Method for electrochemical synthesis of chiral beta-ester nitrile and application of chiral beta-ester nitrile in synthesis of baclofen and roripram

Abstract

The invention discloses a method for electrochemical synthesis of chiral beta-ester nitrile and application of the chiral beta-ester nitrile in synthesis of baclofen and rolipram. The method comprises the following steps: in the presence of a chiral catalyst, performing electrochemical anodic oxidation reaction on olefin as shown in a formula I, alkoxy hydrazide as shown in a formula II and TMSCN or cyano salt to obtain chiral beta-ester nitrile as shown in a formula III, the chiral catalyst is composed of a copper salt and a chiral bisoxazoline ligand. According to the method, the olefin which is low in price, easy to obtain and wide in source is adopted as the raw material, the chiral beta-ester nitrile is constructed through anodic oxidation under the electrochemical condition, the yield is high, and enantioselectivity control is good. According to the present invention, the synthesis method has characteristics of simpleness, high efficiency, further amplification reaction, excellent yield and good control of the chiral center of the product, and can be used for synthesizing chiral gamma-lactam and chiral gamma-aminobutyric acid, such as (R)-baclofen, (R)-Rolipram and (R)-phenibt. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for electrochemically synthesizing chiral β-ester nitriles and their application in the synthesis of baclofen and rolipram. Background Art

[0002] Alkenes are a class of basic chemical raw materials with extremely wide sources and low costs. At the same time, relying on their unique carbon-carbon double bond structure, they exhibit extremely rich chemical reaction activities in the field of organic synthesis. Among them, the metal-catalyzed difunctionalization reaction of alkenes is a very effective means, which can use alkenes to construct complex chemical structures, and thus be efficiently transformed into various bioactive organic synthesis intermediates, drug precursors and natural products, with very high atom economy and step economy, and are widely used in medicine, pesticides, materials, biology, etc. Therefore, it has always been a research hotspot in organic synthesis.

[0003] Organic electrochemistry synthesis is an efficient synthesis method, which can use "electrons" to replace traditional stoichiometric oxidants or reductants, avoiding the use of toxic oxidation and reduction reagents and the generation of corresponding pollutants. Therefore, electrochemistry synthesis has excellent atom economy, avoids waste of resources, and significantly reduces production costs; at the same time, the electrochemistry synthesis process is green and environmentally friendly, showing good sustainability. In addition, electrochemistry synthesis provides mild reaction conditions, showing high reaction activity and excellent chemoselectivity, and a wider range of substrate applicability. The development of electrochemistry synthesis provides new strategies and opportunities for synthetic chemistry.

[0004] As a class of crucial organic intermediates, β-ester nitriles play a pivotal role in the field of drug synthesis. Its core value lies in the ability to achieve directional conversion to γ-lactams and γ-amino acids through a series of efficient chemical reactions, and it is widely used in modern small molecule drugs, especially in antidepressant drugs and GABA (γ-aminobutyric acid) receptor selective agonists. Therefore, developing a simple, efficient and green sustainable method for synthesizing β-ester nitriles has become a research hotspot and frontier direction in the field of medicinal chemistry. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for electrochemically synthesizing chiral β-ester nitriles, which is obtained by electrochemically synthesizing alkenes, alkoxy hydrazides, TMSCN or cyanide salts under the catalysis of copper and chiral bisoxazoline ligands. The reaction conditions are mild, and the raw materials alkoxy hydrazides and TMSCN are commercially available, which can achieve higher yields and chiral control, and can be applied in large quantities.

[0006] The chiral β-ester nitrile electrochemically synthesized by the method of the present invention is an intermediate for synthesizing chiral Baclofen, Rolipram, and Phenibut.

[0007] Specifically, the electrochemical synthesis method for constructing chiral β-ester nitrile from olefins provided by the present invention includes the following steps:

[0008] In the presence of a chiral catalyst, the olefin shown in Formula I, the alkoxy hydrazide shown in Formula II, TMSCN (trimethylsilyl cyanide) or a cyanide salt undergo an electrochemical reaction in an electrolyte to obtain the chiral β-ester nitrile product shown in Formula III;

[0009]

[0010] In Formula I, R 1 is selected from a substituted or unsubstituted C 1-20 hydrocarbon group (alkyl, alkynyl, alkenyl), a substituted or unsubstituted C 6-20 aryl, a substituted or unsubstituted C 4-20 heteroaryl, a substituted or unsubstituted C 1-20 alkyl-O-CO-; R 2 is selected from hydrogen, a substituted or unsubstituted C 1-20 alkyl, wherein the number of carbon atoms of the hydrocarbon group is preferably 1-8, the number of carbon atoms of the aryl is preferably 6-10, the number of carbon atoms of the heteroaryl is preferably 4-10, and the number of carbon atoms of the alkyl-O-CO- is preferably 1-10;

[0011] The chiral catalyst is composed of a copper salt and a chiral bisoxazoline ligand.

[0012] In Formula II, R 3 is selected from a substituted or unsubstituted C 1-20 alkyl, a substituted or unsubstituted C 1-20 alkoxy, a substituted or unsubstituted C 6-20 aryl, a substituted or unsubstituted C 1-20 heteroaryl, wherein the number of carbon atoms of the alkyl is preferably 1-8, the number of carbon atoms of the alkoxy is preferably 1-8, the number of carbon atoms of the aryl is preferably 6-10, and the number of carbon atoms of the heteroaryl is preferably 4-10.

[0013] In any part of the present invention, the substituents in the expression "substituted or unsubstituted" are selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 acyl, halogen, -NO 2 , -CN, -OH, C 6-20 aryl, C 8-20 arylethynyl, C3-20 cycloalkyl, C 6-20 alkyl-O-CO-. For those skilled in the art, it can be understood that the number of substituents in the expression "substituted or unsubstituted" as referred to herein can be one or more. For example, when it is a substituted phenyl group, it can have one, two, three, four or five substituents, and the upper limit of the number of substituents depends on the sites where the group can be substituted.

[0014] In the method of the present invention, the copper salt is selected from CuI, CuOAc, Cu(OAc) 2 , Cu(OTf) 2 , Cu(BF 4 ) 2 , Cu(MeCN) 4 BF 4 , Cu(MeCN) 4 PF 6 , CuF 2 , CuCl 2 , CuBr 2 , CuF, CuCl, CuBr, CuSO 4 , Cu 2 SO 4 , Cu(OTf) 2 , Cu(OTf), Cu(ClO 4 ), Cu(ClO 4 ) 2 , CuSCN, Cu(acac) 2 , Cu(acac) and at least one of them.

[0015] The chiral bisoxazoline ligand is at least one of the compounds shown by the following formula and its opposite configuration:

[0016]

[0017] Wherein, n = 1 to 10; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 are selected from H, substituted or unsubstituted C 1-20 alkyl, substituted or unsubstituted C 1-20 alkoxy, substituted or unsubstituted C 1-20 alkyl-O-CO-, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 1-20 heteroaryl. The substituents in the expression "substituted or unsubstituted" are selected from C 1-6alkyl group of, C 1-6 alkoxy group of, C 1-6 acyl group of, halogen, -NO 2 , -CN, -OH, C 6-20 aryl group of, C 8-20 arylethynyl group of, C 3-20 cycloalkyl group of, C 6-20 alkyl-O-CO-.

[0018] Further preferably, R 9 , R 10 is selected from C 1-5 alkyl group; R 11 is selected from C 6-10 aryl group;

[0019] Further preferably, R 12 is selected from C 1-5 alkyl group;

[0020] Further preferably, n = 1 to 3.

[0021] The electro-chemical reaction of the present invention is carried out under the protection of an inert gas, and the inert gas can specifically be nitrogen or argon.

[0022] The electro-chemical reaction of the present invention is carried out in an electrolytic cell, and the electrolyte used in the electro-chemical reaction is at least one of TBABF 4 , TBAPF 6 , TBAOTf, TBAOAc, TBABr, TBACl, TBAI, NaCl, LiCl, LiClO 4 ; wherein, the electrolyte concentration is 0.001 to 10 mol / L.

[0023] The conditions of the electro-chemical reaction are: current 1 to 200 mA; constant current reaction for 1 to 72 h, or voltage 2 to 5 V, constant voltage reaction for 1 to 72 h; reaction temperature is 0 to 40 °C.

[0024] The proton sacrificial agent used in the electro-chemical reaction is at least one of methanol, ethanol, trifluoroethanol, isopropanol, hexafluoroisopropanol, water, formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, benzoic acid; wherein, the proton sacrificial agent concentration is 0.001 to 100 mol / L.

[0025] The organic solvent used in the electro-chemical reaction of the present invention is N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetonitrile, tetrahydrofuran, dichloroethane; the volume is 0.005 - 20 mol / L based on the amount of substance of the olefin.

[0026] The molar ratio of the alkene shown in Formula I, the alkoxyacyl hydrazide shown in Formula II, TMSCN or the cyanide salt, the copper salt, and the bisoxazoline ligand is 1:(0.2 - 5):(0.2 - 5):(0.001 - 0.6):(0.001 - 0.6), preferably 1:1.1 - 3:1.1 - 3:0.001 - 0.1:0.001 - 0.1.

[0027] The anode material of the electrolytic cell is a carbon material, and the carbon material is any one of carbon felt, graphite rod, RVC, carbon cloth, and glassy carbon electrode; the cathode material of the electrolytic cell is any one of Co, Mg, Pt, Ni, Fe, Cu, Ag, and Au sheets.

[0028] The electrochemical reaction device is an electrolytic cell, and the electrolytic cell is a diaphragm-free electrolytic cell or a divided electrolytic cell.

[0029] Specifically, the operation steps of the electrochemical synthesis method for constructing chiral β-ester nitrile from alkene provided by the present invention are as follows:

[0030] The copper salt and the chiral bisoxazoline ligand are stirred in advance in an organic solvent to form a chiral copper catalyst solution. Under the protection of an inert gas, the alkene shown in Formula I, the alkoxyacyl hydrazide shown in Formula II, and the catalyst solution are respectively added into the electrolytic cell. Using the carbon material electrode as the anode and the metal material electrode as the cathode, the power supply is turned on under the protection of an inert gas, stirred at 0 - 40°C, and reacted at a constant current of 1 - 200 mA for 1 - 72 h, then the power supply is turned off; the organic solvent is removed by rotary evaporation, and the obtained crude product is purified by silica gel column chromatography to obtain the chiral β-ester nitrile product shown in Formula III.

[0031] The present invention uses an alkene that is cheap, easily available, and has a wide source as a raw material, and constructs chiral β-ester nitrile by anodic oxidation under electrochemical conditions, which not only has a high yield but also has good enantioselectivity control. The synthesis method of the present invention is simple and efficient, can be further scaled up for reaction, has an excellent yield, and the chiral centers of the products are well controlled, and can be used for the synthesis of chiral γ-lactam and γ-aminobutyric acid, for example, (R)-Baclofen, (R)-Rolipram, and (R)-Phenibut. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is a reaction flow chart for preparing the target product in Examples 1 and 5 of the present invention.

[0033] Figure 2 It is a reaction flow chart for preparing the target product in Example 2 of the present invention.

[0034] Figure 3This is the reaction flow chart for preparing the target product and synthesizing (R)-Baclofen in Example 3 of the present invention.

[0035] Figure 4 This is the reaction flow chart for preparing the target product and synthesizing (R)-Rolipram in Example 4 of the present invention. Detailed implementation manners

[0036] The present invention will be further described in detail below in conjunction with the specific implementation manners. The examples given are only for clarifying the present invention, rather than limiting the scope of the present invention. The following examples can be used as a guide for those of ordinary skill in the art to make further improvements, and do not limit the present invention in any way.

[0037] The experimental methods in the following examples are all conventional methods unless otherwise specified, and are carried out according to the techniques or conditions described in the literature in this field or according to the product instructions. The materials, reagents, etc. used in the following examples can be obtained from commercial sources unless otherwise specified.

[0038] Example 1

[0039] The reaction equation is as Figure 1 shown.

[0040] Small-scale reaction: A dry reaction tube with a magnetic stir bar, a carbon felt anode (1.0×1.5 cm 2 , connected by a graphite rod 9.0 cm long and 2.0 mm in diameter) and a Pt sheet cathode (1.0×0.5 cm 2 ), add TBAPF 6 (0.3 mmol, 0.1 M), methyl carbazate (0.3 mmol), and then under a nitrogen atmosphere, successively add Cu(OTf) 2 (0.0015 mmol, 1 mol%), chiral bisoxazoline ligand L1 (0.0045 mmol, 3 mol%) solution, 2-vinylnaphthalene (0.15 mmol), TMSCN (0.3 mmol), AcOH (1 mmol), and acetonitrile (a total of 3 mL, 2 mL). Stir at room temperature, react at a constant current of 9 mA for 4 h under an inert atmosphere, terminate the electrolysis, remove the organic solvent from the reaction solution by rotary evaporation to obtain a crude product, purify by column chromatography, collect the eluate containing the target compound, and remove the solvent by rotary evaporation to obtain 28.7 mg of the target product with a yield of 80% and 92% ee. The product is a white solid, R f = 0.49 (PE:EA = 5:1). [α] D 29 = +5.5 (c = 1.27, CHCl 3)。The ee value was determined by HPLC using a Daicel Chiralcel OD-H column (n-hexane solution of 20% isopropanol, 1.0 mL / min, 224 nm, main peak t r = 19.68 min, minor peak t r = 15.99 min). 1 1H NMR (400 MHz, Chloroform-d) δ 7.93–7.78 (m, 4H), 7.58–7.48 (m, 2H), 7.44 (dd, J = 8.4, 2.0 Hz, 1H), 4.48 (dd, J = 8.2, 6.7 Hz, 1H), 3.73 (s, 3H), 3.11 (dd, J = 16.6, 8.2 Hz, 1H), 2.95 (dd, J = 16.6, 6.7 Hz, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.6, 133.3, 133.0, 131.6, 129.4, 128.0, 127.8, 126.9, 126.8, 126.7, 124.6, 119.9, 52.4, 39.8, 33.4. IR (KBr): 2947, 2240, 1731 cm -1 .

[0041] Example 2

[0042] The reaction equation is as Figure 2 shown.

[0043] Small-scale reaction: A dry reaction tube with a magnetic stir bar, a carbon felt anode (1.0 × 1.5 cm 2 , connected by a graphite rod 9.0 cm long and 2.0 mm in diameter) and a Pt sheet cathode (1.0 × 0.5 cm 2 ) was charged with TBAPF 6 (0.3 mmol, 0.1 M), methyl carbazate (0.3 mmol), and then, under a nitrogen atmosphere, a solution of Cu(OTf) 2 (0.0015 mmol, 1 mol%), chiral bisoxazoline ligand L2 (0.0045 mmol, 3 mol%), 1-(but-3-en-1-yn-1-yl)-4-methoxybenzene (0.15 mmol), TMSCN (0.3 mmol), AcOH (1 mmol), and acetonitrile (3 mL in total). Stir at room temperature and react at a constant current of 9 mA for 4 h under an inert atmosphere. Terminate the electrolysis, remove the organic solvent from the reaction solution by rotary evaporation to obtain the crude product, purify it by column chromatography, collect the eluate containing the target compound, and remove the solvent by rotary evaporation to obtain 19.1 mg of the target product with a yield of 50% and 84% ee. The product is a colorless oil, R f= 0.39 (PE:EA = 5:1). [α] D 25 = +5.5 (c = 1.27, CHCl 3 ). The ee value was determined by HPLC using a Daicel Chiralcel AD-H column (n-hexane solution of 2.5% isopropanol, 1.0 mL / min, 251 nm, main peak t r = 30.31 min, minor peak t r = 26.87 min). 1 H NMR (400 MHz, Chloroform-d) δ 7.36 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.32–4.14 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.11–2.89 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 169.1, 160.4, 133.5, 116.9, 114.2, 113.4, 84.7, 78.4, 55.5, 52.7, 38.0, 20.4. HRMS (ESI) calcd for [C14H12NO3]([M-H] - ): 242.0823, found: 242.0819. IR (KBr): 2919, 2854, 2245, 1738 cm -1 .

[0044] Example 3

[0045] The reaction equation is as Figure 3 shown.

[0046] Small-scale reaction: A dry reaction tube equipped with a magnetic stir bar, a carbon felt anode (1.0 × 1.5 cm 2 , connected by a graphite rod 9.0 cm long and 2.0 mm in diameter) and a Pt sheet cathode (1.0 × 0.5 cm 2 ), was charged with TBAPF 6 (0.3 mmol, 0.1 M), methyl carbazate (0.3 mmol), and then, under a nitrogen atmosphere, Cu(OTf) 2(0.0015 mmol, 1 mol%) and chiral bisoxazoline ligand L3 (0.0045 mmol, 3 mol%) solution, 4-chlorostyrene (0.15 mmol), TMSCN (0.3 mmol), AcOH (1 mmol), and acetonitrile (total 3 mL). Stir at room temperature, react at a constant current of 9 mA under an inert atmosphere for 4 h, terminate the electrolysis, remove the organic solvent from the reaction solution by rotary evaporation to obtain the crude product, purify by column chromatography, collect the eluate containing the target compound, and rotary evaporate to remove the solvent to obtain 22.5 mg of the product with a yield of 67% and 90% ee. The product is a colorless oil, R f = 0.49 (PE:EA = 5:1). [α] D 25 = +5.1 (c = 1.07, CHCl 3 ). The ee value was determined by HPLC using a Daicel Chiralcel OJ-H column (n-hexane solution of 20% isopropanol, 1.0 mL / min, 221 nm, main peak t r = 16.79 min, minor peak t r = 15.13 min). 1 H NMR (400 MHz, Chloroform-d) δ 7.37 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.28 (t, J = 7.4 Hz, 1H), 3.71 (s, 3H), 3.01 (dd, J = 16.7, 7.8 Hz, 1H), 2.83 (dd, J = 16.7, 7.0 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 169.4, 134.7, 132.9, 129.5, 128.8, 119.5, 52.5, 39.6, 32.6. IR (KBr): 2956, 2251, 1740 cm -1 .

[0047] The obtained target product was used for the synthesis of (R)-Baclofen:

[0048] NaBH 4 (1.0 mmol, 5.0 equiv) was slowly added to the above product (0.2 mmol) and NiCl 2 ·6H 2In a methanol solution (4 mL) of O (0.40 mmol, 2.0 equiv). The reaction was stirred at room temperature for 1 h under an argon atmosphere and then quenched with saturated ammonium chloride solution. The mixture was filtered through celite, concentrated, and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was then purified by column chromatography to give 26.5 mg of (R)-4-(4-chlorophenyl)pyrrolidin-2-one, a white solid, in 68% yield and 82% ee.

[0049] (R)-4-(4-Chlorophenyl)pyrrolidin-2-one (26.5 mg, 0.136 mmol) was added to concentrated hydrochloric acid (1 mL), and the mixture was heated and stirred at 100 °C for 24 h. The resulting mixture was filtered through a celite pad, and the solvent was removed by rotary evaporation to give 27.5 mg of (R)-Baclofen, a white solid product, in an overall yield of 65% and 90% ee.

[0050] [α] D 29 = -3.2 (c = 0.58, H 2 O). 1 H NMR (400 MHz, Deuterium Oxide) δ 7.64–7.16 (m, 4H), 3.53–3.36 (m, 2H), 3.28 (t, J = 11.7 Hz, 1H), 2.89 (dd, J = 16.1, 5.7 Hz, 1H), 2.79 (dd, J = 16.1, 8.7 Hz, 1H). 13 C NMR (126 MHz, Deuterium Oxide) δ 175.5, 138.3, 129.4, 128.3, 127.9, 43.8, 39.9, 38.3.

[0051] Example 4,

[0052] The reaction equation is as Figure 4 shown.

[0053] Small-scale reaction: A dry reaction tube equipped with a magnetic stir bar, a carbon felt anode (1.0 × 1.5 cm 2 , connected by a graphite rod 9.0 cm long and 2.0 mm in diameter) and a Pt sheet cathode (1.0 × 0.5 cm 2 ) was charged with TBAPF 6 (0.3 mmol, 0.1 M), methyl carbazate (0.3 mmol), and then, under a nitrogen atmosphere, Cu(OTf) 2(0.0015 mmol, 1 mol%) and chiral bisoxazoline ligand L3 (0.0045 mmol, 3 mol%) solution, 2-(cyclopentyloxy)-1-methoxy-4-vinylbenzene (0.15 mmol), TMSCN (0.3 mmol), AcOH (1 mmol), and acetonitrile (total 3 mL). Stir at room temperature, react at a constant current of 9 mA under an inert atmosphere for 4 h, terminate the electrolysis, remove the organic solvent from the reaction solution by rotary evaporation to obtain the crude product, purify by column chromatography, collect the eluate containing the target compound, and rotary evaporate to remove the solvent to obtain 20.5 mg of the target product with a yield of 45% and 82% ee. The product is a white solid, R f = 0.31 (PE:EA = 5:1). [α] D 29 = +4.6 (c = 1.50, CHCl 3 ). The ee value was determined by HPLC using a Daicel Chiralcel OD-H column (a solution of 20% isopropanol in n-hexane, 1.0 mL / min, 208 nm, main peak t r = 8.02 min, minor peak t r = 9.13 min). 1 H NMR (300 MHz, Chloroform-d) δ 6.98–6.72 (m, 3H), 4.81 - 4.73 (m, 1H), 4.22 (t, J = 7.5 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 3.00 (dd, J = 16.5, 8.0 Hz, 1H), 2.82 (dd, J = 16.5, 6.9 Hz, 1H), 2.02–1.74 (m, 6H), 1.70–1.53 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 169.7, 150.1, 148.1, 126.6, 120.1, 119.4, 113.8, 112.2, 80.6, 56.0, 52.3, 40.0, 32.7, 32.7, 32.7, 24.0. HRMS (APCI) calcd for [C17H20NO4]([M-H] - ): 302.1398, found: 302.1394. IR (KBr): 2956, 2245, 1735 cm -1 .

[0054] The obtained target product was used for the synthesis of (R)-Rolipram:

[0055] Add NaBH 4(1.0 mmol, 5.0 equiv) was slowly added to a methanol solution (4 mL) of the above product (0.2 mmol) and NiCl 2 ·6H 2 O (0.40 mmol, 2.0 equiv). The reaction was stirred at room temperature for 1 h under an argon atmosphere and then quenched with saturated ammonium chloride solution. The mixture was filtered through celite, concentrated, and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was then purified by column chromatography to give 36.7 mg of (R)-Rolipram in 66% yield and 82% ee.

[0056] R f =0.2 (EtOAc). [α] D 29 = -6.8 (c = 1.40, CHCl 3 ). 1 H NMR (300 MHz,

[0057] Chloroform-d) δ 6.95–6.64 (m, 3H), 6.05 (s, 1H), 4.83–4.71 (m, 1H), 3.83 (s, 3H), 3.75 (t, J = 8.6 Hz, 1H), 3.62 (p, J = 8.2 Hz, 1H), 3.47–3.21 (m, 1H), 2.71 (dd, J = 16.9, 8.8 Hz, 1H), 2.46 (dd, J = 16.8, 8.8 Hz, 1H), 2.03–1.73 (m, 6H), 1.66–1.51 (m, 2H). 13 C NMR (126 MHz, Chloroform-d) δ 177.6, 149.2, 147.9, 134.5, 118.8, 113.8, 112.2, 80.6, 56.2, 49.7, 40.0, 38.1, 32.8, 24.1. IR (KBr): 3200, 3095, 2957, 1679, 1516 cm -1 .

[0058] Example 5,

[0059] The reaction equation is as Figure 1 shown.

[0060] Large-scale reaction: A dry flask equipped with a Teflon magnetic stir bar, a carbon felt anode (2.0 × 3.5 cm 2 , connected by a graphite rod 9.0 cm long and 2.0 mm in diameter) and a Pt sheet cathode (1.0 × 0.5 cm 2 ), was charged with TBAPF 6(0.3 mmol, 0.1 M), methyl carbazate (12.0 mmol), and then, under a nitrogen atmosphere, Cu(OTf) was added successively 2 (0.03 mmol, 0.5 mol%), a solution of chiral bisoxazoline ligand L1 (0.09 mmol, 1.5 mol%), 2-vinylnaphthalene (6.0 mmol), TMSCN (12 mmol), AcOH (2400 mg, 40 mmol), and acetonitrile (85 mL). Stir at room temperature, react at a constant current of 22 mA for 48 h under an inert atmosphere, terminate the electrolysis, rotary evaporate to remove the reaction organic solvent to obtain a crude product, purify the product by column chromatography, collect the eluate containing the target compound, rotary evaporate to remove the solvent to obtain 889.1 mg of the target product, with a yield of 62% and 92% ee. The product is a white solid. The data are shown in Example 1.

[0061] Comparing with Example 1, it can be seen that the method of the present invention has the potential for large-scale production.

Claims

1. A method for electrochemically synthesizing chiral β-ester nitrile, comprising the following steps: In the presence of a chiral catalyst, the olefin represented by formula I, the alkoxy hydrazide represented by formula II and TMSCN or a cyanide salt are subjected to electrochemical anodic oxidation reaction to obtain a chiral β-ester nitrile represented by formula III; In Formula I, R 1 is selected from substituted or unsubstituted C 1-20 Hydrocarbon, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted C 4-20 Heteroaryl, substituted or unsubstituted C 1-20 Alkyl-O-CO-; R 2 is selected from hydrogen, substituted or unsubstituted C 1-20 The alkyl group; In Formula II, R 3 is selected from substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted C 1-20 Alkoxy, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted C 1-20 heteroaryl; The chiral catalyst consists of copper salt and chiral bisoxazoline ligand.

2. The method according to claim 1, characterized in that: The copper salt is selected from CuI, CuOAc, Cu(OAc)2, Cu(OTf)2, Cu(BF4)2, Cu(MeCN)4BF4, Cu(MeCN)4PF6, CuF2, CuCl2, CuBr2, CuF, At least one of CuCl, CuBr, CuSO4, Cu2SO4, Cu(OTf)2, Cu(OTf), Cu(ClO4), Cu(ClO4)2, CuSCN, Cu(acac)2, Cu(acac).

3. The method according to claim 1 or 2, characterized in that: The chiral bisoxazoline ligand is at least one of a compound having the following structural formula and its opposite configuration: Wherein, n = 1 to 10; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 is selected from H, substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted C 1-20 Alkoxy, substituted or unsubstituted C 1-20 Alkyl-O-CO-, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted C 1-20 The heteroaryl group.

4. The method according to any one of claims 1 to 3, characterized in that: The conditions of the electrochemical anodic oxidation reaction are as follows 1) or 2): 1) The current is 1 to 200 mA; the constant current reaction time is 1 to 72 hours; 2) Voltage 2~5V, constant voltage reaction time 1~72h; The electrochemical anodic oxidation reaction is carried out under the protection of an inert gas, and the inert gas is nitrogen or argon.

5. The method according to any one of claims 1 to 4, characterized in that: The electrochemical anodic oxidation reaction is carried out in an electrolytic cell; The electrolyte used in the electrochemical anodic oxidation reaction is at least one of TBABF4, TBAPF6, TBAOTf, TBAOAc, TBABr, TBACl, TBAI, NaCl, LiCl, and LiClO4, with a concentration of 0.001-10 mol / L.

6. The method according to any one of claims 1 to 5, characterized in that: The proton sacrificial agent used in the electrochemical anodic oxidation reaction is at least one of methanol, ethanol, trifluoroethanol, isopropanol, hexafluoroisopropanol, water, formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, and benzoic acid, and the concentration is 0.001-100 mol / L.

7. The method according to any one of claims 1 to 6, characterized in that: The organic solvent used in the electrochemical anodic oxidation reaction is N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetonitrile, tetrahydrofuran, and dichloroethane, and the volume is 0.005-20 mol / L based on the amount of the olefin substance shown in formula I.

8. The method according to any one of claims 1 to 7, characterized in that: The anode material used in the electrochemical anodic oxidation reaction is a carbon material; the carbon material is any one of carbon felt, graphite rod, RVC, carbon cloth, and glassy carbon electrode; The cathode material used in the electrochemical anodic oxidation reaction is any one of Co, Mg, Pt, Ni, Fe, Cu, Ag, and Au sheets.

9. The method according to any one of claims 1 to 8, characterized in that: The molar ratio of the olefin represented by formula I, the alkoxy hydrazide represented by formula II, TMSCN or cyano salt, the copper salt and the bisoxazoline ligand is 1:(0.2-5):(0.2-5):(0.001-0.6):(0.001-0.6).

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