Method for selectively and asymmetrically hydrogenating 4-substituted-1,2-dihydroquinoline and use thereof

Abstract

The present invention relates to the field of pesticide chemistry technology, and in particular, to a method for selectively and asymmetrically hydrogenating 4-substituted-1,2-dihydroquinoline and use thereof. The present invention discloses a selective, asymmetric hydrogenation reaction conducted on 4-substituted-1,2-dihydroquinoline in the presence of a chiral ligand and a rhodium catalyst. The selective, asymmetric hydrogenation method features ease to operate, a higher conversion rate, and higher enantioselectivity.

Description

A selective asymmetric hydrogenation method for 4-substituted-1,2-dihydroquinoline and its application

[0001] Priority claim: This invention claims priority to Chinese Patent Application No. 2024117141956, filed on November 27, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pesticide chemistry technology, specifically relating to a selective asymmetric hydrogenation method for 4-substituted-1,2-dihydroquinoline and its application. Background Technology

[0003] (3R)-1,1,3-trimethyl-4-aminoindane is an important active intermediate in the next-generation pyrazole carboxamide (Inpyrfluxam) succinate dehydrogenase inhibitor (SDHI) fungicide developed by Sumitomo Corporation of Japan. Inpyrfluxam, CAS Registry No. f1352994-67-2, chemical name: 3-(difluoromethyl)-N-[(R)-2,3-dihydro-1,1,3-trimethyl-1H-indene-4-yl]-1-methylpyrazole-4-carboxamide. Inpyrfluxam works by inhibiting the energy production process of pathogens. It has excellent fungicidal activity, good leaf penetration and systemic action, and is expected to have a significant impact on the future development of SDHI pesticides.

[0004] The original research company, Sumitomo Corporation of Japan, disclosed a method in patent EP3103789A1 (family CN105992755A) to chemically resolve 1,1,3-trimethyl-4-aminoindene by forming a salt with the diastereomeric form of D-tartrate, thus separating the D-tartrate salt of (3R)-1,1,3-trimethyl-4-aminoindene. After alkalization, (R)-1,1,3-trimethyl-4-aminoindene and (S)-1,1,3-trimethyl-4-aminoindene are separated; then, (S)-1,1,3-trimethyl-4-aminoindene is racemiced and re-separated. This synthetic method is cumbersome and generates a significant amount of waste.

[0005] Chinese patent CN114423739A discloses a method for preparing optically active 1,1,3-trimethyl-4-aminoindene, which involves hydrogenating 4-substituted 1,2-dihydroquinoline in the presence of a chiral ligand and a transition metal catalyst. The asymmetric hydrogenation of 4-substituted NH-dihydroquinoline exhibits low conversion (62.6%) and enantioselectivity (maximum 71.3% ee), while the conversion (14%) and enantioselectivity (31% ee) of N-acetyldihydroquinoline are even lower.

[0006] In view of this, in order to overcome the shortcomings of the prior art, the present invention provides a selective asymmetric hydrogenation method for 4-substituted-1,2-dihydroquinoline and its application. Summary of the Invention

[0007] This invention addresses the problems existing in the prior art by providing a selective asymmetric hydrogenation method for 4-substituted-1,2-dihydroquinoline and its applications. The selective asymmetric hydrogenation method disclosed in this invention is not only simple in procedure but also achieves higher conversion and enantioselectivity.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] On one hand, this invention provides a selective asymmetric hydrogenation method for 4-substituted-1,2-dihydroquinoline, in which compound II is prepared from compound I by selective asymmetric hydrogenation in the presence of a chiral ligand and a rhodium catalyst.

[0010] Compound II has a stereochemical structure at the stereocenter of *.

[0011] Preferably, the chiral purity of compound II is greater than or equal to 92%ee.

[0012] Preferably, the chiral ligand is selected from at least one of formula (1a) and formula (1b).

[0013] Among them, X 1 Each is independently selected from O, S, and P;

[0014] X 2 Each is independently selected from F, Cl, and Br;

[0015] R 1 Each is independently selected from -CF3, -(C 1-6 )alkyl, -(C 3-10 )cycloalkyl, -(C 6-10 )aryl, -(5-11) heterocyclic cycloalcoyl;

[0016] R 2 Each independently selected from -PR4 R 5 -CH2PR 4 R 5 -CH2OR 4 R 5 ;

[0017] R 3 Each is independently selected from -H, -(C 1-6 )alkyl, -(C 3-6 -cycloalkyl, -(3-6-membered)heterocycloalkyl, -phenyl, -(5-6-membered)heteroaryl;

[0018] R 2 The R 4 or R 5 Each is independently selected from -(C 1-10 )alkyl, -CF3, -(C 3-10 - (5 to 11) heterocyclic carbonyl groups, - (C 6-10 )Aryl, -(5 to 11)heteroaryl, ferrocene; R 4 or R 5 The -(C) 3-10 - (5 to 11) heterocyclic carbonyl groups, - (C 6-10 The aryl and -(5 to 11) heteroaryl groups can be optionally substituted by 1 to 3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -CF3;

[0019] R 3 The -(C) 1-6 The alkyl group may optionally be substituted with 1 to 3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -(C 3-6 )cycloalkyl, -phenyl, -(5-6)heteroaryl;

[0020] R 3 The -(C) 3-6 Cycloalkyl, -(3-6)heterocycloalkyl, -phenyl, and -(5-6)heteroaryl groups may optionally be substituted by 1-3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -(C 1-6 )alkyl, -(C 1-6 )alkyl, -CF3.

[0021] Preferably, the rhodium catalyst is [Rh(COD)2]X or [Rh(NBD)2]X;

[0022] Wherein, X is selected from any one of methanesulfonate, trifluoromethanesulfonate, tetrafluoroborate, hexafluorophosphate, and hexafluoroantimonate.

[0023] Preferably, X is selected from any one of hexafluorophosphate, hexafluoroantimonate, and tetrafluoroborate.

[0024] Preferably, the temperature at which compound I is prepared into compound II by selective asymmetric hydrogenation is 40-100°C.

[0025] Preferably, the pressure at which compound II is prepared by selective asymmetric hydrogenation of compound I is 0.5-5 MPa.

[0026] Preferably, the mass ratio of the rhodium catalyst to the chiral ligand is 1:0.1-1.5.

[0027] More preferably, the mass ratio of the rhodium catalyst to the chiral ligand is 1:0.9-1.2.

[0028] Preferably, the mass of the rhodium catalyst is 0.001%-0.1% of the mass of compound I.

[0029] More preferably, the mass of the rhodium catalyst is 0.01%-0.05% of the mass of compound I.

[0030] Preferably, the selective asymmetric hydrogenation method for 4-substituted-1,2-dihydroquinoline further includes a rearrangement reaction, wherein the rearrangement reaction uses compound II as a starting material and, in the presence of sulfuric acid, rearranges to synthesize compound III: (3R)-1,1,3-trimethyl-4-aminoindene.

[0031] More preferably, the sulfuric acid has a mass fraction of 98%.

[0032] More preferably, the mass ratio of compound II to sulfuric acid is 1:1.51.

[0033] In another aspect, the present invention provides the application of the above-mentioned selective asymmetric hydrogenation method of 4-substituted-1,2-dihydroquinoline in the preparation of Inpyrfluxam bactericide.

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

[0035] This invention discloses a selective asymmetric hydrogenation reaction of 4-substituted-1,2-dihydroquinoline in the presence of a chiral ligand and a rhodium catalyst. This selective asymmetric hydrogenation method is not only simple in steps, but also has higher conversion rate and enantioselectivity. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. However, the following embodiments are merely preferred embodiments of this invention and not all of them. For clarity, not all features of the actual embodiments are described. Other embodiments obtained by those skilled in the art based on the embodiments described in the implementation details without creative effort are all within the protection scope of this invention.

[0037] The present invention does not limit the source of the raw materials used. Unless otherwise specified, the raw materials used in the present invention are all commercially available products in this technical field.

[0038] Compound I was purchased internally by the company, batch number: TMQA-202205001.

[0039] The chiral ligand R-a6 was synthesized by our company. The synthesis process is described in Examples 6-12.

[0040] The rhodium catalyst was purchased from Xi'an Kaili New Materials Co., Ltd., batch number 220901.

[0041] As used herein, "enantioselectivity" refers to the preferred formation of one of two possible enantiomers of the hydrogenated product. "Enantiomer excess" or "ee" indicates the degree of enantioselectivity.

[0042] Example 1

[0043] Compound II was prepared according to the following procedure:

[0044] The structure of chiral ligands is as follows:

[0045] Among them, X 1 For O, X 2 For F, R 1 For -CF3, R 2 For -PCH3CF3, R 3 It is -H.

[0046] 100g of compound I and 300g of methanol were added to a 1L autoclave. The autoclave was then sealed, and stirring was initiated. Nitrogen was used to purge the mixture three times, followed by bubbling at ≤30℃ for 1-2 hours. A methanol solution of 13mg [Rh(COD)2]PF6 and 10mg chiral ligand 1a (anhydrous and oxygen-free, with a concentration of 0.5% for chiral ligand R-a6) was injected. Hydrogen was used to purge the mixture three times. After purging, hydrogen was introduced to bring the pressure inside the autoclave to a gauge pressure of 3.0-3.5MPa. The temperature was then raised to 60-80℃, and stirring was carried out for 10-14 hours. The mixture was cooled, discharged, and filtered. The filtrate was concentrated under reduced pressure to obtain 93.6g of compound II with an optical purity of 96% ee and a conversion rate of 95%.

[0047] Example 2

[0048] Compound II was prepared according to the following procedure:

[0049] The structure of chiral ligands is as follows:

[0050] Among them, X 1 For O, X 2 For F, R 1 For -CF3, R 2 For -PCH3CF3, R 3 It is -H.

[0051] 100g of compound I and 350g of methanol were added to a 1L autoclave. The autoclave was then sealed, and stirring was started. The air inside the autoclave was purged with nitrogen three times, and then the temperature was maintained at ≤30℃ with nitrogen and bubbled for 1-2 hours. A methanol solution of 10mg [Rh(COD)2]SbF6 and 10mg chiral ligand 1a (anhydrous and oxygen-free, with a concentration of 0.5% for chiral ligand R-a6) was injected. The nitrogen inside the autoclave was then purged with hydrogen three times at a pressure of 3.0-3.5MPa. The temperature was raised to 65-75℃ and maintained for 20-24 hours. After the reaction was completed, the reaction solution was removed, and the temperature was maintained at 45-50℃. The solution was evaporated under reduced pressure until no more liquid dripped out, yielding 90.5g of compound II with an optical purity of 93.5%ee and a conversion rate of 90.2%.

[0052] Example 3

[0053] Compound II was prepared according to the following procedure:

[0054] The structure of chiral ligands is as follows:

[0055] Among them, X 1 For O, X 2 For F, R 1 For -CF3, R2 For -PCH3CF3, R 3 It is -H.

[0056] 100g of compound I and 350g of methanol were added to a 1L autoclave. The autoclave was then sealed, and stirring was started. The air inside the autoclave was purged with nitrogen three times, and then the temperature was maintained at ≤30℃ with nitrogen and bubbled for 1-2 hours. A methanol solution of 11mg [Rh(NBD)2]PF6 and 11mg chiral ligand 1a (anhydrous and oxygen-free, with a concentration of 0.55% for chiral ligand R-a6) was injected. The nitrogen inside the autoclave was then purged with hydrogen three times at a pressure of 3.0-3.5MPa. The temperature was raised to 60-70℃ and maintained for 20-24 hours. After the reaction was completed, the reaction solution was removed, and the temperature was maintained at 45-50℃. The solution was evaporated under reduced pressure until no more liquid dripped out, yielding 92.3g of compound II with an optical purity of 92.5%ee and a conversion rate of 91.8%.

[0057] Example 4

[0058] Compound III was prepared according to the following procedure:

[0059] 100g of compound II was heated to 90℃ and added dropwise to 151g of 98% sulfuric acid while maintaining an internal temperature of 50-60℃. The reaction solution was then added dropwise to 250g of hot water at 98℃. The resulting mixture was kept at 100-105℃ and stirred for 4-5 hours. After the temperature was maintained, the mixture was cooled and the internal temperature was controlled below 80℃. The reaction solution was then added dropwise to 500g of 27% sodium hydroxide aqueous solution. After the addition was complete, the mixture was extracted with toluene and the solvent was removed to obtain compound III with a purity of 94.2% and a yield of 87%.

[0060] Examples 5-11

[0061] Chiral ligands were prepared according to the following procedure:

[0062] Example 5

[0063] Preparation of isobutyl(2,6-dimethoxy-3-fluorophenyl)(methyl)phosphine oxide (a1)

[0064] Under nitrogen protection, add THF (50 mL) and dichloromethylphosphine (6.61 g, 57 mmol, 1.0 equivalent) to the reaction flask and cool, controlling the internal temperature to ≤-10℃. Add 1.0 M iBuMgCl (57 mL, 57 mmol, 1.0 equivalent) dropwise to the above solution. After the addition is complete, control the internal temperature to -10 to 0℃ and keep it at this temperature with stirring for 1 hour. Then slowly raise the temperature to 25℃ and keep it at 25-30℃ with stirring for 1 hour. Set aside for use.

[0065] In another reaction flask, add 1,3-dimethoxy-3-fluorobenzene (10.6 g, 68 mmol, 1.2 equivalents) and THF (50 mL), cool, and control the internal temperature to ≤-10℃. Add 1.0 M BuLi (67.8 mL, 68 mmol, 1.2 equivalents) dropwise, completing the addition in about 1 hour. Keep the mixture at -10 to 0℃ and stir for 0.5 h.

[0066] Controlling the internal temperature to <20℃, the above-mentioned reaction solution was added dropwise to a mixture of 2,6-dimethoxy-3-fluorophenyllithium. The mixture was kept at 20-25℃ and stirred for 1 hour. After cooling, the internal temperature was controlled to ≤0℃. 30% H2O2 was added dropwise to the mixture, and then stirred at 20-25℃ for 0.5 hours. Then, 2N HCl (300 mL) and dichloromethane (300 mL) were added to quench the reaction. The mixture was separated into layers. The dichloromethane layer was washed with brine (300 mL), dried with sodium sulfate, concentrated, and purified by silica gel column chromatography (elution: EtOAc to EtOAc / MeOH 4 / 1) to obtain an oily substance of a1 (13.3 g, 80%).

[0067] 1 HNMR (400MHz, CDCl3: δ = 7.21 (m, 1H), 6.62 (dd, / = 8.4, 3.8Hz, 1H), 3.84 (s, 3H), 3.7 (d, / = 13.2)Hz, 3H), 1.26 (d, / = 15.4Hz, 9H); 31 PNMR (162MHz, CDCl3): S=51.6.

[0068] 13 CNMR (100MHz, CDCl3): S=161.5 (d, / =1.0Hz), 138.7 (d, / =1.0Hz), 107.3 (d, / =82Hz), 104 .5 (d, / = 6Hz), 55.80, 34.5 (d, J = 72Hz), 25.4 (d, / = 1.6Hz), 15.1 (d, / = 69Hz); ESI-MS: m / z 257[M+H] + .

[0069] Example 6

[0070] Preparation of isobutyl(2,6-dimethoxy-3-fluorophenyl)(iodomethyl)phosphine (a2)

[0071] Under nitrogen protection, a1 (10 g, 36.4 mmol, 1 equivalent), TMEDA (8.3 mL, 55 mmol, 1.5 equivalent), and THF (40 mL) were added. The mixture was cooled to ≤-78 °C, and a 2.5 M BuLi hexane solution (17.4 mL, 1.2 equivalent) was added dropwise. The mixture was kept at -80 to -78 °C with stirring for 1 h. While maintaining the internal temperature at ≤-78 °C, a THF solution of iodine (14 g, 1.5 equivalent) (20 mL) was added, while simultaneously controlling the temperature to <-75 °C. After adding the ingredients, the mixture was kept at -80 to -75°C and stirred for 0.5 hours. Then, the temperature was raised to 25°C within 1 hour. 10% NaHSO3 solution (130 mL) and dichloromethane (150 mL) were added dropwise to the mixture to separate the layers. The dichloromethane layer was washed with brine (100 mL), dried with sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (eluent: EtOAc / MeOH = 10 / 1) to obtain a2 oil (9.8 g, 24.4 mmol, 85%).

[0072] 1 HNMR (400MHz, CDCl3): δ = 7.20 (t, / = 8.4Hz, 1H), 6.61 (dd, / = 8.4, 4.0Hz, 1H), 3.83 (s, 6H), 3.79 (m, 2H), 1.22 (d, / = 15.6Hz, 9H); 31 PNMR (162MHz, CDCl3): S=51.0;

[0073] 13 CNMR (100MHz, CDCl3): S=161.2, 137.2, 104.9 (d, / = 63Hz), 103.8 (d, = 6Hz), 55.8, 36.3 (d, 7 = 71Hz)), 25.5, -1.8 (d, / = 59Hz); ESI-MS: m / z 383 [M+H] + .

[0074] Example 7

[0075] Preparation of 3-tert-butyl-5-fluoro-2,3-dihydrobenzo[l,3]oxophosphonate-4-ol (a3)

[0076] At 0°C, a2 (9.1 g, 22.7 mmol) and 1,2-dichloroethane (100 mL) were added to a reaction flask. After cooling to 0°C, BBr3 (29.7 g, 90.8 mmol) was added. The mixture was heated to 60°C and kept at 55-60°C with stirring for 2 hours. After the heating was completed, MeOH (200 mL) was added dropwise to the mixture, and the mixture was concentrated. MeOH (200 mL × 3) was distilled three times to obtain an oily substance. K2CO3 (14.6 g, 105 mmol) and DMF (100 mL) were added to the oily substance, and the mixture was heated to 50-60°C with stirring for 2 hours. Then, it was cooled to 0°C and water (200 mL) was added. The pH of the mixture was adjusted to 1-3 with concentrated HCl. After adjustment, dichloromethane (200 mL) was added, and the dichloromethane layer was separated. The aqueous layer was extracted twice with dichloromethane (50 mL × 2). The combined dichloromethane layers were washed with brine (100 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (elution buffer: EtOAc:MeOH = 4:1) to give a3 as 5.0 g of white solid, yield 90%.

[0077] 1 HNMR (400MHz, CD3OD): δ = 7.27 (t, / = 8.2Hz, 1H), 6.50 (m, 1H), 4.82 (dd, / = 14.3, 3.3Hz, 2H), 1.30 (d, / = 16.6Hz, 9H); 31 PNMR (162MHz, CDCl3): S=68.1;

[0078] 13 CNMR (100MHz, CD3OD): δ=166.5 (d, / =17.2Hz), 159.8 (d, J=2.2Hz), 139.3, 109.3 (d, / =6.1Hz), 105. 7 (d, J=5.4Hz), 101.7 (d, / =94.3Hz), 66.3 (d, / =61Hz), 34.5 (d, / =74Hz), 25.6; ESI-MS: m / z227[M+H] + .

[0079] Example 8

[0080] Preparation of (R)-3-tert-butyl-5-fluoro-2,3-dihydrobenzo[1,3]oxophosphonate-4-ol (R-a3): Racemic compound a3 (4.5 g, 18.4 mmol), triethylamine (3.7 g, 27.4 mmol), dichloromethane (50 mL), and (+)-menthyl chloroformate 4.9 g were added. The mixture was stirred and heated to 25 °C and stirred at 20-25 °C for 2 hours. Water (100 mL) was added dropwise to quench the reaction. The dichloromethane layer was separated, washed with brine, dried over Na2SO4, and purified by silica gel column chromatography (eluent: hexane: EtOAc = 1:1) to obtain (+)-menthyl carbonate: 8.1 g.

[0081] Add 160 mL of EtOH to 8 g of the above solid at 25 °C, then add KOH solution (8.2 g of KOH dissolved in 40 mL of water). Stir at 25 °C for 2 h, cool to 0 °C, control the pH to 3-4 with HCl, and extract with 80 mL of dichloromethane. Separate the dichloromethane layer, wash with brine, dry with sodium sulfate, filter to concentrate, and purify by silica gel column chromatography (elution buffer: EtOAc / MeOH = 4:1) to obtain a white solid R-a3:1.8 g.

[0082] 1 HNMR (400MHz, CD3OD): δ = 7.23 (t, / = 8.2Hz, 1H), 6.50 (m, 2H), 5.10 (dd, / = 14.3, 3.3Hz, 2H), 1.32 (d, / = 16.6Hz, 9H); 31 PNMR (162MHz, CDCl3): S=68.6;

[0083] 13 CNMR (100MHz, CD3OD): δ = 165.5 (d, / = 17.2Hz), 151.4 (d, J = 2.2Hz), 140.1, 109.0 (d, / = 6.1Hz), 105.5 (d, J=5.4Hz), 101.7 (d, / =94.3Hz), 65.8 (d, / =61Hz), 34.5 (d, / =74Hz), 26.3; ESI-MS: m / z 227[M+H] + .

[0084] Example 9

[0085] Preparation of (R)-3-tert-butyl-5-fluoro-4-methoxy-2H-benzo[1,3]phosphonate (R-a4)

[0086] Add 1.5g of R-a3, 100mL of THF, and 1.7g of potassium carbonate. Stir and heat to 20-25℃, then add 2.6g of iodomethane dropwise. After the addition is complete, heat to 30-40℃ and stir for 4-6 hours. Cool, add 100mL of water, and then add 100mL of dichloromethane. Separate the layers, and extract the aqueous layer twice with 20mL of dichloromethane each time. Combine the organic layers, wash with 50mL of brine, dry with sodium sulfate, and concentrate to obtain: R-a4, 1.51g, yield 95%.

[0087] 1 HNMR (400MHz, CD3OD): δ = 7.21 (t, / = 8.2Hz, 1H), 6.56 (m, 1H), 5.15 (dd, / = 14.3, 3.3Hz, 2H), 3.83 (s, 3H), 1.36 (d, / = 16.6Hz, 9H); 31 PNMR (162MHz, CDCl3): S=68.2;

[0088] 13 CNMR (100MHz, CD3OD): δ = 164.5 (d, / = 17.2Hz), 151.3 (d, J = 2.2Hz), 142.1, 108.3 (d, / = 6.1Hz), 104 .8 (d, J=5.4Hz), 101.7 (d, / =94.3Hz), 65.8 (d, / =61Hz), 55.8, 34.5 (d, / =74Hz), 26.7; ESI-MS: m / z 259.2[M+H] + .

[0089] Example 10

[0090] Preparation of R-3-tert-butyl-2-(ethylphosphino)-5-fluoro-4-methoxy-2,3-dihydrobenzo[1,3]oxazole dioxide (R-a5)

[0091] Under nitrogen protection, 1 g of R-a4, 3.9 mmol, and 40 mL of THF were added. The mixture was cooled to ≤-78℃, and 2.4 mL of LDA (2 mol / L) was added dropwise. After the addition was complete, the mixture was kept at -78℃ and stirred for 1 h. Then, 0.45 g of C2H5PCl was added, and the mixture was kept at -82 to -78℃ and stirred for 1 h. The temperature was then raised to 20℃ and stirred for 1 h, while the internal temperature was kept ≤0℃. 0.3 mg of 30% H2O2 solution was added dropwise. The resulting mixture was stirred at 0℃ for 1 h, and 25 mL of water and 40 mL of dichloromethane were added. The dichloromethane layer was separated, concentrated to dryness, and purified by silica gel column chromatography (elution buffer: EtOAc / MeOH = 5 / 2) to obtain 1.16 g of oily R-a5, with a yield of 90%.

[0092] 1HNMR (400MHz, CD2Cl2): δ=7.40 (t, / =8.2Hz, 1H), 6.57 (m, 1H), 3.70 (dd, / =9.0, 3. 5Hz, 1H), 3.83 (s, 3H), 1.21 (d, = 13.5Hz, 9H), 1.12 (d, J = 1.3Hz, 9H), 1.28 (d, J = 9A Hz, 9H); 31 PNMR (162MHz, CDCl3): S = 61.7 (d, 3 / polypropylene = 9.8Hz), 60.9 (d, 3 / polypropylene = 9.8Hz);

[0093] 13 CNMR (100MHz, CD2Cl2): S=171.1, 164.8 (dd, / =14.4, 5.8Hz), 161.6 (d, J=23Hz), 136.7, 106.3 (d, / =5.2Hz), 104.1 (d, / =5.6Hz), 71.3 (d d, / =52.4, 43.0Hz), 56.0, 37.9 (dd, / = 55.7, 3.3Hz), 37.0 (d, / = 57.0Hz)), 35.0 (d, / = 76.5Hz), 27.7, 26.5, 25.9; 15.1, 15.1ESI-MS: m / z 401[M+H] + .

[0094] Example 11

[0095] Preparation of R-3-tert-butyl-2,2-(dimethylphosphino)-5-fluoro-4-methoxy-2,3-dihydrobenzo[1,3]acetoxyphosphine (R-a6)

[0096] Under nitrogen atmosphere, 1 g of R-a5 and 100 mL of toluene were added, along with 0.5 g of triethylamine and 0.8 g of trichlorosilane. The mixture was stirred and heated to 110-120 °C, and maintained at this temperature for 12-16 h. After the heating was complete, 15 g of 30% NaOH solution was added, and the reaction mixture was cooled to 50-60 °C and stirred for about 1 hour. The toluene layer was separated, and the aqueous layer was extracted twice with toluene (20 mL × 2). The combined toluene layers were dried over Na2SO4, concentrated under N2, and purified by neutral alumina column chromatography (eluent: heptane / petroleum ether = 5:1) to give 0.86 g of white solid R-a6, with a yield of 90%.

[0097] 1HNMR (400MHz, CD2Cl2): δ = 7.45 (t, / = 8.2Hz, 1H), 6.59 (m, 1H), 3.90 (dd, / = 9.0, 3.5Hz, 1H), 3.83 (s, 3H), 1.31 (d, = 13.5Hz, 9H), 1.12 (d, J = 1.3Hz, 6H); 31 PNMR (162MHz, CDCl3): S = 61.7 (d, 3 / polypropylene = 9.8Hz), 60.9 (d, 3 / polypropylene = 9.8Hz);

[0098] 13 CNMR (100MHz, CD2Cl2): S=167.1, 164.8 (dd, / =14.4, 5.8Hz), 154.6 (d, J=23Hz), 136.7, 105.3 (d, / =5.2Hz), 103.1 (d, / =5.6H z), 74.3 (dd, / = 52.4, 43.0Hz), 56.0, 35.9 (dd, / = 55.7, 3.3Hz), 33, 90 (d, / = 76.5Hz), 27.7, 26.5, 25.9; 10.1, 10.2ESI-MS: m / z 303.1[M+H] + .

[0099] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A selective asymmetric hydrogenation method for 4-substituted-1,2-dihydroquinoline, characterized in that, Compound II was prepared from compound I by selective asymmetric hydrogenation in the presence of a chiral ligand and a rhodium catalyst. Compound II has a stereochemical structure at the stereocenter of *.

2. The selective asymmetric hydrogenation method according to claim 1, characterized in that, The chiral purity of compound II is greater than 92%ee.

3. The selective asymmetric hydrogenation method according to claim 2, characterized in that, The chiral ligand is selected from at least one of formula (1a) and formula (1b). Among them, X 1 Each is independently selected from O, S, and P; X 2 Each is independently selected from F, Cl, and Br; R 1 Each is independently selected from -CF3, -(C 1-6 )alkyl, -(C 3-10 )cycloalkyl, -(C 6-10 )aryl, -(5-11) heterocyclic cycloalcoyl; R 2 Each independently selected from -PR 4 R 5 -CH2PR 4 R 5 -CH2OR 4 R 5 ; R 3 Each is independently selected from -H, -(C 1-6 )alkyl, -(C 3-6 -cycloalkyl, -(3-6-membered)heterocycloalkyl, -phenyl, -(5-6-membered)heteroaryl; R 2 The R 4 or R 5 Each is independently selected from -(C 1-10 )alkyl, -CF3, -(C 3-10 - (5 to 11) heterocyclic carbonyl groups, - (C 6-10 )Aryl, -(5 to 11)heteroaryl, ferrocene; R 4 or R 5 The -(C) 3-10 - (5 to 11) heterocyclic carbonyl groups, - (C 6-10 The aryl and -(5 to 11) heteroaryl groups can be optionally substituted by 1 to 3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -CF3; R 3 The -(C) 1-6 The alkyl group may optionally be substituted with 1 to 3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -(C 3-6 )cycloalkyl, -phenyl, -(5-6)heteroaryl; R 3 The -(C) 3-6 Cycloalkyl, -(3-6)heterocycloalkyl, -phenyl, and -(5-6)heteroaryl groups may optionally be substituted by 1-3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -(C 1-6 )alkyl, -(C 1-6 )alkyl, -CF3.

4. The selective asymmetric hydrogenation method according to claim 2, characterized in that, The rhodium catalyst is [Rh(COD)2]X or [Rh(NBD)2]X; Wherein, X is selected from any one of methanesulfonate, trifluoromethanesulfonate, tetrafluoroborate, hexafluorophosphate, and hexafluoroantimonate.

5. The selective asymmetric hydrogenation method according to claim 4, characterized in that, X is selected from any one of hexafluorophosphate, hexafluoroantimonate, and tetrafluoroborate.

6. The selective asymmetric hydrogenation method according to claim 2, characterized in that, Compound I was prepared by selective asymmetric hydrogenation at a temperature of 40-100℃ and a pressure of 0.5-5 MPa.

7. The selective asymmetric hydrogenation method according to claim 2, characterized in that, The mass ratio of the rhodium catalyst to the chiral ligand is 1:0.1-1.5; the mass of the rhodium catalyst is 0.001%-0.1% of the mass of compound I.

8. The selective asymmetric hydrogenation method according to any one of claims 1-7, characterized in that, The selective asymmetric hydrogenation method for the 4-substituted-1,2-dihydroquinoline further includes a rearrangement reaction, wherein the rearrangement reaction uses compound II as a starting material and, in the presence of sulfuric acid, rearranges to synthesize compound III: (3R)-1,1,3-trimethyl-4-aminoindene.

9. The selective asymmetric hydrogenation method according to claim 8, characterized in that, The sulfuric acid has a mass fraction of 98%; the mass ratio of compound II to sulfuric acid is 1:1.

51.

10. The application of the selective asymmetric hydrogenation method of 4-substituted-1,2-dihydroquinoline according to any one of claims 1-9 in the preparation of Inpyrfluxam bactericide.

Images