Chiral pentafluorophenylurea compound as well as preparation method and application thereof

Abstract

The invention discloses a chiral pentafluorophenyl urea compound as well as a preparation method and application thereof, and relates to a preparation method and application of a synthetic drug. The synthesized chiral product is used for synthesizing GABA analogue drugs such as (R)-pheibut, (R)-baclofen and the like, an effective method is provided for chiral drug synthesis, and the application of the chiral product in catalysis of asymmetric addition reaction of dithiomalonate and nitroolefin in a water-containing medium is provided. When pentafluorophenylurea catalyzes an asymmetric addition reaction of dithiomalonate and nitroolefin in a water-containing solvent, due to a hydrophobic hydration effect, the reaction rate and stereoselectivity of pentafluorophenylurea are remarkably improved compared with those of pentafluorophenylurea in an organic solvent, the dosage of a catalyst can be remarkably reduced, and green chemical requirements are met.

Description

Technical Field

[0001] The invention relates to a chemical drug and a preparation method and application thereof, in particular to a chiral pentafluorophenyl urea compound and a preparation method and application thereof. Background Art

[0002] Using water as a solvent in chemical reactions not only ensures safety and non-toxicity, but also increases the reaction rate in many cases. [Reviews on chemical reactions using water as a solvent: a) A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725; b) RN Butler, AG Coyne, Chem. Rev. 2010, 110, 6302; c) RN Butler, AG Coyne, Org. Biomol. Chem. 2016, 14, 9945; d) NA Harry, S. Radhika, M. Neetha, G. Anilkumar, Ch emistrySelect.2019,4,12337;e) MFRuiz-Lopez,JSFrancisco,MTCMartins-Costa,JMAnglada,Nat.Rev.Chem.2020,4,459;f)J.Yu,JRAKincaid,P.Walde,F.Gallou,BHLipshutz,M.Cortes-Clerget,Chem.Sci.2021,12,4237.]. In 2005, Sharpless first reported the concept of "on water" organic reactions [S.Narayan,J.Muldoon,MGFinn,VVFokin,HCKolb,KBSharpless,Angew.Chem.Int.Ed.2005,44,3275.], in which hydrophobic reactants aggregate and accelerate the reaction in a vigorously stirred aqueous suspension through the phenomenon of "hydrophobic hydration". Compared with the traditional reaction under organic solvent or solvent-free conditions, the reaction rate is significantly accelerated. Since then, chemists have also developed great interest in the development of asymmetric organic catalytic reactions in water environments. However, the use of water as a solvent in hydrogen-bonded asymmetric catalytic reactions may destroy the hydrogen bonding between the catalyst and the substrate, thereby hindering the catalytic process. However, Schreiner and Rueping [CM Kleiner, PR Schreiner, Chem. Commun. 2006, 41, 4315; T. Theissmann, M. Rueping, Chem. Sci. 2010, 1, 473.] proved that hydrogen-bonded organic catalysis is feasible under aqueous solvent conditions. Shortly thereafter, Song and Bae et al. used cinchona-based square amides and Takemoto-type ureas as catalysts to achieve a series of enantioselective "on-water" asymmetric hydrogen-bonded catalytic reactions. Compared with reactions under organic solvent or solvent-free conditions, the "on-water" reaction rate was significantly accelerated and the stereoselectivity was significantly improved.[HYBae, S.Some, J.S.Oh, Y.S.Lee, C.E.Song, Chem. Commun. 2011, 47, 9621; HYBae, C.E.Song, ACS Catal. 2015, 5, 3613; J.H.Sim, C.E.Song, Angew. Chem. Int. Ed. 2017, 56, 1; J.H.Sim, J.H.Park, P.Maity, C.E.Song, Org. Lett. 2019, 21, 6715; C.E.Song, S.Park, I.S.H.wang, M.J.Jung, S.S.Shim, HYBae, J.Y.Jung, Nat. Commun. 2019, 10, 1]. Despite the above progress, there is still a lack of hydrogen-bonded organic catalysts suitable for "on-water" conditions.

[0003] γ-Aminobutyric acid (GABA) is a non-protein amino acid widely found in animals, plants and microorganisms. It is the most important inhibitory neurotransmitter in the nervous system of mammals, crustaceans and insects. GABA derivatives can pass through the blood-brain barrier more easily than GABA, and many GABA analogs have been developed for the treatment of central nervous system disorders, such as (S)-pregabalin, (R)-phenibut and (R)-baclofen. Summary of the invention

[0004] The primary purpose of the present invention is to provide a chiral pentafluorophenyl urea compound with a novel structure;

[0005] The second invention objective of the present invention is to provide a method for preparing the compound, which is a simple and low-cost method for synthesizing the compound;

[0006] The third invention object of the present invention is to provide the use of the compound in catalyzing the asymmetric addition reaction of malonate dithioester and nitroolefin in an aqueous medium, and the product is used for the synthesis of GABA analogs; the catalytic reaction rate and stereoselectivity of pentafluorophenyl urea in water are significantly improved compared with those in an organic solvent, and the amount of catalyst used is also significantly reduced.

[0007] In order to achieve the purpose of the invention, the technical solution adopted is:

[0008] The first aspect of the present invention provides a chiral pentafluorophenyl urea compound with the structural formula shown in Formula I:

[0009]

[0010] Among them, R 1Selected from II, ent-II, III, ent-III, IV or V as follows;

[0011]

[0012] R2 is selected from hydrogen, methyl, benzyl;

[0013] R3 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkylthio;

[0014] R4 is selected from C1-C6 alkyl, such as methyl, ethyl, etc.;

[0015] R5 is selected from hydrogen or methoxy;

[0016] R6 is selected from vinyl or ethyl;

[0017] The chiral pentafluorophenyl urea compound is selected from the compounds shown in Formula IB, Formula IC, Formula ID, Formula IE, Formula IF, Formula IG, Formula IH or Formula II:

[0018]

[0019] The second aspect of the present invention provides a method for preparing chiral pentafluorophenyl urea, comprising the following steps: adding pyridine and 4-nitrophenyl chloroformate 2 to pentafluoroaniline 1 dissolved in a dichloromethane solvent, and stirring at room temperature for a certain time time 1; then adding compound 3 to the reaction solution obtained in the above step, and then adding N,N-diisopropylethylamine (DIPEA), stirring at room temperature for a specified time time 2 to obtain compound (I). The technical route is shown in formula A.

[0020]

[0021] The third aspect of the present invention proposes the use of chiral pentafluorophenyl urea (I) in the preparation of the desired enantiomer of GABA analog 8, and its technical route is shown in Formula B:

[0022]

[0023] The present invention has at least the following beneficial effects:

[0024] The present invention proposes a novel chiral pentafluorophenyl urea compound with a novel structure, and proposes a simple and low-cost method for synthesizing the compound, and uses the compound to catalyze the asymmetric addition reaction of malonate dithioester and nitroolefin in an aqueous solvent for preparing a GABA analog drug. Due to the hydrophobic hydration effect, the catalytic reaction rate and stereoselectivity of the novel pentafluorophenyl urea in water are significantly improved compared with those in an organic solvent, and the amount of catalyst used is also significantly reduced. Compared with the existing method, the preparation of GABA analogs by the present invention has the advantages of simple steps, mild conditions, high yield, and environmental friendliness. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a comparison chart of the catalyst addition reaction results of Example 8 of the present invention;

[0026] Figure 2 This is a linear relationship diagram between the ee value of pentafluorophenyl urea IB in Example 9 of the present invention and the ee value of product 6a. DETAILED DESCRIPTION

[0027] To make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. In addition, in order to better illustrate the present invention, numerous specific details are given in the specific embodiments below. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In certain embodiments, raw materials, components, methods, means, etc. known to those skilled in the art are not described in detail to highlight the main idea of ​​the present invention.

[0028] The present invention provides a novel chiral pentafluorophenyl urea and a preparation method thereof, as well as its application in "on-water" asymmetric catalysis and the synthesis of GABA analog drugs (R)-phenibut, (R)-baclofen, etc. The claimed novel chiral pentafluorophenyl urea compound (especially a chiral urea compound based on a proline chiral skeleton) and its use as an asymmetric catalyst, add a hydrophobic and strongly electron-withdrawing pentafluorophenyl substituent to the urea part, thereby improving its efficiency in "on-water" asymmetric hydrogen bond catalysis. When catalyzing the asymmetric addition reaction of malonate disulfide and nitroolefin in an aqueous solvent, the reaction rate and stereoselectivity (up to 96%ee) are significantly improved compared with traditional organic solvents. Since the reaction rate is significantly accelerated under "on-water" conditions, the amount of catalyst used is significantly reduced (0.2mol%). In addition, the catalyst does not show significant self-polymerization under such "on-water" conditions, and the nonlinear relationship experiment proves that its catalytic process is a single-molecule catalytic mode.

[0029] The present invention is further described below in conjunction with embodiments.

[0030] 1. Synthesis of chiral pentafluorophenyl urea compounds

[0031]

[0032] Example 1

[0033] Synthesis of compound of formula (IB):

[0034]

[0035] Experimental procedure: 2,3,4,5,6-pentafluoroaniline (98 mg, 0.53 mmol, 1.0 equiv.) and CH2Cl2 (5 mL) were added to a 25 mL dry round-bottom flask. Pyridine (46.5 μL, 0.58 mmol, 1.1 equiv.) was added to the reaction mixture via a microsyringe followed by the addition of 4-nitrobenzene chloroformate 2 (116.9 mg, 0.58 mmol, 1.1 equiv.). The resulting solution was stirred at room temperature for the indicated time time 1. Then, (R)-((S)-1-methylpyrrolidin-2-yl)(phenyl)methanamine 3 (100 mg, 0.53 mmol, 1.0 equiv.) in CH2Cl2 (3 mL) was added to the reaction mixture. Subsequently, N,N-diisopropylethylamine (101 μL, 0.58 mmol, 1.1 equiv.) was introduced into the reaction mixture and stirring was continued at room temperature for another indicated time time 2. The reaction mixture was then concentrated in vacuo, diluted with ethyl acetate, saturated aqueous Na2CO3 solution was added, and the resulting mixture was subsequently extracted with ethyl acetate. The organic layer obtained from the extraction was washed with brine and dried over Na2SO4, then filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate (v / v), 1 / 1) to give 157 mg of a bright yellow solid catalyst IB with a yield of 75%. mp: 118-122°C, 1 H NMR(400MHz,CDCl3)δ11.99(br s,1H),7.40-7.34(m,2H),7.32-7.27(m,3H),4.95(d,J=3.9Hz,1H),3.23-3.13(m,1H),2. 79-2.70(m,1H),2.42(s,3H),2.36-2.26(m,1H),2.24-2.13(m,1H),1.93-1.78(m,3H)ppm, 13 C NMR (101MHz, CDCl3) δ156.8,142.3(m),140.0,137.8(m),129.9(m),129.1,128.1,126.7,114.9(m),71.4,57.7,56.5,40.4,25.1,24.0,0.0ppm, 19 F NMR(377MHz, CDCl3)δ-147.8(s),-161.3(s),-163.6(dt,J=21.6,J=10.9Hz)ppm,IR(K Br):1642,1551,1523,1498,1462,1349,1328,1272,1231,1066,1002,976,747,699cm -1,HRMS(ESI-QTOF)m / z:[M+H] + Calcdfor C 19 H 19 F5N3O 400.1448,found 400.1444,[α] 20 D =-62.2 (c = 1.0, CHCl3).

[0036] Example 2

[0037] Synthesis of compound of formula (ent-IB)

[0038]

[0039] Experimental steps: Implementation steps According to the steps described in Example 1, D-proline was used as the raw material, and the arylamine was 2,3,4,5,6-pentafluoroaniline (78 mg, 0.53 mmol), and 121 mg of yellow solid catalyst ent-IB was obtained with a yield of 74%. [α] 20 D =+60.7 (c=1.0, CHCl3), and the rest of the data are consistent with those in Example 8.

[0040] Example 3

[0041] Synthesis of compound of formula (ID)

[0042]

[0043] Experimental procedure: To a mixture of 2,3,4,5,6-pentafluoroaniline (100 mg, 0.55 mmol) and pyridine (48.5 μL, 0.60 mmol, 1.1 equiv.) in dichloromethane (5 mL) was added 4-nitrobenzene chloroformate (120.9 mg, 0.60 mmol, 1.1 equiv.) at room temperature. The mixture was stirred for 12 h, and then (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (78.2 mg, 0.55 mmol, 1.0 equiv.) in dichloromethane (3 mL) was added to the reaction mixture at room temperature. Subsequently, N,N-diisopropylethylamine (104.5 μL, 0.60 mmol, 1.1 equiv.) was added, and the whole mixture was stirred for another 2 h at room temperature. Next, the reaction mixture was concentrated in vacuo. It was diluted with ethyl acetate, and then a saturated aqueous Na2CO3 solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate (v / v), 10 / 1) to give catalyst ID (45% yield, 86 mg) as a colorless solid. mp: 143-147°C, 1 H NMR(400MHz, CDCl3)δ5.67(br s,1H),3.48-3.40(m,1H),2.43-2.35(m,1H),2.32(s,6H),1.94-1.79(m,2H),1.76-1.68(m,1H),1.33-1.11(m,4H), 13 C NMR (101MHz, CDCl3) δ156.4(m),142.2(m),138.4(m),137.9(m),114.8(m),68.2,52.8,40.4,33.5,24.9,24.7,22.4ppm, 19 F NMR 19F NMR (377MHz, CDCl3) δ-147.79 (s), -160.95 (s), -163.57 (td, J = 21.7, 5.0Hz) ppm, IR (KBr): 2 961,2863,2787,1697,1638,1577,1522,1331,1313,1262,1191,1095,1031,983,872,802.cm -1 ,HRMS(ESI-QTOF)m / z:[M+H] + Calcd for C 15 H 19 F5N3O 352.1448,found 352.1452,[α]20 D =-33.0 (c = 1.0, CHCl3).

[0044] Example 4

[0045] Synthesis of compound of formula (II)

[0046]

[0047] Experimental procedure: 2,3,4,5,6-pentafluoroaniline (100 mg, 0.55 mmol) and CH2Cl2 (5 mL) were added to a 25 mL dry round-bottom flask, pyridine (48.5 μL, 0.60 mmol, 1.1 equiv.) was added to the reaction mixture via a microsyringe at room temperature, followed by 4-nitrobenzene chloroformate (120.9 mg, 0.60 mmol, 1.1 equiv.). The reaction mixture was stirred for 12 h, and then (R)-quinolin-4-yl((1S,2R,4S,5R)-5-vinylquinolin-2-yl)methanamine (CN-NH2) (162.1 mg, 0.55 mmol, 1.0 equiv.) in dichloromethane (3 mL) was added to the reaction mixture at room temperature. Subsequently, N, N-diisopropylethylamine (104.5 μL, 0.60 mmol, 1.1 equiv.) was added, and the entire mixture was stirred for another 2 h at room temperature. Next, the reaction mixture was concentrated in vacuo. Diluted with ethyl acetate, saturated aqueous Na2CO3 solution was then added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane / methanol (v / v), 10 / 1) to give Catalyst II (55% yield, 150.9 mg) in the form of a white solid. mp: 95-100 ° C, 1H NMR (400MHz, CDCl3) δ8.85(d,J=4.5Hz,1H),8.30(d,J=8.5Hz,1H),8.11(d,J=8.1H z,1H),7.71(t,J=7.2Hz,1H),7.59(t,J=7.3Hz,1H),7.45(d,J=4.5Hz,1H),6.77(br s,1H),5.87-5.77(m,1H),5.38(br s,1H),5.13(t,J=15.0Hz,2H),3.12-3.11(m,1H),3.00-2.89(m,2H),2.71-2.87(m,2H), 2.33-2.23(m,2H),1.63(s,1H),1.59-1.45(m,2H),1.30-1.17(m,2H),0.97-0.89(m,1H), 13 C NMR (101MHz, CDCl3) δ155.6(m),150.0,148.5,146.5(m),142.8(m),139.3,139.3(m),137.6(m),130.3,12 9.5,127.1,126.9,123.1,119.2(m),115.5,113.6(m),61.0,48.8,46.7,38.7,29.7,27.1,25.9,24.9ppm, 19 F NMR 19 F NMR(377MHz, CDCl3)δ-146.43(s),-158.84(s),-162.96(t,J=19.6Hz)ppm, IR(KBr ):2936,1684,1653,1591,1524,1396,1323,1261,1092,1021,984,914,803,758.cm -1 ,HRMS(ESI-QTOF)m / z:[M+H] + Calcd for C 26 H 24 F5N4O 503.1870,found 503.1872,[α] 20 D = +115.2 (c = 1.0, CHCl3).

[0048] 2. Study on the performance of chiral pentafluorophenyl urea in the asymmetric addition reaction of malonate disulfide and nitroolefins

[0049] To further describe the present invention, when the chiral urea IB, ID or VI prepared in Example 1, 3 or 4 (0.5 mol% in water solvent; or 5 mol% in toluene solvent) is used as a catalyst for the asymmetric addition reaction of malonate disulfide 5a and nitroolefin 4a (1:1.5) under the conditions of an aqueous solvent (water: toluene (v:v) = 8.8:1) or pure toluene (1.5 mL) as a solvent, the reaction rate and stereoselectivity are significantly improved under the "aqueous" (water: toluene (v:v) = 8.8:1) conditions compared with toluene solvent, and the catalyst loading is significantly reduced. The specific reaction formula is as follows:

[0050]

[0051] The experimental results are as follows: Examples 5, 6 and 7.

[0052] Example 5

[0053] Catalyst IB (aqueous solvent: 0.5 mol% pure or toluene solvent: 5 mol%) was added to a 3 mL reaction bottle, followed by the addition of p-chloronitroolefin 4a (44 mg, 0.24 mmol, 1.5 equivalents) and S, S'-bis (4-methylphenyl) malonate disulfide 5a (50 mg, 0.16 mmol, 1.0 equivalents) to the reaction bottle, and finally the aqueous solvent (water: toluene (v: v) = 8.8: 1) or pure toluene solvent (1.5 mL) was added to the reaction bottle, and then the resulting mixture was stirred at room temperature for 0.5 h (aqueous solvent) or 1.5 h (pure toluene solvent) until the reaction was determined to be complete by TLC analysis. The reaction mixture was then extracted with CH2Cl2 (5 mL × 3), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue obtained by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) was obtained to obtain a white solid product 6a. The specific yield and HPLC analysis ee value are shown in the following table:

[0054]

[0055] Example 6

[0056] Other conditions were the same as those in Example 5, and the catalyst used was ID. The yield and ee value analysis results of HPLC are shown in the following table;

[0057]

[0058]

[0059] Example 7

[0060] The other conditions were the same as those in Example 5, and VI was used as the catalyst. The yield and ee value analysis results of HPLC were shown in the following table;

[0061]

[0062] 3. Effect of the concentration of chiral pentafluorophenylurea compounds on their catalytic asymmetric reaction performance

[0063] Example 8

[0064] The "on-water" Michael addition reaction of 5a and 4a was catalyzed by using different concentrations (0.1-5 mol%) of the reported catalyst PU and the chiral pentafluorophenyl urea IB proposed in the present invention. Figure 1 As shown (the data in brackets represent the yield), the enantioselectivity of the catalyst PU (triangle symbol) has a great relationship with the concentration, while the enantioselectivity of the chiral pentafluorophenyl urea IB (square symbol) proposed by the present invention does not significantly depend on the catalyst concentration. A high ee value can be maintained in a large catalyst concentration range (0.5-5 mol%), which has high practicality. These experimental results show that the chiral pentafluorophenyl urea IB does not show a significant self-aggregation effect in this "on-water" hydrogen bond catalysis.

[0065]

[0066] 4. Study on the nonlinear relationship between the ee value of pentafluorophenylurea IB and the ee value of compound 6a

[0067] Example 9

[0068] The present invention is further described by examining the linear relationship between the ee value of pentafluorophenylurea IB and the ee value of product 6a (see Figure 2 In addition to enantiomerically pure IB and ent-IB, we also prepared IB with different ee values ​​(20%ee, 40%ee, 60%ee, 80%ee) and applied them to the addition reaction of 5a and 4a under "on water" conditions (IB content was 0.5mol%). It was observed that the ee value of catalyst IB was linearly related to the ee value of product 6a. This result indicates that the catalytic mode of IB is a unimolecular catalytic mode.

[0069]

[0070] 5. Asymmetric Michael addition reaction of sulfolipids and nitroolefins catalyzed by pentafluorophenylurea IB

[0071]

[0072] Example 10

[0073] Synthesis of compound of formula (6a)

[0074]

[0075] Experimental procedure: β-Nitroolefin 4 (0.24 mmol, 1.5 equiv.) and saturated brine (1.5 mL) / toluene (10 equiv.) were added to a 3 mL vial equipped with a Teflon-coated magnetic stirrer. Catalyst PU-IB (0.5 mol%) and dithiomalonate 5a (50 mg, 0.16 mmol, 1.0 equiv.) were then introduced into the reaction mixture. The reaction mixture was stirred at room temperature for 0.5 h-3 h. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with CH2Cl2 (5 mL×3), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 74.3 mg of a white solid product 6a with a yield of 93% and an ee value of 87% (on water). R f =0.40(petroleumether / ethyl acetate(v / v),10 / 1), mp:137-140℃, 1 H NMR (400MHz, CDCl3) δ7.35-7.28(m,4H),7.26(d,J=7.9Hz,2H),7.22-7.16(m,4H),7.06(d,J=8.1Hz ,2H),4.81(d,J=6.5Hz,2H),4.42(d,J=9.5Hz,1H),4.39-4.33(m,1H),2.39(s,3H),2.35(s,3H)ppm, 13 C NMR (101MHz, CDCl3) δ190.8,189.9,140.8,140.6,134.6,134.2,134.1,133.9,130.4,130.3,129.7,129.3,122.4,122.4,76.9, 68.9,43.6,21.4,21.4ppm, IR(KBr):2921,1701,1674,1597,1549,1494,1425,1381,1285,1198,1095,1016,999,962,808,768cm -1 , HRMS (ESI-QTOF) m / z: [M+Na] + Calcd for C 25 H 22 ClNO4S2Na 522.0573, found 522.0576, HPLC COSMOSIL5A column, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R=15.39min(minor),t R =18.00min(major),[α] 20 D =-92.2 (c = 1.0, CHCl3). When the catalyst was CNU-II (0.5 mol%), the product 6a was obtained with a yield of 94% and an ee value of 87% (on water); when the catalyst was Takemoto-II (0.5 mol%), the product 6a was obtained with a yield of 95% and an ee value of 83% (on water).

[0076] Embodiment 11

[0077] Synthesis of compound of formula (6b)

[0078]

[0079] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4b (35.7 mg, 0.24 mmol) was used to obtain 70.7 mg of white solid product 6b with a yield of 95% and an ee value of 95%. f =0.38(petroleum ether / ethylacetate(v / v),10 / 1).mp:154-156℃. 1 H NMR (400MHz, CDCl3) δ7.40-7.30(m,4H),7.30-7.25(m,5H),7.16(d,J=8.0Hz,2H),7.03(d,J=8.1Hz,2H ),4.90-4.80(m,2H),4.45(d,J=9.4Hz,1H),4.38(td,J=8.9,5.0Hz,1H),2.40(s,3H),2.34(s,3H)ppm. 13 C NMR (101MHz, CDCl3) δ190.9,190.1,140.7,140.5,135.3,134.2,134.2,130.3,130.2,129.1,128.6,128.4,122.6,122.6,77.2,69.2,44 .3,21.4,21.3ppm.IR(KBr)2960,2923,2854,1705,1597,1679,1597,1548,1495,1456,1424,1379,1295,1261,1090,979,810,749,700cm - 1 .HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C25 H 23 NO4S2Na 488.0961, found 488.0966.HPLCCOSMOSIL 5A column, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R =11.15min(minor),t R =10.09min(major).[α] 20 D =-75.6 (c = 1.0, CHCl3).

[0080] Example 12

[0081] Synthesis of compound of formula (6c)

[0082]

[0083] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4c (40.1 mg, 0.24 mmol) was used, and the reaction time was 0.5 h to obtain 72.6 mg of white solid product 6c with a yield of 94% and an ee value of 92%. f =0.36(petroleumether / ethyl acetate(v / v),10 / 1).mp:163-168℃. 1 H NMR (400MHz, CDCl3) δ7.32-7.28(m,2H),7.28-7.26(m,2H),7.25-7.22(m,2H),7.20-7.16(m,2H),7.08-7.02 (m,4H),4.81(d,J=6.3Hz,2H),4.41(dd,J=8.2,2.7Hz,1H),4.40-4.34(m,1H),2.40(s,3H),2.35(s,3H)ppm. 13C NMR (101MHz, CDCl3) δ190.8, 190.0, 162.7 (d, J = 248.0Hz), 140.8, 140.6, 134.2, 134.1,131.1(d,J=3.4Hz),130.4,130.3,130.2,130.1,122.5(d,J=4.5Hz),116 .1(d,J=21.7Hz),77.1,69.1,43.6,21.4,21.4ppm.IR(KBr)2962,2923,2854,16 98,1607,1552,1513,1491,1426,1373,1261,1227,1164,1104,1016,981,809cm -1 .HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C 25 H 22 FNO4S2Na 506.0869, found 506.0872.HPLC COSMOSIL 5A column, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R =13.05min(minor),t R =11.70min(major).[α] 20 D =-72.4 (c = 1.0, CHCl3).

[0084] Embodiment 13

[0085] Synthesis of compound of formula (6d)

[0086]

[0087] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4d (54.4 mg, 0.24 mmol) was used, and the reaction time was 0.5 h to obtain 78.2 mg of white solid product 6d with a yield of 90% and an ee value of 87%. f =0.42(petroleumether / ethyl acetate(v / v),10 / 1).mp:169-172℃. 1H NMR (400MHz, CDCl3) δ7.51-7.47(m,2H),7.31-7.28(m,2H),7.27-7.24(m,2H),7.20-7.17(m,2H),7.16-7.12(m,2H),7. 07-7.04(m,2H),4.80(d,J=6.7Hz,2H),4.41(d,J=9.4Hz,1H),4.35(dt,J=9.4,6.7Hz,1H),2.39(s,3H),2.35(s,3H)ppm. 13 C NMR (101MHz, CDCl3) δ190.8,189.9,140.8,140.6,134.5,134.2,134.1,132.2,130.4,130.3,130.1,122.7,122.5,122.4,76.8,68 .8,43.7,21.4,21.3ppm.IR(KBr)2960,2922,2853,1699,1673,1597,1549,1493,1425,1378,1261,1196,1076,961,834,807,763cm -1 .HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C 25 H 22 BrNO4S2Na566.0071,568.0051,found 566.0071,568.0052.HPLC COSMOSIL 5A column,i-PrOH / n-hexane=30 / 70,25℃,1.0mL / min,λ=254nm,t R =14.86min(minor),t R =13.00min(major).[α] 20 D =-61.0 (c = 1.0, CHCl3).

[0088] Embodiment 14

[0089] Synthesis of compound of formula (6e)

[0090]

[0091] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4e (52.0 mg, 0.24 mmol) was used, and the reaction time was 0.5 h to obtain 77.6 mg of white solid product 6e with a yield of 91% and an ee value of 82%. f=0.39(petroleumether / ethyl acetate(v / v),10 / 1).mp:167-174℃. 1 H NMR (400MHz, CDCl3) δ7.52 (dd, J=90.2, 8.1Hz, 4H), 7.31-7.25 (m, 4H), 7.19-6.99 (m, 4H) ,4.90-4.82(m,2H),4.49-4.45(m,1H),4.45-4.42(m,1H),2.40(s,3H),2.35(s,3H)ppm. 13 C NMR (101MHz, CDCl3) δ190.7,189.9,140.9,140.7,139.6,134.2,134.1,130.9(q, J=32.7Hz),130.4,130.3,129.0,126.0(q,J=3.8Hz),124.0(q,J=272.3Hz),122. 4,122.3,76.7,68.6,43.9,21.4,21.3ppm.IR(KBr)2961,2923,2853,1708,1674, 1620,1549,1492,1425,1380,1329,1262,1169,1126,1075,1019,966,842,807cm -1 ; HRMS (ESI-QTOF) m / z: [M+Na] + Calcd for C 26 H 22 F3NO4S2Na 556.0836, found 556.0840.HPLC COSMOSIL 5A column, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R =12.26min(minor),t R =10.84min(major).[α] 20 D =-50.8 (c = 1.0, CHCl3).

[0092] Embodiment 15

[0093] Synthesis of compound of formula (6f)

[0094]

[0095] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4e (39.1 mg, 0.24 mmol) was used, and the reaction time was 0.5 h to obtain 71.3 mg of white solid product 6f.R with a yield of 93% and an ee value of 95%. f =0.31(petroleumether / ethyl acetate(v / v),10 / 1).mp:190-193℃. 1 H NMR (400MHz, CDCl3) δ7.32-7.28(m,2H),7.26-7.24(m,1H),7.19-.11(m,7H),7.07-7.03(m,2H),4 .85-4.79(m,2H),4.43(d,J=9.3Hz,1H),4.37-4.30(m,1H),2.39(s,3H),2.34(d,J=2.3Hz,6H)ppm. 13 C NMR (101MHz, CDCl3) δ191.0,190.1,140.6,140.4,138.3,134.2,134.2,132.3,130.3,130.2,129.7,128.2,122.7,122.7,77. 2,69.3,44.1,21.4,21.3,21.1ppm.IR(KBr)1702,1597,1548,1517,1492,1424,1382,1281,1261,1195,1075,1011,969,810cm -1 .HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C 26 H 25 NO4S2Na 502.1124, found 502.1123.HPLC COSMOSIL 5A column, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R =10.72min(minor),t R =9.77min(major).[α] 20 D =-82.2 (c = 1.0, CHCl3).

[0096] Example 16

[0097] Synthesis of compound of formula (6g)

[0098]

[0099] Implementation steps: According to the steps described in Example 8, 4 g (42.9 mg, 0.24 mmol) of β-nitroolefin was used, and the reaction time was 0.5 h to obtain 72.8 mg of a white solid product with a yield of 92% and an ee value of 95%. f =0.28(petroleumether / ethyl acetate(v / v),10 / 1).mp:176-180℃. 1 H NMR (400MHz, CDCl3) δ7.31-7.28(m,2H),7.26-7.23(m,1H),7.20-7.15(m,5H),7.07-7.04(m,2H),6.89-6.85(m,2H),4.8 1-4.78(m,2H),4.42(dd,J=9.5,1.9Hz,1H),4.33(ddd,J=9.3,7.7,6.2Hz,1H),3.79(s,3H),2.39(s,3H),2.34(s,3H)ppm. 13 C NMR (101MHz, CDCl3) δ191.0,190.1,159.6,140.7,140.4,134.2,134.2,130.3,130.2,129.5,127.2,122.7,122.7,114.5,77.3,69.4,5 5.3,43.8,21.4,21.3ppm.IR(KBr)2962,2923,2853,1702,1673,1613,1583,1548,1518,1493,1380,1259,1183,1097,1035,976,807cm -1 ; HRMS (ESI-QTOF) m / z: [M+Na] + Calcd for C 26 H 25 NO5S2Na518.1071, found 518.1072.HPLC COSMOSIL 5A column, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R =14.18min(minor),t R =14.95min(major).[α] 20 D =-81.4 (c = 1.0, CHCl3).

[0100] Embodiment 17

[0101] Synthesis of compound of formula (6h)

[0102]

[0103] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4h (43.9 mg, 0.24 mmol) was used, and the reaction time was 0.5 h to obtain 73.4 mg of a white solid product 6h.R with a yield of 92% and an ee value of 96%. f =0.37(petroleumether / ethyl acetate(v / v),10 / 1).mp:46-50℃. 1 H NMR (400MHz, CDCl3) δ7.47-7.43(m,1H),7.31-7.26(m,3H),7.25(s,4H),7.20-7.11(m,4H),5.02(ddd,J= 17.7,13.8,6.4Hz,2H),4.84(td,J=8.5,4.0Hz,1H),4.75(d,J=8.1Hz,1H),2.39(s,3H),2.35(s,3H)ppm. 13 CNMR(101MHz, CDCl3)δ191.2,190.2,140.7,140.5,134.2,134.2,132.8,130.7,130.3(x2),130.2(x2),129.7,127.3,122.7,122.5,7 5.0,66.6,41.1,21.4,21.4ppm.IR(KBr)2962,2922,2854,1704,1597,1555,1493,1477,1433,1376,1262,1100,1037,1018,963,806cm - 1 .HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C 25 H 22 ClNO4S2Na 522.0579, found522.0576.HPLC COSMOSIL 5A column, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R =12.71min(minor),t R =9.73min(major).[α] 20 D =-31.8 (c = 1.0, CHCl3).

[0104] Embodiment 18

[0105] Synthesis of compound of formula (6i)

[0106]

[0107] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4i (43.9 mg, 0.24 mmol) was used, and the reaction time was 0.5 h to obtain 73.4 mg of white solid product 6i with a yield of 92% and an ee value of 92%. f =0.36(petroleumether / ethyl acetate(v / v),10 / 1).mp:130-133℃. 1 H NMR (400 MHz, CDCl 3 )δ7.34-7.27(m,7H),7.21-7.18(m,2H),7.17-7.15(m,1H),7.10-7.07(m,2H),4.85- 4.83(m,2H),4.40(d,J=9.1Hz,1H),4.38-4.32(m,1H),2.40(s,3H),2.36(s,3H)ppm. 13 C NMR (101MHz, CDCl3) δ190.8,190.0,140.8,140.7,137.5,135.0,134.2,134.2,130.4,130.4,130.3,128.9,128.6,126.5,122.5,122.4, 76.6,68.7,43.9,21.4,21.4ppm.IR(KBr)2961,2921,2851,1706,1596,1573,1551,1493,1423,1377,1262,1202,1181,1088,962,811cm -1 .HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C 25 H 22 ClNO4S2Na 522.0574, found 522.0576.HPLC COSMOSIL5A column, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R =10.38min(minor),t R =9.04min(major).[α] 20 D =-77.8 (c = 1.0, CHCl3).

[0108] Embodiment 19

[0109] Synthesis of compound of formula (6j)

[0110]

[0111] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4j (33.3 mg, 0.24 mmoll) was used, and the reaction time was 0.5 h to obtain 65.5 mg of white solid product 6i with a yield of 90% and an ee value of 94%. f =0.35(petroleumether / ethyl acetate(v / v),10 / 1).mp:120-127℃. 1 H NMR (400MHz, CDCl3) δ7.42(dd,J=1.8,0.7Hz,1H),7.31-7.28(m,2H),7.26-.22(m,2H),7.22-7.17(m,4H),6.34(dd,J=3.3,1.9Hz,1 H),6.26-6.25(m,1H),4.83(dd,J=6.3,5.4Hz,2H),4.59(d,J=8.8Hz,1H),4.49(td,J=8.6,4.4Hz,1H),2.39(s,3H),2.37(s,3H)ppm. 13 C NMR (101MHz, CDCl3) δ190.6,190.2,148.7,143.1,140.7,140.6,134.3,134.2,130.3,130.3,122.6,122.6,110.7,109.4,75.1,66.8,38. 1,21.4,21.4ppm.IR(KBr)2962,2924,2854,1702,1675,1597,1549,1494,1422,1376,1292,1261,1206,1145,1096,1042,980,809,741cm -1 .HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C 23 H 21 NO5S2Na 478.0756, found 478.0759.HPLC COSMOSIL 5Acolumn, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R =11.16min(minor),t R =9.95min(major).[α]20 D =-51.6 (c = 1.0, CHCl3).

[0112] Embodiment 20

[0113] Synthesis of compound of formula (6k)

[0114]

[0115] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4k (37.2 mg, 0.24 mmol) was used, and the reaction time was 0.5 h to obtain 62.5 mg of a white solid product 6k.R with a yield of 83% and an ee value of 91%. f =0.36(petroleumether / ethyl acetate(v / v),10 / 1).mp:125-130℃. 1 H NMR (400MHz, CDCl3) δ7.31-7.29(m,2H),7.29-.24(m,3H),7.22-7.19(m,2H),7.17-7.13(m,2H),6.99-6.96(m, 2H), 4.86 (dd, J=6.5, 3.2Hz, 2H), 4.67 (td, J=8.2, 5.2Hz, 1H), 4.52 (d, J=8.7Hz, 1H), 2.39 (s, 3H), 2.36 (s, 3H). 13 C NMR (101MHz, CDCl3) δ190.9,190.1,140.7,140.6,137.8,134.2,130.4,130.3,127.5,127.2,125.8,122.6,122.6,77.7,69.6,39. 8,21.4,21.4ppm.IR(KBr)2959,2923,2853,1742,1701,1597,1547,1492,1451,1419,1378,1290,1263,1141,1032,972,809,716cm -1 .HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C 23 H 21 NO4S3Na 494.0533, found494.0530.HPLC COSMOSIL 5A column, i-PrOH / n-hexane=10 / 90, 25℃, 1.0mL / min, λ=254nm, t R =23.29min(minor),t R=20.69min(major).[α] 20 D =-23.6 (c = 1.0, CHCl3).

[0116] Embodiment 21

[0117] Synthesis of compound of formula (61)

[0118]

[0119] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4l (31.8 mg, 0.24 mmol) was used, and the reaction time was 0.5 h to obtain 73.3 mg of white solid product 6l with a yield of 89% and an ee value of 77%. f =0.38(petroleumether / ethyl acetate(v / v),10 / 1).mp:169-175℃. 1 H NMR (400MHz, CDCl3) δ7.88-7.80(m,3H),7.72(d,J=1.4Hz,1H),7.53-7.49(m,2H),7.38(dd,J=8.5,1.8Hz,1H),7.31-7.26(m,4H),7.1 1-7.08(m,2H),6.96-6.93(m,2H),5.02-4.90(m,2H),4.56(d,J=3.6Hz,1H),4.54(dd,J=3.8,2.3Hz,1H),2.40(s,3H),2.31(s,3H)ppm. 13 C NMR (101MHz, CDCl3) δ191.1,190.1,140.7,140.5,134.3,134.2,133.3,133.1,132.8,130.4,130.2,129.1,128.0,127.9,127.7,126.6,125.4, 122.6,122.5,76.9,69.2,44.5,21.4,21.3ppm.IR(KBr)2961,2923,285 3,1741,1700,1597,1549,1493,1426,1380,1261,1018,982,808,746cm -1 .HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C 29 H 25NO4S2Na 538.1125, found 538.1123.HPLCCOSMOSIL 5A column, i-PrOH / n-hexane=10 / 90, 25℃, 1.0mL / min, λ=254nm, t R =36.91min(minor),t R =27.98min(major).[α] 20 D = -45.0 (c = 1.0, CHCl3);

[0120] Embodiment 22

[0121] Synthesis of compound of formula (6m)

[0122]

[0123] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4m (37.2 mg, 0.24 mmol) was used, the reaction time was 2 h, the amount of catalyst used was 0.63 mg, 1 mol%, and 60.2 mg of a white solid product 6m.R with a yield of 80% and an ee value of 82% was obtained. f =0.42(petroleum ether / ethyl acetate(v / v),10 / 1).mp:118-122℃. 1 H NMR (400MHz, CDCl3) δ7.36-7.26(m,6H),7.25-7.23(m,2H),4.70(ddd,J=22.0,14.8,5.2Hz,2H),4.40(d,J=5.3Hz ,1H),3.03-2.97(m,1H),2.39(d,J=2.8Hz,6H),1.83-1.67(m,5H),1.12(dddd,J=27.9,24.3,12.4,3.1Hz,6H)ppm. 13 C NMR (101MHz, CDCl3) δ192.1,191.7,140.6,140.6,134.4,134.3,130.3,130.3,122.9,122.8,75.0,65.4,44.3,40.0,30.6,29.8,26.3, 26.3,26.0,21.4ppm.IR(KBr)2926,2855,1703,1595,1549,1492,1453,1429,1373,1302,1262,1208,1180,1091,1014,984,810,764cm -1.HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C 25 H 29 NO4S2Na 494.1431, found 494.1436.HPLC COSMOSIL 5A column, i-PrOH / n-hexane=10 / 90, 25℃, 1.0mL / min, λ=254nm, t R =9.71min(minor),t R =8.06min(major).[α] 20 D =-58.4 (c = 1.0, CHCl3).

[0124] Embodiment 23

[0125] Synthesis of compound of formula (6n)

[0126]

[0127] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4a (37.2 mg, 0.24 mmol) and dithiomalonate 5b (30.7 mg, 0.16 mmol) were used, the reaction time was 2 h, and the amount of catalyst used was 0.64 mg, 1 mol%, to obtain 46.3 mg of a white solid product 6n.R with a yield of 85% and an ee value of 57%. f =0.30(petroleum ether / ethylacetate(v / v),10 / 1). 1 H NMR (400MHz, CDCl3) δ7.33-7.23(m,3H),7.22-7.19(m,2H),4.80-4.72(m,2H),4.37(ddd,J=10.0,8.1,5.8Hz,1H),4.24(d,J =10.0Hz,1H),2.98(q,J=7.4Hz,2H),2.83-2.75(m,1H),2.74-2.66(m,1H),1.29(t,J=7.4Hz,3H),1.02(t,J=7.4Hz,3H)ppm. 13C NMR (101MHz, CDCl3) δ192.1,191.1,135.4,128.9,128.4,128.2,77.2,70.3,44.2,24.5,24.2,14.2,14.1ppm.HPLC Chiracel OD-H column, i-PrOH / n-hexane=5 / 95, 25℃, 1.0mL / min, λ=254nm, t R =14.56min(major),t R =13.69min(minor).[α] 20 D =-28.9 (c = 1.0, CHCl3).

[0128] Embodiment 24

[0129] Synthesis of compound of formula (6o)

[0130]

[0131] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4b (37.2 mg, 0.24 mmol) and malonate dithioester 5c (43.2 mg, 0.16 mmol) were used, the reaction time was 2 h, and the amount of catalyst used was 0.64 mg, 1 mol%, to obtain 59.8 mg of a white solid product 6o.R with a yield of 88% and an ee value of 76%. f =0.41(petroleum ether / ethylacetate(v / v),10 / 1).mp:74-76℃. 1 H NMR (400MHz, CDCl3) δ7.37-7.26(m,5H),4.99(dd,J=13.7,11.1Hz,1H),4.90-4.84(m,2H ),3.03-2.89(m,2H),2.79-2.64(m,2H),1.29(t,J=7.4Hz,3H),1.05(t,J=7.4Hz,3H)ppm. 13 C NMR (101MHz, CDCl3) δ194.2,193.3,132.9,130.1,128.9,128.4,79.4,77.5,49.0,26.2,26.0,13.7,13.5pp m; IR(KBr)2931,1741,1680,1556,1496,1455,1375,1266,1052,1032,970,700.HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C15 H 18 BrNO4S2Na 441.9760,443.9738,found 441.9758,443.9741.HPLCCOSMOSIL 5A column,i-PrOH / n-hexane=10 / 90,25℃,1.0mL / min,λ=254nm,t R =5.93min(minor),t R =5.63min(major).[α] 20 D =-38.4 (c = 1.0, CHCl3).

[0132] Embodiment 25

[0133] Synthesis of compound of formula (6p)

[0134]

[0135] Implementation steps: According to the steps described in Example 8, β-nitroolefin 4b (37.2 mg, 0.24 mmol) and dithiomalonate 5d (52.8 mg, 0.16 mmol) were used, the reaction time was 3 h, the amount of catalyst used was 3.2 mg, 5 mol%, and 65.9 mg of a white solid product 6o was obtained with a yield of 86% and an ee value of 63%. f =0.31(petroleum ether / ethylacetate(v / v),10 / 1).mp:117-118℃. 1 H NMR (400MHz, CDCl3) δ7.36-7.32(m,3H),7.30(s,4H),7.26-7.21(m,6H),5.08-5.01(m,1H),4.8 9(dd,J=13.7,2.9Hz,1H),4.31(dd,J=11.0,2.8Hz,1H),2.40(d,J=10.7Hz,6H),1.72(s,3H)ppm. 13 C NMR (101MHz, CDCl3) δ198.8,197.1,140.6,140.5,134.8,134.6,134.4,130.5,130.3,129.7,128.7,128.6,122.9,122.4,77 .1,69.7,49.9,21.4,21.4,20.2ppm.IR(KBr)2921,1698,1665,1555,1493,1452,1377,1210,1156,1018,954,939,810,725cm -1.HRMS(ESI-QTOF)m / z:[M+Na] + Calcd for C 26 H 25 NO4S2Na 502.1125, found 502.1123.HPLC Chiracel OD-H column, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R =6.12min(minor),t R =7.27min(major).[α] 20 D =-23.9 (c = 1.0, CHCl3).

[0136] 6. Synthesis of GABA Analogs

[0137] Embodiment 26

[0138] Synthesis of compound of formula (7a)

[0139]

[0140] The addition product 6a (99% ee) (500 mg, 1.0 mmol, 1.0 equiv.) and AcOH (25 mL) were added to a 50 mL dry round-bottom flask. Freshly activated zinc powder (10 equiv.) was added and the mixture was stirred at rt for 2 h under argon atmosphere. After that, TiCl3 solution (127 μL, 1.1 mmol, 0.1 equiv.; 12% solution in 5% HCl) was added and the resulting mixture was stirred for an additional 1 h. The mixture was filtered through a pad of celite, the filter cake was washed with EtOAc and the resulting solution was concentrated in vacuo. The crude residue was purified by column chromatography to give compound 7a as a white solid, 236 mg, 93% yield, 87% ee; R f =0.24(petroleum ether:ethyl acetate(v / v),1 / 1); 1 H NMR (400MHz, CDCl3) δ7.36-7.29(m,4H),7.23-7.19(m,4H),6.38(s,1H),4.11(dd,J =15.4,7.9Hz,1H),3.86-3.73(m,2H),3.41(dd,J=9.7,7.1Hz,1H),2.37(s,3H)ppm; 13C NMR (101MHz, CDCl3) δ194.0,171.4,140.2,138.7,134.4,130.1,129.3,128.4,123.4,62.2,47.5,4 3.5,21.4ppm; IR(KBr)2921,1722,1684,1597,1560,1494,1445,1324,1281,1091,1053,1013,821cm -1 ; HRMS (ESI-QTOF) m / z: [M+Na] + Calcd for,found;HPLC COSMOSIL 5A column,i-PrOH / n-hexane=30 / 70,25℃,1.0mL / min,λ=254nm,t R =12.91min(minor),t R =9.05min(major);[α] 20 D =-60.0(c=1.0,CHCl3); mp:127-130℃.

[0141] Embodiment 27

[0142] Synthesis of compound of formula (7b)

[0143]

[0144] The starting material was the addition product 6b (96% ee) (500 mg, 1.1 mmol, 1.0 equiv.), and the remaining steps were carried out according to the operation process of the above Example 24 to obtain the product 7b in the form of a white solid, 314 mg, with a yield of 92% and an ee value of 94% ee. f =0.24 (petroleum ether / ethyl acetate (v / v), 1 / 1); 1 H NMR (400MHz, CDCl3) δ7.39-7.34(m,2H),7.30(d,J=8.2Hz,3H),7.28-7.25(m,2H),7.20(d,J=8.0Hz,2H),7.05(br s,1H),4.12(dd,J=15.4,8.0Hz,1H),3.83(t,J=9.2Hz,2H),3.45(dd,J=9.7,7.1Hz,1H),2.36(s,3H)ppm; 13C NMR (101MHz, CDCl3) δ194.2,172.1,140.4,140.1,134.4,130.1,129.1,127.7,127.0,123.6,62.6,47.9,44 .2,21.4ppm; IR(KBr)1712,1686,1656,1598,1493,1470,1429,1318,1264,1128,1060,1009,912,822,754cm -1 ; HRMS (ESI-QTOF) m / z: [M+H] + Calcd for C 18 H 18 SNO2312.1058, found312.1056; HPLC COSMOSIL 5A column, i-PrOH / n-hexane=30 / 70, 25℃, 1.0mL / min, λ=254nm, t R =7.47min(minor),t R =8.53min(major);[α] 20 D =-23.9(c=1.0,CHCl3); mp:100-104℃.

[0145] Embodiment 28

[0146] Synthesis of compounds of formula (R)-baclofen

[0147]

[0148] Lactam 7a was refluxed in 6N HCl (1.0 mL) for 24 h. After cooling, the reaction mixture was washed with EtOAc. The volatile components were removed under reduced pressure to obtain 60 mg of white (R)-baclofen in the form of hydrochloride with a yield of 90%; 1 H NMR(400MHz,D2O)δ7.41-7.37(m,2H),7.31-7.27(m,2H),3.42-3.30(m,2H),3. 22-3.15(m,1H),2.81(dd,J=16.1,5.9Hz,1H),2.69(dd,J=16.1,8.8Hz,1H)ppm; 13 C NMR (101MHz, D2O) δ175.3,137.0,133.4,129.4,129.3,43.6,39.4,38.2ppm.

[0149] Embodiment 29

[0150] Synthesis of compounds of formula (R)-phenibut

[0151]

[0152] The starting material was lactam 7b (96 mg, 0.31 mmol), and the remaining steps were performed according to the above Example 26. The yield of 58 mg was 87% of white (R)-phenibut. 1 H NMR (400MHz, D2O) δ5.40-5.35(m,2H),5.33-5.29(m,3H),1.40-1.29(m,2H),1.23-1.15(m,1H),0.83-0.77(m,1H),0.74-0.62(m,1H)ppm; 13 C NMR (101MHz, D2O) δ175.5,138.4,129.4,128.3,127.9,43.8,40.0,38.2ppm.

[0153] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A chiral pentafluorophenyl urea compound, characterized in that: The structural formula of the compound is shown in Formula I: Among them, R 1 Selected from II, ent-II, III, ent-III, IV or V as follows; R 2 is selected from hydrogen, methyl, benzyl; R 3 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkylthio; R 4 Selected from C1-C6 alkyl, such as methyl, ethyl, etc.; R 5 is selected from hydrogen or methoxy; R 6 Selected from vinyl or ethyl.

2. The chiral pentafluorophenyl urea compound according to claim 1, characterized in that The chiral pentafluorophenyl urea compound is selected from the compounds shown in Formula IB, Formula IC, Formula ID, Formula IE, Formula IF, Formula IG, Formula IH or Formula II: 。 3. A method for preparing chiral pentafluorophenyl urea, characterized in that: The technical route of the preparation method is shown in Formula A Among them, R 1 Selected from II, ent-II, III, ent-III, IV or V below.

4. The method for preparing chiral pentafluorophenyl urea according to claim 3, characterized in that: The method comprises the following steps: adding pyridine and 4-nitrophenyl chloroformate 2 to pentafluoroaniline 1 dissolved in dichloromethane solvent, and stirring at room temperature for time 1; then adding compound 3 to the reaction solution obtained in the above step, and then adding N,N-diisopropylethylamine (DIPEA), stirring at room temperature for time 2, to obtain compound (I).

5. The method for preparing chiral pentafluorophenyl urea according to claim 3 or 4, characterized in that: In terms of molar amount, the amount of pyridine is 1.1 times that of pentafluoroaniline; the amount of 4-nitrobenzene chloroformate is 1.1 times that of pentafluoroaniline; the amounts of N,N-diisopropylethylamine and compound 3 are 1.1 and 1 times that of pentafluoroaniline, respectively.

6. The method for preparing a chiral pentafluorophenyl urea compound as claimed in claim 3, 4 or 5, characterized in that: The time 1 is 0.5 to 12 hours, and the time 2 is 1 to 12 hours.

7. Application of a chiral pentafluorophenyl urea (I) in the preparation of a desired enantiomer of a GABA analogue 8, the technical route of which is shown in Formula B: It is characterized in that Chiral pentafluorophenyl urea (I) catalyzes the asymmetric addition reaction of malonate dithioester 4 and nitroolefin 5 in an aqueous solvent to prepare the desired enantiomer of compound 6. Due to the hydrophobic hydration effect, the reaction rate and stereoselectivity are significantly improved compared with those in an organic solvent, and the amount of catalyst can be significantly reduced. Subsequently, compound 6 is treated with zinc / acetic acid and titanium chloride to undergo nitro reduction and lactamization to produce chiral γ-lactam 7. Finally, compound 7 is hydrolyzed under acid conditions to obtain GABA analog 8. Where R 7 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, unsubstituted or substituted by (R) m Substituted aryl, aryloxy, aromatic C1-C6 alkyl or heteroaryl; m is selected from 1, 2, 3, 4 or 5, when m>1, R can be the same or different; preferably selected from phenyl, 4-fluorophenyl, 4-Cl phenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2-furyl, 2-thienyl, 2-naphthyl, cyclohexyl; R 8 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, benzyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, trifluoroethyl or 2-pyridyl; preferably one of methyl, ethyl, n-propyl, phenyl, benzyl, p-tolyl or p-methoxyphenyl; R 9 One selected from hydrogen, bromine and methyl; The amount X mol % of chiral pentafluorophenyl urea (I) used in the asymmetric addition reaction of compounds 4 and 5 is 0.1 to 30 mol %; The asymmetric addition reaction of compounds 4 and 5 is carried out in pure water or saturated sodium chloride aqueous solution, and an organic solvent is added; the organic solvent is selected from: one or more of hydrocarbon organic solvents, halogenated hydrocarbon organic solvents, and ether organic solvents; the hydrocarbon organic solvent is preferably one or more of toluene, xylene, trimethylbenzene, phenol, pentane, hexane, octane, and cyclohexane; the halogenated hydrocarbon organic solvent is preferably one or more of chlorobenzene, dichlorobenzene, dichloromethane, and chlorobenzene; the ether organic solvent is preferably one or more of ethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, and diethylene glycol dimethyl ether; the organic solvent is more preferably toluene, xylene, trimethylbenzene, n-hexane, chlorobenzene, dichloromethane, and ethyl ether; and / or, the asymmetric addition reaction time of the compounds 4 and 5 is 0.5 h to 48 h, preferably 3 h to 36 h, And / or, the temperature of the asymmetric addition reaction of compounds 4 and 5 is -78°C to 100°C, preferably 0°C to 50°C, more preferably 25°C.

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