A chiral preparation method for florfenicol

Abstract

This invention relates to a chiral preparation method for florfenicol. Specifically, the method uses p-methylsulfonylbenzaldehyde and glycine ester as starting materials, and synthesizes the key chiral intermediate I through an asymmetric aldol reaction process under the action of a pyridinium salt carbonyl catalyst. Subsequently, through reduction, cyclization, fluorination, and hydrolysis ring-opening reactions, the chiral product florfenicol is obtained. Compared with existing technologies, this invention utilizes the strong catalytic ability of small-molecule pyridinium salt carbonyl catalysts, starting from inexpensive and readily available raw materials, to efficiently control the stereoselectivity of the aldol reaction process, highly selectively constructing the two chiral centers on the florfenicol structure, obtaining the desired chiral configuration, and finally synthesizing florfenicol. The preparation method of this invention is simple, rapid, and efficient.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug synthesis technology, specifically relating to a chiral preparation method of florfenicol. Background Technology

[0002] Florfenicol is a chiral compound with the following structure:

[0003]

[0004] Florfenicol, also known as florfenicol, is a class of animal-specific antibiotics developed by Schering-Plough in the United States in 1979. It is characterized by strong antibacterial activity, low toxicity and side effects, no residue, and low likelihood of developing drug resistance. It is mainly used to treat bacterial diseases and mycoplasma infections in poultry, livestock, and aquatic animals caused by susceptible bacteria.

[0005] Currently, the traditional synthesis process of florfenicol uses p-methylsulfonylbenzaldehyde and glycine as raw materials, involving steps such as copper salt catalysis and chiral resolution with D-tartaric acid participation. However, this method involves a large amount of transition metals, causing pollution problems. Moreover, the chiral resolution process in this method results in a theoretical yield of no more than 50%, leading to significant waste. Therefore, developing a low-cost chiral synthesis method for florfenicol using an asymmetric catalytic strategy is currently one of the hot topics in the florfenicol industry.

[0006] Currently, scientists have developed a series of chiral synthetic methods for the asymmetric catalytic synthesis of florfenicol, but most routes are optimizations or replacements of intermediate processes in traditional synthetic techniques. For example, CN111285789 describes the preparation of the key intermediate I of florfenicol—(2S,3R)-p-methylsulfonylbenzylserine ester—from p-methylthiobenzaldehyde and isocyanoacetate. However, this route requires three steps to obtain intermediate I, which is cumbersome, inefficient, and unsuitable for large-scale industrial application. Another example is the use of bio-enzymes as catalysts, which can catalyze the reaction of p-methylsulfonylbenzaldehyde with amino acid esters to generate the key intermediate I under mild conditions. However, these methods require bio-fermentation technology, demand high aseptic operation, and suffer from drawbacks such as insufficient enzyme stability and easy inactivation, limiting their application.

[0007] Therefore, there is an urgent need in this field for a mild, efficient, environmentally friendly, and cost-effective chiral chemical synthesis method that does not require the introduction of transition metal catalysis. Summary of the Invention

[0008] To address the aforementioned issues, this invention utilizes a pyridinium salt carbonyl catalyst to provide a catalytic reaction mode similar to the asymmetric aldol reaction catalyzed by threonine aldolase in vivo, thus offering a chiral synthesis method for the chiral preparation of florfenicol that is readily available, simple to operate, highly selective, yield-efficient, and environmentally friendly.

[0009] In a first aspect, the present invention provides a chiral method for preparing florfenicol, the method comprising the following steps:

[0010]

[0011] (1) In the presence of pyridinium salt carbonyl catalyst 3, sulfonyl benzaldehyde and glycine ester compound 2 were reacted to obtain (2S,3R)-p-sulfonyl benzene serine ester intermediate I;

[0012] (2) In the presence of a reducing agent, intermediate I undergoes a reduction reaction to obtain intermediate II;

[0013] (3) Intermediate II undergoes a cyclization reaction with dichloroacetonitrile to obtain intermediate III;

[0014] (4) Intermediate III undergoes a fluorination reaction with a fluorinating agent to obtain intermediate IV;

[0015] (5) Under acidic conditions, intermediate IV undergoes a hydrolysis reaction to yield florfenicol;

[0016] Wherein, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and cyclopentyl;

[0017] The pyridinium salt carbonyl catalyst 3 has the chemical structure shown in Formula 3:

[0018]

[0019] Among them, R 1 Selected from the following group:

[0020]

[0021] X1 is N or CR 6 X2 is N or CR 7 X3 is N or CR 8 X4 is N or CR 9 X5 is N or CR 10 X6 is N or CR 11 ;

[0022] R 2 R 4 R 6 R 7 R 8 R 9 R 10 and R 11 Each is independently selected from the following groups: hydrogen, -(CH2). m -C 1～24Alkyl group, -(CH2) m -C 3～24 cycloalkyl, C 1～16 Alkoxy, -C(O)OR d Halogen, nitro, cyano, trifluoromethyl;

[0023] m is 1, 2, or 3;

[0024] n is 0, 1, 2, 3, 4 or 5;

[0025] Each R a Independently selected from the following groups: hydrogen, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 aryl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms a Together with the ring carbon atoms it is attached to, they form C 6～12 Aryl;

[0026] R b R 2b R 3b R c R 2c and R d Each is independently selected from the following groups: hydrogen, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 Aryl;

[0027] R 3 C 1～24 Alkyl group, the above R 3 Optionally by 1, 2 or 3 R f replace;

[0028] R f Selected from the following group: halogens, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 Aryl, C 1～10 Alkoxy, C 1～10 Alkylamine group, -R g -LR 2g -P(O)(OR) h )2;

[0029] L is selected from the following group: -C(O)-, -C(O)NR i -、-C(O)O-、-S(O)2-;

[0030] R g Selected from the following group: key, C 1～8 Alkylene, C 3～8 Cycloalkylene;

[0031] R 2g and R h Each is independently selected from the following groups: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl;

[0032] R i Selected from the following group: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl, C 1～10 Alkoxy, C 1～10 Alkylamine group;

[0033] R 5 Selected from the following group:

[0034]

[0035] in,

[0036] x and y are each independently 0, 1, 2 or 3;

[0037] R 12 and R 13 Each is independently selected from the following groups: hydrogen, C 1～24 alkyl,

[0038] R 14 Selected from the following group: hydrogen, C 1～24 alkyl, Halogens, trifluoromethyl;

[0039] Each R e Independently selected from the following groups: hydrogen, C 1～10 Alkyl, C 1～10 Alkoxy, C 6～12 aryl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms e Together with the ring carbon atoms it is attached to, they form C 6～12 Aryl;

[0040] X - The anions selected from the following group are: fluoride ion, chloride ion, bromide ion, iodide ion, trifluoromethanesulfonate ion, hexafluorophosphate ion, tetrafluoroborate ion, sulfate ion, sulfite ion, hydroxide ion, nitrate ion, phosphate ion, carbonate ion, silicate ion, bicarbonate ion, hydrogen phosphate ion, dihydrogen phosphate ion, iodate ion, cyanide ion, and thiocyanate ion.

[0041] In another preferred embodiment, the C 1～24 Alkyl or C 1～10The alkyl group is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0042] In another preferred embodiment, the C 3～24 cycloalkyl or C 3～8 The cycloalkyl group is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0043] In another preferred embodiment, the C 6～12 The aryl group is phenyl, biphenyl, or naphthyl.

[0044] In another preferred embodiment, the Each of the following is independently selected: phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2,6-diphenyl, 3,5-diphenyl, 1-naphthyl, 2-naphthyl, 3,5-di-tert-butylphenyl, 4-tert-butylphenyl, 3,5-difluorophenyl, 4-fluorophenyl, 3,5-dichlorophenyl, 4-chlorophenyl, 3,5-di-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 4-methylphenyl, 4-methoxyphenyl.

[0045] In another preferred embodiment, the R 1 for Preferred More preferably

[0046] In another preferred embodiment, each R e Independently selected from the following groups: hydrogen, C 1～8 Alkyl, C 1～8 Alkoxy, phenyl, naphthyl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms e Together with the ring carbon atom it is attached to, they form a phenyl group;

[0047] Preferably, each R e Independently selected from the following groups: hydrogen, C 1～6 Alkyl, C 1～6 Alkoxy, phenyl, naphthyl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms e Together with the ring carbon atom it is attached to, they form a phenyl group;

[0048] More preferably, each R e Independently selected from the following groups: hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, phenyl, naphthyl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms e Together with the ring carbon atom it is attached to, they form a phenyl group;

[0049] Most preferably, each R e Selected independently from the group consisting of: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and n-hexyl.

[0050] In another preferred embodiment, the R 2 Selected from the following group: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl, C 1～8 Alkoxy, -C(O)OR d Halogen, nitro, cyano, trifluoromethyl;

[0051] Preferably, the R 2 Selected from the following group: hydrogen, C 1～4 Alkyl, C 3～8 cycloalkyl, C 1～4 Alkoxy, -C(O)OR d Halogen, nitro, cyano, trifluoromethyl;

[0052] More preferably, the R 2 Selected from the following group: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl.

[0053] In another preferred embodiment, the R 3 C 1～12 alkyl;

[0054] Preferably, the R 3 C 1～6 alkyl;

[0055] More preferably, the R 3 C 1～4 alkyl;

[0056] Most preferably, the R 3 Selected from the following group: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl.

[0057] In a preferred embodiment, in step (1), R in the pyridinium salt carbonyl catalyst 3 1 It forms an axial chirality with the pyridine ring, wherein the axial chirality configuration is an R or S configuration;

[0058] The catalyst 3 has the following formula I a , Formula I b Formula II a Or Formula II b The structure shown; where, Equation Ia With Equation I b They are enantiomers, Formula II a With Equation II b Enantiomers:

[0059]

[0060] In a preferred embodiment, in step (1), the reaction is carried out in the presence of an additive; and

[0061] The additive is selected from compounds and their hydrates from the group consisting of: ammonium phosphate, lithium phosphate, sodium phosphate, potassium phosphate, ammonium dihydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, diammonium hydrogen phosphate, dilithium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ammonium acetate, lithium acetate, sodium acetate, potassium acetate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or combinations thereof.

[0062] In a preferred embodiment, in step (1), the molar ratio of p-methylsulfonylbenzaldehyde to glycine ester compound 2 is 1:(0.1-5), preferably 1:(0.5-3.5), and more preferably 1:(1-3).

[0063] In a preferred embodiment, in step (1), the molar ratio of p-methylsulfonylbenzaldehyde to pyridinium salt carbonyl catalyst 3 is 1:(0.00001-0.2), preferably 1:(0.0001-0.02), more preferably 1:(0.0001-0.002), and most preferably 1:(0.0001-0.0003).

[0064] In another preferred embodiment, in step (1), the molar ratio of p-methylsulfonylbenzaldehyde to the additive is 1:(0.1-5), preferably 1:(0.5-2.5), and more preferably 1:(1-2).

[0065] In a preferred embodiment, in step (1), the reaction is carried out in the presence of solvent 1; and

[0066] The solvent 1 is selected from the group consisting of: dichloromethane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, trifluoroethanol, acetonitrile, diethyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, or combinations thereof.

[0067] In another preferred embodiment, in step (1), the mass-to-volume ratio of p-methylsulfonylbenzaldehyde to solvent 1 is 1:(10-60) g / mL, preferably 1:(20-50) g / mL, and more preferably 1:(30-40) g / mL.

[0068] In another preferred embodiment, in step (1), the temperature of the reaction is -60℃ to 90℃, preferably -60℃ to 0℃, more preferably -50℃ to -10℃, and most preferably -30℃ to -10℃.

[0069] In another preferred embodiment, in step (1), the reaction time is 1 to 120 hours, preferably 30 to 90 hours, more preferably 50 to 80 hours, and most preferably 60 to 75 hours.

[0070] In another preferred embodiment, step (1) includes the following steps:

[0071] (1A) Add p-methylsulfonylbenzaldehyde, pyridinium salt carbonyl catalyst 3 and additives to the reaction vessel;

[0072] (1B) Solvent 1 and compound 2 were added sequentially at -50℃ to -10℃, and the reaction was carried out for 60 to 75 hours to obtain intermediate I.

[0073] In a preferred embodiment, in step (2), the reaction is carried out in the presence of solvent 2; and

[0074] The solvent 2 is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, or combinations thereof.

[0075] In another preferred embodiment, in step (2), the mass-to-volume ratio of intermediate I to solvent 2 is 1:(1-25)g / mL, preferably 1:(5-20)g / mL, and more preferably 1:(8-15)g / mL.

[0076] In a preferred embodiment, in step (2), the reducing agent is selected from the group consisting of lithium aluminum hydride, sodium triacetylborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, or combinations thereof.

[0077] In another preferred embodiment, in step (2), the molar ratio of intermediate I to reducing agent is 1:(0.1 to 10), preferably 1:(1 to 7), and more preferably 1:(1 to 4).

[0078] In another preferred embodiment, in step (2), the reducing agent is added at -10°C to 10°C, preferably at -5°C to 5°C, and more preferably at -2°C to 2°C.

[0079] In another preferred embodiment, in step (2), the temperature of the reaction is 20°C to 70°C, preferably 30°C to 60°C, and more preferably 40°C to 50°C.

[0080] In another preferred embodiment, in step (2), the reaction time is 10 to 80 minutes, preferably 10 to 60 minutes, and more preferably 20 to 40 minutes.

[0081] In another preferred embodiment, step (2) includes the following steps:

[0082] (2A) Dissolve intermediate I in solvent 2;

[0083] (2B) Add a reducing agent at -5 to 5°C and react at 40°C to 50°C for 10 to 60 minutes to obtain intermediate II.

[0084] In a preferred embodiment, in step (3), the molar ratio of intermediate II to dichloroacetonitrile is 1:(1-5), preferably 1:(1-3), and more preferably 1:(1.1-1.5).

[0085] In another preferred embodiment, in step (3), the reaction is carried out in the presence of solvent 3; and

[0086] The solvent 3 is selected from the group consisting of methanol, ethanol, isopropanol, or combinations thereof.

[0087] In another preferred embodiment, in step (3), the mass-to-volume ratio of intermediate II to solvent 3 is 1:(1-25)g / mL, preferably 1:(5-20)g / mL, and more preferably 1:(8-15)g / mL.

[0088] In another preferred embodiment, in step (3), the reaction is carried out in the presence of an acid; and

[0089] The acid is hydrochloric acid.

[0090] In another preferred embodiment, in step (3), the mass-to-volume ratio of intermediate II to acid is 1:(0.01-1)g / mL, preferably 1:(0.1-0.8)g / mL, and more preferably 1:(0.1-0.3)g / mL.

[0091] In another preferred embodiment, in step (3), the temperature of the reaction is 40°C to 100°C, preferably 50°C to 90°C, and more preferably 50°C to 70°C.

[0092] In another preferred embodiment, in step (3), the reaction time is 5 to 20 hours, preferably 8 to 18 hours, and more preferably 10 to 15 hours.

[0093] In another preferred embodiment, step (3) includes the following steps:

[0094] (3A) Add intermediate II, solvent 3 and acid to the reaction vessel first, and then add dichloroacetonitrile;

[0095] (3B) React at 60-80°C for 1-3 hours, and at 40-60°C for 8-15 hours to obtain intermediate III.

[0096] In a preferred embodiment, in step (4), the fluorinating agent is selected from the group consisting of N,N-diethyl-1,1,2,3,3,3-hexafluoropropane, diethylaminosulfur trifluoride, sulfuryl fluoride, triethylamine trihydrofluoride, or combinations thereof.

[0097] In another preferred embodiment, in step (4), the molar ratio of intermediate III to fluorinating agent is 1:(0.1 to 10), preferably 1:(1 to 7), and more preferably 1:(1 to 4).

[0098] In another preferred embodiment, in step (4), the reaction is carried out in the presence of solvent 4; and

[0099] The solvent 4 is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, trichloromethane, 1,2-dichloroethane, or combinations thereof.

[0100] In another preferred embodiment, in step (4), the mass-to-volume ratio of intermediate III to solvent 4 is 1:(1-25)g / mL, preferably 1:(5-20)g / mL, and more preferably 1:(8-15)g / mL.

[0101] In another preferred embodiment, in step (4), the reaction is carried out in the presence of a base; and

[0102] The base is selected from the group consisting of pyridine, 2,6-dimethylpyridine, trimethylamine, triethylamine, diisopropylethylamine, dimethylbutylamine, or combinations thereof.

[0103] In another preferred embodiment, in step (4), the molar ratio of intermediate III to base is 1:(0.1 to 10), preferably 1:(2 to 7), and more preferably 1:(2 to 5).

[0104] In another preferred embodiment, in step (4), the reaction is carried out in the presence of perfluorobutylsulfonyl fluoride.

[0105] In another preferred embodiment, in step (4), the molar ratio of intermediate III to perfluorobutylsulfonyl fluoride is 1:(0.1 to 10), preferably 1:(1 to 7), and more preferably 1:(1 to 4).

[0106] In another preferred embodiment, in step (4), the temperature of the reaction is 10°C to 35°C, preferably 20°C to 30°C, and more preferably 22°C to 28°C.

[0107] In another preferred embodiment, in step (4), the reaction time is 1 to 20 hours, preferably 5 to 15 hours, and more preferably 8 to 12 hours.

[0108] In another preferred embodiment, step (4) includes the following steps: dissolving intermediate III in solvent 4, adding alkali, fluorinating agent and perfluorobutyl sulfonyl fluoride in sequence, and reacting at 20°C to 30°C for 5 to 15 hours.

[0109] In another preferred embodiment, in step (5), the acidic condition is a pH of 2 to 6; preferably a pH of 3 to 6; more preferably a pH of 4 to 6.

[0110] In another preferred embodiment, in step (5), the reaction is carried out in the presence of solvent 5; and

[0111] Solvent 5 is a mixed solution of alcohol and water;

[0112] The alcohol is selected from the group consisting of methanol, ethanol, isopropanol, or combinations thereof.

[0113] In another preferred embodiment, in step (5), the volume ratio of the alcohol to water is 1:(0.1 to 5), preferably 1:(0.1 to 3), and more preferably 1:(0.2 to 1).

[0114] In another preferred embodiment, in step (5), the temperature of the reaction is 50°C to 110°C, preferably 60°C to 100°C, and more preferably 70°C to 90°C.

[0115] In another preferred embodiment, in step (5), the reaction time is 1 to 10 hours, preferably 1 to 8 hours, and more preferably 1 to 5 hours.

[0116] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0117] Through long-term and in-depth research and extensive screening, the inventors have developed a chiral preparation method for florfenicol for the first time. The method uses p-methylsulfonylbenzaldehyde and glycine ester as starting materials, and carries out an asymmetric aldol reaction under the action of a pyridinium salt carbonyl catalyst. This is followed by reduction, cyclization, fluorination, and hydrolysis ring-opening reactions to obtain florfenicol. The preparation method of this invention features readily available raw materials, simple operation, no need for resolution, no heavy metal residue, high selectivity, high yield, and is environmentally friendly. Based on these advantages, the inventors completed this invention.

[0118] the term

[0119] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed-ended. In other words, the terms also include “consistently made of” or “made of”.

[0120] As used herein, the term "alkyl" refers to a monovalent, straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, for example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl. In this application, alkyl is also intended to include deuterated alkyl groups, examples of which include, but are not limited to, CD3, CD2CD3, and CD2CD2CD3.

[0121] As used herein, the term "alkylene" refers to the group obtained by removing a hydrogen atom from an alkyl group as described above, such as methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0122] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of carbon and hydrogen atoms, such as "C". 3-8 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, preferably C14. 3-6 Cycloalkyl groups. Cycloalkyl groups can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or similar groups, or bicyclic, such as fused rings, bridged rings or spirocyclic rings.

[0123] As used herein, the term "alkoxy" refers to -O-alkyl, and examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, etc.

[0124] As used herein, "halogen" refers to F, Cl, Br, I, or their isotopes, including but not limited to F, 18 F, Cl, 32 Cl, Br, I.

[0125] As used in this article, the term "nitro" refers to -NO2.

[0126] As used in this article, the term "cyano" refers to -CN.

[0127] As used in this article, the term "amino" refers to -NH2.

[0128] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group (including monocyclic, bicyclic, or polycyclic groups), such as "C 6-12"Aryl" refers to an aromatic cyclic hydrocarbon group having 6-12 (6, 7, 8, 9, 10, 11, or 12) ring carbon atoms. It contains two or more aromatic rings (such as bicyclic rings), and the aromatic rings of the aryl group can be linked by single bonds (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). Examples of aryl groups (especially monocyclic and bicyclic groups) include, but are not limited to, phenyl, biphenyl, or naphthyl. Aryl groups can be fused with heterocyclic groups through single bonds or any two adjacent ring carbon atoms, for example: benzotetrahydrofuranyl, benzotetrahydropyranyl, benzodioxane, etc. wait.

[0129] When a group loses one hydrogen atom, it becomes a subunit of the corresponding group, and it is a divalent group. For example, an alkyl group loses one hydrogen atom to become an alkylene group (e.g., methylene, ethylene, propylene, isopropylene). ), butylide (such as) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as ) etc.; cycloalkyl corresponds to cyclohexane (e.g.: wait).

[0130] Unless otherwise specified, the groups described in this invention may be substituted with substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclic groups, C3-C6 alkyl, ... 12 cycloalkyl, 5-10 heteroaryl and C6-C 10 Aryl.

[0131] In this document, “optionally” means that the event or condition described below may, but is not required to, occur, and the description includes both the possibility that the event or condition occurs and the possibility that the event or condition does not occur.

[0132] In this article, the term "multiple" refers to 2, 3, 4, 5, or a positive integer greater than 5.

[0133] As used in this article, “ee” is an abbreviation for enantiomeric excess, which refers to the enantiomeric excess rate, defined as the percentage of the total amount of one isomer a that is more abundant than another isomer b in an enantiomeric mixture.

[0134] As used in the text, "dr" is an abbreviation for "diastereomeric ratio," which refers to the ratio of one set of diastereomers to another set of diastereomers.

[0135] As used in this article, "room temperature" refers to 25±5℃.

[0136] Preparation of pyridine-onium salt carbonyl catalyst 3

[0137] The catalyst used in this invention is prepared according to the method described in patent PCT / CN2024 / 102778, and the specific preparation process is shown below:

[0138]

[0139] in, Selected from the following group:

[0140] x, y, X1, X2, X3, X4, R 2 R 3 R 4 R 12 R 13 and R 14 The definition is as described above;

[0141] S1. Chiral compound 4 undergoes a condensation reaction with dimethyl squaric acid to give compound 5;

[0142] S2. Compound 5 and primary amine NHR 14 A condensation reaction is carried out to obtain an amide intermediate; the amide intermediate reacts with the halogenated product XR. 3 The reaction proceeds to obtain a quaternary ammonium salt intermediate; the quaternary ammonium salt intermediate is hydrolyzed under acidic conditions to obtain a pyridinium salt carbonyl catalyst 3a.

[0143] Other catalysts can also be prepared using the methods disclosed in the above-mentioned literature.

[0144] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0145] 1. The raw materials used in the method of the present invention are inexpensive and readily available, resulting in low production costs.

[0146] 2. The present invention has mild reaction conditions and simple operation. In the presence of chiral pyridinium salt carbonyl catalyst 3, there is no need to pre-protect the active raw material, and optically pure chiral intermediate I, namely (2S,3R)-p-methylsulfonylbenzeneline ester, can be obtained in one step. Then, after a short conversion, the chiral product florfenicol can be obtained with high enantioselectivity without resolution.

[0147] 3. In the route of the present invention, the stereoselectivity of the product does not need to be controlled by transition metals and can be obtained with only a small amount of catalyst, which not only improves the catalytic efficiency, but also reduces environmental pollution.

[0149] The present invention will now be described in detail with reference to specific embodiments. These embodiments are only used to illustrate the technical solutions of the present invention more clearly, and should not be used to limit the scope of protection of the present invention.

[0150] This embodiment is based on the technical solution of the present invention. Unless otherwise specified, the other raw materials or processing techniques are conventional commercially available raw materials or conventional processing techniques in the art. The following embodiments help to further understand the present invention, but do not limit the scope of the invention.

[0151] Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0152] Example 1: Synthesis of pyridinium salt carbonyl catalysts (S,S)-3a-1 and (S,S)-3a-2

[0153]

[0154] Use primary amine compounds Catalysts (S,S)-3a-1 and (S,S)-3a-2 were prepared separately, as described below:

[0155]

[0156] Compound (S,S)-4 (2.06 mmol) and dimethyl squaric acid (10.30 mmol) were dissolved in anhydrous methanol (10 mL) and reacted at 50 °C for 12 hours. After the reaction was completed, the solvent was removed and compound (S,S)-5a was purified by column chromatography.

[0157] Compound (S,S)-5a (0.54 mmol) and the primary amine compound NH2R were mixed. 14 (where R) 14 They are respectively (2.95 mmol) was dissolved in anhydrous ethanol (3.0 mL), and reacted at 40 °C for 48 hours. The system was concentrated, and column chromatography was used to obtain the amide intermediate. The amide intermediate was dissolved in CH3CN (3.0 mL), and CH3I (1.52 g, 10.7 mmol) was added. After reacting at room temperature for 12 hours, the reaction system was concentrated, and after column chromatography, the solution was evaporated to dryness to obtain the quaternary ammonium salt intermediate. Then, tetrahydrofuran (3.0 mL) and hydrochloric acid (1.0 M, 4.0 mL) were added to the intermediate, and the reaction was carried out at 50 °C for 4 hours. After the reaction was completed, the tetrahydrofuran was evaporated to dryness, and the solution was dried under vacuum with phosphorus pentoxide. After grinding the obtained solid, 5 mL of diethyl ether was added, followed by 10 drops of tetrahydrofuran. The mixture was then shaken and washed, and allowed to stand to separate into layers. The supernatant was aspirated and repeated three times. Finally, the supernatant and solid were filtered together, and the filter cake was dried to obtain brown solid pyridinium salt carbonyl catalysts (S,S)-3a-1 and (S,S)-3a-2.

[0158]

[0159] The basic parameters of catalyst (S,S)-3a-1 are as follows: brown solid, yield 68%; 1 H NMR (400 MHz, DMSO-d6) δ10.36(s,1H),9.91(s,1H),9.37(d,J=10.0 Hz,1H),8.93(s,1H),8.24(d,J=8.8 Hz,1H),8.13(d,J=8.0 Hz,1H),7.69(d,J=8.0 Hz,1H),7.64(t,J=8.4 Hz,1H),7.53(t,J=8.0 Hz,1H),7.48-7.42(m,2H),7.37-7.30(m,4H),7.20(d,J=7.2 Hz,2H),7.10(t,J=1.6Hz,1H),6.25(d,J=9.6Hz,1H),4.30(s,3H),1.83(s,3H),1.27(s,18H); 13 C NMR(100 MHz, DMSO-d6)δ189.0,182.9,179.9,167.1,164.5,155.3,151.6,145.6,140.1,138.1,137.6,136.9,136.1,133.2,132 .3,131.2,130.5,129.2,128.5,128.1,127.7,127.1,127.0,125.1,124.3,116.8,112.6,58.2,47.4,34.7,31.2,15.9.

[0160]

[0161] The basic parameters of catalyst (S,S)-3a-2 are as follows: brownish-yellow solid, yield 67%; 1 H NMR (400 MHz, DMSO-d6) δ10.61 (s, 1H), 9.84 (s, 1H), 9.73 (d, J = 9.6 Hz,1H),8.91(s,1H),8.20(d,J=8.4Hz,1H),8.06(d,J=8.0Hz,1H),7.73(d,J=8 .8Hz,1H),7.60(t,J=7.6Hz,1H),7.48(dd,J=8.4,6.8Hz,1H),7.43-7.38(m,2H ),7.35(d,J=7.2Hz,1H),7.28(d,J=8.4Hz,1H),7.20(d,J=7.2Hz,2H),7.12(s, 2H),6.66(s,1H),6.20(d,J=9.6Hz,1H),4.27(s,3H),2.22(s,6H),1.76(s,3H); 13 C NMR(100MHz,DMSO-d6)δ188.9,183.1,179.7,167.0,164.2,155.0,145.4,139.9,138.6,138.4,137.5,136.8,136.1,133.4, 132.2,131.3,130.4,129.1,128.8,128.4,128.0,127.8,127.2,127.1,125.1,124.5,124.4,115.8,58.4,47.4,21.1,15.9.

[0162] Example 2: A chiral synthesis of florfenicol

[0163] (1) Synthesis of intermediate I-1

[0164]

[0165] In a glove box, (S,S)-3a-1 (2.0 mg, 0.0025 mmol), compound 1 methyl sulfone benzaldehyde (4.60 g, 25.0 mmol), and ammonium dihydrogen phosphate (3.45 g, 30.0 mmol) were added to a 500 mL Shrek tube. The Shrek tube was then removed from the glove box, and tetrahydrofuran (150 mL) was added at -20 °C, with stirring for 10 minutes at this temperature. After the temperature stabilized, compound 2a glycine tert-butyl ester (8.30 g, 63.0 mmol) was added dropwise to the system over 5 minutes at this temperature, and the reaction was carried out at -20 °C for 72 hours.

[0166] After the reaction was complete, hydroxylamine aqueous solution (20 mL, 50 wt.% in water) was added to the system to quench the reaction, and the mixture was diluted with methanol (20 mL). The reaction was maintained at this temperature for 1 hour, then heated to room temperature and continued for another 30 minutes. Subsequently, the system was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:1) to obtain intermediate I-1 (6.73 g, 86% yield, 15:1 dr, 99% ee).

[0167] (2) Synthesis of intermediate II

[0168]

[0169] Intermediate I-1 (6.73 g, 21.4 mmol) was added to a 100 mL round-bottom flask, followed by the addition of methanol (75 mL) to completely dissolve it. The system was then cooled to 0 °C, and after the temperature stabilized, potassium borohydride (1.39 g, 25.8 mmol) was slowly added in portions. The reaction was carried out at 45 °C for half an hour. After the starting material disappeared as detected by thin-layer chromatography, the crude product was obtained by vacuum distillation. The crude product was extracted with ethyl acetate (50 mL) and saturated ammonium chloride aqueous solution (30 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give intermediate II (4.56 g, 87% yield), a white solid.

[0170] (3) Synthesis of intermediate III

[0171]

[0172] Intermediate II (2.56 g, 10.4 mmol) was added to a 100 mL round-bottom flask, followed by isopropanol (30 mL) and concentrated hydrochloric acid (0.3 mL). The mixture was stirred for 10 minutes, then dichloroacetonitrile (1.37 g, 12.5 mmol) was added. The temperature was maintained at approximately 70 °C, and the mixture was stirred for 2 hours. Subsequently, the temperature was lowered to 50 °C, and the reaction was carried out for 12 hours. After the reaction was completed, the solvent was removed by evaporation, and the residue was purified by rapid column chromatography (petroleum ether: ethyl acetate = 2:1) to give intermediate III (2.99 g, 85% yield).

[0173] (4) Synthesis of intermediate IV

[0174]

[0175] Intermediate III (2.99 g, 8.85 mmol) was weighed into a 50 mL pear-shaped flask, and anhydrous tetrahydrofuran (35 mL) was added, followed by triethylamine (2.69 g, 26.6 mmol) and triethylamine trihydrofluoride (2.14 g, 13.3 mmol) sequentially. Then, perfluorobutylsulfonyl fluoride (4.01 g, 13.3 mmol) was added dropwise at room temperature. After the addition was complete, the system was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed, and then dichloromethane (35 mL) and water (35 mL) were added. After separation, the aqueous layer was extracted three times with dichloromethane (3 × 30 mL). The combined organic phases were then washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude intermediate IV.

[0176] (5) Synthesis of the final product florfenicol

[0177]

[0178] The residue was dissolved in isopropanol (20 mL) and water (10 mL), and the pH of the reaction system was adjusted to approximately 5 with sodium acetate. The system was then reacted at 80 °C for 3 hours. After the reaction was complete, the solvent was removed under vacuum, and the resulting residue was rapidly purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid, namely florfenicol (2.67 g, combined yield of 91%). The NMR data were consistent with the standard spectrum (Tetrahedron: Asymmetry 2011, 22, 1337-1341).

[0179] Example 3: A chiral synthesis of florfenicol

[0180] (1) Synthesis of intermediate I-1

[0181]

[0182] In a glove box, (S,S)-3a-2 (2.0 mg, 0.0025 mmol), compound 1, methyl sulfone benzaldehyde (4.60 g, 25.0 mmol), and disodium hydrogen phosphate dodecahydrate (10.7 g, 30.0 mmol) were added to a 500 mL Shrek tube. The Shrek tube was then removed from the glove box, and tetrahydrofuran (150 mL) was added at -20 °C, with stirring for 10 minutes at this temperature. After the temperature stabilized, compound 2a, glycine tert-butyl ester (8.30 g, 63.0 mmol), was added dropwise to the system over 5 minutes at this temperature, and the reaction was carried out at -20 °C for 72 hours.

[0183] After the reaction was complete, hydroxylamine aqueous solution (20 mL, 50 wt.% in water) was added to the system to quench the reaction, and the mixture was diluted with methanol (20 mL). The reaction was maintained at this temperature for 1 hour, then heated to room temperature and continued for another 30 minutes. Subsequently, the system was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:1) to obtain intermediate I-1 (6.29 g, 80% yield, 13:1 dr, 97% ee).

[0184] (2) Synthesis of intermediate II

[0185]

[0186] Intermediate I-1 (2.0 g, 6.30 mmol) was added to a 100 mL pear-shaped flask, followed by methanol (25 mL) to completely dissolve it. The system was then cooled to 0 °C, and after the temperature stabilized, potassium borohydride (0.82 g, 15.2 mmol) was slowly added in portions. The reaction was carried out at 45 °C for half an hour. After the starting material disappeared as detected by thin-layer chromatography, the crude product was obtained by vacuum distillation. The crude product was extracted with ethyl acetate (30 mL) and saturated ammonium chloride aqueous solution (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give intermediate II (1.34 g, 87% yield), a white solid.

[0187] (3) Synthesis of intermediate III

[0188]

[0189] Intermediate II (1.34 g, 5.46 mmol) was added to a 100 mL round-bottom flask, followed by isopropanol (15 mL) and concentrated hydrochloric acid (0.15 mL). The mixture was stirred for 5 minutes, then dichloroacetonitrile (0.72 g, 6.55 mmol) was added. The temperature was maintained at approximately 70 °C, and the mixture was stirred for 2 hours. Subsequently, the temperature was lowered to 50 °C, and the reaction was carried out for 10 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by rapid column chromatography (petroleum ether: ethyl acetate = 2:1) to give intermediate III (1.51 g, 82% yield).

[0190] (4) Synthesis of intermediate IV

[0191]

[0192] Intermediate III (1.51 g, 4.48 mmol) was weighed into a 25 mL pear-shaped flask, and anhydrous tetrahydrofuran (15 mL) was added, followed by triethylamine (1.34 g, 13.3 mmol) and triethylamine trihydrofluoride (1.07 g, 6.65 mmol) in sequence. Then, perfluorobutylsulfonyl fluoride (2.00 g, 6.65 mmol) was added dropwise at room temperature. After the addition was complete, the system was stirred at room temperature for 10 hours. After the reaction was complete, the solvent was removed, and then dichloromethane (15 mL) and water (15 mL) were added. After separation, the aqueous layer was extracted three times with dichloromethane (3 × 15 mL). The combined organic phases were then washed with brine (20 mL), and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude intermediate IV.

[0193] (5) Synthesis of the final product florfenicol

[0194]

[0195] The residue was dissolved in isopropanol (10 mL) and water (5 mL), and the pH of the reaction system was adjusted to ~5 with sodium acetate. The system was then placed at 80 °C for 3 hours. After the reaction was completed, the solvent was removed under vacuum, and the resulting residue was rapidly purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid, namely florfenicol (1.38 g, combined yield of 87%).

[0196] Compared with Example 2, the catalyst in step (1) is different, but the yield of both is higher (≥70%), indicating that the chiral pyridinium salt carbonyl catalyst of the present invention has excellent catalytic activity.

[0197] Example 4: A chiral synthesis of florfenicol

[0198] (1) Synthesis of intermediate I-1

[0199]

[0200] In a glove box, (S,S)-3a-1 (2.0 mg, 0.0025 mmol), compound 1, methyl sulfone benzaldehyde (4.60 g, 25.0 mmol), and disodium hydrogen phosphate dodecahydrate (10.7 g, 30.0 mmol) were added to a 500 mL Shrek tube. The Shrek tube was then removed from the glove box, and dichloromethane (150 mL) was added at -20 °C, with stirring for 10 minutes at this temperature. After the temperature stabilized, compound 2a, glycine tert-butyl ester (8.30 g, 63.0 mmol), was added dropwise to the system over 5 minutes at this temperature, and the reaction was carried out at -20 °C for 72 hours.

[0201] After the reaction was complete, hydroxylamine aqueous solution (20 mL, 50 wt.% in water) was added to the system to quench the reaction, and the mixture was diluted with methanol (20 mL). The reaction was maintained at this temperature for 1 hour, then heated to room temperature and continued for another 30 minutes. Subsequently, the system was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:1) to obtain intermediate I-1 (5.51 g, 70% yield, 12:1 dr, 90% ee).

[0202] (2) Synthesis of intermediate II

[0203]

[0204] Intermediate I-1 (2.0 g, 6.30 mmol) was added to a 100 mL pear-shaped flask, followed by methanol (25 mL) to completely dissolve it. The system was then cooled to 0 °C, and after the temperature stabilized, potassium borohydride (0.82 g, 15.2 mmol) was slowly added in portions. The reaction was carried out at 45 °C for half an hour. After the starting material disappeared as detected by thin-layer chromatography, the crude product was obtained by vacuum distillation. The crude product was extracted with ethyl acetate (30 mL) and saturated ammonium chloride aqueous solution (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give intermediate II (1.30 g, 84% yield), a white solid.

[0205] (3) Synthesis of intermediate III

[0206]

[0207] Intermediate II (1.30 g, 5.29 mmol) was added to a 100 mL round-bottom flask, followed by isopropanol (15 mL) and concentrated hydrochloric acid (0.15 mL). The mixture was stirred for 5 minutes, then dichloroacetonitrile (0.70 g, 6.34 mmol) was added. The temperature was maintained at approximately 70 °C, and the mixture was stirred for 2 hours. Subsequently, the temperature was lowered to 50 °C, and the reaction was carried out for 10 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by rapid column chromatography (petroleum ether: ethyl acetate = 2:1) to give intermediate III (1.50 g, 84% yield).

[0208] (4) Synthesis of intermediate IV

[0209]

[0210] Intermediate III (1.50 g, 4.44 mmol) was weighed into a 25 mL pear-shaped flask, and anhydrous tetrahydrofuran (15 mL) was added, followed by triethylamine (1.34 g, 13.3 mmol) and triethylamine trihydrofluoride (1.07 g, 6.65 mmol) in sequence. Then, perfluorobutylsulfonyl fluoride (2.00 g, 6.65 mmol) was added dropwise at room temperature. After the addition was complete, the system was stirred at room temperature for 10 hours. After the reaction was complete, the solvent was removed, and then dichloromethane (15 mL) and water (15 mL) were added. After separation, the aqueous layer was extracted three times with dichloromethane (3 × 15 mL). The combined organic phases were then washed with brine (20 mL), and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude intermediate IV.

[0211] (5) Synthesis of the final product florfenicol

[0212]

[0213] The residue was dissolved in isopropanol (10 mL) and water (5 mL), and the pH of the reaction system was adjusted to ~5 with sodium acetate. The system was then placed at 80 °C for 3 hours. After the reaction was completed, the solvent was removed under vacuum, and the resulting residue was rapidly purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid, namely florfenicol (1.42 g, 90% yield from both steps).

[0214] Compared with Example 3, the solvent in step (1) is different, but the yield of both is higher (≥70%). Therefore, tetrahydrofuran and dichloromethane are both preferred solvents in step (1).

[0215] Example 5: A chiral synthesis of florfenicol

[0216] (1) Synthesis of intermediate I-1 (catalyst: (S,S)-3a-1)

[0217]

[0218] In a glove box, (S,S)-3a-1 (2.0 mg, 0.0025 mmol), compound 1 methyl sulfone benzaldehyde (4.60 g, 25.0 mmol), and ammonium dihydrogen phosphate (3.45 g, 30.0 mmol) were added to a 500 mL Shrek tube. The Shrek tube was then removed from the glove box, and tetrahydrofuran (150 mL) and triethylamine (5.20 mL, 37.5 mmol) were added at -20 °C, and the mixture was stirred for 10 minutes. After the temperature stabilized, compound 2a glycine tert-butyl ester (8.30 g, 63.0 mmol) was added dropwise to the system over 5 minutes at this temperature, and the reaction was carried out at -20 °C for 72 hours.

[0219] After the reaction was complete, hydroxylamine aqueous solution (20 mL, 50 wt.% in water) was added to the system to quench the reaction, and the mixture was diluted with methanol (20 mL). The reaction was maintained at this temperature for 1 hour, then heated to room temperature and continued for another 30 minutes. Subsequently, the system was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:1) to obtain intermediate I-1 (6.45 g, 82% yield, 13:1 dr, 97% ee).

[0220] (2) Synthesis of intermediate II

[0221]

[0222] Intermediate I-1 (2.0 g, 6.30 mmol) was added to a 100 mL round-bottom flask, followed by the addition of methanol (25 mL) to completely dissolve it. The system was then cooled to 0 °C, and after the temperature stabilized, sodium borohydride (0.57 g, 15.2 mmol) was slowly added in portions. The reaction was carried out at 45 °C for half an hour. After the starting material disappeared as detected by thin-layer chromatography, the crude product was obtained by vacuum distillation. The crude product was extracted with ethyl acetate (30 mL) and saturated ammonium chloride aqueous solution (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give intermediate II (1.28 g, 84% yield), a white solid.

[0223] (3) Synthesis of intermediate III

[0224]

[0225] Intermediate II (1.28 g, 5.2 mmol) was added to a 100 mL round-bottom flask, followed by isopropanol (15 mL) and concentrated hydrochloric acid (0.15 mL). The mixture was stirred for 10 minutes, then dichloroacetonitrile (0.69 g, 6.3 mmol) was added. The temperature was maintained at approximately 70 °C, and the mixture was stirred for 2 hours. Subsequently, the temperature was lowered to 50 °C, and the reaction was carried out for 12 hours. After the reaction was complete, the solvent was removed by evaporation, and the residue was purified by rapid column chromatography (petroleum ether: ethyl acetate = 2:1) to give intermediate III (1.47 g, 84% yield).

[0226] (4) Synthesis of intermediate IV

[0227]

[0228] Intermediate III (1.47 g, 4.35 mmol) was weighed into a 50 mL pear-shaped flask, and anhydrous tetrahydrofuran (20 mL) was added, followed by triethylamine (1.32 g, 13.1 mmol) and triethylamine trihydrofluoride (1.05 g, 6.54 mmol) sequentially. Then, perfluorobutylsulfonyl fluoride (1.97 g, 6.54 mmol) was added dropwise at room temperature. After the addition was complete, the system was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed, and then dichloromethane (20 mL) and water (20 mL) were added. After separation, the aqueous layer was extracted three times with dichloromethane (3 × 15 mL). The combined organic phases were then washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude intermediate IV.

[0229] (5) Synthesis of the final product florfenicol

[0230]

[0231] The residue was dissolved in isopropanol (10 mL) and water (5 mL), and the pH of the reaction system was adjusted to ~5 with sodium acetate. The system was then placed at 80 °C for 3 hours. After the reaction was completed, the solvent was removed under vacuum, and the resulting residue was rapidly purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid, namely florfenicol (1.27 g, combined yield of 88%).

[0232] Compared with Example 2, the reaction conditions in step (1) contain a base (triethylamine), but the yields of the two are similar. Therefore, in order to reduce production costs and simplify operations, it is preferable not to add a base in step (1) of the present invention.

[0233] Comparative Example 1: Synthesis of Intermediate I-1

[0234]

[0235] Add cat.-1 (13 mg, 0.025 mmol), compound 1 methyl sulfone benzaldehyde (0.92 g, 5.0 mmol), and ammonium dihydrogen phosphate (0.69 g, 6.0 mmol) sequentially to a clean 50 mL Shrek tube. After purging with nitrogen three times, cool to -40 °C. Inject dichloromethane (30 mL) at this temperature and maintain the temperature with stirring for 10 minutes. After the system temperature stabilizes, add compound 2a glycine tert-butyl ester (1.74 g, 12.6 mmol) dropwise to the reaction system over 5 minutes, and react at -20 °C for 50 hours.

[0236] After the reaction was complete, 20 mL of hydroxylamine aqueous solution (50 wt.% in water) was added to the system to quench the reaction, and the mixture was diluted with methanol (20 mL). The reaction was maintained at this temperature for 1 hour, then the temperature was raised to room temperature and the reaction continued for another 30 minutes. Thin-layer chromatography analysis showed almost no product in the system.

[0237] Compared with Examples 2 to 5 of this application, the catalyst in step (1) is different. The catalyst in this comparative example is a pyridine-type carbonyl catalyst, which is not a pyridinium salt carbonyl catalyst that forms salts. It has no catalytic effect on the reaction of the present invention. Therefore, the catalyst of the present invention is preferably a pyridinium salt carbonyl catalyst.

[0238] Comparative Example 2: Synthesis of Intermediate I-1

[0239]

[0240] In a glove box, cat.-2 (2.0 mg, 0.0025 mmol), compound 1 methyl sulfonebenzaldehyde (4.60 g, 25.0 mmol), and ammonium dihydrogen phosphate (3.45 g, 30.0 mmol) were added to a 500 mL Shrek tube. The Shrek tube was then removed from the glove box, and dichloromethane (150 mL) was added at -20 °C, with stirring for 10 minutes at this temperature. After the temperature stabilized, compound 2a glycine tert-butyl ester (8.30 g, 63.0 mmol) was added dropwise to the system over 5 minutes at this temperature, and the reaction was carried out at -20 °C for 72 hours.

[0241] After the reaction was complete, hydroxylamine aqueous solution (20 mL, 50 wt.% in water) was added to the system to quench the reaction, and the mixture was diluted with methanol (20 mL). The reaction was maintained at this temperature for 1 hour, then heated to room temperature and continued for another 30 minutes. Subsequently, the system was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:1) to obtain intermediate I-1 (5.08 g, 65% yield, 3:1 dr, 70% ee).

[0242] Compared with Examples 2-5 of this application, the catalyst in step (1) is different, mainly due to the R in the catalyst structure. 14 Unlike the previous example, R in this comparative example is different. 14 Because it is tert-butyl, the product has poor stereoselectivity; therefore, R in the catalyst structure of this invention... 14 Alkyl groups are not preferred.

[0243] In the relevant reactions of benzylamine, the pyridinium salt carbonyl catalyst will undergo interconversion of carbonyl and amino groups under the action of benzylamine, causing the catalyst to lose its catalytic activity. Therefore, in the prior art, the preferred catalyst for the reaction of benzylamine with carbonyl-containing compounds is a pyridine-type carbonyl catalyst, rather than a salt-forming pyridinium salt carbonyl catalyst (Nat Catal. 2022, 1061–1068).

[0244] However, the inventors unexpectedly discovered during the experiment that when other non-benzylamine amine compounds (such as compound 2 glycine ester in this invention) react with carbonyl-containing compounds, the catalytic effect of pyridine-type carbonyl catalysts is inferior to that of pyridinium salt carbonyl catalysts (see Comparative Examples 1 and 2 for details).

[0245] Therefore, in this invention, the applicant selected a preferred class of pyridinium salt carbonyl catalysts for the glycine ester substrate, thereby obtaining (2S,3R)-p-methylsulfonylbenzeneline ester intermediate I in high yield and with high selectivity.

[0246] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A chiral preparation method for florfenicol, characterized in that, The preparation method includes the following steps: (1) In the presence of pyridinium salt carbonyl catalyst 3, sulfonyl benzaldehyde and glycine ester compound 2 were reacted to obtain (2S,3R)-p-sulfonyl benzene serine ester intermediate I; (2) In the presence of a reducing agent, intermediate I undergoes a reduction reaction to obtain intermediate II; (3) Intermediate II undergoes a cyclization reaction with dichloroacetonitrile to obtain intermediate III; (4) Intermediate III undergoes a fluorination reaction with a fluorinating agent to obtain intermediate IV; (5) Under acidic conditions, intermediate IV undergoes a hydrolysis reaction to yield florfenicol; Wherein, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and cyclopentyl; The pyridinium salt carbonyl catalyst 3 has the chemical structure shown in Formula 3: wherein R 1 is selected from the group consisting of X1is N or CR 6 ; X2is N or CR 7 ; X3is N or CR 8 ; X4is N or CR 9 ; X5is N or CR 10 ; X6is N or CR 11 ; R 2 R 4 R 6 R 7 R 8 R 9 R 10 and R 11 Each is independently selected from the following groups: hydrogen, -(CH2). m -C 1～24 Alkyl group, -(CH2) m -C 3～24 cycloalkyl, C 1～16 Alkoxy, -C(O)OR d Halogen, nitro, cyano, trifluoromethyl; m is 1, 2, or 3; n is 0, 1, 2, 3, 4 or 5; each R is independently selected from the group consisting of hydrogen, C a 1～10 alkyl, C 3～10 cycloalkyl, C 6～12 aryl, halogen, nitro, cyano, trifluoromethyl, or two R groups on adjacent ring carbon atoms together form a C a ring with the ring carbon atom to which it is attached; and 6～12 aryl;​ R b R 2b R 3b R c R 2c and R d Each is independently selected from the following groups: hydrogen, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 Aryl; R 3 C 1～24 Alkyl group, the above R 3 Optionally by 1, 2 or 3 R f replace; R f Selected from the following group: halogens, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 Aryl, C 1～10 Alkoxy, C 1～10 Alkylamine group, -R g -LR 2g -P(O)(OR) h )2; L is selected from the following group: -C(O)-, -C(O)NR i -、-C(O)O-、-S(O)2-; R g Selected from the following group: key, C 1～8 Alkylene, C 3～8 Cycloalkylene; R 2g and R h Each is independently selected from the following groups: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl; R i Selected from the following group: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl, C 1～10 Alkoxy, C 1～10 Alkylamine group; R 5 Selected from the following group: in, x and y are each independently 0, 1, 2 or 3; R 12 and R 13 Each is independently selected from the following groups: hydrogen, C 1～24 alkyl, R 14 Selected from the following group: hydrogen, C 1～24 alkyl, Halogens, trifluoromethyl; Each R e Independently selected from the following groups: hydrogen, C 1～10 Alkyl, C 1～10 Alkoxy, C 6～12 aryl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms e Together with the ring carbon atoms it is attached to, they form C 6～12 Aryl; X - The anions selected from the following group are: fluoride ion, chloride ion, bromide ion, iodide ion, trifluoromethanesulfonate ion, hexafluorophosphate ion, tetrafluoroborate ion, sulfate ion, sulfite ion, hydroxide ion, nitrate ion, phosphate ion, carbonate ion, silicate ion, bicarbonate ion, hydrogen phosphate ion, dihydrogen phosphate ion, iodate ion, cyanide ion, and thiocyanate ion.

2. The preparation method according to claim 1, characterized in that, In step (1), R in the pyridinium salt carbonyl catalyst 3 1 It forms an axial chirality with the pyridine ring, wherein the axial chirality configuration is an R or S configuration; The catalyst 3 has the following formula I a , Formula I b Formula II a Or Formula II b The structure shown; where, Equation I a With Equation I b They are enantiomers, Formula II a With Equation II b Enantiomers:

3. The preparation method according to claim 1, characterized in that, In step (1), the reaction is carried out in the presence of an additive; and The additive is selected from compounds and their hydrates from the group consisting of: ammonium phosphate, lithium phosphate, sodium phosphate, potassium phosphate, ammonium dihydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, diammonium hydrogen phosphate, dilithium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ammonium acetate, lithium acetate, sodium acetate, potassium acetate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or combinations thereof.

4. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of p-methylsulfonylbenzaldehyde to glycine ester compound 2 is 1:(0.1-5), preferably 1:(0.5-3.5), and more preferably 1:(1-3).

5. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of p-methylsulfonylbenzaldehyde to pyridinium salt carbonyl catalyst 3 is 1:(0.00001-0.2), preferably 1:(0.0001-0.02), more preferably 1:(0.0001-0.002), and most preferably 1:(0.0001-0.0003).

6. The preparation method according to claim 1, characterized in that, In step (1), the reaction is carried out in the presence of solvent 1; and The solvent 1 is selected from the group consisting of: dichloromethane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, trifluoroethanol, acetonitrile, diethyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, or combinations thereof.

7. The preparation method according to claim 1, characterized in that, In step (2), the reaction is carried out in the presence of solvent 2; and The solvent 2 is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, or combinations thereof.

8. The preparation method according to claim 1, characterized in that, In step (2), the reducing agent is selected from the group consisting of lithium aluminum hydride, sodium triacetylborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, or combinations thereof.

9. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of intermediate II to dichloroacetonitrile is 1:(1-5), preferably 1:(1-3), and more preferably 1:(1.1-1.5).

10. The preparation method according to claim 1, characterized in that, In step (4), the fluorinating agent is selected from the group consisting of N,N-diethyl-1,1,2,3,3,3-hexafluoropropane, diethylaminosulfur trifluoride, sulfuryl fluoride, triethylamine trihydrofluoride, or a combination thereof.

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