Preparation method for oxazolidinone compound

Abstract

Disclosed is a preparation method, wherein a compound of formula (I) and a compound of formula (II) are used as starting materials to synthesize an oxazolidinone compound in the presence of a catalyst. Further disclosed is a use of a non-alkaline lithium salt and / or a quaternary ammonium salt as a catalyst in the synthesis of an oxazolidinone compound.

Description

Preparation methods of oxazolidinone compounds Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for preparing oxazolidinone compounds. Background Technology

[0002] Oxazolidinones are common functional groups in small molecule drugs. Currently, commonly used oxazolidinone drugs mainly include antibacterial drugs and anticoagulants that inhibit factor Xa, such as linezolid, terzizolid, contezolid, and rivaroxaban. For currently approved oxazolidinone drugs, the oxazolidinone ring is the active center of this class of compounds and is an essential group for maintaining their activity.

[0003] Existing methods for preparing oxazolidinone compounds suffer from low yields, high costs, environmental impact, and difficulties in industrial production. For example, Chinese patent CN 101798302B reports the reaction of a carbamate compound and an epoxy compound in an aprotic solvent under alkaline conditions to generate a corresponding oxazolidinone compound, where the base is potassium tert-butoxide or lithium tert-butoxide. However, the applicant found that the substrate is unstable and easily decomposes under strong alkaline conditions such as potassium tert-butoxide, sodium tert-butoxide, and lithium tert-butoxide, resulting in a large number of impurities during synthesis and extremely low reaction yields. Therefore, there is an urgent need to research and develop a novel and efficient method for preparing oxazolidinone compounds. Summary of the Invention

[0004] To address the aforementioned problems, this application provides a novel and efficient method for preparing oxazolidinone compounds, which has the advantages of high synthesis efficiency, economic and environmental friendliness, and ease of industrial production.

[0005] In a first aspect, this application provides a method for preparing oxazolidinone compounds, using compounds of formula (I) and formula (II) as raw materials (substrates) to obtain oxazolidinone compounds under the action of a catalyst; The R 1 and R 2 Each is independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, -arylene-heterocycloalkyl, -arylene-heteroaryl, -arylene-heteroaryl-heteroaryl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocycloalkyl, -alkylene-cycloalkyl, and heteroaryl; The R 3 and R 4 Each is independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or the R 3 and R 4 and together with the atoms they are attached to, form cycloalkyl or heterocycloalkyl groups; the R 5 and R 6Each element is independently selected from hydrogen, halogen, alkyl, -alkylene-OH, -alkylene-NH2, -alkylene-OC(=O)-alkyl, -alkylene-NHC(=O)-heteroaryl, -alkylene-NHC(=O)-alkyl, -alkylene-O-alkenyl, -alkylene-O-alkylene-aryl, -alkylene-O-alkylene-heteroaryl, -alkylene-O-alkylene-heterocyclic alkyl, -alkylene-O-aryl, alkylene-aryl, alkylene-heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclic alkyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl; the catalyst comprises a non-basic lithium salt and / or a quaternary ammonium salt; Wherein, the alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylene, heteroaryl, and heteroaryl groups are optionally and independently substituted by 1-5 substituents in each occurrence, wherein the substituents are deuterium atoms, halogens, =O, hydroxyl groups, -O-, -S-, -C(=O)-, -S(=O)2-, -NH-, C1-C6 alkyl, C1-C6 alkylene, C3-C 10 cycloalkyl, C3-C 10 Cycloalkylene, 3- to 10-membered heterocyclic alkylene, 3- to 10-membered heterocyclic alkylene, cyano, amino, nitro, C6-C 10 Aryl, C6-C 10 A group consisting of one or more of arylene, 5- to 10-membered heteroarylene, and 5- to 10-membered heteroarylene.

[0006] Secondly, the present invention provides the use of non-basic lithium salts and / or quaternary ammonium salts as catalysts in the synthesis of oxazolidinone compounds. Detailed Implementation

[0007] the term

[0008] To facilitate understanding of this invention, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. All references cited herein, including patents, patent applications, papers, textbooks, and the like, and references cited therein, are incorporated herein by reference in their entirety to the extent that they have not already been cited. If one or more of the incorporated references and similar materials differ from or contradict this application, including but not limited to defined terminology, usage of terms, described techniques, and the like, this application shall prevail.

[0009] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0010] The term "oxazolidinone compound" refers to a compound whose molecular structure contains a monovalent, divalent, or trivalent oxazolidinone ring. The oxazolidinone compound can be an antibacterial or anticoagulant containing a monovalent, divalent, or trivalent oxazolidinone ring; non-limiting examples include linezolid, terdizolid, contezolid, rivaroxaban, etc. The oxazolidinone compound can be a compound of formula (III) described in this application. The term "oxazolidinone ring" refers to...

[0011] The term "room temperature" is also called normal temperature or general temperature, and is generally defined as 18 to 26°C. In this specific embodiment, the room temperature is around 20°C.

[0012] The numerical ranges used in this document should be understood to include all numbers (including integers and decimals) within that range. For example, the range 1 to 20 should be understood to include any number, combination of numbers, or subrange from the following group: 1, 1.2, 2, 2.5, 3, 3.1, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0013] The C used in this article m -C n This refers to a portion containing m to n carbon atoms. For example, "C3-C 10 "Cycloalkyl" refers to a cycloalkyl group having 3-10 carbon atoms.

[0014] In this document, the term "i-j-membered" should be understood as a group having i-j ring atoms. For example, "3-10-membered heterocyclic alkyl" should be understood as a heterocyclic alkyl having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein the ring atoms are selected from carbon, nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones).

[0015] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 carbon atoms (i.e., C1-C2). 20Alkyl group. In some embodiments, the alkyl group is an alkyl group having 1 to 6 carbon atoms (i.e., C1-C6 alkyl). In some embodiments, the alkyl group is an alkyl group having 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers.

[0016] The term "alkylene" refers to a divalent alkyl group, wherein the definition of alkyl is as described above. In some embodiments, the alkylene group is an alkylene group having 1 to 6 carbon atoms (i.e., C1-C6 alkylene groups). In some embodiments, the alkylene group is an alkylene group having 1 to 3 carbon atoms (i.e., C1-C3 alkylene groups). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2-CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, etc.

[0017] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as above and has 2 to 12 carbon atoms (i.e., C2-C). 12 (Alkenyl). In some embodiments, the alkenyl group is an alkenyl group having 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc.

[0018] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 ring atoms (i.e., C3-C4). 20 (Cycloalkyl). In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 8 ring atoms (i.e., C3-C8 cycloalkyl). In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 6 ring atoms (i.e., C3-C6 cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl. Non-limiting examples of polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0019] The term "cycloalkylene" refers to a divalent cycloalkyl group, wherein the definition of cycloalkyl is as described above. In some embodiments, the cycloalkylene is a cycloalkylene having 3 to 8 ring atoms (i.e., C3-C8 cycloalkylene). In some embodiments, the cycloalkylene is a cycloalkylene having 3 to 6 ring atoms (i.e., C3-C6 cycloalkylene).

[0020] The terms "heterocyclic alkyl" or "heterocyclic group" refer to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form a nitrogen oxide; the sulfur may optionally be oxidized to form a sulfoxide or sulfone), and having 3 to 20 ring atoms (i.e., 3 to 20-membered heterocyclic group). In some embodiments, the heterocyclic alkyl is a heterocyclic alkyl having 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclic alkyl). In some embodiments, the heterocyclic alkyl is a heterocyclic alkyl having 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclic alkyl). Non-limiting examples of the polycyclic heterocyclic group include spirocyclic heterocyclic groups, fused-ring heterocyclic groups, and bridged-ring heterocyclic groups.

[0021] The term "heterocyclic alkylene" refers to a divalent heterocyclic alkylene, wherein the definition of heterocyclic alkylene is as described above. In some embodiments, the heterocyclic alkylene is a heterocyclic alkylene having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic alkylene). In some embodiments, the heterocyclic alkylene is a heterocyclic alkylene having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic alkylene).

[0022] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 ring atoms (i.e., 6 to 14 membered aryl). In some embodiments, the aryl group is an aryl group having 6 to 10 ring atoms (i.e., C6-C). 10 Aryl groups. Monocyclic aryl groups, such as phenyl groups. Polycyclic aryl groups, non-limiting examples include naphthyl, anthraceneyl, phenanthrene, etc.

[0023] The term "arylene" refers to a divalent aryl group, where the aryl group is defined as described above. In some embodiments, the arylene is an arylene having 6 to 10 ring atoms (i.e., C6-C). 10 (Aspartic acid).

[0024] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., a polycyclic heteroaryl) having a conjugated π-electron system, wherein the ring contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones), having 5 to 14 ring atoms (i.e., a 5 to 14-membered heteroaryl). In some embodiments, the heteroaryl is a heteroaryl having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl). In some embodiments, the heteroaryl is a heteroaryl having 5 to 6 ring atoms (i.e., a 5 to 6-membered heteroaryl). The polycyclic heteroaryl group comprises a phenyl or naphthyl group fused with one or more heterocyclic groups, wherein the linkage is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system; the polycyclic heteroaryl group also includes a heteroaryl group such as pyridyl or pyrimidinyl group fused with one or more cycloalkyl groups, wherein the linkage is on the heteroaryl group such as pyridyl or pyrimidinyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system. Non-limiting examples include pyridine, thiophene, triazole, oxazole, benzofuran, and isoindoline.

[0025] The term "hybrid aryl" refers to a divalent heteroaryl, wherein the definition of heteroaryl is as described above. In some embodiments, the heteroaryl is a heteroaryl having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl). In some embodiments, the heteroaryl is a heteroaryl having 5 to 6 ring atoms (i.e., a 5 to 6-membered heteroaryl).

[0026] The terms “alkyl,” “alkylene,” “alkenyl,” “cycloalkyl,” “cycloalkylene,” “heterocycloalkyl,” “heterocycloalkylene,” “aryl,” “arylene,” “heteroaryl,” and “heteroaryl” are optionally and independently substituted with 1 to 5 substituents in each occurrence, said substituents being deuterium (D) atoms, halogens, =O, hydroxyl groups, -O-, -S-, -C(=O)-, -S(=O)2-, -NH-, C1-C6 alkyl, C1-C6 alkylene, C3-C 10 cycloalkyl, C3-C 10 Cycloalkylene, 3- to 10-membered heterocyclic alkylene, 3- to 10-membered heterocyclic alkylene, cyano, amino, nitro, C6-C 10 Aryl, C6-C 10 A group consisting of 1 to 5 of the following: arylene, 5 to 10 heteroarylene, and 5 to 10 heteroarylene.

[0027] "Optionally" or "optionally" means that the event or environment described below may but not necessarily occur, including both the occurrence and non-occurrence of the event or environment. For example, "optionally substituted alkyl" includes cases where the alkyl group is substituted and cases where the alkyl group is not substituted.

[0028] "Substituted" or "substituted" refers to one or more hydrogen atoms in a group, such as 1 to 6, or 1 to 3 hydrogen atoms, being independently replaced by the corresponding number of substituents. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0029] The compounds disclosed in this article are generally named according to the IUPAC or CAS nomenclature system.

[0030] Preparation method

[0031] This application provides a method for preparing oxazolidinone compounds, using compounds of formula (I) and formula (II) as raw materials (reaction substrates), to obtain oxazolidinone compounds under the action of a catalyst: The R 1 and R 2 Each is independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, -arylene-heterocycloalkyl, -arylene-heteroaryl, -arylene-heteroaryl-heteroaryl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocycloalkyl, -alkylene-cycloalkyl, and heteroaryl; The R 3 and R 4 Each is independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or the R 3 and R 4 and together with the atoms they are attached to, form cycloalkyl or heterocycloalkyl groups; the R 5 and R 6Each element is independently selected from hydrogen, halogen, alkyl, -alkylene-OH, -alkylene-NH2, -alkylene-OC(=O)-alkyl, -alkylene-NHC(=O)-heteroaryl, -alkylene-NHC(=O)-alkyl, -alkylene-O-alkenyl, -alkylene-O-alkylene-aryl, -alkylene-O-alkylene-heteroaryl, -alkylene-O-alkylene-heterocyclic alkyl, -alkylene-O-aryl, alkylene-aryl, alkylene-heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclic alkyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl; the catalyst comprises a non-basic lithium salt and / or a quaternary ammonium salt; Wherein, the alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylene, heteroaryl, and heteroaryl groups are optionally and independently substituted by 1-5 substituents in each occurrence, wherein the substituents are deuterium atoms, halogens, =O, hydroxyl groups, -O-, -S-, -C(=O)-, -S(=O)2-, -NH-, C1-C6 alkyl, C1-C6 alkylene, C3-C 10 cycloalkyl, C3-C 10 Cycloalkylene, 3- to 10-membered heterocyclic alkylene, 3- to 10-membered heterocyclic alkylene, cyano, amino, nitro, C6-C 10 Aryl, C6-C 10 A group consisting of one or more of arylene, 5- to 10-membered heteroarylene, and 5- to 10-membered heteroarylene.

[0032] In some embodiments, the non-alkaline lithium salt includes one or more of lithium bromide, lithium chloride, lithium iodide, lithium carbonate, lithium citrate, and lithium acetate.

[0033] In some embodiments, the quaternary ammonium salt includes one or more of TBAF (tetrabutylammonium fluoride), TBAC (tetrabutylammonium chloride), TBAB (tetrabutylammonium bromide), TBAI (tetrabutylammonium iodide), TBAHS (tetrabutylammonium bisulfate), BTEAC (benzyltriethylammonium chloride), and methyltrioctylammonium chloride.

[0034] In some implementations, the R 1 and R 2 Each is independently selected from C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, -(C6-C 10 (arylene)-(3-10 membered heterocyclic alkyl), -(C6-C 10 (-(5-10 heteroaryl)-(C6-C) 10 (-(5-10 ternary)-(5-10 ternary)-(5-10 ternary), -(C1-C12 alkylene)-(C6-C 10 aryl), -(C1-C 12 alkylene)-(5-10 heteroaryl), -(C1-C 12 alkylene)-(3- to 10-membered heterocyclic alkyl), -(C1-C 12 (alkylene)-(C3-C 10 cycloalkyl) and 5- to 10-membered heteroaryl; the R 3 and R 4 Each is independently selected from hydrogen, halogen, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl and 5-10 heteroaryl; or the R 3 and R 4 And together with the atoms they are attached to, they form C3-C. 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl; the R 5 and R 6 Each is independently selected from hydrogen, halogen, C1-C 12 Alkyl, -(C1-C 12 alkylene)-OH, -(C1-C 12 alkylene)-NH2, -(C1-C 12 Alkylene)-OC(=O)-(C1-C 12 alkyl), -(C1-C 12 alkylene)-NHC(=O)-(5~10-membered heteroaryl),-(C1-C 12 alkylene)-NHC(=O)-(C1-C 12 alkyl), -(C1-C 12 alkylene)-O-(C2-C6 alkenyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(3-10 heterocyclic alkyl), -(C1-C6 alkylene)-O-(C6-C 10 aryl), -(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-(3- to 10-membered heterocycloalkyl), C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10Aryl and 5-10 heteroaryl groups; wherein the alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylene, heteroaryl, and heteroaryl groups are optionally and independently substituted by 1-5 substituents in each occurrence, said substituents being deuterium atoms, halogens, =O, hydroxyl groups, -O-, -S-, -C(=O)-, -S(=O)2-, -NH-, C1-C6 alkyl, C1-C6 alkylene, C3-C 10 cycloalkyl, C3-C 10 Cycloalkylene, 3- to 10-membered heterocyclic alkylene, 3- to 10-membered heterocyclic alkylene, cyano, amino, nitro, C6-C 10 Aryl, C6-C 10 A group consisting of 1 to 5 of the following: arylene, 5 to 10 heteroarylene, and 5 to 10 heteroarylene.

[0035] In some implementations, the R 1 Selected from C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, -(C6-C 10 (Asaryl)-N(Bn)2、-(C6-C 10 (arylene)-(3-10 membered heterocyclic alkyl), -(C6-C 10 (-(5-10 heteroaryl)-(C6-C) 10 (arylene)-(5-10 methylarylene)-(5-10 methylarylene) and 5-10 methylarylene; the R 2 Selected from C1-C 12 Alkyl, -(C1-C 12 alkylene)-(C6-C 10 aryl), -(C1-C 12 alkylene)-(5-10 heteroaryl), -(C1-C 12 alkylene)-(3- to 10-membered heterocyclic alkyl) and -(C1-C 12 (alkylene)-(C3-C 10 (cycloalkyl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, arylene, heteroarylene, and heteroaryl groups are optionally and independently substituted by 1-5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups.

[0036] In some implementations, the R1 The radical is selected from phenyl, -phenylene-N(Bn)2, -phenylene-(3-10-membered heterocyclic alkyl), -phenylene-(5-10-membered heteroaryl), and -phenylene-(5-10-membered heteroaryl)-(5-10-membered heteroaryl); wherein the phenyl, phenylene, heterocyclic alkyl, heteroaryl, and heteroaryl radicals are optionally and independently substituted by 1-5 substituents in each occurrence, and the substituents are independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C. 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups.

[0037] In some implementations, the R 1 Selected from phenyl, -phenylene-N(Bn)2, cyclohexyl, pyridyl, cyclohexenyl, The phenyl and phenylene groups are optionally and independently substituted by 1 to 5 substituents, each substituent being independently selected from halogens (fluorine, chlorine, bromine, iodine), amino groups, hydroxyl groups, and C1-C6 groups. 12 alkyl.

[0038] In some implementations, the R 2 Selected from C1-C6 alkyl, -(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-(3-10 heterocyclic alkyl), and -(C1-C6 alkylene)-(C3-C 10 (cycloalkyl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally and independently substituted by 1 to 5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups.

[0039] In some implementations, the R 2 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, methylene-phenyl, methylene-(5-10-membered heteroaryl), methylene-(3-10-membered heterocycloalkyl), and methylene-(C3-C4) 10(Cycloalkyl); wherein the cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl groups are optionally and independently substituted by 1-5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups.

[0040] In some implementations, the R 3 R 4 and R 5 Each is independently selected from hydrogen, halogens, and C1-C6 alkyl groups; wherein the alkyl group is optionally substituted with 1 to 5 substituents, each substituent being independently selected from deuterium, halogens, amino groups, and hydroxyl groups.

[0041] In some implementations, the R 6 Selected from hydrogen, halogen, C1-C6 alkyl, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-NH2, -(C1-C6 alkylene)-NH-(5-10 heteroaryl), -(C1-C6 alkylene)-OC(=O)-(C1-C6 alkyl), -(C1-C6 alkylene)-NHC(=O)-(5-10 heteroaryl), -(C1-C6 alkylene)-NHC(=O)-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C2-C6 alkenyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(3-10 heterocyclic alkyl), -(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C1-C6 alkylene)-(3- to 10-membered heterocycloalkyl) and -(C1-C6 alkylene)-O-(C6-C 10 Aryl); wherein the alkylene, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally and independently substituted by 1 to 5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C. 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups.

[0042] In some implementations, the R 6 Selected from hydrogen, halogen, C1-C6 alkyl, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-NH2, -(C1-C6 alkylene)-OC(=O)-(C1-C6 alkyl), -(C1-C6 alkylene)-NHC(=O)-(5~10-membered heteroaryl), -(C1-C6 alkylene)-NHC(=O)-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C2-C6 alkenyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(3-10 heterocyclic alkyl), -(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C1-C6 alkylene)-(3- to 10-membered heterocycloalkyl) and -(C1-C6 alkylene)-O-(C6-C 10 Aryl); wherein the alkylene, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally and independently substituted by 1 to 5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C. 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups.

[0043] In some implementations, the R 6 Selected from hydrogen, halogen, C1-C6 alkyl, -methylene-OH, -methylene-OC(=O)-(C1-C6 alkyl), -methylene-NHC(=O)-(5-10 heteroaryl), -methylene-NH-(5-10 heteroaryl), -methylene-NHC(=O)-(C1-C6 alkyl), -methylene-(C6-C 10 aryl) and methylene-(5-10 heteroaryl); wherein, each of the alkyl, methylene, aryl, and heteroaryl groups is optionally and independently substituted by 1-5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups.

[0044] In some embodiments, the compound of formula (I) includes, but is not limited to:

[0045] In some embodiments, the compound of formula (II) includes, but is not limited to:

[0046] In some embodiments, the molar ratio of the compound of formula (I) to the compound of formula (II) is 1:(1 to 10).

[0047] In some embodiments, the molar ratio of the compound of formula (I) to the compound of formula (II) is 1:(1.5 to 5).

[0048] In some embodiments, the molar ratio of the compound of formula (I) to the catalyst is 1:(0.01 to 2).

[0049] In some embodiments, the molar ratio of the compound of formula (I) to the catalyst is 1:(0.1 to 1.5). The amount of catalyst, such as TBAB, is a catalytic equivalent (e.g., 0.1 equivalent, 0.2 equivalent, 0.4 equivalent, 0.8 equivalent, 1.0 equivalent, 1.5 equivalent, where equivalent refers to the molar ratio of the catalyst to the substrate compound of formula (I)).

[0050] In some embodiments, the temperature of the synthesis reaction is 10–90°C.

[0051] In some embodiments, the temperature of the synthesis reaction is 40–80°C.

[0052] In some embodiments, the mass-to-volume ratio of the compound of formula I to the solvent is 1 g : (0.5–20) mL.

[0053] In some embodiments, the mass-to-volume ratio of the compound of formula I to the solvent is 1 g: (1-10) mL.

[0054] In some embodiments, the preparation method includes the steps of mixing a compound of formula I, a compound of formula II, a catalyst, and a solvent, and synthesizing an oxazolidinone compound under the catalysis of the catalyst.

[0055] In some embodiments, the preparation method includes the steps of: mixing a compound of formula I, a compound of formula II, a catalyst and a solvent, controlling the temperature at 10–90°C, and synthesizing an oxazolidinone compound under the catalysis of the catalyst.

[0056] In some embodiments, the solvent includes one or more of tetrahydrofuran, acetonitrile, acetone, isopropyl acetate, isopropanol, ethanol, tert-butanol, tert-amyl alcohol, ethylene glycol, isobutanol, and N,N-dimethylformamide.

[0057] In some embodiments, the general reaction formula of the preparation method is as follows: The oxazolidinone compounds mentioned above are compounds of formula (III); R 1 R 2 R 3 R 4 R 5 and R 6 As described in any of the above implementation schemes.

[0058] In some embodiments, the general reaction formula of the preparation method is as follows: The oxazolidinone compound is a compound of formula (III); R 2 and R 6 As described in any of the above embodiments; R 1a R 1b R 1d and R 1e Each is independently selected from hydrogen, halogens (including fluorine, chlorine, bromine, and iodine), and C1-C6 alkyl groups; R 1c The components are selected from 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl, -(5-10-membered heteroaryl)-(5-10-membered heteroaryl), and -N(Bn)2; wherein the heteroaryl, heterocyclic alkyl, and heteroaryl are optionally and independently substituted by 1-5 substituents in each occurrence, and the substituents are independently selected from halogens, =O, C1-C6 alkyl and hydroxyl.

[0059] In some embodiments, the general reaction formula of the preparation method is as follows: The oxazolidinone compounds mentioned therein are compounds of formula (III).

[0060] The reaction mechanism of this invention is as follows: Amide nitrogen has low nucleophilicity, making it difficult to directly undergo a nucleophilic ring-opening reaction with epoxide at room temperature. Existing preparation methods require the formation of a highly nucleophilic nitrogen anode in the presence of a strongly basic promoter, or the reaction to attack the epoxide at high temperatures for ring-opening addition. Strongly basic promoters (such as sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, etc.) enhance the nucleophilicity of the nucleophile (amide), thus enabling the reaction to proceed. However, under strongly basic conditions, the five-membered ring of the target product is easily hydrolyzed, generating impurities. Therefore, the reaction process requires strict control of water and temperature, resulting in a harsh and difficult-to-control reaction environment and low product yield. The catalysts used in this invention, such as lithium salts and / or quaternary ammonium salts, can form highly active intermediates with the substrate, thereby effectively promoting the reaction. An exemplary reaction mechanism of the quaternary ammonium salt catalyst is shown below: First, the catalyst R4N + X -It reacts with epoxide (II) to form a highly reactive oxygen-negative intermediate A. This highly reactive intermediate A acts as a strong basic promoter, activating amide I to form a highly nucleophilic nitrogen-negative intermediate B and intermediate C. Intermediate B and C interact to yield intermediate D and release the catalyst R4N. + X - Intermediate D undergoes cyclization and the removal of one molecule of alcohol to obtain the target molecule (Ⅲ).

[0061] This invention avoids the use of strong base reagents, resulting in milder reaction conditions, simpler operation, and a significantly improved yield.

[0062] Applications of catalysts

[0063] The present invention also provides the use of non-basic lithium salts and / or quaternary ammonium salts as catalysts in the synthesis of oxazolidinone compounds.

[0064] In some embodiments, the non-alkaline lithium salt includes one or more of lithium bromide, lithium chloride, lithium iodide, lithium carbonate, lithium citrate, and lithium acetate.

[0065] In some embodiments, the quaternary ammonium salt includes one or more of TBAF, TBAC, TBAB, TBAI, tetrabutylammonium bisulfate, benzyltriethylammonium chloride, and methyltrioctylammonium chloride.

[0066] abbreviation

[0067] DBU: 1,8-diazabicyclo(5,4,0)-7-undecene.

[0068] TBAF: Tetrabutylammonium fluoride.

[0069] TBAC: Tetrabutylammonium chloride.

[0070] TBAB: Tetrabutylammonium bromide.

[0071] TBAI: Tetrabutylammonium iodide.

[0072] MeOH: Methanol.

[0073] THF: Tetrahydrofuran.

[0074] Bn: Benzyl.

[0075] The following examples further illustrate the present invention in detail. It should also be understood that the following examples are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of the present invention are within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make appropriate selections within the appropriate range based on the description herein, and are not intended to be limited to the specific values ​​in the examples below.

[0076] Example

[0077] The general synthetic formula for the preparation method is: Where: R 1a R 1b R 1d and R 1e Each is independently selected from hydrogen and halogens (including fluorine, chlorine, bromine, and iodine); R 1c Selected from 5- to 10-membered heteroaryl groups (including ), 3- to 10-membered heterocyclic alkyl groups (including -N(Bn)2; R 2 Selected from C1-C 12 Alkyl groups (including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, etc.), -(C1-C6 alkylene)-(C6-C 10 Aryl (including but not limited to: ); R 6a Selected from C1-C 12 Alkyl groups (including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, etc.).

[0078] In step A above, the molar ratio of compound (I) to compound (II) is 1:(1-10); the molar ratio of compound (I) to catalyst is 1:(0.01-2); and the synthesis temperature is 10-90℃. No further processing is required after step A is completed; the next reaction can proceed directly.

[0079] In step A, a solvent and potassium carbonate are added to the reaction solution. The solvent includes, but is not limited to, methanol. In step B above, the molar ratio of the compound of formula (I) to potassium carbonate is 1:(0.001–2); the synthesis temperature is 10–90°C. After the reaction in step B is complete, acetic acid can be added to quench the reaction. Isopropanol and / or n-butane are added to the quenched reaction solution to precipitate the product. The product is then filtered, dried, and the target product is obtained.

[0080] In step C above, the molar ratio of compound (I) to compound (II) is 1:(0.1–10); the molar ratio of compound (I) to catalyst is 1:(0.01–2); and the synthesis temperature is 10–90 °C. After the reaction in step C is completed, acetic acid can be added to quench the reaction. Isopropanol and / or n-butane are added to the quenched reaction solution to precipitate the product. The product is then filtered, dried, and the target product is obtained.

[0081] The preparation method of this application, for compound I, R 1 Or R 2 Each of these can be independently selected as alkyl (e.g., substituted or unsubstituted methyl, ethyl, n-propyl, n-butyl, n-pentyl), cycloalkyl (e.g., substituted or unsubstituted cyclohexyl), heterocycloalkyl, aryl, -arylene-heteroalkyl, -arylene-heteroaryl, -arylene-heteroaryl-heteroaryl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-heteroalkyl, -alkylene-cycloalkyl and heteroaryl; or R 1 Or R 2 Each independently, arbitrarily chosen according to any one of the definitions herein, can synthesize oxazolidinone compounds. Similarly, the R... 3 and R 4 Each is independently selected from hydrogen, halogen, alkyl (e.g., substituted or unsubstituted methyl, ethyl, n-propyl, n-butyl, n-pentyl), cycloalkyl (e.g., substituted or unsubstituted cyclohexyl), heterocycloalkyl, aryl, and heteroaryl; or said R 3 and R 4 and together with the atoms to which they are attached, form cycloalkyl or heterocycloalkyl groups, wherein the cycloalkyl and heterocycloalkyl groups are each independently formed; the R 5 and R 6Each is independently selected from hydrogen, halogen, alkyl, -alkylene-OH, -alkylene-NH2, -alkylene-OC(=O)-alkyl, -alkylene-NHC(=O)-heteroaryl, -alkylene-NHC(=O)-alkyl, -alkylene-O-enel, -alkylene-O-alkylene-aryl, -alkylene-O-alkylene-heteroaryl, -alkylene-O-aryl, -alkylene-aryl, alkylene-heteroaryl, alkylene-cycloalkyl, alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or R 3 R 4 R 5 Or R 6 Each of the aforementioned alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylene, heteroaryl, and heteroaryl groups can be synthesized by any of the definitions described herein; wherein each of the aforementioned alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylene, heteroaryl, and heteroaryl groups is optionally and independently substituted by 1-5 substituents, said substituents being D atoms, halogens, =O, hydroxyl groups, -O-, -S-, -C(=O)-, -S(=O)2-, -NH-, C1-C6 alkyl, C1-C6 alkylene, C3-C 10 cycloalkyl, C3-C 10 Cycloalkylene, 3- to 10-membered heterocyclic alkylene, 3- to 10-membered heterocyclic alkylene, cyano, amino, nitro, C6-C 10 Aryl, C6-C 10 A group consisting of one or more of arylene, 5- to 10-membered heteroaryl, and 5- to 10-membered heteroarylene. Specifically, for example, R 1 Ethyl, R 2 Methylenecyclohexyl, R 3 Ethyl, R 4 -CH 2 OH, R 5 For H, R 6 For H; or R 1 Ethyl, R 2 Methylene phenyl, R 3 For H, R 4 -CH 2 OH, R 5 For H, R 6 For example, H; or R. 1 For butyl, R 2 Isobutyl, R 3 For H, R 4 -CH 2 OH, R 5 For H, R 6 For example, H. These will not be listed individually here.

[0082] Example 1

[0083] A solution of compound 1 (50.0 g, 0.15 mol), TBAB (47.1 g, 0.15 mol), and compound 2 (42.1 g, 0.29 mol) in acetone (50 mL) was reacted at 60 °C for 13 hours, and then cooled to 10 °C to give a mixture containing intermediate 3-1. LCMS: 413 [M+H].

[0084] Methanol (75 mL) and potassium carbonate (2 g, 0.015 mol) were added sequentially to the mixture containing intermediate 3-1, and the mixture was stirred for 1 hour. The reaction was then quenched with acetic acid and water. Isopropanol and n-heptane were slowly added to the reaction mixture, the temperature was lowered to 0 °C, and the mixture was stirred for 2 hours. The mixture was filtered and dried to give a white solid compound 3 (44.9 g, yield 90%, purity 98.4%). MS (m / z): 343 [M+H]. 1 H NMR (600MHz, DMSO-d6): 7.58-7.49 (m, IH); 7.48 (d, J=7.8Hz, 1H); 5.31 (brs, 1H); 5.09 (d, J=7.8Hz, 1H); 4.81-4 .78(m,1H); 4.13(t,J=8.4Hz,1H); 3.92-3.87(m,3H); 3.73-3.70(m,1H); 3.63-3.59(m,1H); 2.55-2.45(m,2H).

[0085] Example 2

[0086] A solution of compound 1 (5.0 g, 0.015 mol), TBAB (0.47 g, 0.0015 mol), and compound 2 (7.5 g, 0.052 mol) in acetone (5 mL) was heated to 60 °C and reacted for 5 hours, then cooled to 0 °C to give a mixture containing intermediate 3-1. LCMS: 413 [M+H].

[0087] Methanol (10 mL) and potassium carbonate (600 mg, 0.004 mol) were added sequentially to the mixture containing intermediate 3-1. The mixture was stirred for 1 hour, and the reaction was quenched with acetic acid and water. Isopropanol and n-heptane were slowly added, the mixture was cooled to 0°C and stirred for 2 hours, filtered, and dried to obtain a white solid compound 3 (4.4 g, yield 88%, purity 98%). It can be seen that by using the preparation route of this invention and scaling up the preparation of target compound 3, the reaction yield and purity of the target compound did not decrease and remained at a high level.

[0088] Example 3

[0089] Reaction Procedure 1: A solution of compound 1 (5.0 g, 0.015 mol), LiBr (1.27 g, 0.015 mol), and compound 2 (4.18 g, 0.029 mol) in tetrahydrofuran (10 mL) was reacted at room temperature for 18 hours, then cooled to 10 °C to give a mixture containing intermediate 3-1. LCMS: 413 [M+H]. Methanol (0.75 mL) and potassium carbonate (0.2 g, 0.0015 mol) were added sequentially to the mixture containing intermediate 3-1, and the mixture was stirred for 1 hour. The reaction was then quenched with acetic acid. Isopropanol and n-heptane were slowly added, the mixture was cooled to 0 °C and stirred for 2 hours, filtered, and dried to give a white solid compound 3 (4.4 g, yield 88%, purity 96.4%, ee: 100%).

[0090] Reaction Procedure 2: A solution of compound 1 (5.0 g, 0.015 mol), LiCl (0.62 g, 0.015 mol), and compound 2 (4.18 g, 0.029 mol) in tetrahydrofuran (10 mL) was reacted at room temperature for 18 hours, then cooled to 10 °C to give a mixture containing intermediate 3-1. LCMS: 413 [M+H]. Methanol (0.75 mL) and potassium carbonate (0.2 g, 0.0015 mol) were added sequentially to the mixture containing intermediate 3-1, and the mixture was stirred for 1 hour. The reaction was then quenched with acetic acid. Isopropanol and n-heptane were slowly added, the mixture was cooled to 0 °C and stirred for 2 hours, filtered, and dried to give a white solid compound 3 (4.4 g, yield 87%, purity 96%, ee: 100%).

[0091] Example 4

[0092] A solution of compound 1 (5.0 g, 0.015 mol), LiBr (1.27 g, 0.015 mol), and compound 4 (1.95 g, 0.026 mol) in tetrahydrofuran (10 mL) was reacted at room temperature for 18 hours. After quenching the reaction with acetic acid, isopropanol was added, the mixture was cooled to 0 °C and stirred for 2 hours, filtered, and dried to give a white solid compound 3 (4.5 g, yield 90%, purity 97.4%).

[0093] Example 5

[0094] A solution of compound 1 (5.0 g, 0.015 mol), LiCl (0.62 g, 0.015 mol), and compound 4 (1.95 g, 0.026 mol) in tetrahydrofuran (10 mL) was reacted at room temperature for 18 hours. After quenching the reaction with acetic acid, isopropanol was added, the mixture was cooled to 0 °C and stirred for 2 hours, filtered, and dried to give a white solid compound 3 (4.5 g, yield 91%, purity 98.4%).

[0095] Example 6

[0096] A solution of compound 5 (8.4 g, 0.02 mol), LiBr (1.76 g, 0.02 mol), and compound 4 (2.96 g, 0.04 mol) in tetrahydrofuran (20 mL) was reacted at room temperature for 18 hours. After quenching the reaction with acetic acid, isopropanol was added, the mixture was cooled to 0 °C and stirred for 2 hours, filtered, and dried to give a white solid compound 6 (yield 93%, purity 98.7%). MS (m / z): 443 [M+H]. 1 H NMR (400MHz, DMSO-d6): δ7.34-7.22(m,11H); 4.72-4.66(m,1H); 4.26(s,4H); 4.0 5-3.98 (m, 1H); 3.77 (dd, J = 8.5, 6.2 Hz, 1H); 3.57-3.54 (m, 1H); 3.42-3.39 (m, 2H).

[0097] Example 7

[0098] A solution of compound 7-1 (200 mg, 0.5 mmol), TBAB (169 mg, 0.52 mmol), and compound 2 (144 mg, 1 mmol) in acetone (0.2 mL) was heated to 60 °C and reacted for 13 hours, then cooled to 10 °C to give a mixture containing intermediate 7-2. LCMS: 441 [M+H].

[0099] Methanol (0.2 mL) and potassium carbonate (24 mg, 0.03 mmol) were added sequentially to the mixture containing intermediate 7-2. The mixture was stirred for 1 hour, quenched with acetic acid, and then isopropanol was added. The mixture was stirred and filtered to obtain a white solid compound 7 (167 mg, yield 90%, purity: 98.3%). MS (m / z): 371 [M+H]. 1 H NMR (400MHz, DMSO-d6): δ8.94(p,J=1.1Hz,1H); 8.22(m,2H); 7.72(m,2H); 7.53(dd,J=8.6,2.2Hz,1H); 5.26(t,J=5.6Hz,1H); 4.77(m,1H) ; 4.48 (s, 3H); 4.16 (t, J = 9.1Hz, 1H); 3.91 (dd, J = 9.0, 6.1Hz, 1H); 3.71 (ddd, J = 12.4, 5.6, 3.3Hz, 1H); 3.59 (ddd, J = 12.4, 5.7, 4.0Hz, 1H).

[0100] Example 8

[0101] A solution of compound 8-1 (1 g, 3 mmol), TBAB (1.03 g, 3.18 mmol), and compound 2 (1.7 g, 12 mol) in acetone (1 mL) was heated to 60 °C for 13 h, and then heated to 80 °C for 1 h to give a mixture containing intermediate 8-2. LCMS: 367 [M+H].

[0102] Methanol (1 mL) and potassium carbonate (20 mg) were added sequentially to the mixture containing intermediate 8-2, and the mixture was stirred overnight. Acetic acid was added to quench the reaction, followed by the addition of isopropanol and n-heptane. The mixture was filtered to give a white solid compound 8 (800 mg, yield 90%, purity 97.6%). MS (m / z): 297 [M+H]. 1 H NMR (400MHz, DMSO-d6): δ7.52(m,1H); 7.21(m,1H); 7.06(t,J=9.3Hz,1H); 5.20(s,1H); 4.68(m,1H); 4.04(t,J=9.0Hz,1H); 3.79 (dd, J = 8.9, 6.2 Hz, 1H); 3.73 (t, J = 4.7 Hz, 1H); 3.66 (dd, J = 12.3, 3.4 Hz, 1H); 3.55 (dd, J = 12.3, 4.0 Hz, 1H); 2.96 (t, J = 4.7 Hz, 4H).

[0103] Example 9

[0104] Compound 9-1 (100 mg, 0.34 mmol), TBAB (110 mg, 0.34 mol), acetone (1 mL), and compound 9-2 (104 mg, 0.51 mmol) were heated to 60 °C and reacted overnight. After cooling to room temperature, isopropanol and n-heptane were slowly added, and the mixture was stirred for 10 minutes. The mixture was filtered and dried to give a white solid, compound 9 (90 mg, yield 62%). MS (m / z): 422 [M+H]. 1 H NMR (400MHz, DMSO-d6): 7.94-7.86 (m, 4H); 7.54 (d, J = 8Hz, 2H); 7.41 (d, J = 8Hz, 2 H); 4.93-4.90 (m, 1H); 4.22-4.20 (m, 3H); 4.19-3.93 (m, 5H); 3.73-3.70 (m, 2H).

[0105] Example 10

[0106] Compound 10-1 (100 mg, 0.34 mmol), TBAB (110 mg, 0.34 mol), acetone (1 mL), and compound 10-2 (111 mg, 0.51 mmol) were heated to 60 °C and reacted overnight. After cooling to room temperature, isopropanol and n-heptane were slowly added, and the mixture was stirred for 10 minutes. The mixture was filtered and dried to give a white solid, compound 10 (93 mg, yield 62.4%). MS (m / z): 436 [M+H]. 1 H NMR (400MHz, DMSO-d6): 8.97 (t, J = 4Hz, 1H); 7.69 (d, J = 4Hz, 1H); 7.57 (d, J = 8Hz, 2H); 7.40 (d, J = 8Hz, 2H); 7.20 (d, J = 4Hz ,1H); 4.86-4.83(m,1H); 4.22-4.20(m,3H); 3.97-3.95(m,2H); 3.87-3.85(m,1H); 3.72-3.70(m,2H); 3.62-3.61(m,2H).

[0107] Example 11

[0108] Compound 11-1 (1.4 g, 10 mmol), LiCl (0.42 g, 10 mmol), acetone (2.8 mL), and compound 1 (3.42 g, 10 mol) were reacted at room temperature with stirring for 16 hours. TLC analysis showed that the reaction proceeded completely. The reaction was quenched with acetic acid. 3.67 g of compound 11 was obtained after purification, with a yield of 89.9%. MS (m / z): 409 [M+H]. 1 H NMR (400MHz, CD3CN): 8.14 (d, J = 1.7Hz, 1H); 7.31 (ddd, J = 2.4, 6.7, 11.9Hz, 1H); 7.21 (dt, J = 7.9, 1.6, 1.6Hz, 1H); 5.96 (d, J = 1.7Hz, 1H); 5.14(t,J=6.0Hz,1H); 5.10(d,J=7..9Hz,1H); 4.93(m,1H); 4.13(t,J=8.7Hz,1H); 3.83-3.92(o,3H); 3.56(m,2H); 2.54(t,J=7.4Hz,2H).

[0109] Comparative Example 1

[0110] The comparative example used the same reaction substrate as Example 1, but the experimental conditions were changed: Compound 1 (5.0 g, 14.6 mmol) and tetrahydrofuran (100 mL) were added to the reaction flask and stirred to dissolve. Then, DMPU (3.7 g, 29.2 mmol, 2 eq), tert-butyllithium (2.3 g, 29.2 mmol, 2 eq), and Compound 2 (2.3 g, 16.1 mmol, 1.1 eq) were added sequentially. The reaction was carried out at 25 °C for 15 hours. After the reaction was completed, 10% ammonium chloride aqueous solution was added to quench the reaction. The mixture was concentrated under reduced pressure. The residue was then added sequentially with methanol (5 mL) and isopropanol (15 mL), followed by the slow addition of n-heptane (30 mL). After stirring for 0.5 hours, the mixture was filtered. The filter cake was dried to give Compound 3 (2.4 g, 48% yield), an off-white solid. Compared with Example 1, this comparative example uses strongly alkaline alkali metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, and lithium tert-butoxide, which are already disclosed in the prior art, as alkaline reagents, and DMPU is added at the same time. The results show that the yield is very low, which may be because the substrate is still unstable and easily decomposes.

[0111] Compared with existing preparation methods, such as those using strong alkaline reagents like lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, and bis(trimethylsilyl)aminolithium, the preparation method presented in this application is a catalytic preparation method. This method uses a neutral and mild catalyst, which avoids substrate instability and decomposition under alkaline conditions, thus preventing the generation of more impurities. It offers advantages such as higher yield, lower catalyst usage (which is recyclable), economic efficiency, environmental friendliness, suitable reaction temperature, simple operation, and ease of industrial production.

[0112] The above description is merely a basic illustration of the concept of this invention, and any equivalent modifications made based on the technical solutions of this invention should fall within the protection scope of this invention. Furthermore, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of those different embodiments or examples.

Claims

1. A method for preparing an oxazolidinone compound, characterized in that, The preparation method uses compounds of formula (I) and formula (II) as raw materials to obtain oxazolidinone compounds under the action of a catalyst: The R 1 and R 2 Each is independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, -arylene-heterocycloalkyl, -arylene-heteroaryl, -arylene-heteroaryl-heteroaryl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocycloalkyl, -alkylene-cycloalkyl, or heteroaryl; The R 3 and R 4 Each is independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or the R 3 and R 4 And together with the atoms they are attached to, they form cycloalkyl or heteroalkyl groups; The R 5 and R 6 Each is independently selected from hydrogen, halogen, alkyl, -alkylene-OH, -alkylene-NH2, -alkylene-OC(=O)-alkyl, -alkylene-NHC(=O)-heteroaryl, -alkylene-NHC(=O)-alkyl, -alkylene-O-enel, -alkylene-O-alkylene-aryl, -alkylene-O-alkylene-heteroaryl, -alkylene-O-alkylene-heterocyclic alkyl, -alkylene-O-aryl, alkylene-aryl, alkylene-heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclic alkyl, cycloalkyl, heterocyclic alkyl, aryl, or heteroaryl; Wherein, the alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylene, heteroaryl, and heteroaryl groups are optionally and independently substituted by 1-5 substituents in each occurrence, wherein the substituents are deuterium atoms, halogens, =O, hydroxyl groups, -O-, -S-, -C(=O)-, -S(=O)2-, -NH-, C1-C6 alkyl, C1-C6 alkylene, C3-C 10 cycloalkyl, C3-C 10 Cycloalkylene, 3- to 10-membered heterocyclic alkylene, 3- to 10-membered heterocyclic alkylene, cyano, amino, nitro, C6-C 10 Aryl, C6-C 10 A group consisting of one or more of arylene, 5- to 10-membered heteroaryl, and 5- to 10-membered heteroarylene; The catalyst comprises non-basic lithium salts and / or quaternary ammonium salts.

2. The preparation method according to claim 1, characterized in that, The R 1 and R 2 Each is independently selected from C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, -(C6-C 10 (arylene)-(3-10 membered heterocyclic alkyl), -(C6-C 10 (-(5-10 heteroaryl)-(C6-C) 10 (-(5-10 ternary)-(5-10 ternary)-(5-10 ternary), -(C1-C 12 alkylene)-(C6-C 10 aryl), -(C1-C 12 alkylene)-(5-10 heteroaryl), -(C1-C 12 alkylene)-(3- to 10-membered heterocyclic alkyl), -(C1-C 12 (alkylene)-(C3-C 10 Cycloalkyl groups, or 5- to 10-membered heteroaryl groups; The R 3 and R 4 Each is independently selected from hydrogen, halogen, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 heteroaryl; or the R 3 and R 4 And together with the atoms they are attached to, they form C3-C. 10 Cycloalkyl or 3- to 10-membered heterocyclic alkyl groups; The R 5 and R 6 Each is independently selected from hydrogen, halogen, C1-C 12 Alkyl, -(C1-C 12 alkylene)-OH, -(C1-C 12 alkylene)-NH2, -(C1-C 12 Alkylene)-OC(=O)-(C1-C 12 alkyl), -(C1-C 12 alkylene)-NHC(=O)-(5~10-membered heteroaryl),-(C1-C 12 alkylene)-NHC(=O)-(C1-C 12 alkyl), -(C1-C 12 alkylene)-O-(C2-C6 alkenyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(3-10 heterocyclic alkyl), -(C1-C6 alkylene)-O-(C6-C 10 aryl), -(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-(3- to 10-membered heterocycloalkyl), C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl; Wherein, the alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylene, heteroaryl, and heteroaryl groups are optionally and independently substituted by 1-5 substituents in each occurrence, wherein the substituents are deuterium atoms, halogens, =O, hydroxyl groups, -O-, -S-, -C(=O)-, -S(=O)2-, -NH-, C1-C6 alkyl, C1-C6 alkylene, C3-C 10 cycloalkyl, C3-C 10 Cycloalkylene, 3- to 10-membered heterocyclic alkylene, 3- to 10-membered heterocyclic alkylene, cyano, amino, nitro, C6-C 10 Aryl, C6-C 10 A group consisting of 1 to 5 of the following: arylene, 5 to 10 heteroarylene, and 5 to 10 heteroarylene.

3. The preparation method according to claim 1 or 2, characterized in that, The R 1 Selected from C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, -(C6-C 10 (Asaryl)-N(Bn)2、-(C6-C 10 (arylene)-(3-10 membered heterocyclic alkyl), -(C6-C 10 (-(5-10 heteroaryl)-(C6-C) 10 (5-10 methyl aryl)-(5-10 methyl aryl)-(5-10 methyl aryl), or 5-10 methyl aryl; the R 2 Selected from C1-C 12 Alkyl, -(C1-C 12 alkylene)-(C6-C 10 aryl), -(C1-C 12 alkylene)-(5-10 heteroaryl), -(C1-C 12 alkylene)-(3- to 10-membered heterocyclic alkyl), or -(C1-C 12 (alkylene)-(C3-C 10 (cycloalkyl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, arylene, heteroarylene, and heteroaryl groups are optionally and independently substituted by 1-5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 A group consisting of one or more of aryl and 5- to 10-membered heteroaryl groups.

4. The preparation method according to any one of claims 1-3, characterized in that, The R 1 The radical is selected from phenyl, -phenylene-N(Bn)2, -phenylene-(3-10-membered heterocyclic alkyl), -phenylene-(5-10-membered heteroaryl), or -phenylene-(5-10-membered heteroaryl)-(5-10-membered heteroaryl); wherein the phenyl, phenylene, heterocyclic alkyl, heteroaryl, and heteroaryl radicals are optionally and independently substituted by 1-5 substituents in each occurrence, and the substituents are independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C. 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 A group consisting of one or more aryl and 5- to 10-membered heteroaryl groups; optionally, the R 1 Selected from phenyl, -phenylene-N(Bn)2, cyclohexyl, pyridyl, cyclohexenyl, The phenyl and phenylene groups are optionally and independently substituted by 1 to 5 substituents, each substituent being independently selected from halogens, amino groups, hydroxyl groups, and C1-C6 groups. 12 One or more of the alkyl groups.

5. The preparation method according to any one of claims 1-4, characterized in that, The R 2 Selected from C1-C6 alkyl, -(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-(3-10 heterocycloalkyl), or -(C1-C6 alkylene)-(C3-C 10 (cycloalkyl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally and independently substituted by 1 to 5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 A group consisting of one or more aryl and 5- to 10-membered heteroaryl groups; optionally, the R 2 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, methylene-phenyl, methylene-(5-10-membered heteroaryl), methylene-(3-10-membered heterocycloalkyl), or methylene-(C3-C4) 10 (Cycloalkyl); wherein the cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl groups are optionally and independently substituted by 1-5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 A group consisting of one or more of aryl and 5- to 10-membered heteroaryl groups.

6. The preparation method according to any one of claims 1-5, characterized in that, The R 3 R 4 and R 5 Each is independently selected from hydrogen, halogen, or C1-C6 alkyl; wherein the alkyl group is optionally substituted by 1-5 substituents, each of which is independently selected from deuterium, halogen, amino, or hydroxyl.

7. The preparation method according to any one of claims 1-6, characterized in that, The R 6 Selected from hydrogen, halogen, C1-C6 alkyl, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-NH2, -(C1-C6 alkylene)-NH-(5-10 heteroaryl), -(C1-C6 alkylene)-OC(=O)-(C1-C6 alkyl), -(C1-C6 alkylene)-NHC(=O)-(5-10 heteroaryl), -(C1-C6 alkylene)-NHC(=O)-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C2-C6 alkenyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(3-10 heterocyclic alkyl), -(C1-C6 alkylene)-(C6-C 10 aryl), -(C1-C6 alkylene)-(5-10 heteroaryl), -(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-(3- to 10-membered heterocycloalkyl), or -(C1-C6 alkylene)-O-(C6-C 10 Aryl); wherein the alkylene, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally and independently substituted by 1 to 5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C. 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, or 5-10 heteroaryl; optionally, the R 6 Selected from hydrogen, halogen, C1-C6 alkyl, -methylene-OH, -methylene-OC(=O)-(C1-C6 alkyl), -methylene-NHC(=O)-(5-10 heteroaryl), -methylene-NH-(5-10 heteroaryl), -methylene-NHC(=O)-(C1-C6 alkyl), -methylene-(C6-C 10 aryl), or -methylene- (5- to 10-membered heteroaryl); wherein, the alkyl, methylene, aryl, and heteroaryl groups are optionally and independently substituted by 1 to 5 substituents in each occurrence, each substituent being independently selected from deuterium, halogen, amino, hydroxyl, =O, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 A group consisting of one or more of aryl and 5- to 10-membered heteroaryl groups.

8. The preparation method according to any one of claims 1-7, characterized in that, The compound of formula I includes:

9. The preparation method according to any one of claims 1-8, characterized in that, The compound of formula II includes:

10. The preparation method according to any one of claims 1-9, characterized in that, The molar ratio of the compound of formula I to the compound of formula II is 1:(1 to 10).

11. The preparation method according to any one of claims 1-10, characterized in that, The molar ratio of the compound of formula I to the compound of formula II is 1:(1.5 to 5).

12. The preparation method according to any one of claims 1-11, characterized in that, The molar ratio of the compound of Formula I to the catalyst is 1:(0.01-2); optionally, the molar ratio of the compound of Formula I to the catalyst is 1:(0.1-1.5).

13. The preparation method according to any one of claims 1-12, characterized in that, The reaction temperature is 10–90°C; optionally, the reaction temperature is 40–80°C.

14. The preparation method according to any one of claims 1-13, characterized in that, The preparation method includes the following steps: mixing compound of formula I, compound of formula II, catalyst and solvent, and synthesizing oxazolidinone compounds under the catalysis of the catalyst.

15. The preparation method according to claim 14, characterized in that, The solvent includes one or more of tetrahydrofuran, acetonitrile, acetone, isopropyl acetate, isopropanol, ethanol, tert-butanol, tert-amyl alcohol, ethylene glycol, isobutanol, and N,N-dimethylformamide.

16. The preparation method according to claim 14 or 15, characterized in that, The mass-to-volume ratio of the compound of Formula I to the solvent is 1 g:(0.5-20) mL; optionally, the mass-to-volume ratio of the compound of Formula I to the solvent is 1 g:(1-10) mL.

17. The preparation method according to any one of claims 1-16, characterized in that, The general reaction formula for the preparation method is as follows: Among them, R 1 R 2 R 3 R 4 R 5 and R 6 As described in any one of claims 1-9.

18. The preparation method according to any one of claims 1-17, characterized in that, The general reaction formula for the preparation method is as follows: Among them, R 2 and R 6 As described in any one of claims 1-9; R 1a R 1b R 1d and R 1e Each is independently selected from hydrogen, halogen, or C1-C6 alkyl; R 1c Selected from 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl, -(5-10-membered heteroaryl)-(5-10-membered heteroaryl), or -N(Bn)2; wherein, each of the heteroaryl, heterocyclic alkyl, and heteroaryl groups is optionally and independently substituted by 1-5 substituents in each occurrence, each of the substituents being independently selected from halogens, =O, C1-C6 alkyl groups, or hydroxyl groups.

19. The preparation method according to claim 18, characterized in that, The general reaction formula for the preparation method is as follows:

20. The preparation method according to any one of claims 1-19, characterized in that, The non-alkaline lithium salt includes one or more of lithium bromide, lithium chloride, lithium iodide, lithium carbonate, lithium citrate, and lithium acetate; optionally, the quaternary ammonium salt includes one or more of tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, and methyltrioctylammonium chloride.

21. Use of a non-basic lithium salt and / or quaternary ammonium salt as a catalyst in the synthesis of oxazolidinone compounds.

22. The use according to claim 21, characterized in that, The non-alkaline lithium salt includes one or more of lithium bromide, lithium chloride, lithium iodide, lithium carbonate, lithium citrate, and lithium acetate; optionally, the quaternary ammonium salt includes one or more of tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, and methyltrioctylammonium chloride.

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