A process for the synthesis of enantiomerically pure chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivatives

Abstract

This invention discloses a method for synthesizing enantiomeric chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivatives, involving two steps: asymmetric hydrogenation and chemical resolution of the 2-methylquinoline derivative. The catalytic system used is iridium metal, a chiral bisphosphine ligand, and elemental iodine. The chemical resolution reagent is a tartaric acid derivative, and the resolution solvent is one or more of acetone, methanol, ethanol, and 2,2,2-trifluoroethanol. Hydrogenation of the 2-methylquinoline derivative yields the corresponding chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative, and the enantiomeric excess after chemical resolution can exceed 99%. This method is simple and practical, uses readily available raw materials, exhibits high enantioselectivity and good yield, and possesses advantages such as high atom economy and environmental friendliness, making it promising for industrial application.

Description

Technical Field

[0001] This invention relates to a method for the asymmetric hydrogenation and chemical resolution of iridium-catalyzed 2-methylquinoline derivatives to obtain enantiomeric chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivatives. Background Technology

[0002] Chiral 2-methyl-1,2,3,4-tetrahydroquinoline is an important synthetic intermediate used to construct various chiral ligands, natural product alkaloids, and bioactive substances. Therefore, it has attracted increasing attention from chemists as a common structural unit in bioactive compounds and drug development. (Reference 1: (a) Asolka, RN; Schroder, D.; Heckmann, R.; Lang, S.; Wagner-Dobler, I.; Laatsch, H. J. Antibiot. 2004, 57, 17. (b) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Synthesis 2009, 12, 2076.)

[0003] Despite the relatively simple structure of chiral 2-methyl-1,2,3,4-tetrahydroquinoline, large-scale synthesis of high-optically pure chiral 2-methyl-1,2,3,4-tetrahydroquinoline still faces some challenges. In recent years, significant progress has been made in the asymmetric hydrogenation synthesis of tetrahydroquinoline derivatives using metal-catalyzed quinoline derivatives, enabling the large-scale synthesis of 2-methyl-1,2,3,4-tetrahydroquinoline with high optical purity. In 2003, Zhou Yonggui's research group first achieved the asymmetric hydrogenation of 2-methylquinoline using a chiral iridium catalyst under a hydrogen atmosphere. However, due to limitations in the reaction system and conditions, this reaction could only prepare chiral 2-methyl-1,2,3,4-tetrahydroquinoline with a maximum ee of 94% under conditions of S / C = 200. (Reference 2: Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-GJAm. Chem. Soc. 2003, 125, 10536.) In recent years, thanks to the unremitting efforts of chemists, significant progress has also been made in the asymmetric reduction of quinoline derivatives catalyzed by metals. (Reference 3: (a) Xu, L.; Lam, KH; Ji, J.; Wu, J.; Fan, Q.-H.; Loa, W.-H.; Chan, ASC Chem. Commun. 2005, 1390. (b) Guo, Q.-S.; Du, D.-M.; Xu, J. Angew. Chem. Int. Ed. 2008, 47, 759. (c) Li, X.; Tian, ​​J.- J.; Liu, N.; Tu, X.-S.; Zeng, N.-N.; Wang, X.-C. Angew. Chem. Int. Ed. 2019, 58, 4664. (d) Liu, C.; Wang, M.; Liu, S.; Wang, Y.; Peng, Y.; Lan, Y.; Liu, Q. Angew. Chem. Int. Ed. 2021, 60, 5108.)

[0004] Although the development of asymmetric hydrogenation reactions has led to the development of various catalytic systems for the synthesis of tetrahydroquinolines, most of these reaction systems are complex, have low substrate / catalyst ratios, and are expensive, making them unsuitable for industrial scale-up. Currently, there are no reported methods for synthesizing enantiomeric (>99% ee) 2-methyl-1,2,3,4-tetrahydroquinoline under high S / C conditions, while enantiomeric products are essential for the synthesis of related drugs and chiral ligands. Considering the importance of chiral 2-methyl-1,2,3,4-tetrahydroquinoline and its derivative 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, there is an urgent need to develop a green, economical, and large-scale synthetic method for enantiomeric 2-methyl-1,2,3,4-tetrahydroquinoline derivatives. Based on this, the present invention uses iridium as a catalyst to achieve high S / C asymmetric hydrogenation of 2-methylquinoline derivatives, and obtains enantiomeric pure 2-methyl-1,2,3,4-tetrahydroquinoline and its derivative 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline in high yield through chemical resolution. Summary of the Invention

[0005] To address the problems of existing technologies, this invention provides a method for synthesizing enantiomeric chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivatives. The method includes iridium-catalyzed asymmetric hydrogenation of 2-methylquinoline or its derivative 6-fluoro-2-methyl-quinoline, followed by chemical resolution to obtain chiral 2-methyl-1,2,3,4-tetrahydroquinoline or its derivative 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline. This method offers advantages such as simple and practical operation, high S / C ratio, readily available raw materials, high enantioselectivity, good yield, high atom economy, and environmental friendliness. It can be applied to the industrial production of chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivatives.

[0006] To achieve the above objectives, the technical solution provided by the present invention is as follows:

[0007] A method for synthesizing enantiomeric chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivatives includes iridium-catalyzed asymmetric hydrogenation of 2-methylquinoline derivatives to synthesize chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivatives, and obtaining enantiomeric chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivatives by chiral resolution. The method specifically includes the following steps:

[0008] (1) Asymmetric hydrogenation: Using metallic iridium and chiral diphosphorus ligand L as the catalytic system (catalyst), elemental iodine as the additive, 2-methylquinoline derivative 1 as the substrate, and hydrogen as the hydrogen source, an asymmetric hydrogenation reaction is carried out to synthesize the hydrogenation product (chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative) 2.

[0009] The reaction formula is as follows:

[0010]

[0011] In the formula:

[0012] R is either H or F.

[0013] (2) Chemical resolution: Using chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2 as substrate and tartaric acid derivative (TAD) as resolving agent, the reaction was stirred at the solvent reflux temperature to obtain salt 3 formed by chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2 and tartaric acid derivative.

[0014] The reaction formula is as follows:

[0015]

[0016] Based on the above technical solution, further, in step (1), the solvent for the asymmetric hydrogenation reaction is one or more of tetrahydrofuran, 2-methyltetrahydrofuran and toluene.

[0017] Based on the above technical solution, further, in step (1), the preparation method of the metal iridium and chiral bisphosphine ligand L catalytic system (catalyst) is as follows: add the metal iridium precursor ((1,5-cyclooctadiene)iridium chloride (I) dimer) and the chiral bisphosphine ligand into the solvent and stir at room temperature for 5 to 30 minutes to obtain the catalyst.

[0018] Based on the above technical solution, furthermore, the solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

[0019] Based on the above technical solutions, furthermore, the atmosphere used in the preparation process of the metallic iridium and chiral bisphosphorus ligand L catalytic system (catalyst) is an inert atmosphere (such as nitrogen, argon, etc.).

[0020] Based on the above technical solution, the iridium precursor is further described as (1,5-cyclooctadiene)iridium(I) chloride dimer ([Ir(COD)Cl]2).

[0021] Based on the above technical solution, further, in step (1), the temperature of the asymmetric hydrogenation reaction is 25-70℃, preferably 50℃.

[0022] Based on the above technical solution, further, in step (1), the time for the asymmetric hydrogenation reaction is 12 to 72 hours, preferably 30 hours.

[0023] Based on the above technical solution, further, in step (1), the hydrogen pressure is 400 to 1200 psi, preferably 1000 psi.

[0024] Based on the above technical solution, further, in step (1), the molar ratio of the 2-methylquinoline derivative 1 and the metallic iridium precursor ((1,5-cyclooctadiene)iridium chloride (I) dimer) is 100:1 to 100000:1, preferably 80000:1.

[0025] Based on the above technical solution, further, in step (1), the chiral bisphosphonate ligand is a MeO-BiPhep chiral ligand, a TfO-BiPhep chiral ligand, a Garphos chiral ligand, a Synphos chiral ligand, a Tunephos chiral ligand, a Segphos chiral ligand, etc., more preferably a TfO-BiPhep chiral ligand, and even more preferably a TfOPhos chiral ligand, the structure of which is shown below:

[0026]

[0027] Based on the above technical solution, further, in step (1), the molar ratio of the metallic iridium precursor ((1,5-cyclooctadiene)iridium chloride (I) dimer) and the chiral diphosphorus ligand is 1:2 to 1:2.4, preferably 1:2.4.

[0028] Based on the above technical solution, further, in step (1), the molar ratio of iodine and the metallic iridium precursor ((1,5-cyclooctadiene)iridium(I) chloride dimer) is 50:1 to 200:1, preferably 200:1.

[0029] Based on the above technical solution, further, in step (1), the concentration of the substrate in the asymmetric hydrogenation reaction is 3 mol / L to 7 mol / L, preferably 3 mol / L.

[0030] Based on the above technical solution, further, in step (1), a portion of the solvent is added to the weighed metallic iridium precursor ((1,5-cyclooctadiene)iridium chloride (I) dimer) and chiral bisphosphine ligand, stirred at room temperature for 5 to 30 minutes, and then the remaining solvent is used to transfer it to a reactor containing 2-methylquinoline derivative and iodine, and then hydrogen is introduced to carry out the reaction, to obtain the hydrogenated product (chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative)2.

[0031] Based on the above technical solution, further, in step (1), the volume ratio of part of the solvent to the remaining solvent is 1:1 to 15, preferably 1:9.

[0032] Based on the above technical solution, further, in step (2), the temperature of the chemical separation reaction is 25-90℃, preferably 90℃.

[0033] Based on the above technical solution, further, in step (2), the chemical separation reaction time is 1 to 8 hours, preferably 8 hours.

[0034] Based on the above technical solution, further, in step (2), the tartaric acid derivative of the resolving reagent is one or more of diethyl tartrate, dibenzoyl tartaric acid, p-methyldibenzoyl tartaric acid, and di-p-methoxybenzoyl tartaric acid, preferably di-p-methoxybenzoyl tartaric acid ((L)-DMTA).

[0035] Based on the above technical solution, further, in step (2), the solvent for separation is acetone, methanol, ethanol and 2,2,2-trifluoroethanol (trifluoroethanol), etc., preferably ethanol and 2,2,2-trifluoroethanol.

[0036] Based on the above technical solution, further, in step (2), the molar ratio of the chiral resolving reagent tartaric acid derivative and hydrogenated product 2 is 1:2 to 1:1, preferably 1:1.

[0037] Based on the above technical solution, further, in step (2), the amount of chiral resolution solvent used is 7 to 15 liters of solvent per kilogram of hydrogenated product 2.

[0038] Based on the above technical solution, further, in step (2), the atmosphere for chemical separation is air.

[0039] Based on the above technical solution, the steps of the method are further as follows:

[0040] (1) Under an inert atmosphere, a portion of the solvent was added to the weighed (1,5-cyclooctadiene)iridium(I) chloride dimer and chiral bisphosphine ligand, and stirred at room temperature for 5 to 30 minutes. Then, the above solution was transferred to a reactor containing 2-methylquinoline derivative and iodine using the remaining solvent. Then, hydrogen gas was introduced at 400 to 1200 psi, and the reaction was stirred at 25 to 70 °C for 12 to 72 h. After the reaction was concentrated and the solvent was removed, 2-methyl-1,2,3,4-tetrahydroquinoline derivative was obtained.

[0041] (2) Dissolve the product obtained in step (1) in a solvent (such as 2,2,2-trifluoroethanol (or ethanol)) and add it dropwise to a mixture of chiral di-p-methoxybenzoyl tartaric acid and solvent (such as 2,2,2-trifluoroethanol (or ethanol)). Stir at reflux 25-90°C for 1-8 hours, then allow it to cool naturally to precipitate crystals. Filter and dry to obtain 2-methyl-1,2,3,4-tetrahydroquinoline derivative / tartrate.

[0042] Based on the above technical solution, further, in step (1), the enantiomeric excess of the 2-methyl-1,2,3,4-tetrahydroquinoline derivative is 90-95%ee.

[0043] Based on the above technical solution, further, the 2-methylquinoline derivative is synthesized into a chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative via iridium-catalyzed asymmetric hydrogenation. The iridium precursor is (1,5-cyclooctadiene)iridium(I) chloride dimer, the ligand is a chiral TfOPhos ligand, the additive is iodine, the solvent is tetrahydrofuran, the temperature is 50 degrees Celsius, the hydrogen pressure is 1000 psi, the chemical resolution reagent is di-p-methoxybenzoyl tartaric acid, the resolution solvent is ethanol or 2,2,2-trifluoroethanol, and the resolution temperature is 90 degrees Celsius. The results are optimal, with an enantiomeric excess greater than 99%.

[0044] Based on the above technical solutions, further, it also includes: (3) After the salt 3 formed by the chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2 and the tartaric acid derivative is neutralized by an alkaline aqueous solution, the enantiomeric pure chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2 can be obtained.

[0045] The reaction formula is as follows:

[0046]

[0047] Based on the above technical solution, furthermore, the alkaline aqueous solution is one or more of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, and potassium carbonate aqueous solution, with sodium hydroxide aqueous solution being preferred.

[0048] Based on the above technical solution, furthermore, the concentration of the alkaline aqueous solution is 1M to 4M, preferably 2M.

[0049] Based on the above technical solution, furthermore, the pH of the neutralization reaction is 6 to 8, preferably 7.

[0050] Based on the above technical solution, furthermore, the temperature of the neutralization reaction is -5 to 10℃, preferably 0℃.

[0051] Based on the above technical solution, the neutralization reaction time is further 0.5 to 5 hours, preferably 1 hour.

[0052] Based on the above technical solution, furthermore, the atmosphere for the neutralization reaction is air.

[0053] The present invention has the following advantages:

[0054] 1. The asymmetric hydrogenation reaction has high activity and enantioselectivity, complete reaction, convenient separation, and can obtain high enantiomeric excess purity (enantiomeric excess can reach 91%).

[0055] 2. With an S / C ratio as high as 80,000 / 1, the catalytic system is stable and the reaction operation is simple and practical.

[0056] 3. The chemical resolution operation is simple, with a high yield, and the enantiomeric excess can exceed 99%.

[0057] 4. This method is simple to operate, low in cost, the solvent can be recycled and reused, the reaction system can be scaled up, and it has industrial production value.

[0058] In summary, this invention is simple and practical to operate, uses readily available raw materials, has high enantioselectivity, good yield, and the reaction has advantages such as high atom economy and environmental friendliness, and has prospects for industrial application. Detailed Implementation

[0059] The present invention is described in detail below through embodiments; however, the present invention is not limited to the embodiments described below.

[0060] Example 1: Asymmetric hydrogenation reaction of 2-methylquinoline

[0061]

[0062] Add 2-methylquinoline (250.0 g, 1.75 mol) and iodine (1.110 g) to a 2-liter high-pressure reactor. Close the reactor and purge the system with nitrogen four times. Under a N2 atmosphere, add [Ir(COD)Cl]2 (14.7 mg, 21.9 μmol), TfOPhos (43.0 mg, 52.5 μmol), and tetrahydrofuran (58 mL) to a 50 mL reaction flask. Start stirring and stir for 30 minutes until the system is basically dissolved. Transfer the prepared catalyst to a 2-liter high-pressure reactor. Wash the feed pipe with the remaining tetrahydrofuran (526 mL) and transfer all of it to the reactor. Preheat the reactor temperature to 50°C. Purge the reactor environment with hydrogen three times, then purge with 1000 psi of hydrogen and start stirring. Continuously replenish the gas to maintain the reactor pressure at 1000 psi. Continuously monitor the reaction. After 30 hours, the starting material disappears, and the reaction ends. The reaction mixture was opened and concentrated under reduced pressure to quantitatively obtain 257g of the hydrogenated product (2-methyl-1,2,3,4-tetrahydroquinoline), with an S / C ratio of 80000, a yield of >99%, and an enantiomeric excess of 91.4%.

[0063] Analytical data for 2-methyl-1,2,3,4-tetrahydroquinoline: 1 H NMR (400MHz, CDCl3)δ

[0064] 6.99-6.93(m,2H),6.64-6.56(t,J=7.3Hz,1H),6.50-6.43(d,J=8.4Hz,1H),3.69(br s,1H),3.44-3.35(m,1H),2.88-2.79(m,1H),2.76-2.68(m,1H),1.96-1.89(m,1H),1.64-1.53(m,1H),1.20(d,J=6.2Hz,3H). HPLC: ChiracelOJ-H Column, 254nm, 30℃, n-Hexane / i-PrOH=95 / 5, flow=1.0mL / min, retention time 10.9min and 11.9min (major).

[0065] Example 2: Chemical resolution of 2-methyl-1,2,3,4-tetrahydroquinoline

[0066]

[0067] Add (L)-DMTA (568.4 g, 1.359 mol, 1 eq.) and trifluoroethanol (2.67 L) to a 6 L four-necked reaction flask. Heat to 90 °C with stirring. Under reflux, add dropwise a trifluoroethanol (382 mL) solution of 2-methyl-1,2,3,4-tetrahydroquinoline (200.0 g, 1.359 mol, 91.4% ee) prepared in Example 1 (the solution obtained by dissolving 2-methyl-1,2,3,4-tetrahydroquinoline prepared in Example 1 in trifluoroethanol). After the addition is complete, keep the reaction at the temperature for 6 hours. Stop heating and allow it to cool naturally to room temperature while stirring for 15 hours. A large amount of solid precipitates in the system. The filter cake was filtered and washed twice with 200 mL of cold (0 °C) trifluoroethanol. The filtrate was then distilled to recover the trifluoroethanol (recovery rate greater than 98%), washed twice with 200 mL of diethyl ether, and the residual solvent was removed under reduced pressure to obtain 730.1 g of white solid (2-methyl-1,2,3,4-tetrahydroquinoline tartrate), yield 95%.

[0068]

[0069] Add 500 mL of dichloromethane to the obtained white solid product, neutralize with 700 mL of 2M sodium hydroxide solution dropwise under an ice-water bath (0 °C), stir for 1 hour, separate the liquid and extract the aqueous phase with 100 mL of dichloromethane, combine the organic phases, add 50 g of anhydrous sodium sulfate to dry, remove dichloromethane under reduced pressure, and obtain 189.6 g of yellow transparent liquid 2-methyl-1,2,3,4-tetrahydroquinoline. HPLC analysis showed that the enantiomeric excess reached 99.3%.

[0070] Analytical data for 2-methyl-1,2,3,4-tetrahydroquinoline: HPLC: Chiracel OJ-H column, 254 nm, 30 ℃, n-Hexane / i-PrOH = 95 / 5, flow = 1.0 mL / min, retention time 10.6 min and 11.6 min (major).

[0071] Example 3: Chemical resolution of 2-methyltetrahydroquinoline using a repurposed solvent

[0072]

[0073] (L)-DMTA (654.0 g, 1.563 mol, 1 eq.) and trifluoroethanol (2.67 L of trifluoroethanol recovered in Example 2) were added to a 6 L four-necked reaction flask. The mixture was heated to 90 °C with stirring. Under reflux, a solution of 2-methyltetrahydroquinoline (230 g, 1.563 mol, 91.4% ee) in trifluoroethanol (382 mL) was added dropwise (the solution obtained by dissolving 2-methyltetrahydroquinoline prepared in Example 1 in trifluoroethanol). After the addition was complete, the reaction was maintained at this temperature for 6 hours. Heating was then stopped, and the mixture was allowed to cool naturally to room temperature while stirring for 15 hours. A large amount of solid precipitated in the system. The mixture was filtered, and the filter cake was washed twice with 200 mL of cold (0 °C) trifluoroethanol, and then twice with 200 mL of diethyl ether. The residual solvent was removed under reduced pressure to obtain 842 g of a white solid (2-methyl-1,2,3,4-tetrahydroquinoline tartrate), with a yield of 95%.

[0074]

[0075] Add 500 mL of dichloromethane to the obtained white solid product, neutralize with 800 mL of sodium hydroxide solution (2M) dropwise under an ice-water bath (0 °C), stir for 30 minutes, separate the liquid and extract the aqueous phase with 100 mL of dichloromethane, combine the organic phases, add 50 g of anhydrous sodium sulfate to dry, remove dichloromethane under reduced pressure, and obtain 218 g of yellow transparent liquid 2-methyl-1,2,3,4-tetrahydroquinoline. HPLC analysis showed that the enantiomeric excess reached 99.3%.

[0076] Example 4: Asymmetric hydrogenation of 6-fluoro-2-methylquinoline

[0077]

[0078] In a nitrogen-filled glove box, [Ir(COD)Cl]₂ (2.0 mg, 3.0 μmol), TfOPhos (5.9 mg, 7.2 μmol), and tetrahydrofuran (4 mL) were added to an ampoule. Stirring was started and continued for 15 minutes until the system was substantially dissolved. The prepared catalyst was transferred with 36 mL of tetrahydrofuran to a reaction flask containing 6-fluoro-2-methylquinoline (19.34 g, 120 mmol) and I₂ (152 mg, 0.6 mmol). The flask was placed in a high-pressure reactor, and the reactor environment was purged with hydrogen three times. Then, 1000 psi of hydrogen was introduced, and stirring was started. The reaction was carried out at 40 °C for 63 hours. The reaction was then completed. The reactor was opened, and the reaction solution was concentrated under reduced pressure. Quantitatively, 19.82 g of the hydrogenated product (6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline) was obtained, with an S / C ratio of 40000 and an enantiomeric excess of 91.4%.

[0079] Analytical data for 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline: 1 H NMR (400MHz, CDCl3)δ

[0080] 6.68(dddd,J=7.8,4.7,2.8,0.9Hz,2H),6.45-6.36(m,1H),3.51(d,J=51. 8Hz,1H),3.34(dqd,J=10.0,6.3,2.7Hz,1H),2.88-2.74(m,1H),2.69(ddd ,J=16.7,5.5,3.3Hz,1H),1.91(ddt,J=12.4,6.0,3.1Hz,1H),1.56(dddd,J=12.8,11.4,10.0,5.5Hz,1H),1.20(d,J=6.2Hz,3H). HPLC: ChiracelOJ-H column, 254nm, 30℃, n-Hexane / i-PrOH=98.5 / 1.5, flow=1.0mL / min, retention time 13.2min and 14.2min (major).

[0081] Example 5: Chemical resolution of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline

[0082]

[0083] Add (L)-DMTA (63 g, 0.15 mol, 1 eq.) and ethanol (200 mL) to a 1 L reaction flask. Heat to 90 °C with stirring. Under reflux, add dropwise a 50 mL ethanol solution of 6-fluoro-2-methyltetrahydroquinoline (24.2 g, 0.15 mol, 93% ee) (the solution obtained by dissolving 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline prepared in Example 4 in ethanol). After addition, maintain the reaction temperature for 6 hours, then stop heating and allow to cool naturally to room temperature while stirring for 5 hours. A large amount of solid precipitates in the system. Filter, wash the filter cake twice with 50 mL of cold ethanol, then twice with 20 mL of diethyl ether. Remove residual solvent under reduced pressure to obtain 78.3 g of a white solid (6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline tartrate), yield 94%.

[0084]

[0085] Add 50 mL of dichloromethane to the obtained white solid product, neutralize by adding 80 mL of sodium hydroxide solution (2M) dropwise under an ice-water bath (0 °C), stir for 30 minutes, separate the liquid and aqueous phase, extract with 50 mL of dichloromethane, combine the organic phases, add 10 g of anhydrous sodium sulfate to dry, remove dichloromethane under reduced pressure, and obtain 22.6 g of waxy solid 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline. HPLC detection showed that the enantiomeric excess reached 99%.

[0086] Analytical data for 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline: HPLC: Chiracel OJ-H column, 254 nm, 30 ℃, n-Hexane / i-PrOH = 98.5 / 1.5, flow = 1.0 mL / min, retention time 13.2 min and 14.2 min (major).

[0087] This invention provides an iridium-catalyzed asymmetric hydrogenation and chemical resolution process for obtaining enantiomeric chiral 2-methyl-1,2,3,4-tetrahydroquinoline or its derivative 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline. The process is simple and practical, has a high S / C ratio, readily available raw materials, high enantioselectivity, good yield, and is green and economical, showing promising prospects for industrial application.

Claims

1. A process for the synthesis of enantiomerically pure chiral 2-methyl- 1,2,3,4-tetrahydroquinoline derivatives, characterized in that, Includes the following steps: (1) Asymmetric hydrogenation: Using iridium metal and chiral diphosphorus ligand L as the catalytic system, iodine as the additive, 2-methylquinoline derivative 1 as the substrate, and hydrogen as the hydrogen source, an asymmetric hydrogenation reaction was carried out to synthesize chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2. The reaction formula is as follows: In the formula: R is either H or F; (2) Chemical resolution: Using chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2 as substrate and tartaric acid derivative as resolving agent, the reaction was stirred at the solvent reflux temperature to obtain the salt 3 formed by chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2 and tartaric acid derivative. The reaction formula is as follows:

2. The method of claim 1, wherein: In step (1), the preparation method of the iridium metal and chiral ligand L catalytic system is as follows: add the iridium metal precursor and chiral ligand to the solvent and stir at room temperature for 5 to 30 minutes to obtain the system.

3. The method of claim 1 or 2, wherein: In step (1), the solvent for the reaction is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

4. The method of claim 1 or 2, wherein: In step (1), the metallic iridium precursor is a (1,5-cyclooctadiene)iridium(I) chloride dimer; the chiral diphosphorus ligand is one or more of the following: MeO-BiPhep chiral ligand, TfO-BiPhep chiral ligand, Garphos chiral ligand, Synphos chiral ligand, Tunephos chiral ligand, and Segphos chiral ligand; the molar ratio of the 2-methylquinoline derivative 1 to the metallic iridium precursor is 100:1 to 100000:1; the molar ratio of the metallic iridium precursor to the chiral diphosphorus ligand is 1:2 to 1:2.4; and the molar ratio of the iodine to the metallic iridium precursor is 50:1 to 200:

1.

5. The method of claim 1, wherein: In step (1), the reaction temperature is 25–70°C, the time is 12–72 hours, and the hydrogen pressure is 400–1200 psi.

6. The method of claim 1, wherein: In step (2), the resolving reagent tartaric acid derivative is one or more of diethyl tartrate, dibenzoyl tartaric acid, p-methyldibenzoyl tartaric acid, and di-p-methoxybenzoyl tartaric acid; the resolving solvent is one or more of acetone, methanol, ethanol, and 2,2,2-trifluoroethanol; and the molar ratio of the resolving reagent tartaric acid derivative and the chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2 is 1:2 to 1:

1.

7. The method of claim 1, wherein: In step (2), the reaction temperature is 25–90°C and the reaction time is 1–8 hours.

8. The method as described in claim 1, characterized in that: The steps of the method are as follows: The iridium precursor and chiral bisphosphine ligand were added to a solvent and stirred at room temperature for 5–30 minutes. The mixture was then transferred to a reactor containing a 2-methylquinoline derivative and iodine, and hydrogen was introduced to carry out the reaction, yielding chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2.

9. The method as described in claim 1 or 2, characterized in that: Also includes: (3) After the salt 3 formed by the chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2 and the tartaric acid derivative was neutralized by an alkaline aqueous solution, the enantiomeric chiral 2-methyl-1,2,3,4-tetrahydroquinoline derivative 2 was obtained. The reaction formula is as follows:

10. The method as described in claim 9, characterized in that: The alkaline aqueous solution is one or more of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, and potassium carbonate aqueous solution; the concentration of the alkaline aqueous solution is 1M to 4M; the pH of the neutralization reaction is 6 to 8, the temperature is -5 to 10℃, and the time is 0.5 to 5h.

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