Method for synthesizing chiral dihydrobenzoxazinone derivative by manganese-catalyzed bionic asymmetric hydrogenation

Abstract

The invention discloses a method for synthesizing a chiral dihydrobenzoxazinone derivative through manganese-catalyzed bionic asymmetric hydrogenation. A catalytic system used in the method is high-yield metal manganese, phenanthridine, chiral phosphoric acid and a # imgabs0 # molecular sieve. The reaction can be carried out under the following conditions: the temperature is 25-50 DEG C; the solvent is dichloromethane; the pressure ranges from 200 psi to 1200 psi; the ratio of the substrate to the catalyst (phenanthridine, manganese and chiral phosphoric acid) is 100 / 10 / 5 / l; the catalyst is pentacarbonyl manganese bromide, phenanthridine and chiral phosphoric acid. According to the method for obtaining the corresponding chiral hydrogenated benzoxazinone derivative through hydrogenation of benzoxazinone, the enantiomeric excess can reach 95%. The method has the advantages of simple and practical operation, easily available raw materials, high enantioselectivity, good yield, green atom economy, environmental friendliness and the like.

Description

Technical Field

[0001] The invention relates to a method for synthesizing chiral dihydrobenzoxazinone derivatives by hydrogenating benzoxazinone derivatives with high enantioselectivity using a biomimetic catalytic system. Technical Background

[0002] NADPH is an important coenzyme for transferring protons and electrons. The internal reduction process in which it participates includes two parts: NADPH reduction substrate and NADPH regeneration. Figure 1 Based on the above basic principles, people have carried out bionics on this masterpiece of nature. The key is to imitate the coenzyme, regeneration catalyst and transfer catalyst.

[0003] In recent years, three generations of biomimetic chiral reduction systems have been developed. For the first generation of hydrogenation systems, there are two types: chiral NAD(P)H mimics plus achiral transhydrogenation reagents and achiral NAD(P)H mimics plus chiral transfer catalysts. In this system, NAD(P)H mimics reduce substrates to generate pyridine derivatives, and their in situ regeneration conditions are very harsh, which means that the system must use stoichiometric mimics. In order to solve this problem, Zhou Yonggui's research group developed a second generation hydrogenation system, which uses dihydrophenanthridine as NAD(P)H mimic and Ru as regeneration catalyst, and realizes biomimetic asymmetric hydrogenation of imines and nitrogen-containing aromatic heterocycles under mild conditions. (Reference 1: a) Chen, M.-W.; Wu, B.; Zhou, Y.-G. Org. Lett. 2016, 18, 4650; b) Chen, Q.-A.; Gao, K.; Zhou, Y.-G. Am. Chem. Soc. 2012, 134, 2442.). Based on this work, the Beller group used iron as a regeneration catalyst to regenerate dihydrophenanthridine, incorporating cheap metals as regeneration catalysts into the second-generation hydrogenation system, and made good progress in the asymmetric reduction of ketones and imines. However, the relatively harsh conditions of this type of iron catalytic system limit the scope of application. (Reference 2: a) Lu, L.-Q.; Li, Y.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2013, 52, 8382; b) Lu, L.-Q.; Li, Y.; Junge, K.; Beller, M. Am. Chem. Soc. 2015, 137, 2763.). For the second generation catalyst, although the system solves the problems of the first generation, due to the diversity of substrates, the chiral transfer catalyst needs to be re-screened for each type of substrate, and the limitation of the diversity of chiral transfer catalysts and the use of precious metals hinder the further application of this method. The third generation hydrogenation system uses a chiral renewable NAD(P)H analog. The Hu group uses a manganese complex as a regeneration catalyst to achieve the regeneration of the chiral renewable ferrocene skeleton NAD(P)H analog, and achieves the biomimetic asymmetric hydrogenation of imines, achieving good results. However, the complex needs to be prepared in advance and the cumbersome synthesis caused by the relatively complex structure of the NAD(P)H analog of the ferrocene skeleton limits its application, and the system cannot directly use Mn(CO)5Br as a regeneration catalyst to achieve the regeneration of the NAD(P)H analog. (Reference 3: Pan, H.-J.; H, X. Angew. Chem. Int. Ed. 2020, 59, 4942).

[0004] From the above examples, good results have been achieved in the regeneration of NAD(P)H analogs, but they face the problem of using precious metals and relatively harsh conditions. Therefore, developing a method that uses cheap metals to achieve the regeneration of NAD(P)H analogs and can achieve chiral biomimetic hydrogenation with high yield and high stereoselectivity is still a difficult and hot topic in current research. Summary of the invention

[0005] The purpose of the present invention is to provide a method for regenerating a manganese-catalyzed NAD(P)H analog and applying the method to synthesize chiral dihydrobenzoxazinone derivatives by biomimetic catalytic hydrogenation. The method is simple and practical to operate, the metal catalyst is cheap and readily available, the raw materials are readily available, the enantioselectivity is high, the yield is good, and the reaction has the advantages of green atom economy, environmental friendliness, and the like.

[0006] To achieve the above object, the technical solution of the present invention is as follows:

[0007] A method for synthesizing chiral dihydrobenzoxazinone derivatives by manganese-catalyzed bionic asymmetric hydrogenation, wherein the catalytic system is pentacarbonyl manganese bromide (Mn(CO)5Br), phenanthridine (PD) or its derivatives and chiral phosphoric acid, and the chiral dihydrobenzoxazinone derivatives are synthesized by asymmetric hydrogenation with the benzoxazinone derivatives as substrates; the reaction formula and conditions are as follows:

[0008]

[0009] Where:

[0010] Temperature: 25-50℃;

[0011] Solvent: one or more of dichloromethane (DCM), toluene (Toluene), chlorobenzene (PhCl), trifluorotoluene (PhCF3), 1,2-dichloroethane (DCE);

[0012] Hydrogen pressure: 200-1200 psi, preferably 500 psi;

[0013] Time: 16-72 hours;

[0014] Catalyst: pentacarbonyl manganese bromide, phenanthridine and chiral phosphoric acid;

[0015] Ar is an unsubstituted or substituted aromatic ring (e.g., a benzene ring), and the substituents on the aromatic ring are one, two, three, or four substituents selected from Cl, Me, and MeO, and the number of the substituents is 1-4;

[0016] R is C1-C20 (preferably C1-C4) alkyl, C2-C20 (preferably C2-C4) alkenyl, C2-C20 (preferably C2-C4) alkynyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, or thien-2-yl, the substituents on the benzene ring of the substituted phenyl or naphthyl are one, two, three or four substituents selected from CF3, Me, MeO, F, Cl and Br, and the number of substituents is 1-5; naphthyl is 1- or 2-naphthyl;

[0017] The chiral phosphoric acid is CPA, which is a chiral phosphoric acid with an octahydrobinaphthol skeleton or a binaphthol skeleton, Ar' is a 1-naphthyl group, an unsubstituted or substituted benzene ring, and the substituents on the benzene ring are one or two substituents selected from F, Cl, CF3, Me, and MeO, and the number of the substituents is 1-5;

[0018] The phenanthridine or its derivative is a simple phenanthridine, and the 8-position is one or more of phenanthridines substituted with methyl, methoxy or trifluoromethyl.

[0019] Based on the above technical solution, further, the steps of the method are as follows:

[0020] Pentacarbonyl manganese bromide, chiral phosphoric acid, phenanthridine and substrate 1 are added to a solvent and stirred at room temperature for 0-5 minutes; then hydrogen gas is introduced at 200-1200 psi, and the reaction is stirred at 25-50°C for 16-72 hours, and the target product is obtained by column chromatography.

[0021] Based on the above technical scheme, further, the chiral catalyst is chiral phosphoric acid, which is prepared by Suzuki coupling of chiral BINOL or H8-BINOL after iodination at the 3,3' position and the corresponding substituted phenylboronic acid ArB(OH)2. The molar ratio of the amount of the chiral phosphoric acid catalyst used in the reaction to the benzoxazinone derivative 1 is 0.05:1 to 0.02:1, preferably 0.01:1.

[0022] Based on the above technical solution, further, the phenanthridine or its derivative is a NAD(P)H analog required for the reaction, and the molar ratio of the amount used in the reaction to the benzoxazinone derivative 1 is 0.05:1 to 0.2:1, preferably 0.1:1.

[0023] Based on the above technical solution, further, the molar amount of pentacarbonyl manganese bromide is 11% to 10% of the molar amount of the hydrogenation substrate, preferably 5%.

[0024] Based on the above technical solution, further, the amount of the solvent used is 0.5 to 4 ml of solvent per 0.4 mmol of hydrogenation substrate 1.

[0025] Based on the above technical solution, further, the reaction further includes adding an additive, which is added before adding the solvent, and the additive is Molecular sieve( MS), Molecular sieve( MS) or Molecular sieve( MS), preferably Molecular sieve.

[0026] Based on the above technical solution, further, the amount of the additive is 4 to 6 mg of the additive per 0.4 mmol of the hydrogenation substrate 1.

[0027] Based on the above technical scheme, further, the reaction formula is that a benzoxazinone derivative is subjected to biomimetic catalytic asymmetric hydrogenation to obtain a corresponding chiral dihydrobenzoxazinone derivative, manganese is an abundant metal, the manganese precursor is pentacarbonyl manganese bromide, the biomimetic NAD(P)H analog is phenanthridine (10 mol%), the chiral phosphoric acid is (R)-CPA, Ar is 3,4,5-trifluorophenyl, the solvent is dichloromethane, the temperature is 30 degrees Celsius, the hydrogen pressure is 500 psi, the result is the best, and the enantiomeric excess can reach 95%.

[0028] The present invention has the following advantages:

[0029] 1. The reaction activity and enantioselectivity are high, the reaction is complete, the generated product is specific, the separation is convenient, and a high enantiomeric excess pure product can be obtained (enantiomeric excess can reach 95%).

[0030] 2. Various types of chiral hydrogenated benzoxazinone derivatives can be obtained.

[0031] 3. The catalyst is cheap and easy to obtain, and the reaction operation is simple and practical.

[0032] 4. The hydrogenation reaction conditions are mild and the reaction can be carried out at 30 degrees Celsius.

[0033] 5. Compared with the traditional synthesis method, this method can obtain a large number of chiral dihydrobenzoxazinone derivatives with a small amount of chiral catalyst, realizing chiral value-added. In addition, chiral dihydrobenzoxazinone derivatives with different configurations can be obtained by changing the configuration of chiral phosphoric acid, and the substrate range is relatively wide. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Schematic diagram of the bionic reduction cycle. DETAILED DESCRIPTION

[0035] The present invention is described in detail below by examples; however, the present invention is not limited to the following examples.

[0036] Example 1: Optimization of conditions

[0037] Add weighed pentacarbonyl manganese bromide (5 mol% of substrate dosage, 0.01 mmol, 2.8 mg) and chiral phosphoric acid CPA3 (2 mol% of substrate dosage, 0.004 mmol), phenanthridine (10 mol% of substrate dosage, 0.02 mmol, 3.6 mg), benzoxazinone 1a (0.2 mmol), 2.0 ml of solvent to the ampoule and stir for 0.5 minutes. Then put the ampoule into a stainless steel autoclave, pass hydrogen at 500 psi, and react at 30°C for 16 or 48 hours. Slowly release hydrogen, remove the solvent with a rotary evaporator and directly separate the pure product by column chromatography (the volume ratio of eluent petroleum ether, ethyl acetate and dichloromethane is 10:1:1), the reaction formula is as follows:

[0038]

[0039] The yield is the isolated yield, and the enantiomeric excess of the product is determined by chiral liquid chromatography, see Table 1.

[0040] Table 1. Screening of solvents, reaction times and chiral phosphoric acids [a]

[0041]

[0042]

[0043] [a] Reaction conditions: 1a (0.2 mmol), CPA3 (2 mol%), solvent (2.0 mL), phenanthridine (10 mol%), Mn(CO)5Br (5 mol%), H2 (500 psi), 30°C. [b] Reaction conversion determined by 1 H NMR spectroscopy. [c]. Ee was determined by chiral HPLC analysis. [d] CPA3 (5 mol%). [e] Solvent (1.0 mL). [f] 1a (0.4 mmol). [g] Add before adding solvent MS (5.0 mg).

[0044] Example 2: Synthesis of chiral dihydrobenzoxazinone derivatives by biomimetic catalytic asymmetric hydrogenation

[0045] Add weighed pentacarbonyl manganese bromide (0.02 mmol, 5.5 mg) and chiral phosphoric acid (0.004 mmol), phenanthridine (0.04 mmol, 7.2 mg), benzoxazinone 1 (0.4 mmol), 5 mg Molecular sieves, 1.0 ml of dichloromethane, stirred for 0.5 minutes. Then put the ampoule into a stainless steel autoclave, pass hydrogen at 500 psi, and react at 30°C for 48 hours. Slowly release hydrogen, remove the solvent with a rotary evaporator, and directly separate the pure product by column chromatography (the volume ratio of eluent petroleum ether, ethyl acetate and dichloromethane is 10:1:1). The reaction formula is as follows:

[0046]

[0047] (+)-(S)-3-Phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2a):

[0048] 84.0mg,93%yield,white solid,R f =0.37(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),92%ee,[α] 20 D 120.4, 117.0, 114.9, 59.3. HPLC: Chiralcel OD-H column, 230nm, 30°C, n-Hexane / i-PrOH=70 / 30, flow=0.7mL / min, retention time 10.3min and 13.6min (major).

[0049] (+)-(S)-8-Methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2b):

[0050] 89.0mg,93%yield,white solid,R f =0.52(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),91%ee,[α] 20 D 129.1, 127.7, 126.7, 124.7, 122.3, 112.7, 59.4, 15.6. HPLC: Chiralcel OD-H column, 230nm, 30°C, n-Hexane / i-PrOH=70 / 30, flow=0.7mL / min, retention time 13.4min and 14.5min (major).

[0051] (+)-(S)-7-Methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2c):

[0052] 76.5mg,80%yield,white solid,R f =0.52(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),91%ee,[α] 20 D 125.7,117.4,114.9,59.5,20.7.HPLC:Chiralcel OD-H column,230nm,30℃,n-Hexane / i-PrOH=70 / 30,flow=0.7mL / min,retention time 10.9 min and 16.5min(major).

[0053] (+)-(S)-6-Methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2d):

[0054] 47.8mg,50%yield,white solid,R f =0.44(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),77%ee,[α] 20 D 136.7,135.2,132.1,129.1,129.1,127.6,121.1,116.8,115.4,59.4,21.1.HPLC:Chiralcel OD-H column,230nm,30℃,n-Hexane / i-PrOH=70 / 30,flow=0.7mL / min,retention time 9.5min and 12.2min(major).

[0055] (+)-(S)-3-(p-Tolyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2e):

[0056] 87.6 mg,92%yield,white solid,R f=0.51(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),94%ee,[α] 20 D (100MHz,CDCl3)δ165.6,141.0,139.0,133.4,132.6,129.7,127.4,125.2,120.4,117.0,115.0,59.1,21.3.HPLC:Chiralcel OD-H column,230 nm,30℃,n-Hexane / i-PrOH=70 / 30,flow=0.7 mL / min,retention time 9.4 min and 22.5 min(major).

[0057] (-)-(S)-3-(2-Methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2f):

[0058] 101.5mg,99%yield,white solid,R f =0.46(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),92%ee, 4.30(s,1H),3.84(s,3H). 13 C NMR(100MHz,CDCl3)δ165.6,157.2,141.2,132.6,130.3,128.2,125.0,124.9,121.0,120.1,116.8,115.1,111.2,55.7,54.6.HPLC:Chiralcel OD-Hcolumn,230 nm,30℃,n-Hexane / i-PrOH=70 / 30,flow=0.7mL / min,retention time 12.2min and 16.0 min(major).

[0059] (+)-(S)-3-(3-Methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2g):

[0060] 96.5mg,95%yield,white solid,R f=0.34(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),91%ee,[α] 20 D MHz,CDCl3)δ165.3,160.0,140.8,137.9,132.4,130.0,125.3,120.3,119.7,116.9,115.0,114.5,113.0,59.1,55.3.HPLC:Chiralcel OD-H column,230nm,30℃,n-Hexane / i-PrOH=70 / 30,flow=0.7mL / min,retention time 16.4 min and 19.2 min(major).

[0061] (+)-(S)-3-(4-Methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2h):

[0062] 92.9mg,91%yield,white solid,R f =0.29(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),95%ee,[α] 20 D 160.06,140.99,132.59,128.82,128.39,125.15,120.38,116.98,114.87,114.39,58.82,55.35.HPLC:Chiralcel OD-H column,230 nm,30℃,n-Hexane / i-PrOH=70 / 30,flow=0.7mL / min,retention time 11.8 min and 26.0 min(major).

[0063] (+)-(S)-3-(3-Fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2i):

[0064] 85.6mg,88%yield,white solid,R f=0.56(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),91%ee,[α] 20 D CDCl3)δ164.8,δ163.0(d, 1 J F-C =247.5Hz),140.8,138.6(d, 3 J F-C =7.0Hz),132.0,130.6(d, 3 J F-C =8.2Hz),125.4,123.3(d, 4 J F-C =3.0Hz),120.7,117.1,116.1(d, 2 J F-C =21.1Hz),115.0,114.6(d, 2 J F-C =22.6Hz),58.(d, 4 J F-C =1.9Hz).HPLC:Chiralcel AD-H column,230nm,30℃C,n-Hexane / i-PrOH=80 / 20,flow=0.8mL / min,retention time 9.8min(major)and 13.3min.

[0065] (+)-(S)-3-(4-Fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2j):

[0066] 80.2mg,82%yield,white solid,R f =0.43(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),95%ee,[α] 20 D 248.3Hz),140.9,132.3,132.1,129.5(d, 3 J F-C =8.4Hz),125.3,120.7,120.7,117.0,116.0(d, 2 J F-C=21.7Hz),115.0,58.7.HPLC:Chiralcel AD-H column,230nm,30℃,n-Hexane / i-PrOH=80 / 20,flow=0.8mL / min,retention time 10.8 min(major)and 13.5 min.

[0067] (+)-(S)-3-(4-Chlorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2k):

[0068] 89.7mg,86%yield,white solid,R f =0.38(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),95%ee,[α] 20 D 129.3,129.1,125.4,120.8,117.2,115.1,58.8.HPLC:Chiralcel AD-H column,230 nm,30℃,n-Hexane / i-PrOH=80 / 20,flow=0.8mL / min,retention time 11.3min(major)and13.2min.

[0069] (+)-(S)-3-(4-Bromophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2l):

[0070] 99.3mg,82%yield,white solid,R f =0.37(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),95%ee,[α] 20 D 164.9,141.0,135.3,132.3,132.2,129.4,125.4,123.3,120.9,117.2,115.1,58.9.HPLC:Chiralcel AD-H column,230nm,30℃,n-Hexane / i-PrOH=80 / 20,flow=0.8mL / min,retention time 12.0min (major)and 13.2min.

[0071] (+)-(R)-3-(Thiophen-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2m):

[0072] 62.5mg,68%yield,white solid,R f =0.42(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),90%ee,[α] 20 D CDCl3)δ164.2,141.0,138.7,131.6,127.2,127.0,126.6,125.4,121.0,117.1,115.6,55.3.HPLC:Chiralcel AD-H column,230 nm,30℃,n-Hexane / i-PrOH=80 / 20,flow=0.8mL / min,retention time 11.8 min(major)and 27.2 min.

[0073] (+)-(S)-3-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2n):

[0074] 54.4mg,83%yield,white solid,R f =0.37(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),56%ee, 125.0,120.6,117.0,115.1,50.7,17.3.HPLC:Chiralcel OD-H column,230nm,30℃,n-Hexane / i-PrOH=70 / 30,flow=0.7 mL / min,retention time 7.1min and 8.1 min(major).

[0075] (+)-(S)-3-Butyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2o):

[0076] 76.9mg,94%yield,white solid,R f =0.42(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),79%ee,[α] 20 D 13 C NMR(100MHz,CDCl3)δ166.8,141.2,132.5,125.1,120.4,116.9,115.2,55.0,31.1,27.5,22.5,14.0.HPLC:Chiralcel OD-H column,230nm,30℃,n-Hexane / i-PrOH=70 / 30,flow=0.7mL / min,retention time 16.6min and 21.5min(major).

[0077] (+)-(S)-3-Phenethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2p):

[0078] 86.8mg,86%yield,white solid,R f =0.53(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),90%ee,[α] 20 D 2.34-2.24(m,1H),2.132.02(m,1H). 13C NMR(100MHz,CDCl3)δ166.5,141.1,140.4,132.2,128.8,128.5,126.5,125.0,120.4,116.8,115.2,54.5,32.7,31.8.HPLC:Chiralcel OD-Hcolumn,230nm,30℃,n-Hexane / i-PrOH=70 / 30,flow=0.7mL / min,retention time11.7min and 17.1min(major).

[0079] (+)-(S)-6-Chloro-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2q):

[0080] 80.2mg,77%yield,white solid,R f =0.61(hexanes / ethyl acetate / dichoromethane 20 / 3 / 2),87%ee,[α] 20 D 118.1,114.8,58.9.HPLC:Chiralcel OD-H column,230nm,30℃,n-Hexane / i-PrOH=70 / 30,flow=0.7mL / min,retention time 10.0min and 14.1min(major).

[0081] (+)-(S)-6-Methoxy-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one(2r):

[0082] 85.7mg,84%yield,yellow solid,mp 119-120℃,new compound,R f =0.32(hexanes / ethyl 3H). 13C NMR (100MHz, CDCl3) δ165.4,157.1,136.6,135.2,133.1,129.1,129.1,127.5,117.6,105.1,100.7,59.2,55.7.HPLC:Chiralcel AD-3 column,230nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=0.7mL / min,retention time 47.3min(major)and 51.2min.HRMSCalculated for C 15 H 13 NO3[M+H] + 256.0968,found:256.0971.

[0083] The yield was isolated yield and the enantiomeric excess of the product was determined by chiral liquid chromatography.

[0084] The present invention conducts asymmetric hydrogenation of benzoxazinone derivatives to obtain corresponding dihydrobenzoxazinone derivatives, and the enantiomeric excess of the derivatives can reach 95%. The present invention is simple and practical to operate, has high enantioselectivity, good yield, and the reaction has the advantages of atom economy, environmental friendliness, etc.

Claims

1. A method for synthesizing chiral dihydrobenzoxazinone derivatives by manganese-catalyzed biomimetic asymmetric hydrogenation, characterized in that: The catalytic system is pentacarbonyl manganese bromide, phenanthridine or its derivatives and chiral phosphoric acid. The benzoxazinone derivative is used as a substrate to synthesize the chiral dihydrobenzoxazinone derivative by asymmetric hydrogenation. The reaction formula and conditions are as follows: Where: Temperature: 25-50°C; Solvent: one or more of dichloromethane, toluene, chlorobenzene, trifluorotoluene, and 1,2-dichloroethane; Hydrogen pressure: 200-1200psi; Time: 16-72 hours; Ar is an unsubstituted or substituted aromatic ring, the substituents on the aromatic ring are one, two, three or four of Cl, Me and MeO, and the number of the substituents is 1-4; R is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, or thien-2-yl, the substituents on the substituted phenyl or naphthyl benzene ring are one, two, three or four of CF3, Me, MeO, F, Cl, Br, and the number of substituents is 1-5; naphthyl is 1- or 2-naphthyl; The chiral phosphoric acid is CPA, Ar' is a 1-naphthyl group, an unsubstituted or substituted benzene ring, the substituents on the benzene ring are one or two of F, Cl, CF3, Me, MeO, and the number of substituents is 1-5; The phenanthridine derivatives are one or more phenanthridines substituted with a methyl group, a methoxy group or a trifluoromethyl group at the 8-position.

2. The method according to claim 1, characterized in that: The steps of the method are as follows: Pentacarbonyl manganese bromide, chiral phosphoric acid, phenanthridine or its derivative and substrate 1 are added to a solvent and stirred at room temperature for 0-5 minutes; then hydrogen gas is introduced at 200-1200 psi, and the reaction is stirred at 25-50°C for 16-72 hours, and the target product is obtained by column chromatography.

3. The method according to claim 1 or 2, characterized in that: The molar ratio of the chiral catalyst chiral phosphoric acid to the benzoxazinone derivative is 0.005:1 to 0.02:

1.

4. The method according to claim 1 or 2, characterized in that: The molar ratio of the phenanthridine or its derivative to the imine of the benzoxazinone derivative is 0.05:1 to 0.2:

1.

5. The method according to claim 1 or 2, characterized in that: The molar amount of pentacarbonyl manganese bromide is 1% to 10% of the molar amount of the hydrogenation substrate 1.

6. The method according to claim 1 or 2, characterized in that: The amount of the solvent used is 0.5 to 4 ml per 0.4 mmol of the hydrogenation substrate 1.

7. The method according to claim 1 or 2, characterized in that: The reaction further comprises adding an additive, wherein the additive is Molecular sieves, Molecular sieve or Molecular sieve.

8. The method according to claim 7, characterized in that: The additive is used in an amount of 4 to 6 mg per 0.4 mmol of the hydrogenation substrate 1.

9. The method according to claim 1, characterized in that: The manganese precursor is pentacarbonyl manganese bromide, the biomimetic NAD(P)H analog is phenanthridine, the molar ratio of phenanthridine and the imine of the benzoxazinone derivative is 0.1:1, the chiral phosphoric acid is (R)-CPA, the Ar is 3,4,5-trifluorophenyl, the solvent is dichloromethane, the temperature is 30 degrees Celsius, and the hydrogen pressure is 500psi.

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