Pyridine ring C4-position alkyl derivative modified chiral pyridine biazoline ligand as well as synthesis method and application thereof

Abstract

The invention discloses novel pyridine ring C4-site alkyl derivative modified chiral pyridine biazoline ligands as shown in a formula (a) and a formula (b) and a synthesis method of the novel pyridine ring C4-site alkyl derivative modified chiral pyridine biazoline ligands. According to the method, starting from a simple and easily available raw material 4-halogenated-2, 6-dicyanopyridine, the pyridine ring C4-site alkoxy (sulfur, amine) modified pyridine bis-oxazoline PYBOX and pyridine bis-imidazoline PYBIM ligands can be obtained through simple 2 to 3 steps of conversion. The PYBOX and PYBIM ligands disclosed by the invention have the advantages of novel and unique structure, stable property and the like; the synthesis method disclosed by the invention has the advantages of simplicity, mild reaction conditions, simplicity and convenience in operation, wide application range and the like, and has a very wide application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compounds, and particularly relates to a class of chiral pyridine bisoxazoline ligands (including pyridine bisoxazoline PYBOX and pyridine bisimidazoline PYBIM) modified by alkyl derivatives at the C4 position of the pyridine ring, and their synthesis methods and applications. Background Art

[0002] Pyridine bisoxazoline (PYBOX) and pyridine bisimidazoline (PYBIM) ligands, as a series of C2-symmetric tridentate chiral ligands, play a very important role in the field of asymmetric catalysis. The PYBOX ligand was first synthesized by the Nishiyama group and applied to the asymmetric hydrosilylation of ketones to achieve the efficient asymmetric construction of chiral alcohol compounds (H. Nishiyama, et al, Organometallics 1989, 8, 846). The Lewis basicity of the nitrogen atoms on the pyridine ring and oxazoline ring of the PYBOX ligand makes it easy to form complex catalysts with various transition metals such as copper, nickel, iron, zinc, cobalt, rhodium, and iridium; at the same time, because the chiral centers of the ligand are relatively close to the coordinated metal, it has a stronger asymmetric induction effect on the reactions catalyzed by the central metal. Therefore, the PYBOX ligand is widely used in a variety of asymmetric catalytic reactions, such as cyclopropanation reactions, aldol reactions, carbonyl-ene reactions, Diels-Alder reactions, Friedel-Crafts reactions, Mannich reactions, Michael reactions, Strecker reactions, redox reactions, cycloaddition reactions, cross-coupling reactions, propargylic substitution reactions, etc. (G. Anilkumar, et al, Asian J. Org. Chem. 2018, 7, 1033).

[0003] In 2005, the Beller group first synthesized the PYBIM ligand and formed a chiral complex with the transition metal rhodium, realizing the asymmetric epoxidation of olefins to obtain chiral epoxy compounds with a maximum enantioselectivity of 71% (M. Beller, et al, Org. Lett. 2005, 7, 3393). The PYBIM ligand not only has the good coordination ability and high chiral induction ability of the PYBOX ligand; but also can modify the imidazole ring through N-functionalization reactions to improve the electrical properties of the coordinated nitrogen atoms and the chiral environment of the central metal, thereby regulating the reaction activity and the stereoselectivity of catalytic asymmetric reactions. Therefore, in recent years, the PYBIM ligand has gradually been widely used in the fields of oxidation reactions, propargylic substitution reactions, Mannich reactions, Michael reactions, etc.

[0004] Given the unique and very important roles of PYBOX ligands and PYBIM ligands in the field of asymmetric catalysis, the design and development of novel ligands with diverse structures have gradually attracted the attention of organic chemists. Modifying the type of substituents at the C4 position of the pyridine ring to regulate steric hindrance and electronic properties is one of the important methods for constructing diverse PYBOX and PYBIM ligands. For example, in 2021, a research team found that PYBOX ligands with phosphonate substituents at the C4 position of the pyridine ring could significantly improve the enantioselectivity of the asymmetric CuAAC reaction involving tertiary alcohol substrates (Jian Zhou, et al, Angew. Chem. Int. Ed. 2021, 60, 8488); recently, another research team introduced an electron-withdrawing sulfonyl substituent at the pyridine C4 position of the PYBOX ligand, achieving high enantioselectivity in the asymmetric CuAAC reaction of tetrasubstituted alkyl azides (Jian Zhou, et al, Angew. Chem. Int. Ed. 2023, 62, e202301470). After more than 30 years of continuous development, so far, scientists have mainly achieved the synthesis of four types of PYBOX-type ligands modified at the C4 position of the pyridine ring. The first type is halogen substitution, mainly concentrated on chlorine, bromine, or iodine substitution; the second type is simple oxygen or nitrogen substitution; the third type is alkyl or aryl substitution; the fourth type is substitution with other types of heteroatoms, such as sulfonyl or phosphonate groups, etc. In the second and third types of ligands mentioned above, there is no report on the multi-functional group modification of the oxazole ring, and there is also no report on PYBIM ligands modified with different types of substituents at the C4 position.

[0005]

[0006] Although chemists have prepared a series of PYBOX with different substituents at the C4 position of the pyridine ring and PYBIM-type ligands without modification at the C4 position, the structures of these substituents are often relatively simple. There is still no report on PYBOX and PYBIM ligands modified with structurally diverse alkyl derivatives at the C4 position of the pyridine ring. Summary of the Invention

[0007] To address the deficiencies of the existing technology, the objective of the present invention is to provide a novel class of pyridine bisoxazoline ligands (including PYBOX, PYBIM, etc.) modified with alkyl derivatives at the C4 position of the pyridine ring and their synthesis methods. The pyridine bisoxazoline ligands have the advantages of novel and unique structures, stable properties, etc.; the synthesis methods have the advantages of simplicity, mild reaction conditions, easy operation, wide applicability, etc., and have very broad application prospects.

[0008] The specific technical solution to achieve the objective of the present invention is as follows:

[0009] The present invention provides a class of pyridine bisoxazoline ligands modified with alkyl derivatives at the C4 position of the pyridine ring. The pyridine bisoxazoline ligands include pyridine bisoxazoline (PYBOX) ligands and pyridine bisimidazoline (PYBIM) ligands. The structures of the PYBOX ligands and the PYBIM ligands are shown in the following formulas (a) and (b), respectively:

[0010]

[0011] Wherein:

[0012] X is an oxygen atom, a sulfur atom or a nitrogen atom;

[0013] In formula (a), n = 1 to 12; preferably, n = 1; when n = 1, the substituents R 1 , R 4 and R 5 are non-hydrogen functional groups;

[0014] In formula (b), n = 1 to 12; preferably, n = 1;

[0015] R 1 is hydrogen, chiral or achiral alkyl or aryl, etc.; preferably, R 1 is hydrogen, benzene ring, n-hexyl, cyclohexyl, etc.

[0016] R 2 , R 3 , R 4 , R 5 are independently selected from hydrogen, alkyl, aryl, aryl with substituents, etc.; preferably, selected from hydrogen, phenyl, methyl, benzyl, etc.;

[0017] Wherein, the substituent is an electron-withdrawing or electron-donating group;

[0018] The electron-withdrawing group is selected from halogen, trifluoromethyl, nitro, ester group, cyano, etc.; preferably, selected from fluorine atom, trifluoromethyl, cyano, etc.;

[0019] The electron-donating group is selected from C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, C1-C10 alkylamino, etc.; preferably, selected from methyl, methoxy, dimethylamino, etc.;

[0020] R 2 and R 4 may form a ring or not, and when R 2 and R 4 form a ring, it is an aliphatic ring, an aromatic ring, an aliphatic ring containing heteroatoms or an aromatic ring; preferably, it is a benzene ring, a pyridine ring, a cyclohexyl, etc.; the heteroatoms include an oxygen atom, a sulfur atom, a nitrogen atom, etc.;

[0021] R 3and R 5 form a ring or not with each other, when R 3 and R 5 form a ring, it is an alicyclic ring, an aromatic ring, an alicyclic ring containing a heteroatom or an aromatic ring; preferably, it is a benzene ring, a pyridine ring, a cyclohexyl group, etc.; the heteroatoms include an oxygen atom, a sulfur atom, a nitrogen atom, etc.;

[0022] R 6 is selected from an acyl group, a sulfonyl group, a phosphoryl group, an alkyl group or an aryl group; preferably, it is an acetyl group, a benzenesulfonyl group, a benzyl group, etc.

[0023] The present invention also provides a method for synthesizing a pyridine bisoxazoline ligand PYBOX and a pyridine bisimidazoline ligand PYBIM shown in formula (a) and formula (b), comprising the following steps:

[0024] Step (1): In a first solvent, 4-halo-2,6-dicyanopyridine undergoes a substitution reaction with an alkyl compound to obtain 2,6-dicyanopyridine A substituted with a 4-alkyl derivative; the alkyl compound includes an alkyl primary alcohol, an alkyl mercaptan, an alkylamine compound, etc.; the alkyl derivative includes an alkoxy group, an alkylthio group, an alkylamino group, etc.;

[0025] Step (2): In a second solvent, the 2,6-dicyanopyridine A substituted with a 4-alkyl derivative first generates an active intermediate iminoester under the action of a base, and then undergoes a ring closure reaction with a chiral amino alcohol to obtain a pyridine bisoxazoline ligand PYBOX substituted with an alkyl derivative at the C4 position of the pyridine ring; or,

[0026] In a second solvent, the 2,6-dicyanopyridine A substituted with a 4-alkyl derivative first generates an active intermediate iminoester under the action of a base, and then undergoes a ring closure reaction with a chiral diamine to obtain a pyridine bisimidazoline ligand substituted with an alkyl derivative at the C4 position of the pyridine ring;

[0027] Step (3): In a third solvent, under the action of a base, the pyridine bisimidazoline ligand substituted with an alkyl derivative at the C4 position of the pyridine ring undergoes a substitution acylation or alkylation reaction with an acylation or alkylation reagent to obtain an N-functionalized pyridine bisimidazoline ligand PYBIM substituted with an alkyl derivative at the C4 position of the pyridine ring;

[0028] The synthesis reaction is shown in the following reaction formulas (I) and (II):

[0029]

[0030] In step (1),

[0031] the molar ratio of the 4-halo-2,6-dicyanopyridine to the alkyl compound is 1.0:(1.2 - 2.5); preferably, the molar ratio is 1.0:1.2;

[0032] The halogens include fluorine, chlorine, bromine, iodine, etc.; preferably, it is chlorine;

[0033] The first solvent is one or more of dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, etc.; preferably, it is acetonitrile;

[0034] The temperature of the substitution reaction is 60-120 °C; preferably, it is 80 °C;

[0035] The time of the substitution reaction is 5-24 h; preferably, it is 10 h.

[0036] In step (2),

[0037] The second solvent is one or more of methanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, etc.; preferably, it is methanol;

[0038] The base is one or more of sodium iodide, sodium methoxide, sodium, etc.; preferably, it is sodium methoxide;

[0039] During the synthesis of the active intermediate iminoester,

[0040] The reaction temperature is 25-60 °C; preferably, it is 25 °C;

[0041] The reaction time is 24-96 h; preferably, it is 25 h;

[0042] The molar ratio of the 4-alkyl derivative-substituted 2,6-dicyanopyridine A to the chiral amino alcohol or chiral diamine is 1.0:(1.5-3.0); preferably, it is 1.0:2.2;

[0043] The temperature of the ring-closing reaction is 25-60 °C; preferably, it is 50 °C;

[0044] The time of the ring-closing reaction is 24-96 h; preferably, it is 72 h.

[0045] In step (3),

[0046] The third solvent is one or more of methanol, dichloromethane, tetrahydrofuran, etc.; preferably, it is dichloromethane;

[0047] The base is one of potassium carbonate, triethylamine, 4-dimethylaminopyridine, cesium carbonate, etc.; preferably, it is 4-dimethylaminopyridine;

[0048] The acylating agent is one or more of alkyl- or aryl-substituted acyl halides, sulfonyl halides, phosphoryl halides, acid anhydrides, etc., wherein the acyl halide is one or more of acyl chlorides, acyl bromides, etc.; the alkylating agent is an alkyl or aryl halide, and the halide is one or more of chlorides, bromides, iodides, sulfonic acid esters.

[0049] The molar ratio of the pyridine bisimidazoline ligand substituted with a C4-position alkyl derivative to the base is 1.0:(1.0 to 5.0); preferably, it is 1.0:3.0;

[0050] The molar ratio of the pyridine bisimidazoline ligand substituted with a C4-position alkyl derivative to the acylating or alkylating agent is 1.0:(1.0 to 5.0); preferably, it is 1.0:3.0;

[0051] The temperature of the substitution reaction is 0 to 60 °C; preferably, it is 25 °C;

[0052] The time of the substitution reaction is 5 to 24 h; preferably, it is 11 h.

[0053] In the synthesis method of the present invention, further, the target compound is obtained by column chromatography separation.

[0054] In the synthesis method of the present invention, the chiral amino alcohol and the chiral diamine have the following structures:

[0055]

[0056] Among them, the chiral configuration of the amino alcohol can be S (when R 4 and R 5 are hydrogen), R (when R 4 and R 5 are hydrogen), (S,S), (R,S), (S,R) or (R,R), and it is obtained by commercial purchase or through simple synthesis; R 2 、R 3 、R 4 、R 5 are the same as the definition of the substituents on the oxazole ring in formula (I); among them, the chiral configuration of the diamine can be S (when R 4 and R 5 are hydrogen), R (when R 4 and R 5 are hydrogen), (S,S), (R,R), (R,S) or (S,R), and it is obtained by commercial purchase or through simple synthesis; R 2 、R 3 、R 4 、R 5 are the same as the definition of the substituents on the imidazole ring in formula (II).

[0057] The present invention also provides the application of the pyridine ring C4-alkyl derivative (including alkoxy, alkylthio, alkylamino)-substituted pyridine bisoxazoline ligand PYBOX and pyridine bisimidazoline ligand PYBIM in the asymmetric propargylamination reaction of α-ethynyltetrasubstituted carbonate and the asymmetric catalytic total synthesis of the drug molecule L-carbidopa.

[0058] The beneficial effects of the present invention are as follows: Starting from the readily available raw material 4-halo-2,6-dicyanopyridine, the PYBOX ligand or PYBIM ligand modified with a pyridine ring C4-alkyl derivative is obtained through simple 2-3-step transformation. The pyridine bisoxazoline ligand and pyridine bisimidazoline ligand in the present invention have the advantages of novel and unique structures and stable properties; the synthesis method described in the present invention has the advantages of simplicity, mild reaction conditions, easy operation, and wide application scope, and has a very broad application prospect. Detailed implementation manners

[0059] In combination with the following specific embodiments, the present invention will be further described in detail. The processes, conditions, experimental methods, etc. for implementing the present invention, except for the specifically mentioned content below, are all common knowledge and well-known common sense in the art, and the present invention has no particularly restricted content.

[0060] The present invention provides a class of novel chiral pyridine bisoxazoline ligands modified with pyridine ring C4-alkyl derivatives as shown in formula (a) and formula (b) and their synthesis methods. Starting from the readily available raw material 4-halo-2,6-dicyanopyridine, the pyridine bisoxazoline PYBOX and pyridine bisimidazoline PYBIM ligands modified with pyridine ring C4-alkoxy (thio, amino) groups can be obtained through simple 2-3-step transformation. The PYBOX and PYBIM ligands of the present invention have the advantages of novel and unique structures and stable properties; the synthesis method described in the present invention has the advantages of simplicity, mild reaction conditions, easy operation, and wide application scope, and has a very broad application prospect.

[0061] Synthesis of Example 14a:

[0062]

[0063] Under nitrogen protection, 4-chloro-2,6-dicyanopyridine 1a (1.0 equiv), benzyl alcohol 2a (1.2 equivs), and potassium carbonate (6.0 equivs) were added to a Schlenk flask equipped with a septum. Then, acetonitrile was added, and the reaction was carried out at 80 °C overnight. The reaction was monitored by TLC and was found to be complete. The reaction mixture was filtered through diatomaceous earth and concentrated by rotary evaporation. Subsequently, the residue was purified by column chromatography to obtain white solid 3a in a yield of 75%. To a single-neck flask, 3a (1.0 equiv) and sodium methoxide (0.1 equiv) were added successively. Then, anhydrous methanol was added, and the reaction was carried out at 25 °C overnight. The reaction was monitored by TLC and was found to be complete. Acetic acid (0.2 equiv) was added to the reaction mixture, and the mixture was stirred for 30 minutes. After the solvent was removed by suction, chiral amino alcohol (2.0 equivs) and anhydrous dichloromethane were added to the reaction mixture, and the reaction was carried out at 50 °C for 72 h. The reaction was monitored by TLC and was found to be complete. The reaction mixture was concentrated by rotary evaporation directly and then purified by column chromatography to obtain white solid 4a in a yield of 92%. 1 H NMR(500MHz,CDCl 3 ):δ8.06(s,2H),7.47(d,J=7.9Hz,2H),7.44-7.38(m,3H),7.07-7.02(m,12H),6.99-6.96(m,8H),6.13,5.83(AB,J=10.4Hz,4H),5.29(s,2H); 13 C NMR(125MHz,CDCl 3 ):δ165.80,164.04,148.71,137.23,136.01,135.05,128.76,127.91,127.63,127.57,127.41,126.58,113.20,86.29,74.39,70.60.IR(neat):1710,1420,1361,1220,1093,903,787cm -1 ;HRMS(ESI):Exact mass calcd for C 42 H 33 N 3 NaO 3 [M+Na] + :650.2414,Found:650.2429。

[0064] Synthesis of Example 24b:

[0065]

[0066] Under nitrogen protection, 4-chloro-2,6-dicyanopyridine 1a (1.0 equiv), benzyl alcohol 2b (1.2 equivs), potassium carbonate (6.0 equivs) were added to a Schlenk tube sealed tube, and then acetonitrile was added. The reaction was carried out at 80 °C overnight. The reaction was monitored by TLC and found to be complete. The system was filtered through diatomaceous earth and concentrated by rotary evaporation. Subsequently, it was purified by column chromatography to obtain a white solid 3b with a yield of 80%. To a single-necked flask, 3b (1.0 equiv) and sodium methoxide (0.1 equiv) were added in sequence, and then anhydrous methanol was added. The reaction was carried out at 25 °C overnight. The reaction was monitored by TLC and found to be complete. After adding acetic acid (0.2 equiv) to the system, it was stirred for 30 minutes. After drying the solvent, chiral amino alcohol (2.0 equivs) and anhydrous dichloromethane were added to the system. The reaction was carried out at 50 °C for 72 h. The reaction was monitored by TLC and found to be complete. After direct rotary evaporation, it was purified by column chromatography to obtain a white solid 4b with a yield of 79%. 1 H NMR(500MHz,CDCl 3 ):δ8.06(s,2H),7.07-7.04(m,12H),6.99-6.95(m,8H),6.61(d,J=2.0Hz,2H),6.46(s,1H),6.12,5.80(AB,J=130 minutes z,4H),5.23(s,2H),3.79(s,6H); 13 C NMR(125MHz,CDCl 3 ):δ165.70,164.04,161.10,148.71,137.32,137.23,136.00,127.91,127.63,127.57,127.40,127.02,126.58,113.21,105.21,100.52,86.30,74.39,70.47,55.38.IR(neat):1749,1710,1420,1360,1220,1093,910,795cm -1 ;HRMS(ESI):Exact mass calcd for C 44 H 37 N 3 NaO 5 [M+Na] + :710.2625,Found:710.2645。

[0067] Synthesis of Example 34c:

[0068]

[0069] Under nitrogen protection, 4-chloro-2,6-dicyanopyridine 1a (1.0 equiv), benzyl alcohol 2c (1.2 equivs), and potassium carbonate (6.0 equivs) were added to a sealed Schlenk tube. Then acetonitrile was added and the reaction was carried out at 80 °C overnight. The reaction was monitored by TLC and was found to be complete. The system was filtered through diatomaceous earth and concentrated by rotary evaporation. Subsequently, it was purified by column chromatography to obtain white solid 3c in a yield of 76%. To a single-necked flask, 3c (1.0 equiv) and sodium methoxide (0.1 equiv) were added in sequence. Then anhydrous methanol was added and the reaction was carried out at 25 °C overnight. The reaction was monitored by TLC and was found to be complete. After adding acetic acid (0.2 equiv) to the system, it was stirred for 30 minutes. After drying the solvent, chiral amino alcohol (2.0 equivs) and anhydrous dichloromethane were added to the system, and the reaction was carried out at 50 °C for 72 h. The reaction was monitored by TLC and was found to be complete. After direct rotary evaporation, it was purified by column chromatography to obtain white solid 4c in a yield of 67%. 1 H NMR(500MHz,CDCl 3 ):δ8.08(s,2H),7.09-7.05(m,14H),7.02-6.98(m,9H),6.13,5.82(AB,J=10.3Hz,4H),5.21(s,2H),2.35(s,6H); 13 C NMR(125MHz,CDCl 3 ):δ165.78,163.97,148.59,138.27,137.19,135.96,134.81,130.05,127.82,127.52,127.47,127.30,126.92,126.48,125.43,113.13,86.16,74.31,70.62,21.17.IR(neat):1712,1437,1420,1362,1093,570cm -1 ;HRMS(ESI):Exact mass calcd forC 44 H 37 N 3 NaO 3 [M+Na] + :678.2727,Found:678.2738。

[0070] Synthesis of Example 44d:

[0071]

[0072] Under nitrogen protection, 4-chloro-2,6-dicyanopyridine 1a (1.0 equiv), benzyl alcohol 2d (1.2 equivs), potassium carbonate (6.0 equivs) were added to a Schlenk flask sealed tube, and then acetonitrile was added. The reaction was carried out at 80 °C overnight. The reaction was monitored by TLC and found to be complete. The system was filtered through diatomaceous earth and concentrated by rotary evaporation. Subsequently, it was purified by column chromatography to obtain a white solid 3d with a yield of 77%. To a single-neck flask, 3d (1.0 equiv) and sodium methoxide (0.1 equiv) were added in sequence, and then anhydrous methanol was added. The reaction was carried out at 25 °C overnight. The reaction was monitored by TLC and found to be complete. After adding acetic acid (0.2 equiv) to the system, it was stirred for 30 minutes. After drying the solvent, chiral amino alcohol (2.0 equivs) and anhydrous dichloromethane were added to the system. The reaction was carried out at 50 °C for 72 h. The reaction was monitored by TLC and found to be complete. After direct rotary evaporation, it was purified by column chromatography to obtain a white solid 4d with a yield of 64%. 1 H NMR(400MHz,CDCl 3 ):δ8.05(s,2H),7.06-7.01(m,13H),6.99-6.96(m,9H),6.83-6.78(m,1H),6.12,5.81(AB,J=10.4Hz,4H),5.25(s,2H); 13 CNMR(100MHz,CDCl 3 ):δ165.25,164.38(d,J C-F =12.6Hz,1C),163.88,163.80(d,J C-F =12.6Hz,1C),148.81,138.97(t,J C-F =9.1Hz,1C),137.13,135.91,127.86,127.63,127.57,127.43,127.05,126.53,113.00,110.08-109.82(m,1C),103.75(t,J C-F =25.1Hz,1C),86.31,69.00; 19 FNMR(376MHz,CDCl 3 ):δ-108.62(s,1F).IR(neat):1736,1715,1598,1454,1364,1122,1094,697cm -1 ;HRMS(ESI):Exact mass calcd for C 42 H 31 F 2 N 3 NaO 3 [M+Na] +:686.2226, Found: 686.2245。

[0073] Synthesis of Example 54e:

[0074]

[0075] Under nitrogen protection, 4-chloro-2,6-dicyanopyridine 1a (1.0 equiv), benzyl alcohol 2e (1.2 equivs), potassium carbonate (6.0 equivs) were added to a Schlenk flask sealed tube, and then acetonitrile was added. The reaction was carried out at 80 °C overnight. The reaction was monitored by TLC and found to be complete. The system was filtered through diatomaceous earth and concentrated by rotary evaporation. Subsequently, it was purified by column chromatography to obtain a white solid 3e with a yield of 76%. To a single-necked flask, 3e (1.0 equiv) and sodium methoxide (0.1 equiv) were added in sequence, and then anhydrous methanol was added. The reaction was carried out at 25 °C overnight. The reaction was monitored by TLC and found to be complete. After adding acetic acid (0.2 equiv) to the system, it was stirred for 30 minutes. After drying the solvent, chiral amino alcohol (2.0 equivs) and anhydrous dichloromethane were added to the system. The reaction was carried out at 50 °C for 72 h. The reaction was monitored by TLC and found to be complete. After direct rotary evaporation, it was purified by column chromatography to obtain a white solid 4e with a yield of 76%. 1 H NMR (500 MHz, CDCl 3 ): δ 8.09 (s, 2H), 7.91 - 7.89 (m, 2H), 7.07 - 7.03 (m, 12H), 6.98 - 6.96 (m, 8H), 6.12, 5.80 (AB, J = 130 min z, 4H), 5.37 (s, 2H); 13 C NMR (125 MHz, CDCl 3 ): δ 165.08, 163.86, 148.93, 137.80, 137.11, 135.88, 132.08 (q, J C-F = 33.3 Hz, 1C), 127.87, 127.66, 127.59, 127.47, 127.28 (d, J C-F = 3.0 Hz, 1C), 127.09, 126.54, 123.06 (q, J C-F = 270.8 Hz, 1C), 122.36 - 122.24 (m, 1C), 112.93, 86.35, 74.39, 68.76; 19 F NMR (376 MHz, CDCl 3 ): δ -62.86 (s, 3F). IR (neat): 1749, 1735, 1712, 1419, 1361, 1281, 1220, 1179, 1137, 1094 cm -1; HRMS(ESI): Exact mass calcd for C 44 H 31 F 6 N 3 NaO 3 [M+Na] + : 786.2162, Found: 786.2180。

[0076] Example 6 Synthesis of 4f:

[0077]

[0078] Under nitrogen protection, 4-chloro-2,6-dicyanopyridine 1a (1.0 equiv) and benzyl mercaptan 2f (1.2 equivs), potassium carbonate (6.0 equivs) were added to a Schlenk flask sealed tube, and then acetonitrile was added. The reaction was carried out at 80 °C overnight. The reaction was monitored by TLC and found to be complete. The system was filtered through diatomaceous earth and concentrated by rotary evaporation. Subsequently, it was purified by column chromatography to obtain white solid 3f with a yield of 76%. To a single-necked flask, 3f (1.0 equiv) and sodium methoxide (0.1 equiv) were added in sequence, and then anhydrous methanol was added. The reaction was carried out at 25 °C overnight. The reaction was monitored by TLC and found to be complete. After adding acetic acid (0.2 equiv) to the system, it was stirred for 30 minutes. After drying the solvent, chiral amino alcohol (2.0 equivs) and anhydrous dichloromethane were added to the system, and the reaction was carried out at 50 °C for 72 h. The reaction was monitored by TLC and found to be complete. After direct rotary evaporation, it was purified by column chromatography to obtain white solid 4f with a yield of 88%. 1 H NMR 400 MHz, CDCl 3 ): δ8.01(s, 2H), 7.47(d, J = 7.9 Hz, 2H), 7.44 - 7.38(m, 3H), 7.07 - 7.02(m, 12H), 6.99 - 6.96(m, 8H), 6.13, 5.83(AB, J = 10.4 Hz, 4H), 5.29(s, 2H); 13 C NMR(125 MHz, CDCl 3 ): δ165.70, 164.24, 148.51, 136.23, 136.01, 134.05, 128.76, 127.96, 127.63, 127.52, 127.44, 126.59, 113.20, 86.39, 74.49, 71.60.

[0079] Example 7 Synthesis of 4g:

[0080]

[0081] Under nitrogen protection, 4-chloro-2,6-dicyanopyridine 1a (1.0 equiv), benzylamine 2g (1.2 equivs), and potassium carbonate (6.0 equivs) were added to a sealed Schlenk flask. Then acetonitrile was added and the reaction was carried out at 80 °C overnight. The reaction was monitored by TLC and found to be complete. The system was filtered through diatomaceous earth and concentrated by rotary evaporation. Subsequently, it was purified by column chromatography to obtain white solid 3g in a yield of 76%. To a single-neck flask, 3g (1.0 equiv) and sodium methoxide (0.1 equiv) were added in sequence. Then anhydrous methanol was added and the reaction was carried out at 25 °C overnight. The reaction was monitored by TLC and found to be complete. Acetic acid (0.2 equiv) was added to the system and stirred for 30 minutes. After the solvent was removed by suction, chiral amino alcohol (2.0 equivs) and anhydrous dichloromethane were added to the system, and the reaction was carried out at 50 °C for 72h. The reaction was monitored by TLC and found to be complete. After direct rotary evaporation, it was purified by column chromatography to obtain white solid 4g in a yield of 54%. 1 H NMR 400MHz,CDCl 3 ):δ7.54(s,2H),7.44-7.38(m,15H),7.07-7.02(m,10H),6.10(s,br,1H),5.87,5.33(AB,J=10.4Hz,4H),5.29(s,2H); 13 C NMR(125MHz,CDCl 3 ):δ160.00,155.24,154.51,136.03,135.01,132.75,127.66,126.96,126.63,125.52,125.44,123.59,113.20,76.39,74.49,61.60.

[0082] Synthesis of Example 86a:

[0083]

[0084] Under nitrogen protection, 4-chloro-2,6-dicyanopyridine 1a (1.0 equiv), benzyl alcohol 2e (1.2 equivs), potassium carbonate (6.0 equivs) were added to a Schlenk tube under sealing, and then acetonitrile was added. The reaction was carried out at 80 °C overnight. The reaction was monitored by TLC and found to be complete. The system was filtered through diatomaceous earth and concentrated by rotary evaporation. Subsequently, it was purified by column chromatography to obtain white solid 3e with a yield of 76%. To a single-neck flask, 3e (1.0 equiv) and sodium methoxide (0.1 equiv) were added in sequence, and then anhydrous methanol was added. The reaction was carried out at 25 °C overnight. The reaction was monitored by TLC and found to be complete. After adding acetic acid (0.2 equiv) to the system, it was stirred for 30 minutes. After the solvent was dried by suction, chiral amino alcohol (2.0 equivs) and anhydrous dichloromethane were added to the system. The reaction was carried out at 50 °C for 72 hours. The reaction was monitored by TLC and found to be complete. After direct rotary evaporation, it was purified by column chromatography to obtain white solid 5a with a yield of 76%. Subsequently, under nitrogen protection, imidazoline ligand 5a (1.0 equiv), 4-dimethylaminopyridine (3.0 equivs) and benzoyl chloride (3.0 equivs) were added to a Schlenk tube under sealing, and then dichloromethane was added. The reaction was carried out at 25 °C overnight. The reaction was monitored by TLC and found to be complete. Saturated ammonium chloride aqueous solution was added to the system, and it was extracted three times with dichloromethane and washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation and purified by column chromatography to obtain white solid 6a with a yield of 50%. 1 H NMR(400MHz,CDCl 3 )δ7.91(s,3H),7.63(s,2H),7.43-7.25(m,21H),7.10-7.00(m,10H),5.32-5.25(m,2H),5.15-5.14(m,2H),5.10(s,2H); 19 F NMR(376MHz,CDCl 3 )δ-62.84; 13 C NMR(101MHz,CDCl 3 )δ169.90,165.08,160.95,151.40,141.60,139.76,138.03,134.69,132.69,132.36,132.03,131.75,131.69,129.18,129.09,128.50,128.26,127.95,127.70,126.38,125.12,124.50,121.79,111.00,79.49,77.27,71.42,68.61。

[0085] Application Example 1

[0086]

[0087] Add CuBr successively to a single-necked flask 2 (0.025 mmol), novel ligand 4e (0.03 mmol), and n-propanol. Then stir at 25 °C for 1.0 h, add starting material 1b (0.25 mmol), continue stirring for 30 min, transfer to -30 °C, stir at this temperature for 30 min, add triethylamine (1.0 mmol), continue stirring for 30 min, and then add aniline (0.3 mmol). After the reaction was monitored by TLC and the starting materials disappeared, the solvent was distilled off under reduced pressure, and the target product was obtained by column chromatography with a yield of 82%; chiral HPLC analysis showed 92% ee (Chiralpak OD-H, i PrOH / hexane = 10 / 90, 1.0 mL / min, 254 nm; t r (major) = 7.18 min, t r (minor) = 8.82 min), [α] 20 D = +22.1 (c = 1.12, CH 2 Cl 2 ); 1 1H NMR (400 MHz, CDCl 3 ): δ 7.34 - 7.30 (m, 2H), 7.25 - 7.21 (m, 6H), 6.99 - 6.97 (m, 2H), 6.86 - 6.82 (m, 2H), 3.68 (s, 1H), 2.94 - 2.86 (m, 2H), 2.50 (s, 1H), 2.97 - 2.83 (m, 2H), 2.24 - 2.08 (m, 2H), 1.66 (s, 3H); 13 13C NMR (100 MHz, CDCl 3 ): δ 145.30, 141.56, 128.83, 128.45, 128.39, 125.94, 118.81, 116.58, 86.63, 72.13, 51.68, 43.99, 30.86, 27.95. HRMS (ESI): Exact mass calcd for C 18 H 20 N [M+H] + : 250.1590, Found: 250.1597.

[0088] Application Example 2

[0089]

[0090] Add CuCl successively to a single-necked flask 2(0.025 mmol), novel ligand 4c (0.03 mmol), methanol, and then stirred at 25 °C for 1.0 h. Raw material 1d (0.25 mmol) was added, and after stirring for another 30 min, it was transferred to -30 °C. After stirring at this temperature for 30 min, triethylamine (1.0 mmol) was added. After stirring for another 30 min, aniline (0.3 mmol) was added. The reaction was monitored by TLC. After the raw materials disappeared, the solvent was evaporated under reduced pressure, and the target product was obtained by column chromatography with a yield of 95%; determined by chiral HPLC analysis to be 94% ee (Chiralpak AD-H, i PrOH / hexane = 5 / 95, 1.0 mL / min, 254 nm; t r (major) = 6.67 min, t r (minor) = 8.29 min), [α] 20 D = -156.5 (c = 1.00, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.74 (d, J = 7.2 Hz, 2H), 7.40 - 7.37 (m, 2H), 7.32 - 7.29 (m, 1H), 7.12 - 7.09 (m, 2H), 6.76 - 6.73 (m, 1H), 6.58 (d, J = 7.6 Hz, 2H), 4.29 (s, 1H), 2.52 (s, 1H), 1.85 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 144.98, 143.90, 128.61, 128.54, 127.33, 125.52, 118.42, 115.80, 86.04, 72.38, 55.30, 35.83. IR (neat): 1601, 1501, 1447, 1316, 1179, 764, 735, 702 cm -1 ; HRMS (ESI): Exact mass calcd for C 16 H 16 N [M + H] + : 222.1227, Found: 222.1229.

[0091] Application Example 3

[0092]

[0093] Step 1: Add 7 (5.0 mmol), benzohydrazide (1.1 equiv) and ethanol (5.0 mL) successively to a 10 mL round-bottom flask, and then add acetic acid (10 mol%) at room temperature. The reaction system is refluxed for 2 hours, and the solid is slowly precipitated by cooling. The product is obtained by suction filtration and washing three times with frozen ethanol, and dried in vacuo to obtain a white solid 8 with a yield of 86%.

[0094] Step 2: Under a nitrogen atmosphere, add erbium chloride (47.8 mg, 5.0 mol%), ligand 4f (143.1 mg, 7.5 mol%) and anhydrous toluene (35 mL) successively to a dry 100 mL sealed tube. The reaction solution is stirred at room temperature for 2 hours, and the system is slightly turbid and light pink. Add substrate 8 (3.5 mmol) thereto, and then stir at room temperature for 15 minutes and then cool to -40 °C and continue stirring for 30 minutes. Then quickly add trimethylcyanosilane (1.04 g, 3.0 equiv) and methanol (224.0 mg, 2.0 equiv) to the system. If the system cannot be stirred during the reaction, add anhydrous toluene (about 15 mL) frozen at -78 °C to the system until the system can be stirred smoothly. The reaction is monitored by TLC for 4 days until all the raw materials disappear. Filter through a short column at -40 °C, concentrate in vacuo, and then perform column chromatography using a petroleum ether / ethyl acetate (3:1, v / v) elution system to obtain the product (S)-9 with a yield of 98% (1.21 g) and 88% ee. Recrystallize using an ethyl acetate / petroleum ether system to obtain an ee value of 99% (900.2 mg).

[0095] Step 3: Add (S)-9 (351 mg, 1.0 mmol, 99% ee), concentrated hydrochloric acid (3.0 mL) and ethanethiol (6.0 mL) to a 25 mL sealed tube and react at 100 °C overnight. After monitoring by TLC until all the raw materials disappear, the system is cooled to room temperature, and extracted with ether (10 mL × 3). The aqueous phase is combined and concentrated in vacuo to obtain L-carbidopa hydrochloride. Dissolve L-carbidopa hydrochloride in the least amount of isopropanol, and slowly add dimethylamine tetrahydrofuran solution (2 M) to adjust the pH to 6.4. The precipitated brown solid is L-carbidopa monohydrate with a yield of 95% (220 mg), melting point: 203 - 205 °C [α] 20 D =-14.1 (c = 0.3, MeOH); 1 H NMR (400 MHz, DMSO-d 6 ): δ 6.63 - 6.58 (m, 2H), 6.45 (d, J = 8.0 Hz, 1H), 2.80 (d, J = 13.2 Hz, 1H), 2.68 (d, J = 13.2 Hz, 1H), 1.16 (s, 3H); 1313C NMR (100 MHz, DMSO-d 6 6): δ 174.5, 144.8, 144.2, 126.6, 121.3, 118.1, 115.4, 66.1, 40.8, 19.7. IR (neat): 3205, 2970, 2396, 2234, 2108, 1717, 1650, 1456, 1364, 1053, 1024 cm -1 -1; Calculated for C 10 H 15 N 2 O 4 [M + H] + : 227.1026, found: 227.1027.

[0096] The protection scope of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be conceived by those skilled in the art are included in the present invention, and the scope of protection is defined by the appended claims.

Claims

1. A class of pyridine bisoxazoline ligands modified by alkyl derivatives at the C4 position of the pyridine ring, Characterized in that, The pyridine bisoxazoline ligands include the pyridine bisoxazoline PYBOX ligand shown in formula (a) and the pyridine bisimidazoline PYBIM ligand shown in formula (b): Wherein: X is an oxygen atom, a sulfur atom or a nitrogen atom; R 1 is hydrogen, a chiral or achiral alkyl or aryl group; R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, alkyl, aryl, and aryl having substituents; R 6 selected from acyl, sulfonyl, phosphoryl, alkyl or aryl; In formula (a), n = 1 to 12; where when n = 1, R 1 , R 4 , R 5 are non-hydrogen functional groups; In formula (b), n = 1 to 12.

2. The pyridine bisoxazoline ligand according to claim 1, Characterized in that, The substituent in the aryl group with substituents is an electron-withdrawing or electron-donating group; the electron-withdrawing group is selected from halogen, trifluoromethyl, nitro, ester group, cyano group; the electron-donating group is selected from C1-C10 alkyl group, C1-C10 alkoxy group, C1-C10 alkylthio group, C1-C10 alkylamino group; R 2 and R 4 form a ring or not, R 2 and R 4 when forming a ring, it is an aliphatic ring, an aromatic ring, an aliphatic ring containing heteroatoms or an aromatic ring; R 3 and R 5 form a ring or not, R 3 and R 5 when forming a ring, it is an aliphatic ring, an aromatic ring, an aliphatic ring containing heteroatoms or an aromatic ring; the heteroatoms include nitrogen atom, oxygen atom and sulfur atom.

3. A method for synthesizing a PYBOX ligand shown in formula (a) and a PYBIM ligand shown in formula (b), Characterized in that, The synthesis method is shown in reaction formula (I) and reaction formula (II):

4. The synthesis method according to claim 3, Characterized in that, The synthesis method includes the following steps: Step (1): In a first solvent, 4-halo-2,6-dicyanopyridine undergoes a substitution reaction with an alkyl compound to obtain 4-alkyl derivative-substituted 2,6-dicyanopyridine A; Step (2): In a second solvent, the 4-alkyl derivative-substituted 2,6-dicyanopyridine A first obtains an active intermediate iminoester under the action of a base, and then undergoes a ring closure reaction with a chiral amino alcohol to obtain a pyridine bisoxazoline ligand PYBOX substituted by an alkyl derivative at the C4 position of the pyridine ring; or, In a second solvent, the 4-alkyl derivative-substituted 2,6-dicyanopyridine A first generates an active intermediate iminoester under the action of a base, and then undergoes a ring closure reaction with a chiral diamine to obtain a pyridine bisimidazoline ligand substituted by an alkyl derivative at the C4 position of the pyridine ring; The alkyl compound includes alkyl primary alcohol, alkyl mercaptan, alkylamine compound; the alkyl derivative includes alkoxy, alkylthio, alkylamino.

5. The synthesis method according to claim 4, Characterized in that, The synthesis method further includes the following steps: Step (3): In a third solvent, under the action of a base, the pyridine bisimidazoline ligand substituted by an alkyl derivative at the C4 position of the pyridine ring undergoes a substitution acylation or alkylation reaction with an acylation or alkylation reagent to obtain an N-functionalized pyridine bisimidazoline ligand PYBIM substituted by an alkyl derivative at the C4 position of the pyridine ring.

6. The synthesis method according to claim 4, Characterized in that, In step (1), the halogen includes fluorine, chlorine, bromine, iodine; the first solvent is one or more of dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide; the molar ratio of 4-halo-2,6-dicyanopyridine to the alkyl compound is 1.0:(1.2 to 2.5); the temperature of the substitution reaction is 60 to 120 °C; the time of the substitution reaction is 5 to 24 h.

7. The synthesis method according to claim 4, Characterized in that, In step (2), during the synthesis of the active intermediate iminoester, the reaction temperature is 25 to 60 °C; the reaction time is 24 to 96 h; the second solvent is one or more of methanol, acetonitrile, tetrahydrofuran, and dimethyl sulfoxide; the base is one or more of sodium iodide, sodium methoxide, and sodium; the molar ratio of the 4-alkyl derivative-substituted 2,6-dicyanopyridine A to the chiral amino alcohol or chiral diamine is 1.0:(1.5 to 3.0); the temperature of the ring-closing reaction is 25 to 60 °C; the time of the ring-closing reaction is 24 to 96 h.

8. The synthesis method according to claim 5, characterized in that in step (3), the third solvent is one or more of methanol, dichloromethane, and tetrahydrofuran; the base is one of potassium carbonate, triethylamine, 4-dimethylaminopyridine, and cesium carbonate; the molar ratio of the pyridine bisimidazoline ligand substituted with an alkyl derivative at the C4 position of the pyridine ring to the base is 1.0:(1.0 to 5.0); the molar ratio of the pyridine bisimidazoline ligand substituted with an alkyl derivative at the C4 position to the acylation or alkylation reagent is 1.0:(1.0 to 5.0); the temperature of the substitution reaction is 0 to 60 °C; the time of the substitution reaction is 5 to 24 h.

9. The synthesis method according to claim 5, characterized in that in step (3), the acylation reagent is one or more of acyl halides, sulfonyl halides, phosphoryl halides, and acid anhydrides substituted with alkyl or aryl groups, and the acyl halide is one or more of acyl chlorides and acyl bromides; the alkylation reagent is an alkyl or aryl halide, and the halide is one or more of chlorides, bromides, iodides, and sulfonates.

10. Application of the pyridine bisoxazoline ligand PYBOX and pyridine bisimidazoline ligand PYBIM substituted with an alkyl derivative at the C4 position of the pyridine ring in the asymmetric propargylamination reaction of α-ethynyltetrasubstituted carbonate and the asymmetric catalytic total synthesis of the drug molecule L-carbidopa.

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