Adamantyl phosphine ligand with cinchona alkali framework, silver catalyst containing ligand and application

Abstract

The invention discloses an adamantyl phosphine ligand with a cinchona alkali framework, a silver catalyst containing the ligand and application, the ligand has a structure as shown in a formula (I) or a tautomer, an enantiomer and a diastereoisomer of the ligand: # imgabs0 #, in the formula (I), R1 is ethyl or vinyl; and a substituent R2 is a methoxy group or a hydrogen atom. The novel catalyst composed of the adamantyl phosphine ligand with the cinchona alkali skeleton and the silver salt can efficiently catalyze the asymmetric [3 + 2] cycloaddition reaction of aromatic aldehyde and isocyano acetate, and the corresponding chiral oxazoline intermediate is obtained with high stereoselectivity and high yield; the technology can be applied to asymmetric synthesis of florfenicol intermediates and chloramphenicol intermediates, has the advantages of short synthesis route, high yield, good stereoselectivity and the like, and has good economic and social benefits.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to an adamantyl phosphine ligand of a cinchona alkaloid skeleton, a silver catalyst containing the ligand and applications thereof. Background Art

[0002] In asymmetric synthesis catalyzed by small organic molecules, cinchona alkaloids have become one of the hottest research topics since they were first reported as chiral auxiliary agents in 1853 (Tetrahedron 2011, 67, 1725-1762). This is closely related to their natural chiral environment structure and strong late-stage modifiability. It can be summarized as follows: (1) Quinine and quinoline rings can produce chiral pockets similar to enzymes to provide a chiral environment; (2) R, OH and quinuclidine are all modifiable; (3) The free rotation of C8 and C9 creates a dynamic environment that can produce conformations of different stabilities; (4) The tertiary amine nitrogen atom in the quinuclidine ring has nucleophilic characteristics and can act as a nucleophilic reagent to activate the substrate; (5) The flat quinoline ring is electron-rich and can form an electron donor complex (EDA) with electron-deficient molecules; (6) The hydroxyl group at the C9 position can act as an electrophilic reagent to activate the substrate through hydrogen bonding. In the past few decades, many representative cinchona alkaloid derivatives have been derived through the modification of the structure of cinchona alkaloids, such as C9-amine, urea / thiourea, amide, sulfonamide, square amide, ether, etc.; C6'-hydroxyl and dimeric or polymeric polymer compounds (Chin. J. Org. Chem. 2020, 40, 3493-3516).

[0003]

[0004] In 2016, Dixon et al. (Org. Biomol. Chem., 2016, 14, 93-96) reported the synthesis of chloramphenicol intermediates using p-nitrobenzaldehyde and isocyanoacetate as raw materials via an asymmetric [3+2] cycloaddition reaction catalyzed by Ag2O and diphenylphosphine ligands of cinchona alkaloid skeleton.

[0005] This method has the disadvantages of excessive catalyst dosage, insufficient stereoselectivity and low yield.

[0006]

[0007] In 2023, Zhong Weihui et al. (CN118084745A) reported a method for preparing florfenicol intermediate D-ester. This method still uses the diphenylphosphine ligand of the cinchona alkaloid skeleton and the asymmetric [3+2] cycloaddition reaction catalyzed by silver salt for preparation, and its stereoselectivity and total yield (76.5%) need to be improved.

[0008]

[0009] Based on this, we plan to further modify the chiral phosphine ligands of the cinchona alkaloid skeleton. Further experimental verification shows that the steric hindrance and electrical properties of the substituents on phosphorus have an important influence on the catalytic performance.

[0010] Therefore, transforming the diphenylphosphine ligand of the cinchona alkaloid skeleton into an adamantylphosphine ligand of the cinchona alkaloid skeleton will help improve the catalytic performance and application range of this type of catalyst, and has important application prospects. Summary of the invention

[0011] In view of the above problems existing in the prior art, the object of the present invention is to provide a cinchona alkaloid skeleton adamantylphosphine ligand, a silver catalyst containing such a ligand and applications. The ligand provided by the present invention has the characteristics of simple synthesis, stability to water, high activity and high selectivity in catalyzing asymmetric [3+2] cycloaddition reaction and asymmetric synthesis of florfenicol intermediates and chloramphenicol intermediates.

[0012] The technical solution adopted by the present invention is as follows:

[0013] A cinchona alkaloid skeleton adamantylphosphine ligand having a structure of formula (I) or its tautomers, enantiomers, and diastereomers:

[0014]

[0015] In formula (I), the substituent R 1 is ethyl or vinyl; R 2 is a methoxy group or a hydrogen atom.

[0016] Specifically, the adamantylphosphine ligand (I) of the cinchona alkaloid skeleton is selected from one of compounds L1 to L4:

[0017]

[0018] The preparation method of the adamantylphosphine ligand of the cinchona alkaloid skeleton comprises the following steps:

[0019] 1) di(adamantyl)phosphine hydrogen S1 reacts with methyl o-bromobenzoate to obtain intermediate S2;

[0020] 2) Intermediate S2 is hydrolyzed to obtain intermediate S3;

[0021] 3) The intermediate S3 and the quinidine derivative S4 undergo condensation acylation reaction to obtain product I; the reaction formula is as follows:

[0022]

[0023] Substituent R in Quinidine Derivative S4 1 and R 2 The definitions are the same as those of formula (I).

[0024] Further, the reaction in step 1) is carried out in the presence of sodium tert-butoxide, palladium acetate and 1,1'-bis(diphenylphosphino)ferrocene, the molar ratio of di(adamantyl)phosphine hydrogen S1, methyl o-bromobenzoate, sodium tert-butoxide, palladium acetate and 1,1'-bis(diphenylphosphino)ferrocene is 1:1.1-1.5:1.1-1.5:0.02-0.08:0.02-0.08, preferably 1:1.2:1.2:0.05:0.06, the reaction solvent is toluene, the reaction temperature is 100-120°C, and the reaction time is 10-15h. After the reaction is completed, the intermediate S2 is obtained by post-treatment.

[0025] Furthermore, in step 2), the intermediate S2 is hydrolyzed in a 20% by mass aqueous potassium hydroxide solution / 1,4-dioxane solution (the volume ratio of the two is 1:1), stirred at 90° C. for 24 hours, and then post-treated to obtain the intermediate S3.

[0026] Furthermore, the intermediate S3, quinidine derivative S4, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1-hydroxybenzotriazole are dissolved in dichloromethane at a molar ratio of (1:1:1.2:1.2), reacted at room temperature, and post-treated to obtain the adamantyl phosphine ligand of the cinchona alkaloid skeleton shown in formula (I).

[0027] The prepared adamantylphosphine ligand of the cinchona alkaloid skeleton can be complexed with a silver salt to obtain a silver catalyst; wherein the silver salt is selected from one of silver acetate, silver oxide, silver methanesulfonate and silver phosphate, or a mixture of two or more thereof.

[0028] The silver catalyst can catalyze an asymmetric [3+2] cycloaddition reaction to efficiently prepare a chiral oxazoline intermediate as shown in formula (IV).

[0029] Specifically, a method for preparing the product shown in formula (IV) comprises the following steps:

[0030] The aromatic aldehyde shown in formula (II) is dissolved in solvent A, and adamantyl phosphine ligand of cinchona alkaloid skeleton and silver salt are added. A mixed solution of isocyanoacetate shown in formula (III) and solvent A is added dropwise within 1 to 5 hours at -20°C to 60°C in a nitrogen atmosphere, and then the mixture is kept warm for 1 to 24 hours. The ligand and the silver salt are complexed to form a silver catalyst and catalyze an asymmetric [3+2] cycloaddition reaction. After the reaction is completed, the solvent is recovered by concentration under reduced pressure, and the residue is separated by column chromatography to obtain a chiral oxazoline intermediate shown in formula (IV).

[0031] The specific reaction route is as follows:

[0032]

[0033] In the general formula (II), Ar represents a phenyl group, a substituted aryl group or a heterocyclic aryl group, and the substituent on the aryl group of the substituted aryl group is a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, a cyano group, a methylsulfone group, a halogen group or a H atom; R 3 It is represented by methyl, ethyl, isopropyl, tert-butyl or benzhydryl.

[0034] Furthermore, the solvent A is selected from one or a mixed solvent of two or more selected from ethyl acetate, toluene, methyl tert-butyl ether, dichloromethane, and tetrahydrofuran.

[0035] Furthermore, the eluent for column chromatography separation is petroleum ether-ethyl acetate in a volume ratio of 2-5:1.

[0036] Furthermore, the molar ratio of the compound of formula (III), the compound of formula (II), the adamantylphosphine ligand of the cinchona alkaloid skeleton and the silver salt is 1:1.0-1.2:0.001-0.05:0.001-0.05.

[0037] Furthermore, the silver-catalyzed asymmetric [3+2] cycloaddition reaction can be applied to the asymmetric synthesis of florfenicol intermediates or chloramphenicol intermediates.

[0038] Compared with the existing diphenylphosphine ligand of cinchona alkaloid skeleton, the adamantylphosphine ligand of cinchona alkaloid skeleton provided by the present invention has greater steric hindrance and stronger coordination ability, which is beneficial to improving the catalytic reaction activity and project selectivity. The ligand has a simple preparation process and is suitable for large-scale preparation. After complexing with silver salt, it can efficiently catalyze the asymmetric [3+2] cycloaddition reaction, obtain chiral oxazoline intermediates with high yield and high stereoselectivity, and is applied to the asymmetric synthesis of florfenicol intermediates and chloramphenicol intermediates. DETAILED DESCRIPTION

[0039] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0040] In the embodiment of the present invention, the mass concentration of concentrated hydrochloric acid is 31%, and the mass concentration of aqueous ammonia is 10%.

[0041] Example 1: Synthesis of ligand L1

[0042]

[0043] (1) Under nitrogen atmosphere, di(adamantyl)phosphine hydrogen (S1, 2.30 g, 7.6 mmol), methyl o-bromobenzoate (1.96 g, 9.1 mmol), sodium tert-butoxide (0.87 g, 9.1 mmol), palladium acetate (86 mg, 0.38 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (253 mg, 0.45 mmol) were dissolved in toluene (100 mL) and refluxed at 110°C for 12 hours. The filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1, v / v) to obtain intermediate S2 (2.32 g, yield 69%)

[0044] Structural characterization of intermediate S2: mp: 178-179 °C; 1 H NMR (400MHz, CDCl3) δ7.69 (dd, J=7.0, 1.2Hz, 1H), 7.42 (ddd, J=5.6, 4.6, 1.2Hz, 1H), 7.35 (dd, J= 5.2,1.2Hz,1H),7.29(td,J=6.0,1.2Hz,1H),3.85(s,3H),1.97-1.91(m,6H),1.72-1.59(m,24H). 13 C NMR (100MHz, CDCl3) δ167.83,148.59,134.20,133.31,132.71,128.85,127.50,52.36,49.20,43.72,43.03,38.73,37.10,29.81.

[0045] (2) Under nitrogen atmosphere, intermediate S2 (1.7 g, 3.9 mmol) was added to a mixture of 20% KOH solution (30 mL) and 1,4-dioxane (30 mL), and stirred at 90°C for 24 h. The reaction solvent was removed by concentration under reduced pressure, and dichloromethane (20 mL) was added at room temperature, and 3M hydrochloric acid (20 mL) was added dropwise. After the addition was completed, the organic layer was extracted and separated. After the solvent was removed by concentration under reduced pressure, intermediate S3 (1.65 g, yield 99%) was obtained.

[0046] Structural characterization of intermediate S3: mp: 203-205°C; 1 H NMR (400MHz, CDCl3) δ7.70 (dd, J=6.6, 1.2Hz, 1H), 7.43 (ddd, J=6.0, 5.0, 1.4Hz, 1H), 7 .32(dd,J=5.0,1.2Hz,1H),7.26-7.19(m,1H),1.97-1.90(m,6H),1.71-1.56(m,24H). 13C NMR (100MHz, CDCl3) δ169.68,148.48,134.20,133.78,132.41,128.91,127.38,48.82,43.72,43.03,38.73,37.10,29.81.

[0047] (3) Under nitrogen atmosphere, intermediate S3 (423 mg, 1 mmol), quinidine derivative S4-1 (323 mg, 1 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg, 1.2 mmol), and 1-hydroxybenzotriazole (162 mg, 1.2 mmol) were added to dichloromethane (10 mL). The reaction was stirred at room temperature for 24 hours and quenched by adding water. The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate: methanol = 20:1, v / v) to obtain a white solid L1 (516 mg, yield 71%).

[0048] Structural characterization of ligand L1: mp: 253-256°C; 1 H NMR (400MHz, CDCl3) δ8.59(d,J=3.4Hz,1H),7.90(d,J=6.8Hz,1H),7.66(dd,J=6.0,1.2Hz,1H),7.55-7.45(m,1H),7.40(d,J= 3.4Hz,1H),7.39-7.33(m,3H),7.25(dd,J=6.6,2.2Hz,1H),7.10(s,1H),5.88-5.70(m,1H),5.32-5.24(m,1H),5.19(dt,J=13 .2,1.6Hz,1H),4.94(dt,J=8.8,1.6Hz,1H),3.80(s,3H),3.49(dt,J=5.4,4.4Hz,1H),3.04-2.93(m,2H),2.86(ddd,J=9.6,6. 0,3.8Hz,1H),2.74(ddd,J=8.8,3.0,0.8Hz,1H),2.60-2.55(m,1H),2.03-1.90(m,8H),1.87-1.81(m,1H),1.79-1.54(m,26H). 13C NMR (100MHz, CDCl3) δ168.59,159.25,147.51,147.38,144.42,141.94,140.56,137.30,133.76,131.62,131.30,129.12,127.80,126.51,1 21.92,118.80,115.02,105.37,61.00,55.90,55.69,55.46,49.18,4 9.01,43.45,42.82,40.35,38.73,37.10,31.73,29.81,27.98,26.74.

[0049] Example 2: Synthesis of ligand L2

[0050]

[0051] Under nitrogen atmosphere, intermediate S3 (423 mg, 1 mmol), quinidine derivative S4-2 (325 mg, 1 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (230 mg, 1.2 mmol), 1-hydroxybenzotriazole (162 mg, 1.2 mmol) were added to dichloromethane (10 mL). The reaction was stirred at room temperature for 24 hours and quenched by adding water. The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate: methanol = 20: 1, v / v) to obtain ligand L2 (474 ​​mg, yield 65%).

[0052] Structural characterization of ligand L2: mp: 245-246°C; 1 H NMR (400MHz, CDCl3) δ8.59(d,J=3.4Hz,1H),7.90(d,J=6.8Hz,1H),7.66(dd,J=6.0,1.2Hz,1H),7.54-7.45( m,1H),7.40(d,J=3.4Hz,1H),7.39-7.33(m,3H),7.25(dd,J=6.6,2.0Hz,1H),7.10(s,1H),5.49-5.01(m,1H ),3.80(s,3H),3.47(dt,J=6.6,5.7Hz,1H),2.99-2.87(m,2H),2.80(ddd,J=11.7,7.1,4.6Hz,1H),2.68(dd ,J=11.0,4.2Hz,1H),2.05-1.57(m,36H),1.42-1.49(m,1H),1.19-1.25(m,1H),0.85(td,J=7.4,1.5Hz,3H). 13C NMR (100MHz, CDCl3) δ168.59,159.25,147.51,147.38,144.42,141.84,137.30,133.76,131.62,131.30,129.12,127.80,126.51,121.92, 118.80,105.37,61.17,55.94,55.69,54.60,49.48,49.01,43.45,42 .82,39.86,38.73,37.10,31.60,29.81,28.83,27.98,25.43,11.88.

[0053] Example 3: Synthesis of ligand L3

[0054]

[0055] Under nitrogen atmosphere, intermediate S3 (423 mg, 1 mmol), quinidine derivative S4-3 (293 mg, 1 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (230 mg, 1.2 mmol), 1-hydroxybenzotriazole (162 mg, 1.2 mmol) were added to dichloromethane (10 mL). The reaction was stirred at room temperature for 24 hours and quenched by adding water. The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate: methanol = 20: 1, v / v) to obtain ligand L3 (509 mg, yield 73%).

[0056] Structural characterization of ligand L3: mp: 271-273°C; 1 H NMR (400MHz, CDCl3) δ8.62 (d, J=3.4Hz, 1H), 8.09 (dd, J=6.4, 1.2Hz, 1H), 7.98 (dd, J=7 .2,1.2Hz,1H),7.73-7.62(m,2H),7.52-7.32(m,5H),7.10(s,1H),5.87-5.73(m,1H), 5.27-5.13(m,2H),4.94(dt,J=8.8,1.4Hz,1H),3.49(dt,J=6.0,4.8Hz,1H),3.03-2.9 4(m,2H),2.89-2.83(m,1H),2.74(ddd,J=8.8,3.2,0.8Hz,1H),2.54-2.61(m,1H),2.03 -1.80(m,9H),1.78-1.54(m,26H). 13C NMR (100MHz, CDCl3) δ168.59,149.61,147.38,146.83,143.07,140.56,137.30,133.76,131.30,130.62,129.35,129.12,128.17,127.8 0,126.68,123.83,121.08,115.02,60.99,55.66,55.46,49.18,49.01,43.45,42.82,40.35,38.73,37.10,31.73,29.81,27.98,26.74.

[0057] Example 4: Synthesis of ligand L4

[0058]

[0059] Under nitrogen atmosphere, intermediate S3 (423 mg, 1 mmol), quinidine derivative S4-4 (295 mg, 1 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (230 mg, 1.2 mmol), 1-hydroxybenzotriazole (162 mg, 1.2 mmol) were added to dichloromethane (10 mL). The reaction was stirred at room temperature for 24 hours and quenched by adding water. The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate: methanol = 20: 1, v / v) to obtain ligand L4 (441 mg, yield 63%).

[0060] Structural characterization of ligand L4: mp: 269-271°C; 1 H NMR (400MHz, CDCl3) δ8.62(d,J=3.4Hz,1H),8.09(dd,J=6.4,1.2Hz,1H),7.98(dd,J=7.0,0.8 Hz,1H),7.75-7.62(m,2H),7.52-7.30(m,5H),7.10(s,1H),5.24-5.10(m,1H),3.47(dt,J=5.2 ,4.6Hz,1H),2.96-2.89(m,2H),2.77-2.83(m,1H),2.68(dd,J=8.8,3.2Hz,1H),2.05-1.73(m ,11H),1.71-1.57(m,25H),1.49-1.44(m,1H),1.25-1.20(m,1H),0.85(td,J=6.0,1.2Hz,3H). 13C NMR (100MHz, CDCl3) δ168.59,149.61,147.38,146.83,143.07,137.30,133.76,131.30,130.62,129.35,129.12,128.17,127.80,126. 68,123.83,121.08,61.20,55.66,54.60,49.48,49.01,43.45,42.82,39.86,38.73,37.10,31.60,29.81,28.83,27.98,25.43,11.88.

[0061] Example 5: Preparation of (4S,5R)-5-(3-nitrophenyl)-4,5-dihydrooxazole-4-carboxylic acid diphenylmethyl ester (IVaa)

[0062]

[0063] Under nitrogen atmosphere and at 25°C, m-nitrobenzaldehyde (166 mg, 1.1 mmol), silver acetate (8.3 mg, 0.05 mmol), and chiral ligand L1 (44 mg, 0.05 mmol) were dissolved in ethyl acetate (20 mL). A solution of diphenylmethyl isocyanoacetate (251 mg, 1 mmol) in ethyl acetate (2 mL) was added dropwise within 1 hour. After keeping warm for 3 hours, the mixture was concentrated under reduced pressure to recover the solvent. The residue was separated by column chromatography (petroleum ether: ethyl acetate = 2:1, v / v) to obtain 343 mg of light yellow oily liquid (4S, 5R)-5-(3-nitrophenyl)-4,5-dihydrooxazole-4-carboxylic acid benzyl ester (IVaa), with a product yield of 85%, an ee value of 96.5%, and a dr value of 99 / 1.

[0064] Structural characterization of IVaa: 1 H NMR (400MHz, DMSO-d6) δ8.25(t,J=1.6Hz,1H),8.09(dt,J=6.0,1.6Hz,1H),7.75(t,J=1.4Hz,1H),7.60-7.51 (m,2H),7.45-7.27(m,10H),6.68(d,J=0.8Hz,1H),6.03(dd,J=7.2,1.2Hz,1H),4.73(dd,J=7.2,1.2Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ168.31,161.27,147.84,139.48,136.64,132.13,130.07,129.86,129.00,127.46,123.08,121.75,81.61,81.02,71.31.

[0065] Example 6: Preparation of (4S,5R)-5-(4-bromophenyl)-4,5-dihydrooxazole-4-carboxylic acid diphenylmethyl ester (IVba)

[0066]

[0067] Under nitrogen atmosphere and at 40°C, p-bromobenzaldehyde (203 mg, 1.1 mmol), silver methanesulfonate (10.2 mg, 0.05 mmol) and chiral ligand L2 (44 mg, 0.05 mmol) were dissolved in toluene (20 mL). A solution of diphenylmethyl isocyanoacetate (251 mg, 1 mmol) in toluene (2 mL) was added dropwise within 1 hour. After the mixture was kept warm for 1 hour, the solvent was recovered by concentration under reduced pressure. The residue was separated by column chromatography (petroleum ether: ethyl acetate = 4:1, v / v) to obtain 325 mg of off-white oily liquid (4S, 5R)-5-(4-bromophenyl)-4,5-dihydrooxazole-4-carboxylic acid diphenylmethyl ester (IVba) with a yield of 79%, an ee value of 93.1%, and a dr value of 49 / 1.

[0068] Structural Characterization of IVba: 1 H NMR(400MHz,DMSO-d6)δ7.75(t,J=1.2Hz,1H),7.53-7.46(m,2H),7.45-7.35(m,10H),7 .34-7.28(m,2H),6.68(t,J=0.6Hz,1H),5.99-5.84(m,1H),4.68(dd,J=7.2,1.2Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ168.12,161.41,139.48,134.38,131.64,129.86,129.00,127.79,127.46,122.30,81.88,81.02,71.09.

[0069] Example 7: Preparation of (4S,5R)-5-(4-cyanophenyl)-4,5-dihydrooxazole-4-carboxylic acid diphenylmethyl ester (IVca)

[0070]

[0071] Under nitrogen atmosphere and at -20°C, p-cyanobenzaldehyde (203 mg, 1.1 mmol), silver oxide (5.8 mg, 0.025 mmol), and chiral ligand L3 (38 mg, 0.05 mmol) were dissolved in methyl tert-butyl ether (20 mL), and a solution of diphenylmethyl isocyanoacetate (251 mg, 1 mmol) in methyl tert-butyl ether (2 mL) was added dropwise within 1 hour. After the reaction was kept warm for 24 hours, the solvent was recovered by concentration under reduced pressure. The residue was separated by column chromatography (petroleum ether: ethyl acetate = 2:1, v / v) to obtain 302 mg of colorless, transparent, oily liquid (4S, 5R)-5-(4-cyanophenyl)-4,5-dihydrooxazole-4-carboxylic acid diphenylmethyl ester (IVca), with a yield of 80%, an ee value of 94.2%, and a dr value of 49 / 1.

[0072] Structural characterization of IVca: 1 H NMR(400MHz,DMSO-d6)δ7.75(t,J=1.2Hz,1H),7.65-7.58(m,2H),7.47-7.27(m,12 H), 6.68 (t, J = 0.8Hz, 1H), 5.91 (dt, J = 7.2, 1.2Hz, 1H), 4.68 (dd, J = 7.2, 1.2Hz, 1H). 13 CNMR(100MHz,DMSO-d6)δ168.12,161.41,139.48,136.17,132.66,129.86,129.00,127.46,127.01,118.64,110.81,82.75,81.02,71.09.

[0073] Example 8: Preparation of (4S,5R)-5-(pyridin-3-yl)-4,5-dihydrooxazole-4-carboxylic acid diphenylmethyl ester (IVda)

[0074]

[0075] Under nitrogen atmosphere and 25°C, pyridine-3-carboxaldehyde (118 mg, 1.1 mmol), silver acetate (8.3 mg, 0.05 mmol), and chiral ligand L4 (38 mg, 0.05 mmol) were dissolved in dichloromethane (20 mL). A 2 mL dichloromethane solution of diphenylmethyl isocyanoacetate (251 mg, 1 mmol) was added dropwise within 1 hour. After keeping warm for 2 hours, the solvent was recovered by concentration under reduced pressure. The residue was separated by column chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain 276 mg of light yellow transparent oily (4S, 5R)-5-(pyridin-3-yl)-4,5-dihydrooxazole-4-carboxylic acid diphenylmethyl ester (IVda) with a yield of 77%, an ee value of 95.3%, and a dr value of 99 / 1.

[0076] Structural characterization of IVda: 1 H NMR (400MHz, DMSO-d6) δ8.73-8.63(m,1H),8.52(dt,J=3.8,1.2Hz,1H),7.74(dt,J=4.6,1.2Hz, 2H),7.48-7.23(m,11H),6.68(d,J=0.8Hz,1H),6.01-5.89(m,1H),4.88(dd,J=8.0,1.2Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ168.30,161.19,149.44,148.76,139.48,133.40,130.64,129.86,129.00,127.46,125.20,81.12,81.02,70.79.

[0077] Example 9: Preparation of (4S,5R)-5-(pyridin-2-yl)-4,5-dihydrooxazole-4-carboxylic acid diphenylmethyl ester (IVea)

[0078]

[0079] Under nitrogen atmosphere and at 25°C, pyridine-2-carboxaldehyde (118 mg, 1.1 mmol), silver oxide (5.8 mg, 0.025 mmol), and chiral ligand L1 (44 mg, 0.05 mmol) were dissolved in tetrahydrofuran (20 mL), and a solution of diphenylmethyl isocyanoacetate (251 mg, 1 mmol) in tetrahydrofuran (2 mL) was added dropwise within 1 hour. After keeping warm for 2 hours, the solvent was recovered by concentration under reduced pressure. The residue was separated by column chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain 284 mg of (4S, 5R)-5-(pyridin-2-yl)-4,5-dihydrooxazole-4-carboxylic acid diphenylmethyl ester (IVea) as a light yellow transparent oil with a yield of 81%, an ee value of 91.2%, and a dr value of 24 / 1.

[0080] Structural Characterization of IVea: 1 H NMR(400MHz, DMSO-d6)δ8.63(dd,J=3.6,1.2Hz,1H),7.88(t,J=1.2Hz,1H),7.79-7.73(m,1H),7.67-7 .60(m,2H),7.46-7.27(m,10H),6.68(d,J=0.8Hz,1H),6.09-5.96(m,1H),4.94(dd,J=7.2,1.2Hz,1H). 13C NMR (100MHz, DMSO-d6) δ167.46,161.01,152.62,148.70,139.50,136.56,129.86,129.00,127.46,122.78,120.75,81.90,81.00,65.91.

[0081] Example 10: Preparation of chloramphenicol intermediate (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrophenyl) propionic acid diphenylmethyl ester

[0082]

[0083] Under nitrogen atmosphere and at 25°C, p-nitrobenzaldehyde (16.62 g, 0.11 mol), silver oxide (0.058 g, 0.00025 mol), and chiral ligand L1 (0.44 g, 0.0005 mol) were dissolved in ethyl acetate (1000 mL). A solution of diphenylmethyl isocyanoacetate (25.12 g, 0.1 mol) in ethyl acetate (100 mL) was added dropwise within 1 hour. After keeping the temperature for 1 hour, the temperature was slowly lowered to -20°C to precipitate a white solid, which was then filtered off; the filter cake (intermediate IVfa) was dissolved in methanol (100mL), add concentrated hydrochloric acid (0.53g) dropwise at 50℃, keep warm for 2 hours, add water (200mL) to dilute and cool to 20℃, add 500mL dichloromethane to stand for phase separation, remove the organic phase, adjust the pH of the aqueous phase to 8 with ammonia water (60g), filter, and vacuum dry the filter cake to obtain 33.01g of chloramphenicol intermediate (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl) propionic acid diphenylmethyl ester, the total yield of the two-step reaction is 82.1%, the ee value is 99.3%, and the dr value is>99:1. mp:115-116℃.

[0084] Example 11: Preparation of chloramphenicol intermediate (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrophenyl) propionic acid diphenylmethyl ester (Comparative Example)

[0085]

[0086] In a nitrogen atmosphere at 25°C, p-nitrobenzaldehyde (16.62 g, 0.11 mol), silver oxide (0.058 g, 0.00025 mol), chiral ligand L a(0.30g, 0.0005mol) was dissolved in ethyl acetate (1000mL), and a solution of diphenylmethyl isocyanoacetate (25.12g, 0.1mol) in ethyl acetate (100mL) was added dropwise within 1 hour. After keeping warm for 1 hour, the temperature was slowly lowered to -20°C to precipitate a white solid, which was filtered off by suction; the filter cake (intermediate IVfa) was dissolved in methanol (100mL), and concentrated hydrochloric acid (0.53g) was added dropwise at 50°C, and the reaction was kept warm for 2 hours. , dilute with water (200 mL) and cool to 20°C, add 500 mL of dichloromethane and stand for phase separation, remove the organic phase, adjust the pH of the aqueous phase to 8 with ammonia water (60 g), filter, and vacuum dry the filter cake to obtain 21.36 g of chloramphenicol intermediate (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrophenyl) propionic acid diphenylmethyl ester, the total yield of the two-step reaction is 52.3%, the ee value is 86.4%, and the dr value is 90:10.

[0087] Example 12: Preparation of chloramphenicol intermediate (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrophenyl) propionic acid diphenylmethyl ester

[0088]

[0089] Under nitrogen atmosphere and 25°C, p-nitrobenzaldehyde (16.62 g, 0.11 mol), silver oxide (0.116 g, 0.0005 mol), and chiral ligand L1 (0.88 g, 0.001 mol) were dissolved in ethyl acetate (1000 mL). A solution of diphenylmethyl isocyanoacetate (25.12 g, 0.1 mol) in ethyl acetate (100 mL) was added dropwise within 1 hour. After keeping the temperature for 1 hour, the temperature was slowly lowered to -20°C to precipitate a white solid, which was then filtered off. The filter cake (intermediate IVfa) was dissolved in methanol ( 100mL), concentrated hydrochloric acid (0.53g) was added dropwise at 50°C, and the reaction was kept warm for 2 hours. Water (200mL) was added to dilute and the temperature was lowered to 20°C. 500mL of dichloromethane was added and the phases were allowed to stand for separation. The organic phase was removed, and the aqueous phase was adjusted to pH=8 with ammonia water (60g). The filter cake was vacuum dried to obtain 33.16g of chloramphenicol intermediate (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl) propionic acid diphenylmethyl ester. The total yield of the two-step reaction was 82.9%, the ee value was 99.3%, and the dr value was>99:1.

[0090] Example 13: Preparation of chloramphenicol intermediate (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrophenyl) propionic acid diphenylmethyl ester

[0091]

[0092] Under nitrogen atmosphere and at 40°C, p-nitrobenzaldehyde (16.62 g, 0.11 mol), silver acetate (0.8335 g, 0.005 mol), and chiral ligand L1 (3.64 g, 0.005 mol) were dissolved in ethyl acetate (1000 mL). A solution of diphenylmethyl isocyanoacetate (25.12 g, 0.1 mol) in ethyl acetate (100 mL) was added dropwise within 1 hour. After keeping the temperature for 1 hour, the temperature was slowly lowered to -20°C to precipitate a white solid, which was then filtered off. The filter cake (intermediate IVfa) was dissolved in methanol ( 100mL), concentrated hydrochloric acid (0.53g) was added dropwise at 50°C, and the reaction was kept warm for 2 hours. Water (200mL) was added to dilute and the temperature was lowered to 20°C. 500mL of dichloromethane was added and the phases were allowed to stand for separation. The organic phase was removed, and the aqueous phase was adjusted to pH=8 with ammonia water (60g). The filter cake was vacuum dried to obtain 31.64g of chloramphenicol intermediate (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl) propionic acid diphenylmethyl ester. The total yield of the two-step reaction was 79.1%, the ee value was 99.0%, and the dr value was>99:1.

[0093] Example 14: Preparation of Florfenicol Intermediate (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionic acid tert-butyl ester

[0094]

[0095] Under nitrogen atmosphere and 40°C, p-methylsulfonylbenzaldehyde (20.24 g, 0.11 mol), silver oxide (0.578 g, 0.0025 mol), and chiral ligand L1 (3.64 g, 0.005 mol) were dissolved in ethyl acetate (200 mL). A solution of tert-butyl isocyanoacetate (14.15 g, 0.1 mol) in ethyl acetate (30 mL) was added dropwise within 1 hour. After keeping the temperature for 1 hour, the temperature was slowly lowered to -20°C to precipitate a white solid, which was then filtered off; the filter cake (intermediate IVgb) was dissolved in methanol Add concentrated hydrochloric acid (0.53 g) dropwise to alcohol (200 mL) at 50°C, keep warm for 2 hours, dilute with water (400 mL) and cool to 20°C, add dichloromethane (500 mL) and stand for phase separation, remove the organic phase, adjust the pH of the aqueous phase to 8 with ammonia water (60 g), filter, and vacuum dry the filter cake to obtain 25.51 g of (2S, 3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl) propionic acid tert-butyl ester, with a total yield of 78.5% for the two-step reaction, ee value of 99.3%, and dr value>99:1. mp:119-121°C

[0096] Example 15: Preparation of Florfenicol Intermediate (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionic acid tert-butyl ester

[0097]

[0098] In a nitrogen atmosphere at 60°C, p-methylsulfonylbenzaldehyde (20.24 g, 0.11 mol), silver phosphate (0.697 g, 0.0017 mol), chiral ligand L a (3.05 g, 0.005 mol) was dissolved in methyl tert-butyl ether (200 mL), and a solution of tert-butyl isocyanoacetate (14.15 g, 0.1 mol) in methyl tert-butyl ether (30 mL) was added dropwise within 1 hour. After the reaction was kept warm for 1 hour, the temperature was slowly lowered to -20 °C to precipitate a white solid, which was then filtered off with suction. The filter cake (intermediate IVgb) was dissolved in isopropanol (200 mL), and concentrated hydrochloric acid (0.53 g) was added dropwise at 50 °C. The mixture was kept warm for 2 hours. The mixture was reacted for 2 hours, diluted with water (400 mL) and cooled to 20°C, and dichloromethane (500 mL) was added to stand for phase separation. The organic phase was removed, and the aqueous phase was adjusted to pH 8 with aqueous ammonia (60 g), filtered, and the filter cake was vacuum dried to obtain 25.32 g of tert-butyl (2S, 3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl) propionate. The total yield of the two-step reaction was 78.2%, the ee value was 98.3%, and the dr value was 49:1.

[0099] Chiral ligand L used in Examples 11 and 15 of the present invention a , is a compound of the following structure mentioned in the background technology:

[0100]

[0101] Example 16: Preparation of Florfenicol Intermediate (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionic acid tert-butyl ester

[0102]

[0103] Under nitrogen atmosphere and 40°C, p-methylsulfonylbenzaldehyde (20.24 g, 0.11 mol), silver acetate (0.0166 g, 0.0001 mol), and chiral ligand L1 (0.0611 g, 0.0001 mol) were dissolved in methyl tert-butyl ether (200 mL), and a solution of tert-butyl isocyanoacetate (14.15 g, 0.1 mol) in methyl tert-butyl ether (30 mL) was added dropwise within 1 hour. After keeping the temperature for 1 hour, the temperature was slowly lowered to -20°C to precipitate a white solid, which was filtered off; the filter cake (intermediate IVgb ) was dissolved in methanol (200 mL), concentrated hydrochloric acid (0.53 g) was added dropwise at 50°C, the reaction was kept warm for 2 hours, water (400 mL) was added to dilute and the temperature was lowered to 20°C, dichloromethane (500 mL) was added and the phases were allowed to stand, the organic phase was removed, and the aqueous phase was adjusted to pH = 8 with ammonia water (60 g), filtered, and the filter cake was dried in vacuo to obtain 25.31 g of tert-butyl (2S, 3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl) propionate. The total yield of the two-step reaction was 77.9%, the ee value was 98.9%, and the dr value was >99:1.

[0104] Example 17: Preparation of Florfenicol Intermediate (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionic acid tert-butyl ester

[0105]

[0106] Under nitrogen atmosphere and 25°C, p-methylsulfonylbenzaldehyde (22.08 g, 0.12 mol), methanesulfonic acid (0.203 g, 0.001 mol), and chiral ligand L1 (3.64 g, 0.001 mol) were dissolved in tetrahydrofuran (200 mL), and a solution of tert-butyl isocyanoacetate (14.15 g, 0.1 mol) in tetrahydrofuran (30 mL) was added dropwise within 1 hour. After keeping the temperature for 3 hours, the temperature was slowly lowered to -20°C to precipitate a white solid, which was then filtered; the filter cake (intermediate IVgb) was dissolved in methanol and the mixture was stirred for 3 hours. In alcohol (200 mL), concentrated hydrochloric acid (0.53 g) was added dropwise at 50 ° C, and the reaction was kept warm for 2 hours. Water (400 mL) was added to dilute and the temperature was lowered to 20 ° C. Dichloromethane (500 mL) was added and the phases were allowed to stand for separation. The organic phase was removed, and the aqueous phase was adjusted to pH = 8 with ammonia water (60 g). The filter cake was vacuum dried to obtain 24.54 g of (2S, 3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl) propionic acid tert-butyl ester. The total yield of the two-step reaction was 75.5%, the ee value was 98.2%, and the dr value was >99:1.

[0107] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. An adamantylphosphine ligand of a cinchona alkaloid skeleton, characterized in that Having a structure of formula (I) or a tautomer, enantiomer or diastereomer thereof: Among them, the substituent R 1 is ethyl or vinyl; R 2 is a methoxy group or a hydrogen atom.

2. The adamantylphosphine ligand of a cinchona alkaloid skeleton as claimed in claim 1, characterized in that The structure of formula (I) is selected from one of compounds L1 to L4:

3. The adamantylphosphine ligand of a cinchona alkaloid skeleton as claimed in claim 1, characterized in that The preparation method comprises the following steps: 1) di(adamantyl)phosphine hydrogen S1 reacts with methyl o-bromobenzoate to obtain intermediate S2; 2) Intermediate S2 is hydrolyzed to obtain intermediate S3; 3) The intermediate S3 and the quinidine derivative S4 undergo condensation acylation reaction to obtain product I; the reaction formula is as follows: Substituent R in Quinidine Derivative S4 1 and R 2 The definitions are the same as those of formula (I).

4. The adamantylphosphine ligand of a cinchona alkaloid skeleton as claimed in claim 3, characterized in that In step 1), the reaction is carried out in the presence of sodium tert-butoxide, palladium acetate and 1,1'-bis(diphenylphosphino)ferrocene, the molar ratio of di(adamantyl)phosphine hydrogen S1, methyl o-bromobenzoate, sodium tert-butoxide, palladium acetate and 1,1'-bis(diphenylphosphino)ferrocene is 1:1.1-1.5:1.1-1.5:0.02-0.08:0.02-0.08, the reaction solvent is toluene, the reaction temperature is 100-120°C, and the reaction time is 10-15h.

5. A silver catalyst, characterized in that The invention relates to a diatomaceous earth catalyst comprising an adamantylphosphine ligand of a cinchona alkali skeleton as described in claim 1 or 2 and a silver salt, wherein the molar ratio of the ligand to the silver salt is 1:0.8-1.2, and a complex formed by complexation between the two is the silver catalyst; wherein the silver salt is selected from one of silver acetate, silver oxide, silver methanesulfonate, and silver phosphate, or a mixture of two or more thereof.

6. Use of the silver catalyst as claimed in claim 5 in an asymmetric [3+2] cycloaddition reaction.

7. The use according to claim 6, characterized in that The application method comprises the following steps: the aromatic aldehyde represented by formula (II) is dissolved in solvent A, adamantyl phosphine ligand of cinchona alkaloid skeleton and silver salt are added, a mixed solution of isocyanoacetate represented by formula (III) and solvent A is added dropwise within 1 to 5 hours at -20°C to 60°C in a nitrogen atmosphere, and then the mixture is kept warm for 1 to 24 hours, the ligand and silver salt are complexed to form a silver catalyst and catalyze an asymmetric [3+2] cycloaddition reaction, and after the reaction is completed, the solvent is recovered by concentration under reduced pressure, and the residue is separated by column chromatography to obtain a chiral oxazoline intermediate represented by formula (IV); The specific reaction route is as follows: In the general formula (II), Ar represents a phenyl group, a substituted aryl group or a heterocyclic aryl group, and the substituent on the aryl group of the substituted aryl group is a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, a cyano group, a methylsulfone group, a halogen group or a H atom; R 3 It is represented by methyl, ethyl, isopropyl, tert-butyl or benzhydryl.

8. The use according to claim 7, characterized in that The solvent A is selected from one or a mixed solvent of ethyl acetate, toluene, methyl tert-butyl ether, dichloromethane and tetrahydrofuran; and the eluent for column chromatography separation is petroleum ether-ethyl acetate in a volume ratio of 2-5:

1.

9. The use according to claim 7, characterized in that The molar ratio of the compound of formula (III), the compound of formula (II), the adamantyl phosphine ligand of the cinchona alkaloid skeleton and the silver salt is 1:1.0-1.2:0.001-0.05:0.001-0.

05.

10. Use of the silver catalyst according to any one of claims 5 to 9 in an asymmetric [3+2] cycloaddition reaction, characterized in that The silver catalyst can be applied to the asymmetric synthesis of florfenicol intermediates or chloramphenicol intermediates.

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