylpiperidine-3-ol). Furthermore, chiral aryl (pyrrolidone-2-yl)methanol directly targets drug molecules with significant clinical value. The aforementioned chiral piperidine structure is a key pharmacodynamic unit for potent neurokinin-1 (NK-1) receptor antagonists. Classical ligands such as (+)-L-733,060 and (+)-CP-99,994, as well as vorfipteran, which has entered clinical trials for post-traumatic stress disorder (PTSD), all demonstrate the enormous potential of molecules based on this structural unit in treating anxiety and nausea. It can be seen that from basic active structures to efficient synthetic tools, and finally to clinical drugs, chiral aryl (pyrrolidone-2-yl)methanol permeates many key stages of modern drug discovery. Due to its extreme importance at multiple levels, developing efficient, highly enantioselective, and universal synthetic methods to achieve diverse preparations of this type of structure remains a cutting-edge research focus for synthetic chemists, possessing profound scientific significance and application value.

[0005] Currently, several synthetic methods have been established to prepare chiral aryl (pyrrolidine-2-yl) methanol. (Literature) Tetrahedron Lett 2001, 42 (36), 6223-6225; Org. Lett 2009, 11 (9), 1935-1938; Org. Lett 2020, 22 The synthetic methods reported in (24), 9740–9744, etc., suffer from low yields, room for improvement in stereoselectivity, limited substrate scope, and stringent reaction conditions, making them unsuitable for large-scale production. (Literature) Adv. Synth. Catal 2011, 353 (11-12), 1955-1960, described the asymmetric hydrogenation of a series of aryl heterocyclic alkyl ketones via dynamic kinetic resolution; however, this literature only provides one example for the structure of pyrrolidine aryl ketones, conducted under conditions of 10 bar hydrogen pressure and S / C = 200. Therefore, there is a need in the art for a simpler, more substrate-compatible process for preparing chiral aryl (pyrrolidine-2-yl) methanol that yields products with high chiral purity. Summary of the Invention

[0006] The purpose of this invention is to provide an asymmetric catalytic hydrogenation synthesis method for chiral aryl (pyrrolidine-2-yl) methanol, in order to solve the problems of existing synthesis methods, such as low yield, room for further improvement in stereoselectivity, limited substrate range, and harsh reaction conditions, which make them difficult to use for large-scale production.

[0007] To achieve the above objectives, the present invention employs the following technical solution: an asymmetric catalytic hydrogenation synthesis method for chiral aryl (pyrrolidine-2-yl) methanol, wherein, under a preset temperature and hydrogen atmosphere, in a solvent and in the presence of a base, the compound shown in Formula I undergoes an asymmetric catalytic hydrogenation reaction using a complex formed by a chiral metallocene ligand and a ruthenium salt as a catalyst (Ru Cat.), to form the compound shown in Formula II, with the reaction formula as follows: .

[0008] Furthermore, in Formulas I to II, Ar is a substituted or unsubstituted aromatic or heteroaromatic group; R is selected from any one of aryl or alkoxyacyl groups; Furthermore, the chiral metallocene ligand is selected from any one of the compounds shown in Formulas III to VI: .

[0009] Furthermore, in Formulas III to VI, R is selected from any one of H, straight-chain or branched alkyl groups containing 1 to 8 carbons, cycloalkyl groups containing 1 to 8 carbons, aryl, and benzyl; Ar is a substituted or unsubstituted aromatic or heteroaromatic group; R′ is any one or a combination of several of phenyl, tolyl, p-methylisopropylphenyl, triarylphosphine, trialkylphosphine, and 1,5-cyclooctadiene.

[0010] Furthermore, the chiral metallocene ligands are selected from the compounds shown in structure IV.

[0011] Furthermore, the catalyst is selected from any one of the compounds shown in the following structures: .

[0012] Furthermore, the catalyst is selected from compounds with the following structure (Ru Cat.1): .

[0013] Furthermore, the reaction temperature is -78~100℃.

[0014] Furthermore, the reaction temperature is 20~50℃; for example, 25~35℃.

[0015] Furthermore, the pressure ranges from 1 to 100 bar.

[0016] Furthermore, the pressure ranges from 2 to 50 bar; for example, 2, 10, 20, 30, 40, and 5 bar.

[0017] Furthermore, the solvent is selected from any one or a combination of several of the following: methanol, ethanol, isopropanol, propanol, butanol, isobutanol, acetone, 1,4-dioxane, tetrahydrofuran, tetrahydrofuran / water, dichloromethane, dichloromethane / water, acetonitrile, toluene, toluene / water, xylene, N,N-dicarboxamide, dimethyl sulfoxide, N-methylpyrrolidine, and N-ethylpyrrolidine.

[0018] Furthermore, the solvent is selected from any one of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, toluene, and hexafluoroisopropanol.

[0019] Furthermore, the molar ratio of the reaction substrate (i.e., the compound shown in Formula I) to the catalyst is 100000:1 to 100:1.

[0020] Furthermore, the molar ratio of the reaction substrate (i.e., the compound shown in Formula I) to the catalyst is 5,000:1 to 200:1.

[0021] Furthermore, the molar ratio of the compound shown in Formula I to the base is 1:0.1 to 1:3.

[0022] Furthermore, the molar ratio of the compound shown in Formula I to the base is 1:0.8 to 1.5; for example, the molar ratio is 1:1.

[0023] Furthermore, the alkali is selected from... t BuOK t BuONa t Any one or a combination of several of the following: BuOLi, NaOH, KOH, MeONa, EtONa, TMSOK, TMSONa, Na2CO3, Cs2CO3, NaHCO3, and 1,4-diazabicyclo[2.2.2]octane.

[0024] Furthermore, the alkali is selected from... t BuONa.

[0025] The beneficial effects of this invention are: 1. The method of this invention has mild reaction conditions; extensive experimental studies have demonstrated that the asymmetric hydrogenation reaction using the Ru Cat.1 catalyst system exhibits very high reactivity and enantioselectivity, with a reaction S / C ratio exceeding 1000 and an ee value of up to 99% for the hydrogenation products; the above catalyst is simple to synthesize, with a mature synthesis process already in place and applied in industrial production; the above synthesis method has advantages such as simple operation, low cost, and high atom economy, meeting the requirements of green chemistry and possessing potential for industrial production. 2. The asymmetric catalytic hydrogenation synthesis method for chiral aryl (pyrrolidine-2-yl) methanol provided by this invention successfully develops a method for synthesizing chiral aryl (pyrrolidine-2-yl) methanol by asymmetric catalytic hydrogenation. The catalyst used has the advantages of low cost and good catalytic effect. In particular, when using a catalyst formed by a faceted chiral metallocene ligand and ruthenium salt, the substrate conversion rate is high, the stereoselectivity is good, and the product ee value is high. This method is economical and efficient, exhibits excellent reactivity and stereoselectivity, and is simple and reliable to operate, making it suitable for industrial production.

[0026] Other technical effects resulting from the additional features will be further illustrated in the corresponding embodiments. Attached Figure Description

[0027] Figure 1 This is a synthesis route diagram of the method of the present invention. Detailed Implementation

[0028] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Experimental methods not specifically described in the embodiments are generally performed under conventional conditions and those described in the manual. Unless otherwise specified, all commercially available reagents and solvents used are directly from the reagent supplier and have not undergone further purification.

[0029] The asymmetric catalytic hydrogenation synthesis method of the compound shown in Formula II in this invention includes: under a hydrogen atmosphere, in a solvent, the compound shown in Formula I undergoes asymmetric hydrogenation reduction in the presence of a catalyst formed by a faceted chiral ruthenium ligand and a ruthenium salt, and in the presence of a base, to generate the compound shown in Formula II, as shown in the following reaction formula: , The catalysts used in Examples 1-19 are shown below: .

[0030] Example 1 Preparation of the compound shown in Formula II-j

[0031] The compound shown in Formula I-j (1.0 g, 3.7 mmol), sodium tert-butoxide (0.33 g, 3.7 mmol, 1.0 equiv), and RuCat.1 (5.8 mg, 3.36 μmol, 0.1 mol%) were sequentially added to a 50 mL dry round-bottom flask equipped with a magnetic stirrer. After purging with nitrogen, degassed isopropanol (10 mL) was added and stirred until homogeneous (the solution turned green). The round-bottom flask was then placed in a hydrogenation reactor. After purging the reactor with hydrogen three times, hydrogen was added until the pressure reached 40 bar. After stirring at room temperature for 12 h, the reaction solution was cooled to room temperature, hydrogen was slowly released, the solvent was evaporated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated to obtain the residue (substrate conversion >99% conv., >1.0 g, dr value 18:1, ee value >99%).

[0032] The crude product was separated by silica gel column chromatography to obtain the pure product. The 1H NMR spectrum of the pure product is as follows: 1 H NMR (400 MHz, CDCl3) δ 7.37 – 7.19 (m, 7H), 6.97 (t, J = 8.5 Hz, 2H),5.51 (s, 1H), 4.99 (s, 1H), 4.66 – 4.56 (m, 1H), 3.23 (m, 1H), 2.82 (td, J =10.4, 6.2 Hz, 1H), 1.95 (m, 1H), 1.83 (m, 1H), 1.58 – 1.40 (m, 2H); The crude product was analyzed by HPLC, and the HPLC information is as follows: [DAICEL CHIRALPAK IA Column,n -hexane / i -PrOH = 80 / 20, 210 nm, 1.0 mL / min, t R1 = 7.677 (major), t R2 = 10.413 (minor)], ee value is greater than 99%.

[0033] Example 2 Preparation of the compound shown in Formula II-j

[0034] The compound shown in Formula I-j (1.0 g, 3.7 mmol), sodium hydroxide (0.148 g, 3.7 mmol, 1.0 equiv), and Ru Cat.1 (5.8 mg, 3.36 μmol, 0.1 mol%) were sequentially added to a 50 mL dry round-bottom flask equipped with a magnetic stirrer. After purging with nitrogen, degassed isopropanol (10 mL) was added and stirred until homogeneous (the solution turned green). The round-bottom flask was then placed in a hydrogenation reactor. The gas in the reactor was purged with hydrogen three times, and hydrogen was added until the pressure reached 40 bar. After stirring at room temperature for 12 h, the reaction solution was cooled to room temperature, hydrogen was slowly released, the solvent was evaporated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated to obtain the residue (substrate conversion >99% conv., >1.0 g, dr value 10:1, ee value 98%).

[0035] The crude product was analyzed by HPLC, and the HPLC information is as follows: [DAICEL CHIRALPAK IA Column, n -hexane / i -PrOH = 80 / 20, 210 nm, 1.0 mL / min, t R1 = 7.677 (major), t R2 = 10.413 (minor)], ee value is 98%.

[0036] Example 3 Preparation of the compound shown in Formula II-j

[0037] Compound I-j (1.0 g, 3.7 mmol), cesium carbonate (1.2 g, 3.7 mmol, 1.0 equiv), and RuCat.1 (5.8 mg, 3.36 μmol, 0.1 mol%) were sequentially added to a 50 mL dry round-bottom flask equipped with a magnetic stirrer. After purging with nitrogen, degassed isopropanol (10 mL) was added and stirred until homogeneous (the solution turned green). The round-bottom flask was then placed in a hydrogenation reactor. The reactor was purged with hydrogen three times, and hydrogen was added until the pressure reached 40 bar. After stirring at room temperature for 12 h, the reaction solution was cooled to room temperature, hydrogen was slowly released, the solvent was evaporated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated to obtain the residue. The crude product was separated by silica gel column chromatography to obtain the hydrogenated product (substrate conversion rate 8% conv., 75 mg, dr value 2:1, ee value 76%).

[0038] The crude product was analyzed by HPLC, and the HPLC information is as follows: [DAICEL CHIRALPAK IA Column, n -hexane / i -PrOH = 80 / 20, 210 nm, 1.0 mL / min, t R1 = 7.677 (major), t R2 = 10.413 (minor)], ee value is 76%.

[0039] Examples 4-19 The catalysts used in Examples 4-19 and the reaction results are shown in Table 1 below, wherein the molar ratio of substrate (compounds shown in Formula I-j) to catalyst is approximately 1000:1 (the ee values ​​in Table 1 are the ee values ​​of the crude product).

[0040]

[0041] Table 1

[0042] As can be seen from Examples 1-19, the catalyst Ru Cat.1 has the best catalytic effect on the asymmetric hydrogenation of Formula I-a.

[0043] Examples 20-32 Asymmetric hydrogenation of the compound shown in Formula I was catalyzed using Ru Cat.1 as a catalyst, and the temperature, time, hydrogen pressure, solvent, and other factors of catalytic reduction were screened.

[0044] Examples 20-32 below use catalyst 1 to asymmetricly catalyze the hydrogenation of the compound shown in formula I to synthesize the compound shown in formula II, wherein the molar ratio of substrate to catalyst is approximately 100:1. The solvent, base, reaction system temperature (solvent temperature), hydrogen pressure, reaction time, and reaction results (substrate conversion rate, ee value) are shown in Table 2 below (the ee values ​​in Table 2 are all ee values ​​of the crude product).

[0045]

[0046] Table 2

[0047] As can be seen from Examples 20-32 above, the catalyst Ru Cat.1 showed good asymmetric catalytic hydrogenation effect when reacted for about 2 hours at room temperature and with sodium tert-butoxide as the base and isopropanol as the reaction solvent, at room temperature and a hydrogen pressure of about 2 bar.

[0048] Examples 33-35 Preparation of the compound shown in Formula II-j The preparation of Examples 33-35 was carried out in accordance with the description in Example 1, except that the molar ratio of the substrate (the compound shown in Formula I-a) to the catalyst (Ru Cat.1) was different. The specific molar ratio of the substrate to the catalyst and the reaction results are shown in Table 3 below.

[0049]

[0050] Table 3

[0051] As can be seen from Examples 33-35 above, Ru Cat.1 reacts with sodium tert-butoxide as the base and isopropanol as the reaction solvent at room temperature to 50°C. o At a temperature of C and a hydrogen pressure of 2–50 bar, the reaction time is 3–48 h. A substrate-to-catalyst molar ratio of 2,000:1 can achieve a conversion rate >99%. However, the conversion rate decreases when the molar ratio exceeds 5,000:1. Furthermore, in actual experiments, it was found that by appropriately extending the reaction time, a substrate-to-catalyst molar ratio of 5,000:1 can also achieve complete conversion and excellent ee values, and this ratio can be further increased. However, considering the synthesis cost, a substrate-to-catalyst molar ratio of 5,000–200:1 is preferred.

[0052] Example 36 Preparation of the compound shown in Formula II.

[0053] To further investigate the substrate applicability of this asymmetric hydrogenation synthesis method, different substrates were subjected to asymmetric hydrogenation under the following conditions: Ru Cat.1 as catalyst (S / C=100), sodium tert-butoxide as base, isopropanol as solvent, hydrogen pressure of 2 bar, reaction temperature of 25℃, and reaction time of 2 h. The substrate applicability of this method was then examined, and the results are shown below:

[0054] At room temperature and 2 bar hydrogen pressure, the compound shown in Formula I (1 mmol), Ru Cat.1 (1 mol%, S / C = 100), and t BuONa (1 equiv) dissolves in i PrOH was reacted for 2 h; HPLC analysis was performed using a chiral Daicel Chiralcel column to determine the bottom conversion and ee value.

[0055] This invention is not limited to the preferred embodiments described above. Anyone can derive other forms of products under the guidance of this invention. However, regardless of any changes made in their shape or structure, any technical solution that is the same as or similar to this application falls within the protection scope of this invention.

Claims

1. An asymmetric catalytic hydrogenation synthesis method for chiral aryl (pyrrolidine-2-yl) methanol, characterized in that: The compound shown in Formula I undergoes an asymmetric catalytic hydrogenation reaction using a complex formed by a chiral metallocene ligand and a ruthenium salt as a catalyst to form the compound shown in Formula II. The reaction formula is as follows: 。 2. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol according to claim 1, characterized in that: In Formulas I to II, Ar includes substituted or unsubstituted aromatic groups and substituted or unsubstituted heteroaromatic groups; R includes aryl groups and alkanoyl groups.

3. The asymmetric catalytic hydrogenation synthesis method for chiral aryl (pyrrolidine-2-yl) methanol according to claim 1, characterized in that, The chiral metallocene ligands described herein include compounds as shown in Formulas III to VI: 。 4. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol according to claim 3, characterized in that: In the aforementioned formulas III to VI, R includes H, a straight-chain alkyl group containing 1 to 8 carbons, a branched alkyl group containing 1 to 8 carbons, a cycloalkyl group containing 1 to 8 carbons, an aryl group, and a benzyl group; Ar includes substituted or unsubstituted aromatic groups and substituted or unsubstituted heteroaromatic groups; R′ includes phenyl, tolyl, p-methylisopropylphenyl, triarylphosphine, trialkylphosphine, and 1,5-cyclooctadiene.

5. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol according to claim 3, characterized in that, The catalysts include compounds as shown in formulas Ru Cat.1 to Ru Cat.16: 。 6. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol according to claim 1, characterized in that: The asymmetric catalytic hydrogenation reaction is carried out at a temperature of -78 to 100°C and a pressure of 1 to 100 bar.

7. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol according to claim 1, characterized in that: The solvents for the asymmetric catalytic hydrogenation reaction include methanol, ethanol, isopropanol, propanol, butanol, isobutanol, acetone, 1,4-dioxane, tetrahydrofuran, tetrahydrofuran / water, dichloromethane, dichloromethane / water, acetonitrile, toluene, toluene / water, xylene, N,N-dicarboxamide, dimethyl sulfoxide, N-methylpyrrolidine, and N-ethylpyrrolidine.

8. The asymmetric catalytic hydrogenation synthesis method of chiral chiral aryl (pyrrolidine-2-yl) methanol according to claim 1, characterized in that: The asymmetric catalytic hydrogenation reaction further includes the addition of a base, which includes... t BuOK t BuONa t BuOLi, NaOH, KOH, MeONa, EtONa, TMSOK, TMSONa, Na2CO3, Cs2CO3, NaHCO3 and 1,4-diazabicyclo[2.2.2]octane.

9. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol according to claim 8, characterized in that: The molar ratio of the compound represented by Formula I to the base is 1:0.1~3.

10. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol according to claim 1, characterized in that: The molar ratio of the compound represented by Formula I to the catalyst is 100,000 to 100:1.

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