A method for preparing a compound containing a hydantoin skeleton and having optical activity

Abstract

The invention discloses a method for synthesizing a compound containing a hydantoin skeleton with optical activity, comprising the steps of: directly adding L-homoproline, a derivative of acetophenone hydrazone, and copper acetylacetonate to an organic solvent, acetonitrile, heating an oil bath to 90-120°C under a nitrogen atmosphere, reacting for 12-24 hours, and post-processing to obtain the optically pure hydantoin derivative. The method utilizes simple, easy-to-prepare, stable acetophenone hydrazone derivatives and L-homoproline as reaction substrates, and in the absence of an oxidant, a strong acid, and a strong base, smoothly realizes the one-step preparation of an optically pure hydantoin skeleton via a tandem cyclization reaction process under a copper catalysis system. The conversion has excellent atom economy and step economy, a wide substrate range, and good functional group compatibility, and provides a new and efficient synthesis method for the preparation of optically pure derivatives containing a hydantoin skeleton with biological activity.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a compound having an optically active hydantoin skeleton through a tandem cyclization reaction of an acetophenone hydrazone derivative and an L-homoproline compound. Background Art

[0002] Hydantoin is a very important class of nitrogen-containing heterocyclic compounds, widely found in pharmaceutical, bioactive, and functional molecules, and has extensive applications in both medicine and materials. For example, the nonsteroidal antiandrogen nilutamide and the bactericide iprodione both contain a hydantoin skeleton. Furthermore, the introduction of chirality into the hydantoin skeleton can also serve as a chiral auxiliary to achieve asymmetric transformations. Therefore, the development of efficient methods for the preparation of optically pure hydantoin skeletons is of great practical significance. In this invention, we propose, through retrosynthetic analysis, the construction of a hydantoin skeleton containing a chiral carbon through a tandem cyclization reaction of L-homoproline and an isocyanate intermediate. This invention utilizes readily available L-homoproline and an acetophenonehydrazone derivative as substrates, copper acetylacetonate as an additive, and acetonitrile as a reaction solvent. By controlling the temperature at 90-120°C and reacting under a nitrogen atmosphere for 9 hours, the target product containing the hydantoin skeleton is obtained in excellent yield and optical purity. This transformation does not require additional oxidants, has excellent chemical selectivity and step economy, and provides a new green and efficient synthetic method for the preparation of hydantoin skeletons containing chiral carbon. Summary of the Invention

[0003] The present invention provides a simple and efficient copper-catalyzed one-pot synthesis method for preparing an optically pure hydantoin skeleton via a tandem cyclization reaction of L-homoproline and an acetophenone hydrazone substrate. The transformation has excellent atom economy and step economy, a wide substrate range, and good functional group compatibility.

[0004] A method for synthesizing an optically active compound containing a hydantoin skeleton comprises the following steps: adding L-homoproline, an acetophenone hydrazone derivative, and copper acetylacetonate to an organic solvent, acetonitrile, heating to 90-120° C. under nitrogen atmosphere for reaction for 12-24 hours, and after completion of the reaction, separating the obtained compound by column chromatography to obtain the corresponding optically pure hydantoin skeleton;

[0005] The structure of the acetophenone hydrazone derivative is shown in formula (II):

[0006]

[0007] The structure of the L-homoproline is shown in formula (III):

[0008]

[0009] The structure of the optically pure hydantoin is shown in formula (I):

[0010]

[0011] In formulas (I) to (III), R 1 Selected from methoxy, phenoxy, halogen, nitro, thiophene, furan, naphthyl, etc.;

[0012] R 2 Selected from methyl, ethyl, propyl, etc.;

[0013] In the present invention, derivatives of L-homoproline and acetophenone hydrazone, which are easily available, are directly used as reaction substrates. In the absence of oxidants, strong acids and strong bases, a copper-catalyzed tandem cyclization reaction is used to efficiently prepare an optically pure hydantoin skeleton in one pot.

[0014] Preferably, the organic solvent is acetonitrile.

[0015] Preferably, the reaction temperature is 90-120° C., and the reaction time is 12-24 h.

[0016] Compared with the prior art, the beneficial effects of the present invention are embodied in:

[0017] (1) The reaction conditions for this transformation are simple and mild, and it can proceed smoothly without the presence of oxidants, strong acids, or strong bases.

[0018] (2) The synthetic method of the present invention is simple to operate, has excellent chemical selectivity and reactivity, a wide substrate range and good functional group compatibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 1 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 1;

[0020] Figure 2 1H and 1C spectra of the compound obtained in Example 2;

[0021] Figure 3 1H and 1C spectra of the compound obtained in Example 3;

[0022] Figure 4 The hydrogen spectrum, carbon spectrum and fluorine spectrum of the compound obtained in Example 4 are shown below:

[0023] Figure 5 1H and 1C spectra of the compound obtained in Example 5;

[0024] Figure 6 1H and 1C spectra of the compound obtained in Example 6;

[0025] Figure 7 1H and 1C spectra of the compound obtained in Example 7;

[0026] Figure 8 1H and 1C spectra of the compound obtained in Example 8;

[0027] Figure 9 1H and 1C spectra of the compound obtained in Example 9;

[0028] Figure 10 1H and C spectroscopy of the compound obtained in Example 10;

[0029] Figure 11 1H and C 1O spectra of the compound obtained in Example 11;

[0030] Figure 12 1H and C spectroscopy of the compound obtained in Example 12;

[0031] Figure 13 1H and C 1O spectra of the compound obtained in Example 13;

[0032] Figure 14 The liquid chromatography conditions are as follows: Daicel Chiralpak IA, n-hexane / i-PrOH=80 / 20, Flow rate=0.80 mL / min, 25°C, UV=254 nm, t R =21.0min(major)and t R =23.7min(minor);

[0033] Figure 15 The liquid chromatography conditions are as follows: Daicel Chiralpak IA, n-hexane / i-PrOH=92 / 8, Flow rate=1.00 mL / min, 25°C, UV=254 nm, t R =82.3min(major)and t R =92.0min(minor).

[0034] Figure 16 The liquid chromatography conditions are as follows: Daicel Chiralpak IA, n-hexane / i-PrOH=80 / 20, Flow rate=0.80 mL / min, 25°C, UV=254 nm, t R=27.7min(major)and t R =30.3min(minor).

[0035] Proton spectra were measured on a 500 MHz or 400 MHz NMR instrument. Carbon spectra were measured on a 125 MHz NMR instrument. All tests were performed at room temperature using tetramethylsilane as the internal standard and deuterated chloroform as the sample. DETAILED DESCRIPTION

[0036] The present invention will be further described below with reference to specific embodiments. The following specific embodiments are all optimal implementations of the present invention.

[0037] Examples 1 to 13

[0038] According to the raw material ratios in Table 1, an acetophenone hydrazone derivative (II, 0.3 mmol), L-homoproline (III, 0.2 mmol), copper acetylacetonate as a catalyst (0.1 mmol), and acetonitrile (2 mL) as an organic solvent were added to a 25 mL sealed tube. The mixture was stirred uniformly and reacted in an oil bath (90-120°C) under a nitrogen atmosphere for 12-24 hours. After the reaction was completed according to the reaction conditions in Table 2, the mixture was cooled, the organic phase was extracted, and dried over sodium sulfate. The sample was then washed with silica gel and purified by column chromatography to obtain the corresponding optically pure hydantoin skeleton (I). The reaction process is shown below:

[0039]

[0040] Table 1 Raw material ratios of Examples 1 to 13

[0041]

[0042] Table 2 Reaction conditions and reaction results of Examples 1 to 13

[0043]

[0044]

[0045] In Table 1 and Table 2, T is the reaction temperature and t is the reaction time.

[0046] The structural confirmation data of some compounds prepared in Examples 1 to 13 are as follows:

[0047]

[0048] (S,E)-2-((1-phenylethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-1):White solid(45.6mg,84%,99.0%ee).mp:128-129℃,[α] D 25 =-0.526(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,60 / 1). 1 H NMR(400MHz,CDCl3)δ7.92-7.90(m,2H),7.47-7.44(m,1H),7.41-7.38(m,2H),4.21(d,J=13.6Hz,1H),3.88(d,J=10.4Hz,1H),2.88(t,J=12.4Hz,1H),2.28-2.25(m,4H),2.00(d,J=11.6Hz,1H),1.76(d,J=12.4Hz,1H),1.53-1.39(m,3H). 13 C NMR(125MHz,CDCl3)δ174.9,167.7,151.9,136.3,131.4,128.4,127.7,56.6,39.6,28.0,25.0,22.7,17.8.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 15 H 18 N3O2272.1394;Found 272.1404.HPLC conditions:Daicel Chiralpak IA,n-hexane / i-PrOH=80 / 20,Flow rate=0.80mL / min,25℃,UV=254nm,t R =21.0min(major)and t R =23.7min(minor).

[0049]

[0050] (S,E)-2-((1-(4-methoxyphenyl)ethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-2):White solid(51.8mg,86%,92.4%ee).mp:147-148℃,[α] D 25 =-0.455(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,50 / 1). 1 H NMR(400MHz,CDCl3)δ7.89(d,J=8.4Hz,2H),6.89(d,J=8.8Hz,2H),4.21(dd,J1=14.4Hz,J2=4.0Hz,1H),3.89-3.82(m,4H),2.88(t,J=11.2Hz,1H),2.28-2.24(m,4H),2.01(d,J=11.2Hz,1H),1.76(d,J=12.4Hz,1H),1.50-1.39(m,3H). 13 C NMR(125MHz,CDCl3)δ174.3,167.9,162.3,152.0,129.4,128.8,113.7,56.6,55.4,39.6,28.0,25.0,22.7,17.3.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 16 H 20 N3O3 302.1499;Found 302.1489.

[0051] HPLC conditions:Daicel Chiralpak IA,n-hexane / i-PrOH=92 / 8,Flow rate=1.00mL / min,25℃,UV=254nm,t R =82.3min(major)and t R =92.0min(minor).

[0052]

[0053] (S,E)-2-((1-(4-phenoxyphenyl)ethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-3):White solid(56.6mg,78%,99.2%ee).mp:136-137℃,[α] D 25 =-0.370(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:petroleum dichloromethane / ethyl acetate,60 / 1). 1 H NMR(500MHz,CDCl3)δ7.91(d,J=8.0Hz,2H),7.37-7.34(m,2H),7.16-7.13(m,1H),7.03(d,J=8.0Hz,2H),6.98(d,J=8.0Hz,2H),4.22(dd,J1=14.0Hz,J2=4.5Hz,1H),3.88(dd,J1=12Hz,J2=4.0Hz,1H),2.88(td,J1=13.0Hz,J2=3.5Hz,1H),2.29-2.26(m,4H),2.01(d,J=13.0Hz,1H),1.76(d,J=12.5Hz,1H),1.53-1.40(m,3H). 13 C NMR(125MHz,CDCl3)δ174.1,167.8,160.5,156.1,152.0,130.8,129.9,129.6,124.1,119.7,117.8,56.6,39.7,28.0,25.0,22.7,17.5.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 21 H 22 N3O3 364.1656;Found 364.1632.HPLCconditions:Daicel Chiralpak IA,n-hexane / i-PrOH=80 / 20,Flow rate=0.80 mL / min,25℃,UV=254nm,t R =27.7min(major)and t R =30.3min(minor).

[0054]

[0055] (S,E)-2-((1-(4-fluorophenyl)ethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-4):White solid(46.6mg,80%,97.3%ee).mp:84-85℃,[α] D 25 =-0.450(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,60 / 1). 1 H NMR(400MHz,CDCl3)δ7.95-7.91(m,2H),7.10-7.06(m,2H),4.21(dd,J1=14.4Hz,J2=4.4Hz,1H),3.88(dd,J1=11.2Hz,J2=4.4Hz,1H),2.89(td,J1=12.4Hz,J2=3.6Hz,1H),2.29-2.24(m,4H),2.01(d,J=9.2Hz,1H),1.77(d,J=12.4Hz,1H),1.54-1.40(m,3H). 13 C NMR(125MHz,CDCl3)δ173.5,167.7,164.8(d,J C-F =251.2Hz),151.8,132.5,129.9(d,J C-F =8.8Hz),115.5(d,J C-F =22.5Hz),56.6,39.6,28.0,25.0,22.7,17.7. 19 F NMR(471MHz,CDCl3)δ-108.5.HRMS(ESI-TOF)m / z:[M+H] + Calcd forC 15 H 17 FN3O2 290.1299;Found 290.1312.HPLC conditions:Daicel Chiralpak IA,n-hexane / i-PrOH=92 / 8,Flow rate=1.00mL / min,25℃,UV=254nm,t R =41.8min(major)and t R=45.5min(minor).

[0056]

[0057] (S,E)-2-((1-(4-chlorophenyl)ethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-5):White solid(54.9mg,90%,96.3%ee).mp:126-127℃,[α] D 25 =-0.399(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,60 / 1). 1 H NMR(400MHz,CDCl3)δ7.86(d,J=8.0Hz,2H),7.37(d,J=8.4Hz,2H),4.22(dd,J1=14.0Hz,J2=4.4Hz,1H),3.88(dd,J1=11.6Hz,J2=4.4Hz,1H),2.89(t,J=12.0Hz,1H),2.29-2.26(m,4H),2.01(d,J=7.2Hz,1H),1.77(d,J=12.0Hz,1H),1.55-1.40(m,3H). 13 C NMR(125MHz,CDCl3)δ173.3,167.6,151.8,137.6,134.7,129.0,128.7,56.6,39.7,28.0,25.0,22.7,17.7.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 15 H 17 ClN3O2 306.1004;Found 306.0997.HPLC conditions:DaicelChiralpak IA,n-hexane / i-PrOH=90 / 10,Flowrate=1.00mL / min,25℃,UV=254nm,t R =41.8min(major)and t R =45.1min(minor).

[0058]

[0059] (S,E)-2-((1-(4-bromophenyl)ethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-6):White solid(60.9mg,87%,94.2%ee).mp:126-127℃,[α] D 25 =-0.415(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,60 / 1). 1 H NMR(400MHz,CDCl3)δ7.79(d,J=8.0Hz,2H),7.53(d,J=8.4Hz,2H),4.22(dd,J1=14.0Hz,J2=4.4Hz,1H),3.89(dd,J1=11.6Hz,J2=4.0Hz,1H),2.89(td,J1=12.8Hz,J2=3.2Hz,1H),2.29-2.25(m,4H),2.01(d,J=6.8Hz,1H),1.77(d,J=12.4Hz,1H),1.54-1.40(m,3H). 13 C NMR(125MHz,CDCl3)δ173.5,167.6,151.8,135.2,131.6,129.2,126,56.6,39.7,28.0,25.0,22.7,17.7.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 15 H 17 BrN3O2350.0499;Found 350.0521.HPLC conditions:DaicelChiralpak IA,n-hexane / i-PrOH=80 / 20 Flow rate=1.00mL / min,25℃,UV=254nm,t R =23.7min(major)and t R =26.3min(minor).

[0060]

[0061] (S,E)-2-((1-(4-iodophenyl)ethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-7):White solid(55.7mg,70%,97.1%ee).mp:165-166℃,[α] D 25 =-0.338(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,60 / 1). 1 H NMR(500MHz,CDCl3)δ7.76(d,J=8.0Hz,2H),7.65(d,J=8.0Hz,2H),4.24(dd,J1=14.0Hz,J2=5.0Hz,1H),3.90(dd,J1=12.0Hz,J2=4.0Hz,1H),2.90(td,J1=12.5Hz,J2=3.5Hz,1H),2.30-2.26(m,4H),2.03(d,J=9.6Hz,1H),1.79(d,J=10.0Hz,1H),1.64-1.42(m,3H). 13 C NMR(125MHz,CDCl3)δ173.6,167.6,151.8,137.6,135.8,129.2,98.5,56.6,39.7,28.0,25.0,22.7,17.6.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 15 H 16 IN3O2Na420.0179;Found 420.0187.HPLC conditions:Daicel Chiralpak IA,n-hexane / i-PrOH=70 / 30,Flow rate=0.80mL / min,UV=254nm,t R =23.5min(major)and t R =30.8min(minor).

[0062]

[0063] (S,E)-2-((1-(4-nitrophenyl)ethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-8):White solid(40.6 mg,64%,95.0%ee).mp:134-135℃,[α] D 25 =-0.351(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,60 / 11). 1 H NMR(500MHz,CDCl3)δ8.23(d,J=9.0Hz,2H),8.07(d,J=9.0Hz,2H),4.23-4.19(dd,J1=12.0Hz,J2=4.0Hz,1H),3.92(dd,J1=12.0Hz,J2=4.0Hz,1H),2.90(td,J1=13.5Hz,J2=4.5Hz,1H),2.32-2.26(m,4H),2.02(d,J=12.0Hz,1H),1.78(d,J=13.5Hz,1H),1.49-1.44(m,3H). 13 C NMR(125MHz,CDCl3)δ171.9,167.3,151.5,149.4,142.0,128.7,123.5,56.7,39.6,27.9,24.9,22.7,18.2.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 15 H 17 N4O4 317.1244;Found 317.1236.HPLC condition:Daicel Chiralpak IA,n-hexane / i-PrOH=80 / 20,Flow rate=0.80mL / min,25℃,UV=254nm,t R =39.7min(major)and t R =45.9min(minor).

[0064]

[0065] (S,E)-2-((1-(p-tolyl)propylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-9):Colourless oil(44.4mg,74%,98.2%ee).[α] D 25 =-0.384(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,60 / 1). 1 H NMR(500MHz,CDCl3)δ7.75(d,J=7.5Hz,2H),7.21(d,J=8.0Hz,2H),4.22(dd,J1=13.5Hz,J2=4.0Hz,1H),3.89(dd,J1=12.0Hz,J2=4.0Hz,1H),2.89(td,J1=13.0Hz,J2=3.5Hz,1H),2.64(q,J=7.5Hz,2H),2.37(s,3H),2.27(d,J=13.5Hz,1H),2.01(d,J=13.0Hz,1H),1.76(d,J=13.0Hz,1H),1.53-1.40(m,3H),1.12(t,J=7.5Hz,3H). 13 C NMR(125MHz,CDCl3)δ181.6,168.1,152.0,141.7,132.2,129.2,128.1,56.7,39.6,28.0,25.0,23.8,22.7,21.5,11.7.HRMS(ESI-TOF)m / z:[M+Na] + Calcdfor C 17 H 21 N3O2Na 322.1526;Found 322.1520.HPLC conditions:Daicel Chiralpak IA,n-hexane / i-PrOH=80 / 20,Flow rate=0.80mL / min,25℃,UV=254nm,t R =25.1min(major)and t R =19.2min(minor).

[0066]

[0067] (S,E)-2-((1-phenylbutylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-10):Colourless oil(36.1mg,60%,92.0%ee).[α] D 25 =-0.340(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,60 / 1). 1 H NMR(500MHz,CDCl3)δ7.85(d,J=7.5Hz,2H),7.48-7.45(m,1H),7.42-7.39(m,2H),4.23(dd,J1=14.0Hz,J2=5.0Hz,1H),3.89(dd,J1=12.0Hz,J2=4.0Hz,1H),2.90(td,J1=13.0Hz,J2=3.5Hz,1H),2.62(t,J=7.5Hz,2H),2.28(d,J=13.0Hz,1H),2.02(d,J=13.0Hz,1H),1.79-1.76(m,1H),1.56-1.49(m,3H),1.47-1.39(m,2H),0.90(t,J=7.5Hz,3H). 13 C NMR(125MHz,CDCl3)δ180.6,168.0,152.0,135.5,131.2,128.5,128.0,56.6,39.7,32.8,28.1,25.1,22.7,20.6,14.3.HRMS(ESI-TOF)m / z:[M+Na] + Calcd forC 17 H 21 N3O2Na 322.1526;Found 322.1520.HPLC conditions:Daicel Chiralpak IA,n-hexane / i-PrOH=80 / 20,Flow rate=0.80mL / min,25℃,UV=254nm,t R =19.0min(major)and t R =16.7min(minor).

[0068]

[0069] (S,E)-2-((1-(naphthalen-2-yl)ethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-11):White solid(50.9 mg,79%,91.7%ee).mp:210-211℃,[α] D 25 =-0.435(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,60 / 1). 1 H NMR(400MHz,CDCl3)δ8.32(s,1H),8.14(d,J=8.8Hz,1H),7.88(d,J=7.6Hz,1H),7.85-7.83(m,2H),7.55-7.48(m,2H),4.23(dd,J1=14.8Hz,J2=4.0Hz,1H),3.92(dd,J1=11.6Hz,J2=4.0Hz,1H),2.90(t,J=10.4Hz,1H),2.41(s,3H),2.30-2.27(d,J=11.6Hz,1H),2.03-2.00(d,J=10.0Hz,1H),1.77(d,J=12.0Hz,1H),1.54-1.42(m,3H). 13 C NMR(125MHz,CDCl3)δ174.5,167.7,151.9,134.8,133.7,132.7,129.0,128.6,128.1,127.7,127.6,126.5,124.2,56.7,39.7,28.0,25.0,22.7,17.8.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 19 H 20 N3O2 322.1550;Found322.1522.HPLC conditions:Daicel Chiralpak IA,n-hexane / i-PrOH=80 / 20,Flow rate=0.80mL / min,25℃,UV=254nm,t R =31.3min(major)and t R =28.6min(minor).

[0070]

[0071] (S,E)-2-((1-(thiophen-2-yl)ethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-12):White solid(47.8mg,86%,90.8%ee).mp:161-162℃,[α] D 25 =-0.415(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,50 / 1). 1 H NMR(500MHz,CDCl3)δ7.53(d,J=3.5Hz,1H),7.47(d,J=5.0Hz,1H),7.07-7.05(m,1H),4.20(dd,J1=13.5Hz,J2=4.5Hz,1H),3.86(dd,J1=13.0Hz,J2=4.0Hz,1H),2.87(td,J1=13.0Hz,J2=3.5Hz,1H),2.29-2.23(m,4H),2.00(d,J=9.5Hz,1H),1.75(d,J=13.0Hz,1H),1.52-1.39(m,3H). 13 C NMR(125MHz,CDCl3)δ167.7,164.9,151.8,150.5,145.7,115.1,112.1,56.6,39.7,28.0,25.0,22.7,16.5.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 13 H 15 N3O2SNa 300.0777;Found300.0790.HPLC conditions:Daicel Chiralpak IA,n-hexane / i-PrOH=80 / 20,Flow rate=0.80mL / min,25℃,UV=254nm,t R =23.7min(major)and t R =29.2min(minor).

[0072]

[0073] (S,E)-2-((1-(furan-2-yl)ethylidene)amino)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(I-13):White solid(48.7mg,93%,82.2%ee).mp:130-131℃,[α] D 20 =-0.480(c=25mg / 10mL,DCM).Column chromatography on silica gel(Eluent:dichloromethane / ethyl acetate,50 / 1). 1 H NMR(500MHz,CDCl3)δ7.56(s,1H),7.06(d,J=3.5Hz,1H),6.51-6.50(m,1H),4.22(dd,J1=13.5Hz,J2=4.5Hz,1H),3.88(dd,J1=12.0Hz,J2=4.5Hz,1H),2.89(td,J1=13.0Hz,J2=3.5Hz,1H),2.29-2.23(m,4H),2.02(d,J=8.0Hz,1H),1.77(d,J=12.5Hz,1H),1.5-1.39(m,3H). 13 C NMR(125MHz,CDCl3)δ167.7,164.9,151.8,150.5,145.7,115.1,112.1,56.6,39.7,28.0,25.0,22.7,16.5.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 13 H 16 N3O3 262.1186;Found 262.1184.HPLCconditions:Daicel Chiralpak IA,n-hexane / i-PrOH=80 / 20,Flow rate=0.80mL / min,25℃,UV=254nm,t R =21.5min(major)and t R =29.6min(minor)。

Claims

1. A method for synthesizing a compound containing a hydantoin skeleton having optical activity, characterized in that: The method comprises the following steps: adding an acetophenone hydrazone derivative, L-homoproline and copper acetylacetonate to an organic solvent, controlling the temperature at 90 to 120° C. under a nitrogen atmosphere for reaction for 12 to 24 hours, and after the reaction is complete, post-treating to obtain an optically active hydantoin product; The structure of the acetophenone hydrazone derivative is shown in formula (II): The structure of the L-homoproline is shown in formula (III): The structure of the optically active hydantoin product is shown in formula (I): In formulas (I) to (III), R 1 is selected from methoxy, phenoxy, halogen, nitro, thiophene, furan or naphthyl; R 2 Selected from methyl, ethyl or propyl.

2. The method for synthesizing a compound containing a hydantoin skeleton having optical activity according to claim 1, wherein: The organic solvent is acetonitrile.

3. The method for synthesizing the optically active compound containing a hydantoin skeleton according to claim 1, wherein The reaction conditions do not require ligands, oxidants, strong acids or strong bases.

4. The method for synthesizing the optically active hydantoin skeleton-containing compound according to claim 1, wherein The optically active hydantoin skeleton is one of the following compounds:

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