A cinchona alkaloid skeleton with adamantylphosphine ligand, a silver catalyst containing such ligand, and its applications

Abstract

This invention discloses an adamantylphosphine ligand with a cinchona alkaloid skeleton, a silver catalyst containing such ligand, and its applications. The ligand has a structure as shown in formula (I) or its tautomers, enantiomers, and diastereomers: In formula (I), R 1 is ethyl or vinyl; the substituent R 2 The novel catalyst, composed of a cinchona alkaloid skeleton adamantylphosphine ligand and a silver salt, can efficiently catalyze the asymmetric [3+2] cycloaddition reaction of aromatic aldehydes and isocyanatoacetic acid esters, obtaining the corresponding chiral oxazoline intermediates with high stereoselectivity and high yield. This technology can be applied to the asymmetric synthesis of florfenicol intermediates and chloramphenicol intermediates, and has the advantages of a short synthetic route, high yield, and good stereoselectivity, thus providing good economic and social benefits.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to an adamantylphosphine ligand with a cinchona alkaloid skeleton, a silver catalyst containing such ligand, and its applications. Background Technology

[0002] In asymmetric synthesis catalyzed by small organic molecules, cinchona alkaloids have been a popular research topic since they were first reported as chiral auxiliaries in 1853. Their role as organic catalysts or chiral ligands in asymmetric synthesis is closely related to their naturally occurring chiral structure and strong late-stage modifiability. The following points can be summarized: (1) Quinine and quinoline rings can generate chiral pockets similar to enzymes to provide a chiral environment; (2) R, OH and quinine rings are all modifiable; (3) The free rotation of C8 and C9 creates a dynamic environment that can produce conformations with different stability; (4) The tertiary amine nitrogen atom in the quinine ring has nucleophilic characteristics and can be used as a nucleophilic reagent to activate the substrate; (5) The flat quinoline ring is electron-rich and can form an electron donor-electron complex (EDA) with electron-deficient molecules; (6) The hydroxyl group at the C9 position can be used as an electrophilic reagent to activate the substrate through hydrogen bonding. In the past few decades, through the modification of the structure of cinchona alkaloids, many representative cinchona alkaloid derivatives have been derived, such as C9-amine, urea / thiourea, amide, sulfonamide, squaramide, ether, etc.; C6'-hydroxyl and dimer or polymeric polymers (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 via an asymmetric [3+2] cycloaddition reaction catalyzed by p-nitrobenzaldehyde, isocyanate, Ag2O, and diphenylphosphine ligands of the cinchona alkaloid skeleton.

[0005] This method has drawbacks such as excessive catalyst usage, insufficient stereoselectivity, and low yield.

[0006]

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

[0008]

[0009] Based on this, we plan to further modify the chiral phosphine ligand of the cinchona alkaloid skeleton. Further experimental verification shows that the steric hindrance and electronic properties of the substituents on phosphorus have a significant impact on catalytic performance.

[0010] Therefore, modifying the diphenylphosphine ligand of the cinchona alkaloid skeleton to an adamantylphosphine ligand of the cinchona alkaloid skeleton can help improve the catalytic performance and application range of this type of catalyst, and has important application prospects. Summary of the Invention

[0011] To address the aforementioned problems in the prior art, the present invention aims to provide an adamantylphosphine ligand with a cinchona alkaloid skeleton, a silver catalyst containing such ligand, and its applications. The ligand provided by the present invention is characterized by simple synthesis, water stability, and high activity and selectivity in catalyzing asymmetric [3+2] cycloaddition reactions and in the asymmetric synthesis of florfenicol intermediates and chloramphenicol intermediates.

[0012] The technical solution adopted in 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 It is ethyl or vinyl; R 2 It consists of 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 includes the following steps:

[0019] 1) The reaction of bis(adamantyl)phosphine hydrogen S1 with methyl o-bromobenzoate yields intermediate S2;

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

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

[0022]

[0023] The substituent R in quinidine derivative S4 1 and R 2 Define the same structure (I).

[0024] Further, the reaction in step 1) is carried out in the presence of sodium tert-butoxide, palladium acetate, and 1,1'-bis(diphenylphosphine)ferrocene. The molar ratio of bis(adamantyl)phosphine hydrogen S1, methyl o-bromobenzoate, sodium tert-butoxide, palladium acetate, and 1,1'-bis(diphenylphosphine)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℃, and the reaction time is 10-15 h. After the reaction is completed, the intermediate S2 is obtained through post-processing.

[0025] Further, in step 2), intermediate S2 undergoes a hydrolysis reaction in a 20% potassium hydroxide aqueous solution / 1,4-dioxane solution (volume ratio of the two is 1:1), and is stirred at 90°C for 24 hours. After post-processing, intermediate S3 is obtained.

[0026] Further, intermediate S3, quinidine derivative S4, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1-hydroxybenzotriazole were dissolved in dichloromethane in a molar ratio of (1:1:1.2:1.2) and reacted at room temperature. After post-treatment, adamantylphosphine ligands with a cinchona alkaloid skeleton as shown in formula (I) were obtained.

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

[0028] The silver catalyst described above can catalyze asymmetric [3+2] cycloaddition reactions to efficiently prepare chiral oxazoline intermediates as shown in formula (IV).

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

[0030] The aromatic aldehyde shown in formula (II) is dissolved in solvent A. Adamantylphosphine ligands of the cinchona alkaloid skeleton and silver salt are added. Under a nitrogen atmosphere and at -20℃ to 60℃, a mixture of isocyanate ester shown in formula (III) and solvent A is added dropwise over 1 to 5 hours. The reaction is then maintained at this temperature for 1 to 24 hours. The ligand complexes with the silver salt to form a silver catalyst and catalyzes an asymmetric [3+2] cycloaddition reaction. After the reaction is completed, the solvent is recovered by vacuum concentration. The residue is separated by column chromatography to obtain the chiral oxazoline intermediate shown in formula (IV).

[0031] The specific reaction route is as follows:

[0032]

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

[0034] Furthermore, solvent A is selected from one or more mixed solvents 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 with a volume ratio of 2-5:1.

[0036] Furthermore, the molar ratio of compound (III), compound (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 existing diphenylphosphine ligands of the cinchona alkaloid skeleton, the adamantylphosphine ligand of the cinchona alkaloid skeleton provided by this invention has greater steric hindrance and stronger coordination ability, which is beneficial to improving catalytic activity and selectivity. The preparation process of this ligand is simple and suitable for large-scale preparation. After complexation with silver salt, it can efficiently catalyze asymmetric [3+2] cycloaddition reactions, obtaining chiral oxazoline intermediates in high yield and with high stereoselectivity, and can be applied to the asymmetric synthesis of florfenicol intermediates and chloramphenicol intermediates. Detailed Implementation

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

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

[0041] Example 1: Synthesis of ligand L1

[0042]

[0043] (1) Under a nitrogen atmosphere, bis(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(diphenylphosphine)ferrocene (253 mg, 0.45 mmol) were dissolved in toluene (100 mL) and refluxed at 110 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 20:1, v / v) to give intermediate S2 (2.32 g, yield 69%).

[0044] Structural characterization of intermediate S2: mp: 178-179℃; 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 a 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 vacuum concentration, and dichloromethane (20 mL) was added at room temperature, followed by dropwise addition of 3M hydrochloric acid (20 mL). After the addition was complete, the mixture was extracted and separated. The resulting organic layer was concentrated under vacuum to remove the solvent, yielding intermediate S3 (1.65 g, 99% yield).

[0046] Structural characterization of intermediate S3: mp: 203-205℃; 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 a 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 then quenched with water. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:methanol = 20:1, v / v) to give a white solid L1 (516 mg, yield 71%).

[0048] Structural characterization of ligand L1: mp: 253-256℃; 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 a 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), and 1-hydroxybenzotriazole (162 mg, 1.2 mmol) were added to 10 mL of dichloromethane. The reaction was stirred at room temperature for 24 hours, and then quenched with water. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:methanol = 20:1, v / v) to give ligand L2 (474 ​​mg, 65% yield).

[0052] Structural characterization of ligand L2: mp: 245-246℃; 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 a 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), and 1-hydroxybenzotriazole (162 mg, 1.2 mmol) were added to 10 mL of dichloromethane. The reaction was stirred at room temperature for 24 hours, and then quenched with water. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:methanol = 20:1, v / v) to give ligand L3 (509 mg, 73% yield).

[0056] Structural characterization of ligand L3: mp: 271-273℃; 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 a 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), and 1-hydroxybenzotriazole (162 mg, 1.2 mmol) were added to 10 mL of dichloromethane. The reaction was stirred at room temperature for 24 hours, and then quenched with water. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:methanol = 20:1, v / v) to give ligand L4 (441 mg, yield 63%).

[0060] Structural characterization of ligand L4: mp: 269-271℃; 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-dihydrooxazol-4-carboxylic acid diphenyl methyl ester (IVaa)

[0062]

[0063] Under a 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 diphenyl isocyanate (251 mg, 1 mmol) in ethyl acetate (2 mL) was added dropwise over 1 hour. After reacting at this temperature for 3 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 a pale yellow oily liquid (4S,5R)-5-(3-nitrophenyl)-4,5-dihydrooxazol-4-carboxylic acid benzyl ester (IVaa) 343 mg. The product yield was 85%, ee value was 96.5%, and dr value was 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-dihydrooxazol-4-carboxylic acid diphenyl methyl ester (IVba)

[0066]

[0067] Under a 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 toluene (2 mL) solution of diphenyl isocyanate (251 mg, 1 mmol) was added dropwise over 1 hour. After reacting at this temperature 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 a grayish-white oily liquid (4S,5R)-5-(4-bromophenyl)-4,5-dihydrooxazol-4-carboxylic acid diphenyl methyl ester (IVba) 325 mg, 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-dihydrooxazol-4-carboxylic acid diphenylmethyl ester (IVca)

[0070]

[0071] Under a 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). A solution of diphenyl isocyanate (251 mg, 1 mmol) in methyl tert-butyl ether (2 mL) was added dropwise over 1 hour. After reacting at this temperature 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 a colorless, transparent, oily liquid (4S,5R)-5-(4-cyanophenyl)-4,5-dihydrooxazol-4-carboxylic acid diphenyl methyl ester (IVca) 302 mg, 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-dihydrooxazol-4-carboxylic acid diphenyl methyl ester (IVda)

[0074]

[0075] Under a nitrogen atmosphere and at 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 solution of dichloromethane containing diphenyl isocyanate (251 mg, 1 mmol) was added dropwise over 1 hour. After reacting at this temperature 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 a pale yellow, transparent, oily (4S,5R)-5-(pyridin-3-yl)-4,5-dihydrooxazol-4-carboxylic acid diphenyl methyl 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-dihydrooxazol-4-carboxylic acid diphenyl methyl ester (IVea)

[0078]

[0079] Under a 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). A tetrahydrofuran (2 mL) solution of diphenyl isocyanate (251 mg, 1 mmol) was added dropwise over 1 hour. After reacting at this temperature 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-dihydrooxazol-4-carboxylic acid diphenyl methyl ester (IVea), yield 81%, ee value 91.2%, dr value 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 diphenylmethyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl)propionate intermediate for chloramphenicol

[0082]

[0083] Under a 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 diphenyl isocyanate (25.12 g, 0.1 mol) in ethyl acetate (100 mL) was added dropwise over 1 hour. After maintaining the reaction temperature for 1 hour, the mixture was slowly cooled to -20°C, precipitating a white solid. The solid was filtered. The filter cake (intermediate IVfa) dissolved in methanol. In 100 mL of solution, concentrated hydrochloric acid (0.53 g) was added dropwise at 50 °C, and the reaction was maintained at this temperature for 2 hours. The solution was then diluted with 200 mL of water and cooled to 20 °C. 500 mL of dichloromethane was added, and the mixture was allowed to stand for phase separation. The organic phase was removed, and the aqueous phase was adjusted to pH 8 with 60 g of ammonia. The mixture was filtered, and the filter cake was vacuum dried to obtain 33.01 g of diphenyl methyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl)propionate, an intermediate for chloramphenicol. The overall yield of the two-step reaction was 82.1%, with an ee value of 99.3% and a dr value > 99:1. mp: 115-116 °C.

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

[0085]

[0086] Under a 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 L were added. a(0.30 g, 0.0005 mol) was dissolved in ethyl acetate (1000 mL), and a solution of diphenyl methyl isocyanate (25.12 g, 0.1 mol) in ethyl acetate (100 mL) was added dropwise over 1 hour. After reacting at this temperature for 1 hour, the mixture was slowly cooled to -20 °C, and a white solid precipitated. The solid was then filtered. The filter cake (intermediate IVfa) was dissolved in methanol (100 mL), and concentrated hydrochloric acid (0.53 g) was added dropwise at 50 °C. The mixture was then reacted at this temperature for 2 hours. Dilute with water (200 mL) and cool to 20 °C. Add 500 mL of dichloromethane and allow to stand for phase separation. Remove the organic phase. Adjust the pH of the aqueous phase to 8 with ammonia (60 g). Filter and vacuum dry the filter cake to obtain 21.36 g of diphenyl methyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl)propionate intermediate. The overall 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 diphenylmethyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl)propionate intermediate for chloramphenicol

[0088]

[0089] Under a nitrogen atmosphere and at 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 diphenyl isocyanate (25.12 g, 0.1 mol) in ethyl acetate (100 mL) was added dropwise over 1 hour. After maintaining the reaction temperature for 1 hour, the mixture was slowly cooled to -20°C, precipitating a white solid. The solid was filtered. The filter cake (intermediate IVfa) was dissolved in methanol. In 100 mL of water, concentrated hydrochloric acid (0.53 g) was added dropwise at 50 °C, and the reaction was maintained at this temperature for 2 hours. The mixture was then diluted with water (200 mL) and cooled to 20 °C. 500 mL of dichloromethane was added, and the mixture was allowed to stand and separate the phases. The organic phase was removed, and the pH of the aqueous phase was adjusted to 8 with ammonia (60 g). The mixture was filtered, and the filter cake was dried under vacuum to obtain 33.16 g of diphenyl methyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl)propionate intermediate. The overall 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 diphenylmethyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl)propionate intermediate for chloramphenicol

[0091]

[0092] Under a 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 diphenyl isocyanate (25.12 g, 0.1 mol) in ethyl acetate (100 mL) was added dropwise over 1 hour. After maintaining the reaction temperature for 1 hour, the mixture was slowly cooled to -20°C, precipitating a white solid, which was then filtered. The filter cake (intermediate IVfa) was dissolved in methanol. In 100 mL of water, concentrated hydrochloric acid (0.53 g) was added dropwise at 50 °C, and the reaction was maintained at this temperature for 2 hours. The mixture was then diluted with water (200 mL) and cooled to 20 °C. 500 mL of dichloromethane was added, and the mixture was allowed to stand and separate the phases. The organic phase was removed, and the pH of the aqueous phase was adjusted to 8 with ammonia (60 g). The mixture was filtered, and the filter cake was dried under vacuum to obtain 31.64 g of diphenyl methyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl)propionate, an intermediate of chloramphenicol. The overall 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 tert-butyl (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionate intermediate, florfenicol

[0094]

[0095] Under a nitrogen atmosphere and at 40°C, 20.24 g (0.11 mol) of p-methylsulfonylbenzaldehyde, 0.578 g (0.0025 mol) of silver oxide, and 3.64 g (0.005 mol) of chiral ligand L1 were dissolved in 200 mL of ethyl acetate. A solution of 14.15 g (0.1 mol) of tert-butyl isocyanate in 30 mL of ethyl acetate was added dropwise over 1 hour. After reacting at this temperature for 1 hour, the mixture was slowly cooled to -20°C, precipitating a white solid. The solid was filtered. The filter cake (intermediate IVgb) was dissolved in methyl acetate. In 200 mL of alcohol, concentrated hydrochloric acid (0.53 g) was added dropwise at 50 °C, and the reaction was maintained at this temperature for 2 hours. The mixture was then diluted with 400 mL of water and cooled to 20 °C. Dichloromethane (500 mL) was added, and the mixture was allowed to stand for phase separation. The organic phase was removed, and the aqueous phase was adjusted to pH 8 with 60 g of ammonia. After filtration and vacuum drying of the filter cake, 25.51 g of tert-butyl (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionate was obtained. The overall yield of the two-step reaction was 78.5%, the ee value was 99.3%, and the dr value was >99:1. mp: 119-121 °C

[0096] Example 15: Preparation of tert-butyl (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionate intermediate, florfenicol

[0097]

[0098] Under a nitrogen atmosphere and at 60°C, p-methylsulfonylbenzaldehyde (20.24 g, 0.11 mol), silver phosphate (0.697 g, 0.0017 mol), and chiral ligand L were added. a (3.05 g, 0.005 mol) was dissolved in methyl tert-butyl ether (200 mL). A solution of methyl tert-butyl ether (30 mL) containing 14.15 g, 0.1 mol of tert-butyl isocyanate was added dropwise over 1 hour. After incubating the reaction at this temperature for 1 hour, the temperature was slowly lowered to -20°C, and a white solid precipitated. The solid was filtered. The filter cake (intermediate IV gb) was dissolved in isopropanol (200 mL). Concentrated hydrochloric acid (0.53 g) was added dropwise at 50°C. The reaction was incubated at this temperature. After reacting for 2 hours, the mixture was diluted with water (400 mL) and cooled to 20°C. Dichloromethane (500 mL) was added, and the mixture was allowed to stand for phase separation. The organic phase was removed, and the aqueous phase was adjusted to pH 8 with ammonia (60 g). The mixture was filtered, and the filter cake was dried under vacuum to obtain 25.32 g of tert-butyl (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionate. The overall yield of the two-step reaction was 78.2%, the ee value was 98.3%, and the dr value was 49:1.

[0099] The chiral ligand L used in Examples 11 and 15 of this invention a The following compounds, as mentioned in the background section, have the following structures:

[0100]

[0101] Example 16: Preparation of tert-butyl (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionate intermediate, florfenicol

[0102]

[0103] Under a nitrogen atmosphere and at 40°C, 20.24 g (0.11 mol) of p-methylsulfonylbenzaldehyde, 0.0166 g (0.0001 mol) of silver acetate, and 0.0611 g (0.0001 mol) of chiral ligand L1 were dissolved in 200 mL of methyl tert-butyl ether. A solution of 14.15 g (0.1 mol) of tert-butyl isocyanate in 30 mL of methyl tert-butyl ether was added dropwise over 1 hour. After reacting at this temperature for 1 hour, the mixture was slowly cooled to -20°C, precipitating a white solid. The solid was then filtered. The filter cake (intermediate IV gb) Dissolved in methanol (200 mL), concentrated hydrochloric acid (0.53 g) was added dropwise at 50 °C, and the reaction was maintained at this temperature for 2 hours. The mixture was then diluted with water (400 mL) and cooled to 20 °C. Dichloromethane (500 mL) was added, and the mixture was allowed to stand for phase separation. The organic phase was removed, and the aqueous phase was adjusted to pH 8 with ammonia (60 g). The mixture was filtered, and the filter cake was dried under vacuum to obtain 25.31 g of tert-butyl (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionate. The overall 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 tert-butyl (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionate intermediate, florfenicol

[0105]

[0106] Under a nitrogen atmosphere and at 25°C, 22.08 g (0.12 mol) of p-methylsulfonylbenzaldehyde, 0.203 g (0.001 mol) of methanesulfonic acid, and 3.64 g (0.001 mol) of chiral ligand L1 were dissolved in 200 mL of tetrahydrofuran. A solution of 14.15 g (0.1 mol) of tert-butyl isocyanate in 30 mL of tetrahydrofuran was added dropwise over 1 hour. After reacting at this temperature for 3 hours, the mixture was slowly cooled to -20°C, precipitating a white solid, which was then filtered. The filter cake (intermediate IVgb) dissolved in methyl... In 200 mL of alcohol, concentrated hydrochloric acid (0.53 g) was added dropwise at 50 °C, and the reaction was maintained at this temperature for 2 hours. The mixture was then diluted with 400 mL of water and cooled to 20 °C. Dichloromethane (500 mL) was added, and the mixture was allowed to stand for phase separation. The organic phase was removed, and the aqueous phase was adjusted to pH 8 with ammonia (60 g). The mixture was filtered, and the filter cake was dried under vacuum to obtain 24.54 g of tert-butyl (2S,3R)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionate. The overall 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 the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.

Claims

1. A cinchona alkaloid skeleton adamantylphosphine ligand, characterized in that... It has a structure as shown in equation (I): ； Among them, substituent R 1 It is ethyl or vinyl; R 2 It consists of a methoxy group or a hydrogen atom.

2. The adamantylphosphine ligand of the cinchona alkaloid skeleton as described in claim 1, characterized in that... The structure of formula (I) is selected from one of compounds L1 to L4: 。 3. The method for preparing an adamantylphosphine ligand with a cinchona alkaloid skeleton as described in claim 1, characterized in that... Includes the following steps: 1) The reaction of bis(adamantyl)phosphine hydrogen S1 with methyl o-bromobenzoate yields intermediate S2; 2) Intermediate S2 is hydrolyzed to obtain intermediate S3; 3) Intermediate S3 and quinidine derivative S4 undergo a condensation acylation reaction to give product I; the reaction formula is as follows: ； The substituent R in quinidine derivative S4 1 and R 2 Define the same structure (I).

4. The method for preparing an adamantylphosphine ligand with a cinchona alkaloid skeleton as described 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(diphenylphosphine)ferrocene. The molar ratio of bis(adamantyl)phosphine hydrogen S1, methyl o-bromobenzoate, sodium tert-butoxide, palladium acetate, and 1,1'-bis(diphenylphosphine)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℃, and the reaction time is 10-15 h.

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

6. An application of the silver catalyst as described in claim 5 in an asymmetric [3+2] cycloaddition reaction, the application method comprising the following steps: the aromatic aldehyde of formula (II) is dissolved in solvent A, an adamantylphosphine ligand of the cinchona alkaloid skeleton and a silver salt are added, and a mixture of isocyanate of formula (III) and solvent A is added dropwise over 1 to 5 hours under a nitrogen atmosphere and at -20°C to 60°C, and then the reaction is kept at a constant temperature for 1 to 24 hours, the adamantylphosphine ligand of the cinchona alkaloid skeleton complexes with the silver salt to form a silver catalyst and catalyzes the asymmetric [3+2] cycloaddition reaction, after the reaction is completed, the solvent is recovered by vacuum concentration, and the residue is separated by column chromatography to obtain a chiral oxazoline intermediate as shown in formula (IV); The specific reaction route is as follows: ； In general formula (II), Ar is a phenyl, substituted aryl, or heterocyclic aryl, wherein the substituent on the aryl group of the substituted aryl group is a C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, sulfone, halogen, or H atom; R 3 It can be methyl, ethyl, isopropyl, tert-butyl, or diphenylmethyl.

7. The application as described in claim 6, characterized in that... Solvent A is selected from one or more of the following solvents: ethyl acetate, toluene, methyl tert-butyl ether, dichloromethane, and tetrahydrofuran; the eluent for column chromatography is petroleum ether-ethyl acetate in a volume ratio of 2-5:

1.

8. The application as described in claim 6, characterized in that... The molar ratio of compound (III), compound (II), adamantylphosphine ligand of cinchona alkaloid skeleton and silver salt is 1 : 1.0~1.2 : 0.001~0.05 : 0.001~0.

05.

9. The application as described in claim 6, characterized in that... The silver catalyst is used in the asymmetric synthesis of florfenicol intermediates or chloramphenicol intermediates; The structural formula of the florfenicol intermediate is as follows: ； The structural formula of the chloramphenicol intermediate is as follows: 。

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