Selective asymmetric hydrogenation method of 4-substituted-1, 2-dihydroquinoline and application thereof

Abstract

The invention discloses a selective asymmetric hydrogenation method of 4-substituted-1, 2-dihydroquinoline and application of the selective asymmetric hydrogenation method, and relates to the technical field of pesticide chemistry. According to the present invention, in the presence of the chiral ligand and the rhodium catalyst, the 4-substituted-1, 2-dihydroquinoline is subjected to the selective asymmetric hydrogenation reaction, and the selective asymmetric hydrogenation method has advantages of simple steps, high conversion rate and high enantioselectivity.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticide chemistry, and specifically relates to a selective asymmetric hydrogenation method of 4-substituted-1,2-dihydroquinoline and application thereof. Background Art

[0002] (3R)-1,1,3-trimethyl-4-aminoindane is an important active intermediate of the new generation of pyrazolecarboxamide (Inpyrfluxam) succinate dehydrogenase inhibitor (SDHI) fungicide developed by Sumitomo Corporation of Japan. Inpyrfluxam, CAS registration number f1352994-67-2, chemical name: 3-(difluoromethyl)-N-[(R)-2,3-dihydro-1,1,3-trimethyl-1H-inden-4-yl]-1-methylpyrazole-4-carboxamide. Inpyrfluxam works by inhibiting the energy production process of pathogens. It has excellent fungicidal effect, good leaf penetration and systemic effect, and will have a greater influence on the future pesticide SDHI.

[0003]

[0004] The original Japanese Sumitomo patent EP3103789A1 (same family CN105992755A) discloses a method for chemically splitting 1,1,3-trimethyl-4-aminoindene by salifying a mixture of 1,1,3-trimethyl-4-aminoindene enantiomers with the diastereomers of D-tartaric acid, separating the D-tartaric acid salt of (3R)-1,1,3-trimethyl-4-aminoindene, and then alkalizing to separate (R)-1,1,3-trimethyl-4-aminoindene and (S)-1,1,3-trimethyl-4-aminoindene; and then racemizing (S)-1,1,3-trimethyl-4-aminoindene and splitting it again. This synthesis method has complicated steps and produces a lot of three wastes.

[0005] Chinese patent CN114423739A discloses a method for preparing optically active 1,1,3-trimethyl-4-aminoindene, which hydrogenates 4-substituted 1,2-dihydroquinoline in the presence of a chiral ligand and a transition metal catalyst. The conversion rate (62.6%) and enantioselectivity (up to 71.3% ee) of the asymmetric hydrogenation of 4-substituted NH-dihydroquinoline are not high, while the conversion rate (14%) and enantioselectivity (31% ee) of N-acetyldihydroquinoline are even lower.

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

[0007] The present invention aims at the problems existing in the prior art and provides a selective asymmetric hydrogenation method of 4-substituted-1,2-dihydroquinoline and its application. The selective asymmetric hydrogenation method disclosed in the present invention not only has simple steps, but also has higher conversion rate and enantioselectivity.

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

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

[0010]

[0011] The compound II has a stereochemical structure at the stereocenter of *.

[0012] Preferably, the chiral purity of compound II is greater than or equal to 92% ee.

[0013] Preferably, the chiral ligand is selected from at least one of formula (1a) and formula (1b),

[0014]

[0015] Among them, X 1 Each independently selected from O, S, P;

[0016] X 2 Each independently selected from F, Cl, Br;

[0017] R 1 Each independently selected from -CF 3 、-(C 1-6 )alkyl, -(C 3-10 )cycloalkyl, -(C 6-10 )aryl, -(5-11 membered)heterocarbocyclyl;

[0018] R 2 Each independently selected from -PR 4 R 5 、-CH 2 PR 4 R 5 、-CH 2 OR 4 R 5 ;

[0019] R 3 Each independently selected from -H, -(C 1-6 )alkyl, -(C 3-6)cycloalkyl, -(3-6 membered)heterocycloalkyl, -phenyl, -(5-6 membered)heteroaryl;

[0020] R 2 The R 4 or R 5 Each independently selected from -(C 1-10 )alkyl, -CF 3 、-(C 3-10 ) carbocyclic group, -(5- to 11-membered) heterocarbocyclic group, -(C 6-10 )aryl, -(5- to 11-membered)heteroaryl, ferrocenyl; R 4 or R 5 The -(C 3-10 ) carbocyclic group, -(5- to 11-membered) heterocarbocyclic group, -(C 6-10 )aryl, -(5 to 11 membered)heteroaryl may be optionally substituted by 1 to 3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -CF 3 ;

[0021] R 3 Said-(C 1-6 )alkyl may be optionally substituted by 1 to 3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -(C 3-6 )cycloalkyl, -phenyl, -(5-6 membered)heteroaryl;

[0022] R 3 Said-(C 3-6 )cycloalkyl, -(3-6 membered)heterocycloalkyl, -phenyl, -(5-6 membered)heteroaryl may be optionally substituted by 1-3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -(C 1-6 )alkyl, -(C 1-6 )alkyl, -CF 3 .

[0023] Preferably, the rhodium catalyst is [Rh(COD) 2 ]X or [Rh(NBD) 2 ]X;

[0024] Wherein, the X is selected from any one of methanesulfonate, trifluoromethanesulfonate, tetrafluoroborate, hexafluorophosphate, and hexafluoroantimonate.

[0025] Preferably, X is selected from any one of hexafluorophosphate, hexafluoroantimonate and tetrafluoroborate.

[0026] Preferably, the temperature for preparing compound II from compound I by selective asymmetric hydrogenation is 40-100°C.

[0027] Preferably, the pressure at which the compound I is prepared into the compound II by a selective asymmetric hydrogenation method is 0.5-5 MPa.

[0028] Preferably, the mass ratio of the rhodium catalyst to the chiral ligand is 1:0.1-1.5.

[0029] Further preferably, the mass ratio of the rhodium catalyst to the chiral ligand is 1:0.9-1.2.

[0030] Preferably, the mass of the rhodium catalyst is 0.001%-0.1% of the mass of compound I.

[0031] More preferably, the mass of the rhodium catalyst is 0.01%-0.05% of the mass of compound I.

[0032] Preferably, the selective asymmetric hydrogenation method of 4-substituted-1,2-dihydroquinoline further comprises a rearrangement reaction, wherein the rearrangement reaction uses compound II as a raw material, and in the presence of sulfuric acid, rearranges to synthesize compound III: (3R)-1,1,3-trimethyl-4-aminoindene,

[0033]

[0034] Further preferably, the mass fraction of the sulfuric acid is 98%.

[0035] More preferably, the mass ratio of compound II to sulfuric acid is 1:1.51.

[0036] In another aspect, the present invention provides the use of the above-mentioned selective asymmetric hydrogenation method of 4-substituted-1,2-dihydroquinoline in the preparation of Inpyrfluxam fungicide.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] The invention discloses a selective asymmetric hydrogenation reaction of 4-substituted-1,2-dihydroquinoline in the presence of a chiral ligand and a rhodium catalyst. The selective asymmetric hydrogenation method has not only simple steps but also higher conversion rate and enantioselectivity. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical scheme and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. However, the following embodiments are only preferred embodiments of the present invention, not all. For the sake of clarity, all features of the actual embodiments are not described. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention.

[0040] The present invention does not limit the sources of the raw materials used. Unless otherwise specified, the raw materials used in the present invention are common commercial products in the technical field.

[0041] Among them, compound I was purchased internally by the company, batch number: TMQA-202205001.

[0042] Chiral ligand R-a6 was synthesized by our company. The synthesis process is shown in Examples 6-12.

[0043] The rhodium catalyst was purchased from Xi'an Kaili New Materials Co., Ltd., batch number 220901.

[0044] As used herein, "enantioselectivity" refers to the preference for forming one of the two possible enantiomers of the hydrogenation product. "Enantiomeric excess" or "ee" refers to the degree of enantioselectivity:

[0045]

[0046] Example 1

[0047] Compound II was prepared according to the following process:

[0048]

[0049] The structure of the chiral ligand is as follows:

[0050]

[0051] Among them, X 1 O, X 2 For F, R 1 For-CF 3 , R 2 For-PCH 3 CF 3 , R 3 is -H.

[0052] After 100 g of compound I and 300 g of methanol were loaded into a 1 L autoclave, the autoclave was sealed, stirred, and replaced with nitrogen three times. Then, nitrogen was bubbled at a temperature of ≤30°C for 1-2 h, and 13 mg [Rh(COD) 2 ]PF 6 and 10 mg of chiral ligand 1a in methanol solution (anhydrous and oxygen-free, the concentration of chiral ligand R-a6 in methanol solution is 0.5%), hydrogen replacement three times, after replacement, hydrogen is introduced to make the pressure in the kettle reach 3.0-3.5 MPa, start heating to 60-80°C, stir for 10-14 hours. Cool, discharge, filter. The obtained filtrate is concentrated under reduced pressure to obtain 93.6 g of compound II, with an optical purity of 96% ee and a conversion rate of 95%.

[0053] Example 2

[0054] Compound II was prepared according to the following process:

[0055]

[0056] The structure of the chiral ligand is as follows:

[0057]

[0058] Among them, X 1 O, X 2 For F, R 1 For-CF 3 , R 2 For-PCH 3 CF 3 , R 3 is -H.

[0059] After adding 100g of compound I and 350g of methanol into a 1L autoclave, the autoclave was sealed and stirred. The air in the autoclave was replaced with nitrogen three times, and then nitrogen was bubbled at a temperature of ≤30℃ for 1-2h. 10mg [Rh(COD) 2 ]SbF 6 and 10 mg of chiral ligand 1a in methanol solution (anhydrous and oxygen-free, the concentration of chiral ligand R-a6 in methanol solution is 0.5%), and then replace the nitrogen in the kettle with hydrogen three times, the hydrogen filling pressure is 3.0-3.5MPa, the temperature is raised to 65-75°C in the kettle, and the reaction is kept warm for 20-24h. After the reaction is completed, the reaction liquid is taken out, the temperature is controlled at 45-50°C, and it is evaporated to dryness under reduced pressure until no droplets flow out, to obtain 90.5g of compound II, the optical purity is 93.5%ee, and the conversion rate is 90.2%.

[0060] Example 3

[0061] Compound II was prepared according to the following process:

[0062]

[0063] The structure of the chiral ligand is as follows:

[0064]

[0065] Among them, X 1 O, X 2 For F, R 1 For-CF 3 , R 2 For-PCH 3 CF 3 , R 3 is -H.

[0066] After adding 100g of compound I and 350g of methanol into a 1L autoclave, the autoclave was sealed and stirred. The air in the autoclave was replaced with nitrogen three times, and then nitrogen was bubbled at a temperature of ≤30℃ for 1-2h. 11mg [Rh(NBD) 2 ]PF 6 and 11 mg of methanol solution of chiral ligand 1a (anhydrous and oxygen-free, the concentration of methanol solution of chiral ligand R-a6 is 0.55%), and then replace the nitrogen in the kettle with hydrogen three times, the hydrogen filling pressure is 3.0-3.5MPa, the temperature is raised to 60-70°C in the kettle, and the reaction is kept warm for 20-24h. After the reaction is completed, the reaction liquid is taken out, the temperature is controlled at 45-50°C, and it is evaporated to dryness under reduced pressure until no droplets flow out, to obtain 92.3g of compound II, the optical purity is 92.5%ee, and the conversion rate is 91.8%.

[0067] Example 4

[0068] Compound III was prepared according to the following scheme:

[0069]

[0070] Heat 100g of compound II to 90°C, control the internal temperature at 50-60°C and add it dropwise to 151g of 98% sulfuric acid, then add the reaction solution dropwise to 250g of 98°C hot water, keep the resulting mixture warm and stirred at 100-105°C for 4-5 hours, cool after the insulation is completed, control the internal temperature to <80°C, add the above reaction solution dropwise to 500g of 27% aqueous sodium hydroxide solution, extract with toluene, and desolventize to obtain compound III with a purity of 94.2% and a yield of 87%.

[0071] Example 5-11

[0072] Chiral ligands were prepared according to the following procedure:

[0073]

[0074] Example 5

[0075] Preparation of isobutyl (2,6-dimethoxy-3-fluorophenyl) (methyl) phosphine oxide (a1)

[0076] Under nitrogen protection, THF (50 mL) and dichloromethylphosphine (6.61 g, 57 mmol, 1.0 equiv) were added into the reaction flask and cooled. The internal temperature was controlled to be ≤-10°C. 1.0 M iBuMgCl (57 mL, 57 mmol, 1.0 equiv) was added dropwise to the above solution. After the addition, the internal temperature was controlled to -10-0°C, and the mixture was stirred for 1 hour. Then the temperature was slowly raised to 25°C, and stirred for 1 hour at 25-30°C for standby use.

[0077] In another reaction flask, place 1,3-dimethoxy-3-fluorobenzene (10.6 g, 68 mmol, 1.2 equiv.) and THF (50 mL), cool, control the internal temperature to ≤ -10°C, add 1.0 M BuLi (67.8 mL, 68 mmol, 1.2 equiv.) dropwise, add in about 1 hour, and stir at -10-0°C for 0.5 h.

[0078] Control the internal temperature <20°C, add the above reaction solution to the mixed solution of 2,6-dimethoxy-3-fluorophenyl lithium, control the internal temperature at 20-25°C, keep stirring for 1 hour, cool, control the internal temperature ≤0°C, and add 30% H 2 O 2 , then stirred at 20-25°C for 0.5h, then quenched by adding 2N HCl (300mL) and dichloromethane (300mL). Layers were separated, the dichloromethane layer was washed with brine (300mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel column (eluent: EtOAc to EtOAc / MeOH 4 / 1) to give a1 as an oil (13.3g, 80%).

[0079] 1 HNMR (400 MHz, CDCl 3 : 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, CDCl 3 ): S = 51.6.

[0080] 13 CNMR (100MHz, CDCl 3 ): S=161.5(d, / =1.0Hz), 138.7(d, / =1.0Hz), 107.3(d, / =82Hz), 104.5(d, / =6 Hz), 55.80, 34.5 (d, J=72Hz), 25.4 (d, / =1.6Hz), 15.1 (d, / =69Hz); ESI-MS: m / z 257[M+H] + .

[0081] Example 6

[0082] Preparation of isobutyl (2,6-dimethoxy-3-fluorophenyl) (iodomethyl) phosphine (a2)

[0083] Under nitrogen protection, add a1 (10 g, 36.4 mmol, 1 equivalent), TMEDA (8.3 mL, 55 mmol, 1.5 equivalents) and THF (40 mL), cool to ≤-78°C, add 2.5 M BuLi hexane solution (17.4 mL, 1.2 equivalents) dropwise, and stir at -80 to -78°C for 1 hour. Control the internal temperature to ≤-78°C, add iodine (14 g, 1.5 equivalents) in THF (20 mL), and control the temperature to <-75°C. After the addition, stir at -80 to -75°C for 0.5 hour, then raise the temperature to 25°C within 1 hour, and add 10% NaHSO 3 The solution (130 mL) and dichloromethane (150 mL) were layered, and the dichloromethane layer was washed with brine (100 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel column (eluent: EtOAc / MeOH=10 / 1) to give a2 as an oil (9.8 g, 24.4 mmol, 85%).

[0084] 1 HNMR (400 MHz, CDCl 3 ): 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, CDCl 3 ): S = 51.0;

[0085] 13 CNMR (100MHz, CDCl 3 ): 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] + .

[0086] Example 7

[0087] Preparation of 3-tert-butyl-5-fluoro-2,3-dihydrobenzo[1,3]oxophosphonate-4-ol (a3)

[0088] At 0°C, a2 (9.1 g, 22.7 mmol) and 1,2-dichloroethane (100 mL) were added to the reaction flask, cooled to 0°C, and BBr 3(29.7 g, 90.8 mmol). Heat the mixture to 60°C and keep it at 55-60°C with stirring for 2 hours. After the heat preservation is completed, MeOH (200 mL) is added dropwise to the mixture and concentrated. MeOH (200 mL × 3) is evaporated 3 times to obtain an oil. Add K 2 CO 3 (14.6 g, 105 mmol) and DMF (100 mL), heated to 50-60 ° C and stirred for 2 h, then cooled to 0 ° C and added with water (200 mL), and 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 water 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 to dryness, and purified on a silica gel column (eluent: EtOAc: MeOH = 4: 1) to obtain a3 as a white solid 5.0 g, with a yield of 90%.

[0089] 1 HNMR (400 MHz, CD 3 OD): 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, CDCl 3 ): S = 68.1;

[0090] 13 CNMR (100MHz, CD 3 OD): 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 / z 227[M+H] + .

[0091] Example 8

[0092] Preparation of (R)-3-tert-butyl-5-fluoro-2,3-dihydrobenzo[1,3]phosphonoxoate-4-ol (R-a3)

[0093] Add racemate a3 (4.5 g, 18.4 mmol), triethylamine (3.7 g, 27.4 mmol), dichloromethane (50 mL), add (+)-menthyl chloroformate 4.9 g, stir and warm to 25 ° C, and stir at 20-25 ° C for 2 hours, add water (100 mL) dropwise to quench, separate the dichloromethane layer, wash with brine, and add Na 2 SO 4 The residue was dried and purified by silica gel column (eluent: hexane: EtOAc = 1:1) to obtain 8.1 g of (+)-menthyl carbonate.

[0094] Add EtOH (160 mL) to 8 g of the above solid at 25°C, 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 pH to 3-4 with HCl, add 80 mL of dichloromethane for extraction. Separate the dichloromethane layer, wash with brine, dry with sodium sulfate, filter and concentrate, purify with silica gel column (eluent: EtOAc / MeOH=4:1), and obtain 1.8 g of white solid R-a3.

[0095] 1 HNMR (400 MHz, CD 3 OD): 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, CDCl 3 ): S = 68.6;

[0096] 13 CNMR (100MHz, CD 3 OD): 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] + .

[0097] Example 9

[0098] Preparation of (R)-3-tert-butyl-5-fluoro-4-methoxy-2H-benzo[1,3]phosphonate (R-a4)

[0099] Add R-a31.5g, THF 100mL, add potassium carbonate 1.7g, stir and heat to 20-25℃, add iodomethane 2.6g dropwise, heat to 30-40℃ after addition, keep warm and stir for 4-6 hours, cool, add water 100mL dropwise, add dichloromethane 100mL, separate the layers, separate the organic layer, extract the aqueous layer twice with dichloromethane 20mL×2, combine the organic layers, wash with brine 50mL, dry with sodium sulfate, and concentrate to obtain: R-a4, 1.51g, yield 95%.

[0100] 1 HNMR (400 MHz, CD 3 OD): 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, CDCl 3 ): S = 68.2;

[0101] 13 CNMR (100MHz, CD 3 OD): 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] + .

[0102] Example 10

[0103] Preparation of R-3-tert-butyl-2-(ethylphosphino)-5-fluoro-4-methoxy-2,3-dihydrobenzo[1,3]oxazole dioxide (R-a5)

[0104] Under nitrogen protection, add R-a41g, 3.9mmol, THF 40mL, cool to ≤-78℃, add LDA 2.4mL (2mol / L) dropwise, keep warm and stir at -78℃ for 1h, then add C 2 H 5 PCl 0.45g, control -82 ~ -78 ℃ and keep stirring for 1h, then heat to 20 ℃ and keep stirring for 1h, control the internal temperature ≤ 0 ℃, add 30% H 2 0 2The solution was added with 0.3 mg, and the resulting mixture was stirred at 0°C for 1 h. 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 (eluent: EtOAc / MeOH=5 / 2) to obtain 1.16 g of oily product R-a5 with a yield of 90%.

[0105] 1 HNMR (400 MHz, CD 2 Cl 2 ): 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, CDCl 3 ): S = 61.7 (d, 3 / polypropylene = 9.8 Hz), 60.9 (d, 3 / polypropylene = 9.8 Hz);

[0106] 13 CNMR (100MHz, CD 2 Cl 2 ): 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 (dd, / =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] + .

[0107] Embodiment 11

[0108] Preparation of R-3-tert-butyl-2,2-(dimethylphosphino)-5-fluoro-4-methoxy-2,3-dihydrobenzo[1,3]acetoxyphosphine (R-a6)

[0109] Under nitrogen, add 1 g of R-a5, 100 mL of toluene, 0.5 g of triethylamine, and 0.8 g of trichlorosilane. Stir and heat to 110-120°C. Keep warm for 12-16 hours. After the heat preservation, add 15 g of 30% NaOH solution. Cool the reaction solution to 50-60°C and stir for about 1 hour. Separate the toluene layer and extract the water layer twice with toluene (20 mL x 2). 2 S04 Dry in N 2 The residue was concentrated under reduced pressure and purified by a neutral alumina column (eluent: heptane / petroleum ether = 5:1) to obtain 0.86 g of white solid R-a6 in a yield of 90%.

[0110] 1 HNMR (400 MHz, CD 2 Cl 2 ): 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, CDCl 3 ): S = 61.7 (d, 3 / polypropylene = 9.8 Hz), 60.9 (d, 3 / polypropylene = 9.8 Hz);

[0111] 13 CNMR (100MHz, CD 2 Cl 2 ): 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, / =5.6Hz), 74.3 (dd, / =5 2.4, 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 / z303.1[M+H] + .

[0112] 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 principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for the selective asymmetric hydrogenation of 4-substituted-1,2-dihydroquinoline, characterized in that: In the presence of a chiral ligand and a rhodium catalyst, compound II is prepared from compound I by a selective asymmetric hydrogenation method. The 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 the 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 independently selected from O, S, P; X 2 Each independently selected from F, Cl, Br; R 1 Each independently selected from -CF3, -(C 1-6 )alkyl, -(C 3-10 )cycloalkyl, -(C 6-10 )aryl, -(5-11 membered)heterocarbocyclyl; R 2 Each independently selected from -PR 4 R 5 、-CH2PR 4 R 5 、-CH2OR 4 R 5 ; R 3 Each 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 independently selected from -(C 1-10 )alkyl, -CF3, -(C 3-10 ) carbocyclic group, -(5- to 11-membered) heterocarbocyclic group, -(C 6-10 )aryl, -(5- to 11-membered)heteroaryl, ferrocenyl; R 4 or R 5 Said-(C 3-10 ) carbocyclic group, -(5- to 11-membered) heterocarbocyclic group, -(C 6-10 )aryl, -(5 to 11 membered)heteroaryl may be optionally substituted by 1 to 3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -CF3; R 3 Said-(C 1-6 )alkyl may be optionally substituted by 1 to 3 substituents, each of which is independently selected from -(C 1-6 )alkyl, -(C 3-6 )cycloalkyl, -phenyl, -(5-6 membered)heteroaryl; R 3 Said-(C 3-6 )cycloalkyl, -(3-6 membered)heterocycloalkyl, -phenyl, -(5-6 membered)heteroaryl may be optionally 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, the 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 The X is selected from any one of hexafluorophosphate, hexafluoroantimonate, and tetrafluoroborate.

6. The selective asymmetric hydrogenation method according to claim 2, characterized in that The temperature for preparing compound II by selective asymmetric hydrogenation of compound I is 40-100°C and the pressure is 0.5-5MPa.

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 process according to any one of claims 1 to 7, characterized in that: The selective asymmetric hydrogenation method of 4-substituted-1,2-dihydroquinoline also includes a rearrangement reaction, wherein the rearrangement reaction uses compound II as a raw 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 mass fraction of the sulfuric acid is 98%; the mass ratio of the compound II to the sulfuric acid is 1:1.

51.

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

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