A chiral preparation method of thiamphenicol

Abstract

This invention relates to a chiral method for preparing thiamphenicol. Specifically, the method uses p-methylsulfonylbenzaldehyde and glycine ester as starting materials, and carries out an asymmetric aldol reaction in the presence of a pyridinium salt carbonyl catalyst, followed by a reduction and amidation reaction to obtain thiamphenicol. This invention utilizes the strong catalytic ability of small-molecule pyridinium salt carbonyl catalysts, starts with inexpensive and readily available raw materials, reduces the steps of introducing and removing protecting groups, shortens the synthetic route, and efficiently synthesizes optically pure thiamphenicol. Furthermore, the preparation method of this invention is simple to operate and environmentally friendly.

Description

Technical Field

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

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

[0003]

[0004] Thiamphenicol belongs to the amide alcohol class of broad-spectrum antibacterial drugs. It has the advantages of strong antibacterial activity, rapid absorption, and long-lasting effect. Clinically, it is mainly used to treat respiratory, urinary, hepatobiliary, typhoid fever, and other intestinal surgical, obstetric and gynecological, and ENT infections. It is especially effective for mild to moderate infections.

[0005] Most of the synthetic methods for thiamphenicol currently in production both domestically and internationally include a chiral resolution step (e.g., US3733352 and US3927054). Due to the inherent drawbacks of chiral resolution, the yield cannot exceed 50%, resulting in low production efficiency and high production costs.

[0006] While chiral catalysis can avoid chiral resolution steps and efficiently construct product compounds with a single configuration, current chiral synthetic methods still suffer from problems such as long synthetic routes and low catalytic efficiency (e.g., CN1743308A, CN102863361 and J.Org.Chem.2021,86,11557-11570).

[0007] In recent years, a chiral synthetic method for preparing thiamphenicol has been developed, using bio-fermentation technology to prepare chiral intermediate I—D-p-methylsulfonylbenzylserine ethyl ester (e.g., CN117126897). This method mimics enzymatic reactions in vivo, specifically the reaction process by which threonine aldolase catalyzes the direct addition of glycine to acetaldehyde to produce β-hydroxy-α-aminobutyric acid (threonine) under mild conditions. Using p-methylsulfonylbenzaldehyde and amino acid esters as reactants, intermediate I can be obtained. However, this method requires bio-fermentation technology, demanding strict aseptic operation, and suffers from drawbacks such as insufficient enzyme stability and easy inactivation, limiting its application.

[0008] Therefore, there is an urgent need in this field for a simple, efficient, environmentally friendly, easy-to-operate, and cost-effective method for the synthesis of chiral chemicals. Summary of the Invention

[0009] 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. This provides a chiral synthesis method for the chiral preparation of thiamphenicol that is characterized by readily available raw materials, simple operation, avoidance of resolution, reduced heavy metal residues, high selectivity, high yield, and environmental friendliness.

[0010] In a first aspect of the present invention, a chiral method for preparing thiamphenicol is provided, the method comprising the following steps:

[0011]

[0012] (1) In the presence of pyridinium salt carbonyl catalyst 3, sulfone benzaldehyde and glycine ester compound 2 were reacted to obtain (2S,3R)-p-sulfone benzene serine ester intermediate I;

[0013] (2) In the presence of a reducing agent, intermediate I undergoes a reduction reaction to obtain intermediate II;

[0014] (3) Intermediate II undergoes an amidation reaction with methyl dichloroacetate to obtain thiamphenicol;

[0015] Wherein, R is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and cyclopentyl;

[0016] The pyridinium salt carbonyl catalyst 3 has the chemical structure shown in Formula 3:

[0017]

[0018] Among them, R 1 Selected from the following group:

[0019]

[0020] 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 ;

[0021] 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;

[0022] m is 1, 2, or 3;

[0023] n is 0, 1, 2, 3, 4 or 5;

[0024] 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;

[0025] 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;

[0026] R 3 C 1～24 Alkyl group, the above R 3 Optionally by 1, 2 or 3 R f replace;

[0027] 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;

[0028] L is selected from the following group: -C(O)-, -C(O)NR i -、-C(O)O-、-S(O)2-;

[0029] R g Selected from the following group: key, C 1～8 Alkylene, C3～8 Cycloalkylene;

[0030] R 2g and R h Each is independently selected from the following groups: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl;

[0031] 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;

[0032] R 5 Selected from the following group:

[0033]

[0034] in,

[0035] x and y are each independently 0, 1, 2 or 3;

[0036] R 12 and R 13 Each is independently selected from the following groups: hydrogen, C 1～24 alkyl,

[0037] R 14 Selected from the following group: hydrogen, C 1～24 alkyl, Halogens, trifluoromethyl;

[0038] 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;

[0039] 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.

[0040] 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.

[0041] 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.

[0042] In another preferred embodiment, the C 6～12 The aryl group is phenyl, biphenyl, or naphthyl.

[0043] In another preferred embodiment, the and 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.

[0044] In another preferred embodiment, the R 1 for Preferred More preferably

[0045]

[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 atomse 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 IIa 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:

[0059]

[0060] In a preferred embodiment, in step (1), the reaction is further 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), solvent 1 is tetrahydrofuran.

[0068] 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.

[0069] In a 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℃.

[0070] In a preferred embodiment, in step (1), the reaction time is 1 to 80 hours, preferably 30 to 75 hours, more preferably 50 to 75 hours, and most preferably 60 to 75 hours.

[0071] In another preferred embodiment, step (1) includes the following steps:

[0072] (1A) Add p-methylsulfonylbenzaldehyde, pyridinium salt carbonyl catalyst 3 and additives to the reaction vessel;

[0073] (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.

[0074] In a preferred embodiment, in step (2), the reaction is carried out in the presence of solvent 2; and

[0075] The solvent 2 is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, or combinations thereof.

[0076] 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.

[0077] 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.

[0078] 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).

[0079] 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.

[0080] 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.

[0081] 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.

[0082] In another preferred embodiment, step (2) includes the following steps:

[0083] (2A) Dissolve intermediate I in solvent 2;

[0084] (2B) Add a reducing agent at -5 to 5°C and reflux for 10 to 60 minutes to obtain intermediate II.

[0085] In another preferred embodiment, in step (3), the mass-to-volume ratio of intermediate II to methyl dichloroacetate is 1:(1-20) g / mL, preferably 1:(2-18) g / mL, and more preferably 1:(5-15) g / mL.

[0086] In another preferred embodiment, in step (3), the temperature of the reaction is 80°C to 130°C, preferably 90°C to 120°C, and more preferably 100°C to 110°C.

[0087] In another preferred embodiment, in step (3), the reaction time is 1 to 10 hours, preferably 1 to 8 hours, and more preferably 1 to 5 hours.

[0088] 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

[0089] After long-term and in-depth research and extensive screening, the inventors have developed a chiral preparation method for thiamphenicol for the first time. The preparation method of this invention uses p-methylsulfonylbenzaldehyde and glycine ester as starting materials, and carries out an asymmetric aldol reaction process under the action of a pyridinium salt carbonyl catalyst, followed by reduction and amidation reactions to obtain thiamphenicol. 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.

[0090] the term

[0091] 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”.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] As used in this article, the term "nitro" refers to -NO2.

[0098] As used in this article, the term "cyano" refers to -CN.

[0099] As used in this article, the term "amino" refers to -NH2.

[0100] 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.

[0101] 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).

[0102] 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.

[0103] 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.

[0104] In this article, the term "multiple" refers to 2, 3, 4, 5, or a positive integer greater than 5.

[0105] 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.

[0106] 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.

[0107] Preparation of pyridine-onium salt carbonyl catalyst 3

[0108] 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:

[0109] 1. Preparation of pyridinium salt carbonyl catalyst 3a

[0110]

[0111] in, Selected from the following group:

[0112] 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;

[0113] S1. Chiral compound 4 undergoes a condensation reaction with dimethyl squaric acid to give compound 5;

[0114] 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.

[0115] 2. Preparation of pyridinium salt carbonyl catalyst 3b

[0116]

[0117] in, Selected from the following group:

[0118] 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;

[0119] S1. Chiral compound 4 and thioisocyanate SCNR 14 or isocyanate OCNR 14 A condensation reaction is carried out to give compound 6 or 7;

[0120] S2. Compound 6 or 7 with a haloalkane XR 3The reaction yields a quaternary ammonium salt intermediate; the quaternary ammonium salt intermediate is hydrolyzed under acidic conditions to give pyridinium salt carbonyl catalysts 3b or 3c.

[0121] Other catalysts can also be prepared using the methods disclosed in the above-mentioned literature.

[0122] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0123] 1. The raw materials used in the method of the present invention are inexpensive and readily available, resulting in low production costs.

[0124] 2. The reaction conditions of the present invention are mild and the operation is simple. In the presence of a chiral pyridinium salt carbonyl catalyst, there is no need to pre-protect the active raw material, and optically pure chiral intermediate I can be obtained in one step. Subsequently, the chiral product thiamphenicol can be obtained with high enantioselectivity after a short conversion without resolution.

[0125] 3. The synthesis route of the method of the present invention is short and can avoid the use of transition metals, which is environmentally friendly.

[0126] 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.

[0127] 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.

[0128] Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0129] Example 1: Synthesis of pyridinium salt carbonyl catalysts (S,S)-3a-1 and (S,S)-3a-2

[0130]

[0131] Using the primary amine compound NH2R 14 (R 14 Catalysts (S,S)-3a-1 and (S,S)-3a-2 were prepared from 3,5-di-tert-butylphenyl and 3,5-dimethylphenyl, respectively, according to the following steps:

[0132]

[0133] 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.

[0134] Compound (S,S)-5a (0.54 mmol) and the primary amine compound NH2R were mixed. 14 (R 14 3,5-Di-tert-butylphenyl and 3,5-dimethylphenyl (2.95 mmol) were dissolved in anhydrous ethanol (3.0 mL) and reacted at 40 °C for 48 hours. The system was concentrated and column chromatography was performed to obtain an amide intermediate. The amide intermediate was dissolved in CH3CN (3.0 mL), and CH3I (1.52 g, 10.7 mmol) was added. The reaction was carried out at room temperature for 12 hours. The reaction system was concentrated, and column chromatography was performed followed by rotary evaporation to obtain a quaternary ammonium salt intermediate. Tetrahydrofuran (3.0 mL) and hydrochloric acid (1.0 M, 4.0 mL) were then 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 dried under vacuum with phosphorus pentoxide.

[0135] 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.

[0136]

[0137] The basic parameters of catalyst (S,S)-3a-1 are as follows: brown solid, yield 68%; 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.91(s,1H),9.37(d,J=10.0Hz,1H),8.93(s,1H) ,8.24(d,J=8.8Hz,1H),8.13(d,J=8.0Hz,1H),7.69(d,J=8.0Hz,1H),7.64(t,J=8.4Hz, 1H),7.53(t,J=8.0Hz,1H),7.48-7.42(m,2H),7.37-7.30(m,4H),7.20(d,J=7.2Hz,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); 13C NMR (100MHz, 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.

[0138]

[0139] The basic parameters of catalyst (S,S)-3a-2 are as follows: brownish-yellow solid, yield 67%; 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.84(s,1H),9.73(d,J=9.6Hz,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=7.2H z,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.

[0140] Example 2: Synthesis of pyridinium salt carbonyl catalyst 3b-1

[0141]

[0142] Under a nitrogen atmosphere, compound (S,S)-4 (0.146 g, 0.3 mmol) and 1,3-di-tert-butyl-5-isocyanobenzene (0.072 g, 0.315 mmol) were dissolved in DMF (1.5 mL) and reacted at room temperature for 24 hours. After the reaction was complete, ethyl acetate (3 mL) was added and the mixture was washed three times with water (3 mL × 3), and once with saturated brine (3 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain a urea intermediate. The urea intermediate was dissolved in anhydrous acetonitrile (1.5 mL), and CH3I (0.851 g, 6.00 mmol) was added. The mixture was reacted at room temperature for 8 hours. After the reactants disappeared, the mixture was concentrated and purified by column chromatography to obtain a crude quaternary ammonium salt intermediate. Tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added to the crude product, and the mixture was reacted at 55 °C for 6 hours.

[0143] After the reaction was completed, the reaction solvent was removed and the product was dried to obtain crude catalyst. The crude product was pulverized into powder, 4 mL of diethyl ether was added, followed by 7 drops of tetrahydrofuran. The powder was thoroughly cleaned by ultrasonication. After standing, the supernatant was removed. This operation was repeated 3 times. Finally, the filter cake obtained by vacuum filtration was dried to obtain catalyst (S,S)-3b-1.

[0144] The basic parameters of catalyst (S,S)-3b-1 are as follows: brownish-yellow solid, yield 57%; 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.91(s,1H),9.33(d,J=10.4Hz,1H),8.92(s,1H) ,8.24(d,J=8.4Hz,1H),8.06(d,J=8.4Hz,1H),7.67(d,J=8.4Hz,1H),7.63(t,J=8.0Hz, 1H),7.49(t,J=8.4Hz,1H),7.49-7.36(m,2H),7.39-7.32(m,4H),7.21(d,J=6.8Hz,2H) ,7.08(t,J=1.6Hz,1H),6.25(d,J=9.6Hz,1H),4.29(s,3H),1.81(s,3H),1.26(s,18H); 13C NMR(101MHz,DMSO-d6)δ188.9,182.8,179.8,167.1,164.7,155.4,151.6,145.6,140.1,138.3,137.8,136.8,136.4,133.4 ,132.2,131.3,130.3,129.2,128.5,128.2,127.8,127.1,127.1,125.1,124.3,116.5,112.7,58.3,47.3,34.8,31.1,15.9.

[0145] Example 3: A chiral synthesis of thiamphenicol

[0146] (1) Synthesis of intermediate I-1 (catalyst: (S,S)-3a-1)

[0147]

[0148] In a glove box, (S,S)-3a-1 (2.0 mg, 0.0025 mmol), compound 1, p-methylsulfonylbenzaldehyde (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.

[0149] 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 half hour. 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, 14:1 dr, 98% ee).

[0150] NMR data of intermediate I-1: 1 H NMR (400MHz, CDCl3) δ7.90(d,J=8.0Hz,2H),7.59(d,J=8.0Hz,2H),4.85(d,J=4.8Hz,1H),3.51(d,J=4.8Hz,1H),3.01(s,3H),1.36(s,9H); 13CNMR (100MHz, CDCl3) δ172.1,147.9,140.1,127.8,127.6,82.5,73.8,60.7,44.4,28.3.

[0151] (2) Synthesis of intermediate II

[0152]

[0153] Intermediate I-1 (6.45 g, 20.5 mmol) was added to a 100 mL round-bottom flask, followed by methanol (68 mL) to completely dissolve it. The system was then cooled to 0 °C, and sodium borohydride (0.93 g, 24.6 mmol) was slowly added in portions after the temperature stabilized. 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 obtain a white solid intermediate II (4.16 g, 83% yield). The NMR spectrum was consistent with the standard spectrum (J. Catal. 2023, 417, 35-40).

[0154] (3) Synthesis of the final product, thiamphenicol

[0155]

[0156] Intermediate II (4.16 g, 17.0 mmol) and methyl dichloroacetate (52 mL) were added sequentially to a single-necked flask and reacted at 100–110 °C for approximately 3 hours. After the starting material disappeared as detected by thin-layer chromatography, the mixture was distilled under reduced pressure. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and petroleum ether to give thiamphenicol (5.26 g, 87% yield). The NMR spectrum was consistent with the standard spectrum (Tetrahedron 2008, 64, 7822-7827).

[0157] Example 4: A chiral synthesis of thiamphenicol

[0158] (1) Synthesis of intermediate I-1 (catalyst: (S,S)-3a-2)

[0159]

[0160] In a glove box, (S,S)-3a-2 (2.0 mg, 0.0025 mmol), compound 1, p-methylsulfonylbenzaldehyde (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.

[0161] 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).

[0162] (2) Synthesis of intermediate II

[0163]

[0164] 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 sodium borohydride (0.57 g, 15.2 mmol) was slowly added in portions after the temperature stabilized. 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 (1.31 g, 85% yield), a white solid.

[0165] (3) Synthesis of the final product, thiamphenicol

[0166]

[0167] Intermediate II (1.31 g, 5.35 mmol) and methyl dichloroacetate (20 mL) were added sequentially to a single-necked flask and reacted at 100–110 °C for about 2 hours. After the starting material disappeared as detected by thin-layer chromatography, the mixture was distilled under reduced pressure. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and petroleum ether to give thiamphenicol (1.62 g, 85% yield).

[0168] Compared with Example 3, the catalyst in step (1) is different, but the yields are similar, indicating that the chiral pyridinium salt carbonyl catalysts of the present invention all have excellent catalytic activity.

[0169] Example 5: A chiral synthesis of thiamphenicol

[0170] (1) Synthesis of intermediate I-1 (catalyst: (S,S)-3b-1)

[0171]

[0172] In a glove box, (S,S)-3b-1 (2.0 mg, 0.0025 mmol), compound 1, p-methylsulfonylbenzaldehyde (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.

[0173] 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 half hour. 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 (5.48 g, 70% yield, 4:1 dr, 90% ee).

[0174] (2) Synthesis of intermediate II

[0175]

[0176] Intermediate I-1 (2.0 g, 6.30 mmol) was added to a 100 mL round-bottom flask, followed by methanol (25 mL) to completely dissolve it. The system was then cooled to 0 °C, and sodium borohydride (0.57 g, 15.2 mmol) was slowly added in portions after the temperature stabilized. 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.

[0177] (3) Synthesis of the final product, thiamphenicol

[0178]

[0179] Intermediate II (1.34 g, 5.46 mmol) and methyl dichloroacetate (20 mL) were added sequentially to a single-necked flask and reacted at 100–110 °C for about 3 hours. After the starting material disappeared as detected by thin-layer chromatography, the mixture was distilled under reduced pressure. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and petroleum ether to give thiamphenicol (1.62 g, 84% yield).

[0180] Compared with Examples 3 and 4, the catalyst in step (1) is different, but the yields of all three are higher (≥70%), further demonstrating that the chiral pyridinium salt carbonyl catalysts of the present invention have excellent catalytic activity.

[0181] Example 6: A chiral synthesis of thiamphenicol

[0182] (1) Synthesis of intermediate I-1 (catalyst: (S,S)-3a-1)

[0183]

[0184] In a glove box, (S,S)-3a-1 (2.0 mg, 0.0025 mmol), compound 1, p-methylsulfonylbenzaldehyde (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.

[0185] 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 half hour. 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, 98% ee).

[0186] (2) Synthesis of intermediate II

[0187]

[0188] Intermediate I-1 (5.51 g, 17.4 mmol) was added to a 100 mL pear-shaped flask, followed by methanol (60 mL) to completely dissolve it. The system was then cooled to 0 °C, and after the temperature stabilized, potassium borohydride (1.13 g, 20.9 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 (40 mL) and saturated ammonium chloride aqueous solution (20 mL), and the aqueous phase was extracted with ethyl acetate (40 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 (3.83 g, 90% yield), a white solid.

[0189] (3) Synthesis of the final product, thiamphenicol

[0190]

[0191] Intermediate II (2.38 g, 9.70 mmol) and methyl dichloroacetate (30 mL) were added sequentially to a single-necked flask and reacted at 100–110 °C for about 2 hours. After the starting material disappeared as detected by thin-layer chromatography, the mixture was distilled under reduced pressure. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and petroleum ether to give thiamphenicol (3.06 g, 89% yield).

[0192] 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).

[0193] Compared with Example 3, the reducing agent in step (2) is different, but the yields of the two are similar. Therefore, potassium borohydride and sodium borohydride are both preferred reducing agents in step (2).

[0194] Example 7: A chiral synthesis of thiamphenicol

[0195] (1) Synthesis of intermediate I-1 (catalyst: (S,S)-3a-1)

[0196]

[0197] In a glove box, (S,S)-3a-1 (2.0 mg, 0.0025 mmol), compound 1, p-methylsulfonylbenzaldehyde (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.

[0198] 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).

[0199] (2) Synthesis of intermediate II

[0200]

[0201] 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.

[0202] (3) Synthesis of the final product, thiamphenicol

[0203]

[0204] Intermediate II (2.00 g, 5.62 mmol) and methyl dichloroacetate (15 mL) were added sequentially to a single-necked flask and reacted at 100 °C for about 2 hours. After the starting material disappeared as detected by thin-layer chromatography, the mixture was distilled under reduced pressure. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and petroleum ether to give thiamphenicol (1.66 g, 83% yield).

[0205] Compared with Example 3, the additives in step (1) are different, but the yields of both are higher (≥70%). Therefore, disodium hydrogen phosphate dodecahydrate and ammonium dihydrogen phosphate are preferred additives in step (1).

[0206] Example 8: A chiral synthesis of thiamphenicol

[0207] (1) Synthesis of intermediate I-2 (catalyst: (S,S)-3a-1)

[0208]

[0209] In a glove box, (S,S)-3a-1 (4.0 mg, 0.0050 mmol), compound 1, p-methylsulfonylbenzaldehyde (4.60 g, 25.0 mmol), and sodium dihydrogen phosphate (3.60 g, 30.0 mmol) were added to a 250 mL Shrek tube. The Shrek tube was then removed from the glove box, and tetrahydrofuran (150 mL) was added at -40 °C, with stirring for 10 minutes at this temperature. After the temperature stabilized, compound 2b, glycine ethyl ester (6.19 g, 60.0 mmol), was added dropwise to the system over 5 minutes at this temperature, and the reaction was carried out at -40 °C for 60 hours.

[0210] After the reaction was complete, hydroxylamine hydrochloride (1.04 g, 15 mmol) 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 the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:2) to obtain intermediate I-2 (5.24 g, 73% yield, 13:1 dr, 98% ee).

[0211] NMR data of intermediate I-2: 1 H NMR (400MHz, CDCl3) δ7.94(d,J=8.0Hz,2H),7.60(d,J=8.0Hz,2H),5.00(d,J=4.4Hz, 1H), 4.20 (q, J = 7.2Hz, 2H), 3.66 (d, J = 4.8Hz, 1H), 3.10 (s, 3H), 1.25 (t, J = 7.2Hz, 3H); 13 C NMR (100MHz, CDCl3) δ172.8,147.6,140.0,127.5,127.3,73.4,61.6,60.2,44.5,14.1.

[0212] (2) Synthesis of intermediate II

[0213]

[0214] Intermediate I-2 (5.24 g, 18.3 mmol) was added to a 100 mL pear-shaped flask, followed by methanol (65 mL) to completely dissolve it. The system was then cooled to 0 °C, and after the temperature stabilized, potassium borohydride (1.19 g, 22.0 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 (40 mL) and saturated ammonium chloride aqueous solution (25 mL), and the aqueous phase was extracted with ethyl acetate (40 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 (4.30 g, 90% yield), a white solid.

[0215] (3) Synthesis of the final product, thiamphenicol

[0216]

[0217] Intermediate II (2.00 g, 5.62 mmol) and methyl dichloroacetate (15 mL) were added sequentially to a single-necked flask and reacted at 100 °C for about 2 hours. After the starting material disappeared as detected by thin-layer chromatography, the mixture was distilled under reduced pressure. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and petroleum ether to give thiamphenicol (1.72 g, 86% yield).

[0218] Compared with Example 7, the reaction substrate 2, reaction temperature and reaction time in step (1) are different, but the yields of both are higher (≥70%), indicating that the chiral pyridinium salt carbonyl catalyst of the present invention has universality.

[0219] Example 9: A chiral synthesis of thiamphenicol

[0220] (1) Synthesis of intermediate I-1 (catalyst: (S,S)-3a-1)

[0221]

[0222] In a glove box, (S,S)-3a-1 (2.0 mg, 0.0025 mmol), compound 1, p-methylsulfonylbenzaldehyde (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.

[0223] 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 half hour. 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 (6.57 g, 84% yield, 12:1 dr, 97% ee).

[0224] (2) Synthesis of intermediate II

[0225]

[0226] Intermediate I-1 (2.0 g, 6.30 mmol) was added to a 100 mL round-bottom flask, followed by 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 (1.26 g, 83% yield), a white solid.

[0227] (3) Synthesis of the final product, thiamphenicol

[0228]

[0229] Intermediate II (1.26 g, 5.15 mmol) and methyl dichloroacetate (20 mL) were added sequentially to a single-necked flask and reacted at 100–110 °C for about 2 hours. After the starting material disappeared as detected by thin-layer chromatography, the mixture was distilled under reduced pressure. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and petroleum ether to give thiamphenicol (1.57 g, 86% yield).

[0230] Compared with Example 7, 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.

[0231] Comparative Example 1: Synthesis of Intermediate I-1 (catalyst is pyridine-type carbonyl catalyst)

[0232]

[0233] Add cat.-1 (13 mg, 0.025 mmol), compound 1 p-methylsulfonylbenzaldehyde (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.

[0234] 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.

[0235] Compared with Examples 2-8 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 for salt formation and 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.

[0236] Comparative Example 2: Synthesis of Intermediate I-1

[0237]

[0238] In a glove box, cat.-2 (2.0 mg, 0.0025 mmol), compound 1 p-methylsulfonylbenzaldehyde (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.

[0239] 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).

[0240] Compared with Examples 2-8 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.

[0241] 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).

[0242] 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).

[0243] 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.

[0244] 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 thiamphenicol, characterized in that, The preparation method includes the following steps: (1) In the presence of pyridinium salt carbonyl catalyst 3, sulfone benzaldehyde and glycine ester compound 2 were reacted to obtain (2S,3R)-p-sulfone 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 an amidation reaction with methyl dichloroacetate to obtain thiamphenicol; Wherein, R is selected from the group consisting of: 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: Among them, R 1 Selected from the following group: 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 ; 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 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; 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 further 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 (1), the reaction temperature is -60℃ to 90℃, preferably -60℃ to 0℃, more preferably -50℃ to -10℃, and most preferably -30℃ to -10℃.

8. The preparation method according to claim 1, characterized in that, In step (1), the reaction time is 1 to 80 hours, preferably 30 to 75 hours, more preferably 50 to 75 hours, and most preferably 60 to 75 hours.

9. 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.

10. 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.

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