Method for preparing acyl chloride compound containing pyrimidine structure and use thereof

Abstract

The present application provides a method for preparing an acyl chloride compound containing a pyrimidine structure and the use thereof. The present application further provides a preparation method for an intermediate used therein or a salt thereof and the use thereof. The preparation method of the present application features readily available raw materials, mild reaction conditions, simple operation, and a high product purity, and is suitable for scalable synthesis.

Description

A method for preparing an acyl chloride compound containing a pyrimidine structure and its uses

[0001] This application claims priority to Chinese patent applications filed on January 7, 2025 (2025), 2025100208582, June 12, 2025 (2025), and August 4, 2025 (2025), 2025110820683 (2025). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This application belongs to the field of medicinal chemistry. Specifically, this application relates to a method for preparing an acyl chloride compound containing a pyrimidine structure and its use, and also provides a method for preparing the intermediate used or its salt and its use. Background Technology

[0003] Amide bonds are important components of bioactive molecules and have attracted widespread attention due to their unique structure and properties; amide groups are present in numerous drug molecules. Of the 37 new drugs approved by the FDA in 2022, 11 are small molecules containing at least one amide bond. In addition, 19 large molecule new drugs were approved for marketing, some of which have peptide structures and therefore also contain one or more amide bonds.

[0004] With the continuous development of organic chemistry, the methods for synthesizing amide bonds have become increasingly diverse, such as the acyl chloride method, acid anhydride method, condensation agent method, and amine ester exchange method. Among them, the acyl chloride method has advantages such as fast reaction speed, high conversion rate, simple purification, good atom economy, and low cost. Currently, linkers synthesized based on acyl chloride are used in multiple ADCs (antibody-drug conjugates) (WO2022170971A1), and have extremely wide applications in drug synthesis reactions.

[0005] The most common method for preparing acyl chlorides is the reaction of carboxylic acids with chlorinating reagents. Generally, carboxylic acids are obtained by hydrolysis of the ester group under alkaline conditions. This process has several drawbacks. First, it requires two chemical steps (hydrolysis and chlorination) to produce acyl chlorides. Industrial production involves numerous equipment steps, high energy consumption, and the generation of large amounts of waste liquid, resulting in high costs and an unfriendly environment. Second, because the hydrolysis reaction must be carried out in water, the resulting carboxylic acid contains a large amount of water, and the reaction to form acyl chlorides requires extremely high moisture content, making the drying of carboxylic acids quite difficult. Third, when the molecule contains a base-sensitive group (such as pyrimidine methanesulfonyl), it is difficult to obtain carboxylic acids through simple steps, requiring more reactions (CN109438364).

[0006] Developing a method for synthesizing acyl chlorides that is short in reaction steps, simple in operation, low in cost, low in pollution, and has a wide range of applications is of great importance. This invention uses carboxylic esters as substrates to obtain acyl chlorides through a one-step reaction. The reaction conditions are mild, the operation is simple, and the product has high purity, making it suitable for scale-up synthesis. Summary of the Invention

[0007] This application provides a method for preparing a compound of formula I, a method for preparing the intermediate used therein or its salt, and the uses of the intermediate or its salt. The preparation method described in this application involves readily available raw materials, is simple to operate, produces a product with high purity, and is suitable for large-scale synthesis.

[0008] On one hand, this application provides a method for preparing a compound of formula II, comprising the following steps: reacting a compound of formula A with a chlorinating reagent to obtain a compound of formula II.

[0009] Where R is C 1-6 Alkyl groups, wherein the alkyl group may be substituted with one or more of the following substituents: hydrogen, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, aryl, heteroaryl, C 3-10 Cycloalkyl and 4-20 membered heterocyclic groups, which may be the same or different when there are multiple substituents;

[0010] X is selected from -SR 1 -S(O)2-R 1 The R mentioned above 1 Selected from C 1-6 Alkyl, C3-C7 cycloalkyl;

[0011] n is selected from any integer from 1 to 3, with n preferably being 1.

[0012] In some implementations, R is tert-butyl.

[0013] In some implementations, X is selected from -S(O)2-R 1 .

[0014] In some implementations, the R 1 Selected from C 1-6 Alkyl groups, such as methyl groups.

[0015] In some embodiments, the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, and phosphorus pentachloride.

[0016] In some embodiments, under conditions in the presence or absence of a protic acid, compound A reacts with a chlorinating reagent to yield compound II.

[0017] In some embodiments, the reaction is carried out in the absence of a protic acid, whereby compound A reacts with a chlorinating reagent to give compound II.

[0018] In some embodiments, the reaction is carried out in the absence of a protic acid, in the presence of a solvent, where compound A reacts with a chlorinating reagent to give compound II.

[0019] On one hand, this application provides a method for preparing a compound of formula I, comprising the following steps: reacting a compound of formula a with a chlorinating reagent to obtain a compound of formula I.

[0020] in,

[0021] R is C 1-6 Alkyl groups, wherein the alkyl group may be substituted with one or more of the following substituents: hydrogen, halogen, C1-6 alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Alkoxy, aryl, heteroaryl, C 3-10 Cycloalkyl and 4-20 membered heterocyclic groups, which may be the same or different when there are multiple substituents.

[0022] In some implementations, R is preferably tert-butyl.

[0023] In some embodiments, the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, and phosphorus pentachloride.

[0024] In some embodiments, the compound of formula a reacts with a chlorination reagent to yield the compound of formula I, with or without a protic acid.

[0025] In some embodiments, the reaction is carried out in the absence of a protic acid, whereby the compound of formula a reacts with a chlorination reagent to give the compound of formula I.

[0026] In some embodiments, the reaction is carried out in the absence of a protic acid, in the presence of a solvent, whereby compound a reacts with a chlorinating reagent to give compound I.

[0027] In some embodiments, this application provides a method for preparing a compound of formula I, comprising the following steps: reacting a compound of formula a-1 with a chlorination reagent to obtain a compound of formula I.

[0028] In some embodiments, the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, and phosphorus pentachloride.

[0029] In some embodiments, the chlorinating agent is thionyl chloride.

[0030] In some embodiments, the compound of formula a-1 is reacted with a chlorination reagent to yield the compound of formula I, with or without a protic acid.

[0031] In some embodiments, the reaction is carried out in the absence of a protic acid, whereby the compound of formula a-1 reacts with a chlorinating reagent to give the compound of formula I.

[0032] In some embodiments, the reaction is carried out in the absence of a protic acid, in the presence of a solvent, where the compound of formula a-1 reacts with a chlorinating reagent to give the compound of formula I.

[0033] In some embodiments, the molar ratio of the compound of formula A (or compound a or compound a-1) to the chlorinating agent is selected from 1:1 to 1:50, for example 1:1 to 1:22, preferably 1:1.5 to 1:11, more preferably 1:1.5 to 1:3, for example 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10 and 1:11.

[0034] In some embodiments, the mass-to-volume ratio of the compound of formula A (or compound of formula a or compound a-1) to the selected solvent is selected from 1:4 to 1:10 g / mL, preferably 1:5 to 1:10 g / mL, for example 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 and 1:10 g / mL.

[0035] In some embodiments, in the preparation method of the compound of formula II or the compound of formula I, the solvent is selected from organic solvents or water, or two or more organic solvents mixed in any proportion, or organic solvents and water mixed in any proportion.

[0036] In some embodiments, in the method for preparing the compound of formula II or the compound of formula I, the solvent is selected from organic solvents, or two or more organic solvents mixed in any proportion.

[0037] In some embodiments, in the preparation method of the compound of formula II or the compound of formula I, the solvent is selected from organic solvents, or organic solvents mixed with water in any proportion.

[0038] In some embodiments, in the preparation method of the compound of formula II or formula I, the water content in the organic solvent is not greater than 50 ppm.

[0039] In some embodiments, in the preparation method of the compound of formula II or the compound of formula I, when the solvent is an organic solvent mixed with water in any proportion, the organic solvent is selected from one or more of haloalkanes, ether solvents, nitrile solvents and aromatic hydrocarbon solvents mixed in any proportion; preferably, it is an ether solvent.

[0040] In some embodiments, in the preparation method of the compound of formula II or the compound of formula I, when the solvent is an organic solvent mixed with water in any proportion, the organic solvent is selected from one or more of 1,4-dioxane, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile and toluene in any proportion; preferably 1,4-dioxane.

[0041] In some embodiments, when the solvent is an organic solvent mixed with water, the volume ratio of the organic solvent to water is 1:0.05-1:0.2, for example, 1:0.1.

[0042] In some embodiments, in the preparation method of the compound of formula II or the compound of formula I, the solvent is selected from one or more of 1,4-dioxane, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, and toluene, mixed in any proportion.

[0043] In some embodiments, in the method for preparing the compound of formula II or formula I, the solvent is selected from acetonitrile, dichloromethane / acetonitrile, trichloromethane / acetonitrile, and tetrahydrofuran / acetonitrile.

[0044] In some embodiments, the solvent in the preparation method of the compound of formula II or formula I is acetonitrile.

[0045] In some embodiments, the water content in the reaction system is not greater than 50 ppm in the preparation method of the compound of formula II or the compound of formula I.

[0046] In some embodiments, in the method for preparing the compound of formula II or formula I, when the solvent is selected from organic solvents, the organic solvent is a nitrile solvent; preferably acetonitrile.

[0047] In some embodiments, the reaction temperature in the preparation method of the compound of formula II or the compound of formula I is selected from 25-120°C; for example 25-85°C; preferably 40-60°C; preferably 50°C, for example 25°C, 30°C, 40°C, 50°C and 60°C.

[0048] In some embodiments, the reaction progress in the preparation method of the compound of formula II or formula I can be monitored according to conventional detection methods in the art (e.g., HPLC, TLC, or GC), and the reaction endpoint is generally taken as the disappearance of the starting material. For example, the reaction time is selected from 0.5-4 h, such as 1-4 h, preferably 1-2 h, such as 0.5 h, 1 h, 2 h, 3 h, and 4 h.

[0049] In some embodiments, the compound of formula a-1 is reacted with thionyl chloride in acetonitrile to give the compound of formula I, wherein the molar ratio of the compound of formula a-1 to thionyl chloride is selected from 1:1.5 to 1:11 (preferably 1:1.5 to 1:3), the mass-volume ratio of the compound of formula a-1 to acetonitrile is selected from 1:4 to 1:10 g / mL (preferably 1:5 to 1:10 g / mL), and the reaction temperature is selected from 40 to 60 °C (preferably 50 °C).

[0050] In some embodiments, the preparation method of the compound of formula II or formula I further includes a post-processing step, specifically a solvent removal step. Preferably, the post-processing step is only solvent removal.

[0051] In some embodiments, the reaction is carried out in the presence of a protic acid, whereby the compound of formula a-1 reacts with a chlorinating reagent to give the compound of formula I.

[0052] In some embodiments, the reaction is carried out in the presence of a protic acid, in solvent-free conditions, whereby the compound of formula a-1 reacts with a chlorinating reagent to give the compound of formula I.

[0053] In some embodiments, the protic acid is selected from HCl, HBr, sulfuric acid, dichloroacetic acid, and trifluoroacetic acid. For example, HCl, and concentrated hydrochloric acid.

[0054] On the other hand, this application provides a method for preparing a compound of formula a-1 (method 1), wherein compound a-1-1 and compound a-1-2 are coupled together to obtain compound a-1.

[0055] In some embodiments, compound a-1-1 and compound a-1-2 are coupled to obtain compound a-1 via a coupling reaction in the presence of a palladium catalyst, and / or a copper catalyst, and / or a base.

[0056] In some embodiments, compound a-1-1 and compound a-1-2 are coupled via a Sonogashira reaction to yield compound a-1, in the presence of a palladium catalyst, a copper catalyst, and a base.

[0057] In some embodiments, the palladium catalyst is selected from Pd(PPh3)4, Pd(OAc)2, Pd(PPh3)2Cl2 and Pd2(dba)3.

[0058] In some embodiments, the palladium catalyst is Pd(PPh3)2Cl2.

[0059] In some embodiments, the molar ratio of the compound of formula a-1-1 to the palladium catalyst is selected from 1:0.01 to 1:0.5, for example 1:0.1.

[0060] In some embodiments, the copper catalyst is selected from CuI, CuBr, and CuCl.

[0061] In some embodiments, the copper catalyst is CuI.

[0062] In some embodiments, the molar ratio of the compound of formula a-1-1 to the copper catalyst is selected from 1:0.01 to 1:0.5, for example 1:0.1.

[0063] In some embodiments, the base is selected from triethylamine, N,N-diisopropylethylamine, DBU, potassium carbonate, and cesium carbonate.

[0064] In some embodiments, the base is triethylamine.

[0065] In some embodiments, the mass-to-volume ratio of the compound of formula a-1-1 to the base is selected from 1:1 to 1:5 g / mL; for example, 1:1.69 g / mL.

[0066] On the other hand, this application provides a method for preparing a compound of formula a-1 (method two), which includes the following steps:

[0067] (1) Compound a-1-3 and compound a-1-2 are coupled together to obtain compound a-1-4;

[0068] (2) Compound a-1-4 is obtained by oxidation reaction of an oxidant to obtain compound a-1.

[0069] In some embodiments, in step (1), the compounds of formula a-1-3 and a-1-2 are coupled to obtain the compound of formula a-1-4 in the presence of a palladium catalyst, and / or a copper catalyst, and / or a base.

[0070] In some embodiments, in step (1), the compounds of formula a-1-3 and a-1-2 are coupled via a Sonogashira reaction to yield the compound of formula a-1-4 in the presence of a palladium catalyst, a copper catalyst and a base.

[0071] In some embodiments, in step (1), the palladium catalyst is selected from Pd(PPh3)4, Pd(OAc)2, Pd(PPh3)2Cl2 and Pd2(dba)3.

[0072] In some embodiments, the palladium catalyst is Pd(PPh3)2Cl2.

[0073] In some embodiments, in step (1), the molar ratio of the compound of formula a-1-3 to the palladium catalyst is selected from 1:0.01 to 1:0.5, for example 1:0.03.

[0074] In some embodiments, in step (1), the copper catalyst is selected from CuI, CuBr and CuCl.

[0075] In some embodiments, in step (1), the copper catalyst is CuI.

[0076] In some embodiments, in step (1), the molar ratio of the compound of formula a-1-3 to the copper catalyst is selected from 1:0.01 to 1:0.5, for example 1:0.02.

[0077] In some embodiments, in step (1), the base is selected from triethylamine, N,N-diisopropylethylamine, DBU, potassium carbonate and cesium carbonate.

[0078] In some implementations, in step (1), the base is triethylamine.

[0079] In some embodiments, in step (1), the molar ratio of the compound of formula a-1-3 to the base is selected from 1:1 to 1:5, for example 1:4.

[0080] In some embodiments, in step (2), the oxidant is selected from hydrogen peroxide, sodium hypochlorite, m-chloroperoxybenzoic acid, and potassium persulfate complex salt. Sodium tungstate and sodium periodate.

[0081] In some embodiments, in step (2), the oxidant is a potassium persulfate complex salt.

[0082] In some embodiments, the above preparation method further includes a purification and separation step, wherein the purification and separation method includes, but is not limited to, recrystallization, column chromatography, distillation, and pulping.

[0083] In some embodiments, the compound of formula a-1-4 can be obtained by column chromatography or distillation purification.

[0084] On the other hand, this application provides the following compounds or salts thereof.

[0085] On the other hand, this application provides for the use of compounds of formula I as shown below.

[0086] On the other hand, this application provides the use of the following compounds in the preparation of linkers.

[0087] On the other hand, this application provides the use of the following compounds in the preparation of drug linker conjugates.

[0088] On the other hand, this application provides the use of the following compounds in the preparation of antibody-drug conjugates.

[0089] On the other hand, this application provides the following compounds,

[0090] Definitions and Terms

[0091] Unless otherwise stated, the terms and phrases used herein have the meanings listed below. Specific terms or phrases, unless otherwise defined, should not be considered uncertain or unclear, but should be interpreted in accordance with their meaning as commonly understood by those skilled in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0092] In this application, the compound of formula I was quenched with methanol to obtain the corresponding methyl ester (compound b-1) with the following structure:

[0093] The mass spectrometry and 1H NMR spectrometry information of compound b-1 are as follows:

[0094] LCMS(ESI)[M+H] + =283.0.

[0095] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,2H),3.93(s,3H),3.60(s,3H),2.52-2.45(m,4H),1.84-1.77(m,2H).

[0096] In this application, the singular form of a word includes its plural form unless otherwise stated or implied by the context. Therefore, references to singular terms and the words “the” and “the” generally include the plural form of the respective terms. The terms “comprising” and “including” should be interpreted as encompassing, not as excluding.

[0097] In this application, the term "C" 1-6 "Alkyl" refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, "C". 1-3 Alkyl or C 1-4 Alkyl, tert-butyl, etc., specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.

[0098] In this application, the term "C" 2-6 "Alkenyl" refers to a straight-chain, branched, or cyclic alkenyl group containing at least one double bond and having 2-6 carbon atoms, including, for example, "C". 2-4 Examples of these include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, etc.

[0099] In this application, the term "C" 2-6 "Alkyne group" refers to a straight-chain or branched alkynyl group containing at least one triple bond and having 2-6 carbon atoms, including, for example, "C". 2-4 Examples of "alkynyl" include, but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl, etc.

[0100] In this application, the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0101] In this application, the term "C" 1-6 "Alkoxy" refers to an alkyl group as defined above, which is attached to the parent molecule via an oxygen atom, including, for example, "C". 1-3 "alkoxy" or "C" 1-4 Alkoxy groups. Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy.

[0102] In this application, the term "aryl" refers to a monocyclic or polycyclic hydrocarbon group that has aromatic properties, such as C10. 6-10 Aryl. Specific examples include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthrene, etc. The "C" mentioned... 6-10 "Aryl" refers to an aryl group containing 6-10 ring atoms. The "C"... 6-10 "Aryl" refers to an aryl group containing 6-10 carbon atoms.

[0103] In this application, the term "heteroaryl" refers to an aromatic cyclic group wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom. Optionally, the ring atom (e.g., a carbon atom, nitrogen atom, or sulfur atom) in the cyclic structure may be oxidized. Specific examples include, but are not limited to, 5-10-membered heteroaryl, 5-6-membered heteroaryl, 5-10-membered nitrogen-containing heteroaryl, 6-10-membered oxygen-containing heteroaryl, 6-8-membered nitrogen-containing heteroaryl, 5-8-membered oxygen-containing heteroaryl, etc., such as furanyl, thiophene, pyrrole, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazole, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-Oxadiazolyl, pyridyl, 2-pyridoneyl, 4-pyridoneyl, pyrimidinyl, 1,4-dioxazadienyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl, azacycloheptatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl, etc. The bonds in the structural formulas indicated by tildes “~~” in this application are intended to represent cis or trans isomers, or mixtures of cis and trans isomers in any proportion.

[0104] In this application, the term "cycloalkyl" refers to a cyclic alkyl group containing 3-10 or 3-7 carbon atoms, including monocyclic, fused, spirocyclic, bridged, saturated, or partially saturated rings. Optionally, the carbon atoms in the cyclic structure may be substituted with oxygen. Examples include cyclopropane (i.e., cyclopropyl), cyclobutane (i.e., cyclobutyl), cyclopentane (i.e., cyclopentyl), and cyclohexyl.

[0105] In this application, the term "4-20 membered heterocyclic group" refers to a cyclic group containing 4-20 ring atoms (wherein at least one ring atom is a heteroatom, such as a carbon atom, nitrogen atom, or sulfur atom). "4-10 membered heterocyclic group" refers to a cyclic group containing 4-10 ring atoms (wherein at least one ring atom is a heteroatom, such as a carbon atom, nitrogen atom, or sulfur atom). The term "4-6 membered heterocyclic group" refers to a cyclic group containing 4-6 ring atoms (wherein at least one ring atom is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom). The term "3-6 membered heterocyclic group" refers to a cyclic group containing 3-6 ring atoms (wherein at least one ring atom is a heteroatom, such as a carbon atom, nitrogen atom, or sulfur atom). Optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be oxidized. "4-8 membered heterocyclic groups" include, for example, "4-8 membered nitrogen-containing heterocyclic groups", "4-8 membered oxygen-containing heterocyclic groups", "4-7 membered heterocyclic groups", "4-7 membered oxygen-containing heterocyclic groups", "4-7 membered heterocyclic groups", "4-6 membered heterocyclic groups", "5-7 membered heterocyclic groups", "5-6 membered heterocyclic groups", and "5-6 membered nitrogen-containing heterocyclic groups", including but not limited to oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, etc.

[0106] In this application, the term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0107] In this application, the term "anhydrous" refers to a solvent that contains no or substantially no water, and water cannot be detected.

[0108] In this application, the water content in the anhydrous solvent is ≤50ppm, and the anhydrous solvent is anhydrous acetonitrile.

[0109] As used herein, the term “one or more” means one or more under reasonable conditions, such as two, three, four, five, six, seven, eight, nine, ten, or twenty.

[0110] In this application, the term "two or more" means two or more types, such as two, three, or four.

[0111] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0112] In this application, if both the name and structural formula of a compound are given, and the two are inconsistent, the structure of the compound shall prevail, unless the context indicates that the structure of the compound is incorrect while the name is correct. Beneficial effects

[0113] The preparation method of this application can obtain the corresponding acyl chloride compound from the carboxylic acid ester in one step, which has the following advantages:

[0114] 1. Using esters as raw materials, acyl chlorides can be obtained in a single step, reducing the number of synthesis steps and energy consumption. Specifically, the preparation method provided by this invention uses a specific substrate (R is tert-butyl), allowing the corresponding acyl chloride compound to be obtained from a carboxylic acid ester without hydrolysis to a carboxylic acid, but through a single step. However, in the prior art, when R is methyl, two chemical reactions (hydrolysis and chlorination) are required to obtain the acyl chloride compound. Therefore, the method of this invention reduces organic synthesis steps and lowers industrial pollution and energy consumption.

[0115] 2. The method of the present invention does not require the addition of water during the reaction process, which greatly enhances the safety and scalability of the reaction;

[0116] 3. The method of this invention has a high conversion rate of acyl chloride (up to 99%);

[0117] 4. The chlorination reagent used in the method of this invention has a high utilization rate, reducing industrial pollution;

[0118] Meanwhile, the product obtained by the method of this invention has extremely high purity and yield, the raw materials are readily available, purification is simple, the reaction conditions are mild, and the operation is convenient, making it suitable for industrial production. Detailed Implementation

[0119] All features or steps in any method or process claimed in this specification may be combined in any way, except for mutually exclusive features and / or steps.

[0120] Unless otherwise stated, any feature claimed in this specification may be replaced by other equivalent or similar features. That is, unless otherwise stated, each feature is merely one example of a series of equivalent or similar features.

[0121] The implementation conditions used in the examples can be further adjusted according to specific requirements. Implementation conditions not specified are usually those in routine experiments.

[0122] In the following examples, all chemical reagents used were commercially available.

[0123] In an exemplary embodiment of this application, the compound of formula I is synthesized using the following route:

[0124] Route 1:

[0125] Route 2:

[0126] Example 1 Synthesis of tert-butyl 6-(2-(methanesulfonyl)pyrimidin-5-yl)-5-hexynate (compound a-1)

[0127] tert-butyl 6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynoate

[0128] In a 100 mL single-necked flask, compound a-1-1 (3.54 g, 15.0 mmol), compound a-1-2 (3.25 g, 19.3 mmol), bis(triphenylphosphine)palladium dichloride (1.05 g, 1.5 mmol), cuprous iodide (0.30 g, 1.5 mmol), triethylamine (6 mL), and N,N-dimethylformamide (30 mL) were added sequentially, purging three times with argon. The reaction was heated at 65 °C for 6 hours. Ethyl acetate (200 mL) was added, followed by washing with water (50 mL × 3), then washing with saturated brine (50 mL × 3), and drying the organic phase with anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE:EA = 70:30) to obtain 3.05 g of compound a-1.

[0129] LC-MS(ESI)[M+H] + =325.1.

[0130] 1 H NMR (400MHz, CDCl3) δ8.84 (s, 2H), 3.33 (s, 3H), 2.55 (t, J = 7.1Hz, 2H), 2.38 (t, J = 7.3Hz, 2H), 1.95-1.88 (m, 2H), 1.44 (s, 9H).

[0131] Example 2 Synthesis of 6-(2-(methanesulfonyl)pyrimidin-5-yl)-5-hexyneyl chloride (compound of formula I)

[0132] 6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynoyl chloride

[0133] Filtering by criteria:

[0134] The general operation description is as follows:

[0135] General Procedure 1: Add a chlorination reagent to compound a-1 and react at different temperatures. After the reaction is complete, take a sample of the reaction solution, quench it with methanol, and detect the reaction conversion rate by HPLC. Concentrate the remaining reaction solution to dryness.

[0136] For the chlorination reaction, detailed conditions were screened, including the amount of chlorination reagent and the reaction temperature. The specific results are shown in Table 1 (where v represents the mass-volume ratio of a-1 to the chlorination reagent (g / mL)).

[0137] Table 1 Conditional Filtering

[0138] As shown in Table 1, when using only thionyl chloride as the chlorination reagent for the reaction (pure reaction, solvent-free), it was found that compound a-1 could not be completely converted to compound 1 under various conditions (including different equivalences and temperatures). Even under optimal conditions, 14.4% of compound a-1 remained unreacted.

[0139] General Procedure 2: Dissolve compound a-1 in a solvent, add a chlorination reagent, and react at different temperatures. After the reaction is complete, take a sample of the reaction solution, quench it with methanol, and detect the reaction conversion rate by HPLC. Concentrate the remaining reaction solution to dryness.

[0140] For the chlorination reaction, detailed conditions were screened based on solvent type, solvent volume, amount of chlorination reagent, and reaction temperature. The specific results are shown in Tables 2 and 3 (where v represents the mass-volume ratio of a-1 to solvent (g / mL), and eq represents the molar ratio of a-1 to chlorination reagent).

[0141] Table 2 Solvent Screening

[0142] As shown in Table 2, different anhydrous solvents were screened. When acetonitrile was used as the solvent, the conversion rate of compound 1 was 98.72%. In contrast, when 1,4-dioxane, tetrahydrofuran, and dichloromethane were used as solvents, the conversion rate of compound 1 was approximately 30%, and when toluene was used as the solvent, the conversion rate was less than 1%.

[0143] Table 3 Conditional Filtering

[0144] As shown in Table 3, further screening was conducted on reaction temperature, reaction time, and the amount of chlorinating reagent. The results showed that the highest conversion rate, reaching 99.37%, was achieved using acetonitrile as solvent (5 v), thionyl chloride as chlorinating reagent (3 eq), a reaction temperature of 50 °C, and a reaction time of 1 h. In contrast, the conversion rate was less than 5% when DCM was used as the solvent.

[0145] Mass production synthesis:

[0146] Method 1: In a 250 mL single-neck flask, dissolve compound a-1 (5.65 g, 17.4 mmol) in ultradry acetonitrile (63 mL, water not detected), add thionyl chloride (6.22 g, 52.2 mmol), and stir at 50 °C for 1.5 hours. Take the reaction solution, quench it with methanol. HPLC monitoring shows that the reaction conversion rate is greater than 99%. Stop the reaction, and concentrate the reaction solution to dryness. Add ultradry acetonitrile (31.4 mL) and concentrate to dryness. Repeat this operation three times to obtain 5.2 g of the compound of formula I (yield calculated according to 100%, for the next reaction).

[0147] Method 2: In a 250 mL single-neck flask, dissolve compound a-1 (5.65 g, 17.4 mmol) in ultradry acetonitrile (32 mL, water not detected), add thionyl chloride (6.22 g, 52.2 mmol), and stir at 50 °C for 1.5 hours. Take the reaction solution, quench it with methanol. HPLC monitoring shows that the reaction conversion rate is greater than 99%. Stop the reaction, and concentrate the reaction solution to dryness. Add ultradry acetonitrile (31.4 mL) and concentrate to dryness. Repeat this operation three times to obtain 5.2 g of the compound of formula I (yield calculated according to 100%, for the next reaction).

[0148] Method 3: Under an ice bath, in a 50 mL reaction flask, dissolve compound a-1 (0.5 g, 1.5 mmol) in 1,4-dioxane (2.5 mL), add thionyl chloride (2.3 mL), slowly add water (0.22 mL), and stir at room temperature for 0.5 hours. Take the reaction solution, quench it with methanol. HPLC monitoring shows that the reaction conversion rate is greater than 99%. Stop the reaction, add toluene (10 mL), and concentrate to dryness. Repeat this operation once. Obtain 0.51 g of the compound of formula I.

[0149] 1 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 2H), 3.32 (s, 3H), 3.07 (t, J = 7.1 Hz, 2H), 2.60 (t, J = 6.9 Hz, 2H), 2.07 - 2.00 (m, 3H).

[0150] Example 3 Synthesis of N-((10S,13S)-10-(4-(dipropylamino)butyl)-1,1,1-trifluoro-14-methyl-6,9,12-trioxo-3-oxa-5,8,11-triaza-15-alkyl-13-yl)-6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynamide (Compound of formula b-3)

[0151] N-((10S,13S)-10-(4-(dipropylamino)butyl)-1,1,1-trifluoro-14-methyl-6,9,12-trioxo-3-oxa-5,8,11-triazapentadecan-13-yl)-6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynamide

[0152] Under the condition of 30 °C, dissolve compound b-2 (7.88 g, 15.83 mmol) in acetonitrile (40 ml), and add N,N-diisopropylethylamine (0.41 g, 3.17 mmol). Dropwise add the acetonitrile solution (20 ml) of compound I, and stir the reaction at 30 °C for 1 h. After the reaction is completed, add 2-methyltetrahydrofuran (420 ml), stir to precipitate a solid, and dry the filter cake to obtain 10.3 g of the hydrochloride of the title compound b-3.

[0153] LC-MS(ESI)[M+H] + = 748.4.

[0154] 1 H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.13(s,2H),8.85(t,J = 6.8Hz,1H),8.28(t,J = 5.8Hz,1H),8.13(d,J = 7.3Hz,1H),7.98(d,J = 8.5Hz,1H),4.75 - 4.56(m,2H),4.24(q,J = 7.2Hz,1H),4.20 - 4.13(m,1H),4.00(q,J = 9.4Hz,2H),3.74(d,J = 6.3Hz,2H),3.41(s,3H),3.07 - 2.87(m,6H),2.55(t,J = 7.1Hz,2H),2.46 - 2.28(m,2H),2.04 - 1.91(m,1H),1.86 - 1.75(m,2H),1.73 - 1.52(m,8H),1.39 - 1.23(m,2H),0.89(t,J = 7.3Hz,6H),0.84(t,J = 7.1Hz,6H).

[0155] Example 4 Synthesis of 6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynoyl chloride (Compound I)

[0156] 6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynoyl chloride

[0157] In a 100 mL single-neck flask, dissolve compound a-1 (1.61 g, 5.0 mmol) in thionyl chloride (7 mL), add concentrated hydrochloric acid (concentration 12 M, 0.4 mL), and stir at room temperature for 16 hours. Take the reaction solution, add methanol to quench it. HPLC monitoring shows that the reaction conversion rate is 96%. Stop the reaction, add toluene (10 mL), and concentrate to dryness. Repeat this operation once. 1.6 g of compound of formula I is obtained.

[0158] 1 H NMR (400 MHz, CDCl3) δ 8.84 (s, 2H), 3.32 (s, 3H), 3.07 (t, J = 7.1 Hz, 2H), 2.60 (t, J = 6.9 Hz, 2H), 2.07 - 2.00 (m, 3H).

[0159] Example 5 Synthesis of tert-butyl 6-(2-(methylthio)pyrimidin-5-yl)hex-5-ynoate (compound of formula a-1-4)

[0160] tert-butyl 6-(2-(methylthio)pyrimidin-5-yl)hex-5-ynoate

[0161] In a 250 mL three-neck flask, dissolve compound a-1-3 (10 g, 48.8 mmol), compound a-1-2 (9.8 g, 58.5 mmol), copper(I) iodide (0.22 g), and bis(triphenylphosphine)palladium(II) dichloride (0.93 g) in DMF (50 mL). Under nitrogen protection, add triethylamine (19.7 g) dropwise and react at 90 °C for 1 hour. When the reaction system cools to room temperature, add n-heptane (100 mL) and 20% aqueous ammonium chloride solution (100 mL), stir for 0.5 hour, separate the layers, wash the organic layer with 20% aqueous ammonium chloride solution (100 mL) again, dry and concentrate the organic layer, and purify by silica gel column chromatography (EA:PE = 10:90) to obtain 12.1 g of compound of formula a-1-4.

[0162] LC-MS (ESI) [M+H] + = 293.2.

[0163] 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 2H), 2.55 (s, 3H), 2.48 (t, J = 7.1 Hz, 2H), 2.38 (t, J = 7.4 Hz, 2H), 1.94–1.83 (m, 2H), 1.45 (s, 9H).

[0164] Example 6 Synthesis of tert-butyl 6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynoate (compound of formula a-1)

[0165] 6-(2-(甲基磺酰基)嘧啶-5-基)己-5-炔酸叔丁酯

[0166] Under nitrogen protection, at room temperature, potassium peroxymonosulfate compound salt (26.50 g) and water (42 mL) were added to a 150 mL three-necked flask, and a THF solution of compound a-1-4 (0.1 g / mL, 42 mL) was added dropwise. The mixture was stirred for 4 h. The insoluble matter was filtered off, and the filtrate was extracted with ethyl acetate (100 mL). The organic phase was washed successively with 1% aqueous sodium bisulfite solution (50 mL), 2% aqueous sodium bicarbonate solution (50 mL), and water (100 mL). The organic phase was dried, concentrated, crystallized, filtered, and the filter cake was dried to obtain 3.70 g of compound a-1.

[0167] LC-MS(ESI)[M+H] + = 325.1.

[0168] 1 H NMR(400MHz,CDCl3)δ8.84(s,2H),3.33(s,3H),2.55(t,J = 7.1Hz,2H),2.38(t,J = 7.3Hz,2H),1.95 - 1.88(m,2H),1.44(s,9H).

[0169] Example 7 Synthesis of 4-nitrophenyl 6-(2-(methylsulfonyl)pyrimidin-5-yl)-5-hexynoate (Compound of formula c-1)

[0170] 4-硝基苯基6-(2-(甲磺酰基)嘧啶-5-基)-5-己炔酸酯

[0171] The compound of formula I (880 mg, 3.07 mmol) was dissolved in dichloromethane (5.9 mL), and 4-nitrophenol (390 mg, 2.80 mmol) and triethylamine (425 mg, 4.20 mmol) were added at 0 - 5 °C. The reaction was carried out at 25 °C for 2 h. After the reaction, water (5 mL) was added and stirred for 5 min. The organic phase was washed once with dilute hydrochloric acid (5 mL), 5% aqueous NaHCO3 solution (4 mL), and saturated brine (3 mL) respectively. The organic phase was concentrated under reduced pressure to dryness to obtain the title compound, 962 mg.

[0172] LCMS(ESI)[M+H] + = 390.09.

[0173] 1 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 2H), 8.34–8.23 (m, 2H), 7.53–7.40 (m, 2H), 3.41 (s, 3H), 2.85 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.1 Hz, 2H), 2.06–1.93 (m, 2H).

[0174] Example 8 Synthesis of 1,3-dioxoisoindolin-2-yl 6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynoate (Compound of Formula c-2)

[0175] 1,3 - 二氧代异吲哚啉 - 2 - 基 6 - (2 - (甲磺酰基)嘧啶 - 5 - 基)己 - 5 - 炔酸酯

[0176] Dissolve N - hydroxyphthalimide (500 mg, 3.07 mmol) in dichloromethane (10 mL). Add triethylamine (425 mg, 4.20 mmol) and a solution of Compound of Formula I (880 mg, 3.07 mmol) in DCM (3 mL) at 0 - 5 °C, and react at 25 °C for 2 h. After the reaction, add water (5 mL). The organic phase is washed once with dilute hydrochloric acid (5 mL), 5% aqueous NaHCO3 solution (4 mL), and saturated brine (3 mL) respectively. The organic phase is concentrated under reduced pressure to dryness to obtain the title compound, 1.1 g.

[0177] LCMS (ESI) [M + H] + = 414.12.

[0178] 1 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 2H), 8.02–7.88 (m, 4H), 3.42 (s, 3H), 2.98 (t, J = 7.3 Hz, 2H), 2.72 (t, J = 7.1 Hz, 2H), 2.08–1.94 (m, 2H).

[0179] Example 9 Synthesis of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynoate (Compound of Formula c-3)

[0180] 3H - [1,2,3]三唑并[4,5 - b]吡啶 - 3 - 基 6 - (2 - (甲磺酰基)嘧啶 - 5 - 基)己 - 5 - 炔酸酯

[0181] Dissolve N-hydroxy-7-azabenzotriazole (500 mg, 3.07 mmol) in dichloromethane (10 mL). Add triethylamine (425 mg, 4.20 mmol) and a solution of Compound I (880 mg, 3.07 mmol) in DCM (3 mL) at 0 - 5 °C, and react at 25 °C for 2 h. After the reaction, add water (5 mL). Wash the organic phase once with dilute hydrochloric acid (5 mL), 5% aqueous NaHCO₃ solution (4 mL), and saturated brine (3 mL) respectively. Concentrate the organic phase under reduced pressure to dryness to obtain the title compound, 900 mg.

[0182] LCMS(ESI)[M+H] + =386.13.

[0183] 1 H NMR(400MHz,DMSO-d6)δ9.13–9.09(m,2H),8.37–8.30(m,1H),8.06–7.96(m,1H),7.94–7.84(m,1H),7.75–7.69(m,0H),7.69–7.62(m,1H),7.59–7.50(m,1H),7.46–7.37(m,1H),3.41(s,3H),3.29(t,J=7.2Hz,1H),2.74(t,J=7.1Hz,1H).

[0184] Example 10 Synthesis of Pentafluorophenyl 6-(2-(methylsulfonyl)pyrimidin-5-yl)-5-hexynoate (Compound c-4)

[0185] Dissolve pentafluorophenol (565 mg, 3.07 mmol) in dichloromethane (10 mL). Add triethylamine (425 mg, 4.20 mmol) and a solution of Compound I (880 mg, 3.07 mmol) in dichloromethane (3 mL) at 0 - 5 °C, and react at 25 °C for 2 h. After the reaction, add water (5 mL). Wash the organic phase once with dilute hydrochloric acid (5 mL), 5% aqueous NaHCO₃ solution (4 mL), and saturated brine (3 mL) respectively. Concentrate the organic phase under reduced pressure to dryness to obtain the title compound, 1.15 g.

[0186] LCMS(ESI)[M+H] + =435.17.

[0187] 1 H NMR(400MHz,DMSO-d6)δ9.13(s,2H),3.41(s,3H),3.00(t,J=7.4Hz,2H),2.70(t,J=7.1Hz,2H),2.07–1.94(m,2H).

[0188] Example 11 Synthesis of N-((10S,13S)-10-(4-(dipropylamino)butyl)-1,1,1-trifluoro-14-methyl-6,9,12-trioxo-3-oxa-5,8,11-triazapentadecan-13-yl)-6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynamide (Compound of Formula b-3)

[0189] N-((10S,13S)-10-(4-(dipropylamino)butyl)-1,1,1-trifluoro-14-methyl-6,9,12-trioxo-3-oxa-5,8,11-triazapentadecan-13-yl)-6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynamide

[0190] Scheme 1:

[0191] Dissolve Compound b-2 (100 mg, 0.20 mmol) in DMF (1 mL), add Compound c-1 (86 mg, 0.22 mmol) and N,N-diisopropylethylamine (39 mg, 0.30 mmol) at 20 - 25 °C, and react for 1 h. The reaction solution was directly purified by preparative high performance liquid chromatography (acetonitrile: H2O containing 0.05% FA = 5% - 50%) to obtain the formate of Compound b-3, 125 mg.

[0192] LCMS(ESI)[M+H] + = 748.34.

[0193] Scheme 2:

[0194] Replace Compound c-1 in Scheme 1 with Compound c-2, and refer to the synthesis method of Scheme 1 to obtain the formate of Compound b-3, 81 mg.

[0195] LCMS(ESI)[M+H] + = 748.36.

[0196] Scheme 3:

[0197] Replace Compound c-1 in Scheme 1 with Compound c-3, and refer to the synthesis method of Scheme 1 to obtain the formate of Compound b-3, 63 mg.

[0198] LCMS(ESI)[M+H] + = 748.39.

[0199] Scheme 4:

[0200] Replace compound c-1 in Scheme 1 with compound c-4. Referring to the synthesis method of Scheme 1, the formate of compound b-3, 120 mg, was obtained.

[0201] LCMS(ESI)[M+H] + = 748.34.

[0202] The present invention is not limited to the foregoing specific embodiments. The present invention extends to any new feature or any new combination disclosed in this specification, as well as to any step of any new method or process disclosed or any new combination.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: reacting a compound of formula a-1 with a chlorination reagent in the presence or absence of a protic acid to obtain a compound of formula I. in, When the reaction is carried out in the absence of a protic acid, in the presence of a solvent, said solvent is selected from organic solvents, or organic solvents mixed with water in any proportion; When the solvent is an organic solvent, the organic solvent is a nitrile solvent.

2. The method for preparing the compound of formula I as described in claim 1, characterized in that, Choose one or more of the following conditions: (1) The chlorination reagent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride and phosphorus pentachloride; (2) The molar ratio of the compound of formula a-1 to the chlorinated reagent is selected from 1:1 to 1:50; (3) The mass-to-volume ratio of the compound of formula a-1 to the selected solvent is selected from 1:4 to 1:10 g / mL; (4) When the solvent is an organic solvent, the organic solvent is acetonitrile; (5) When the solvent is an organic solvent mixed with water, the organic solvent is selected from one or more of haloalkanes, ether solvents, nitrile solvents and aromatic hydrocarbon solvents, and mixed in any proportion; (6) When the solvent is a mixture of an organic solvent and water, the volume ratio of the organic solvent to water is 1:0.05-1:0.2; (7) The water content in the organic solvent is not greater than 50 ppm; (8) The reaction temperature is selected from 25-120℃; (9) The reaction time is selected from 0.5-4h; (10) When the reaction is carried out in the presence of a protic acid, the reaction is carried out under solvent-free conditions; (11) When the protic acid is present, the protic acid is selected from HCl, HBr, sulfuric acid, dichloroacetic acid and trifluoroacetic acid; (12) The preparation method of the compound of formula I also includes a post-processing step, specifically including a solvent removal step.

3. The method for preparing the compound of formula I as described in claim 1, characterized in that, Choose one or more of the following conditions: (1) The chlorination reagent is selected from thionyl chloride; (2) The molar ratio of the compound of formula a-1 to the chlorinated reagent is selected from 1:1 to 1:22, preferably 1:1.5 to 1:11, and more preferably 1:1.5 to 1:3; (3) The mass-to-volume ratio of the compound of formula a-1 to the selected solvent is selected from 1:5 to 1:10 g / mL; (4) When the solvent is an organic solvent and water mixed in any proportion, the organic solvent is selected from one or more of 1,4-dioxane, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile and toluene mixed in any proportion, preferably 1,4-dioxane; (5) The reaction temperature is selected from 25-85℃; preferably 40-60℃; (6) The reaction time is selected from 1-4h, preferably 1-2h; (7) When the protic acid is present, the protic acid is HCl, such as concentrated hydrochloric acid; (8) The preparation method of the compound of formula I further includes a post-treatment step, which only requires the removal of solvent.

4. The method for preparing the compound of formula I as described in claim 1, characterized in that, Choose one or more of the following conditions: (1) Under the condition that the protic acid is absent and the solvent is present, the compound of formula a-1 reacts with the chlorination reagent to obtain the compound of formula I; (2) The solvent is a nitrile solvent, preferably acetonitrile; (3) The water content in the reaction system shall not exceed 50 ppm.

5. The method for preparing the compound of formula I as described in claim 1, characterized in that, The method for preparing the compound of formula I further includes a method for preparing the compound of formula a-1, wherein the method for preparing the compound of formula a-1 is method one or method two: Method 1 includes the following steps: Compound a-1-1 and compound a-1-2 are coupled to obtain compound a-1. Method 2 includes the following steps: (1) Compound a-1-3 and compound a-1-2 are coupled together to obtain compound a-1-4; (2) Compound a-1-4 is oxidized by an oxidizing agent to obtain compound a-1; 6. The method for preparing the compound of formula I according to claim 1, characterized in that, Choose one or more of the following conditions: (1) In Method 1, under the action of a palladium catalyst, and / or a copper catalyst, and / or a base, compound a-1-1 and compound a-1-2 are coupled to obtain compound a-1; preferably, under the action of a palladium catalyst, a copper catalyst and a base, compound a-1-1 and compound a-1-2 are coupled to obtain compound a-1 via a Sonogashira coupling reaction. (2) In Method 1, the palladium catalyst is selected from Pd(PPh3)4, Pd(OAc)2, Pd(PPh3)2Cl2 and Pd2(dba)3; preferably Pd(PPh3)2Cl2; (3) In Method 1, the molar ratio of the compound of formula a-1-1 to the palladium catalyst is selected from 1:0.01 to 1:0.5; (4) In Method 1, the copper catalyst is selected from CuI, CuBr and CuCl, preferably CuI; (5) In Method 1, the molar ratio of the compound of formula a-1-1 to the copper catalyst is selected from 1:0.01 to 1:0.5; (6) In Method 1, the base is selected from triethylamine, N,N-diisopropylethylamine, DBU, potassium carbonate and cesium carbonate; preferably triethylamine; (7) In Method 1, the mass-to-volume ratio of the compound of formula a-1-1 to the base is selected from 1:1 to 1:5 g / mL; (8) In Method 2, in step (1), under the action of a palladium catalyst, and / or a copper catalyst, and / or a base, compound a-1-3 and compound a-1-2 are coupled to obtain compound a-1-4; preferably, in step (1), under the action of a palladium catalyst, a copper catalyst and a base, compound a-1-3 and compound a-1-2 are coupled to obtain compound a-1-4 via a Sonogashira coupling reaction; (9) In Method 2, in step (1), the palladium catalyst is selected from Pd(PPh3)4, Pd(OAc)2, Pd(PPh3)2Cl2 and Pd2(dba)3; preferably Pd(PPh3)2Cl2; (10) In Method 2, in step (1), the molar ratio of the compound of formula a-1-3 to the palladium catalyst is selected from 1:0.01 to 1:0.5; (11) In method two, in step (1), the copper catalyst is selected from CuI, CuBr and CuCl; preferably CuI; (12) In Method 2, in step (1), the molar ratio of the compound of formula a-1-3 to the copper catalyst is selected from 1:0.01 to 1:0.5; (13) In Method 2, in step (1), the base is selected from triethylamine, N,N-diisopropylethylamine, DBU, potassium carbonate and cesium carbonate; preferably triethylamine; (14) In Method 2, in step (1), the molar ratio of the compound of formula a-1-3 to the base is selected from 1:1 to 1:5; (15) In Method 2, in step (2), the oxidant is selected from hydrogen peroxide, sodium hypochlorite, m-chloroperoxybenzoic acid, and potassium persulfate complex salt. Sodium tungstate and sodium periodate; preferably potassium peroxymonosulfate compound salt.

7. A method for preparing a compound of formula a-1, characterized in that, The preparation method of the compound of formula a-1 is either method one or method two: Method 1 includes the following steps: Compound a-1-1 and compound a-1-2 are coupled to obtain compound a-1. Method 2 includes the following steps: (3) Compound a-1-3 and compound a-1-2 are coupled together to obtain compound a-1-4; (4) Compound a-1-4 is oxidized by an oxidizing agent to obtain compound a-1; 8. The method for preparing the compound of formula a-1 as described in claim 7, characterized in that, Choose one or more of the following conditions: (1) In Method 1, under the action of a palladium catalyst, and / or a copper catalyst, and / or a base, compound a-1-1 and compound a-1-2 are coupled to obtain compound a-1; preferably, under the action of a palladium catalyst, a copper catalyst and a base, compound a-1-1 and compound a-1-2 are coupled to obtain compound a-1 via a Sonogashira coupling reaction. (2) In Method 1, the palladium catalyst is selected from Pd(PPh3)4, Pd(OAc)2, Pd(PPh3)2Cl2 and Pd2(dba)3; preferably Pd(PPh3)2Cl2; (3) In Method 1, the molar ratio of the compound of formula a-1-1 to the palladium catalyst is selected from 1:0.01 to 1:0.5; (4) In Method 1, the copper catalyst is selected from CuI, CuBr and CuCl, preferably CuI; (5) In Method 1, the molar ratio of the compound of formula a-1-1 to the copper catalyst is selected from 1:0.01 to 1:0.5; (6) In Method 1, the base is selected from triethylamine, N,N-diisopropylethylamine, DBU, potassium carbonate and cesium carbonate; preferably triethylamine; (7) In Method 1, the mass-to-volume ratio of the compound of formula a-1-1 to the base is selected from 1:1 to 1:5 g / mL; (8) In Method 2, in step (1), under the action of a palladium catalyst, and / or a copper catalyst, and / or a base, compound a-1-3 and compound a-1-2 are coupled to obtain compound a-1-4; preferably, in step (1), under the action of a palladium catalyst, a copper catalyst and a base, compound a-1-3 and compound a-1-2 are coupled to obtain compound a-1-4 via a Sonogashira coupling reaction; (9) In Method 2, in step (1), the palladium catalyst is selected from Pd(PPh3)4, Pd(OAc)2, Pd(PPh3)2Cl2 and Pd2(dba)3; preferably Pd(PPh3)2Cl2; (10) In Method 2, in step (1), the molar ratio of the compound of formula a-1-3 to the palladium catalyst is selected from 1:0.01 to 1:0.5; (11) In method two, in step (1), the copper catalyst is selected from CuI, CuBr and CuCl; preferably CuI; (12) In Method 2, in step (1), the molar ratio of the compound of formula a-1-3 to the copper catalyst is selected from 1:0.01 to 1:0.5; (13) In Method 2, in step (1), the base is selected from triethylamine, N,N-diisopropylethylamine, DBU, potassium carbonate and cesium carbonate; preferably triethylamine; (14) In Method 2, in step (1), the molar ratio of the compound of formula a-1-3 to the base is selected from 1:1 to 1:5; (15) In Method 2, in step (2), the oxidant is selected from hydrogen peroxide, sodium hypochlorite, m-chloroperoxybenzoic acid, and potassium persulfate complex salt. Sodium tungstate and sodium periodate; preferably potassium peroxymonosulfate compound salt.

9. Any of the following compounds or their salts, 10. Use of the compound as described in claim 9, such as a-1 or a-1-4, wherein the use is selected from: (1) Uses in preparing compounds of formula I: (2) Uses in the preparation of connectors; (3) Use in the preparation of drug linker conjugates; (4) Use in the preparation of antibody-drug conjugates.

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