Method for preparing N-alkylated chiral amine

Abstract

The present disclosure relates to a process for the preparation of N-alkylated chiral amines. Specifically, the method comprises the step of carrying out hydrogenation reaction on reactants under the action of a metal iridium catalyst Ir-L or a salt thereof. The enantiomerically enriched chiral secondary amine can be used for asymmetric synthesis of molecules with biological activity.

Description

Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical synthesis and relates to a method for preparing N-alkylated chiral amines. Background Art

[0002] α-chiral amines refer to organic amine compounds in which the amino group is located on a chiral carbon atom and have wide applications in the field of biomedicine. Some of these chiral compounds have certain biological activities, and some are intermediates in the synthesis of complex drug molecules. Due to the importance of their structures, there are many preparation methods for α-chiral amines. Asymmetric reductive amination has become an important strategy for constructing α-chiral amines due to its simplicity and high efficiency. Asymmetric reductive amination starts from ketone compounds and undergoes the condensation of ketones and amines to form imine intermediates and the asymmetric hydrogenation reaction of this intermediate containing a C=N bond to construct chiral amines in one pot. Although reports on the asymmetric hydrogenation of imines are not rare, some imine intermediates have poor stability and cannot be separated and purified. Therefore, reductive amination is still a very important method for asymmetric synthesis of chiral amines.

[0003] Although there are many reports on the asymmetric reductive amination catalyzed by transition metals, the amine sources often focus on ammonia molecules (NH 3 or its cation NH 4 ) or aromatic amines, and there are few reports on alkylamines. The successful cases using alkylamines as amine sources mostly focus on large steric hindrance amine sources with protecting groups such as dibenzylamine (for example, Angew. Chem. Int. Ed. 2016, 55, 5309-5312 and Org. Chem. Front. 2017, 4, 1976-1980) or secondary amines (CN 109734611 B and Chem. Sci. 2019, 10, 4509-4514). However, there is still a lack of an asymmetric reductive amination synthesis method for the N-alkyl α-chiral amine structure widely present in drug molecules. And in the existing methods, there are problems such as expensive solvents, difficult synthesis of catalysts or high catalyst dosage, resulting in an increase in production costs. Summary of the Invention

[0004] On the one hand, the present disclosure provides a method for preparing a compound of formula (III-A) or a salt thereof, including the step of hydrogenation reaction of a compound of formula (I-A) and a compound of formula (II-A) under the action of a metal iridium catalyst Ir-L or a salt thereof,

[0005]

[0006] wherein, Ir is a salt of metal iridium, and L is a ligand Walphos;

[0007] Ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl;

[0008] R 1 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heteroalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl are optionally substituted by one or more substituent groups Q 1 ;

[0009] R 2 each independently is selected from C 1 -C 6 alkyl, halogen, hydroxy, mercapto, amino optionally protected by an amino protecting group, oxo, thioxo, -C(O)R k , -C(O)OR k , -S(O)R k , -S(O)OR k , -S(O)(O)R k , -S(O)(O)OR k , -C(S)R k , nitro, cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heteroalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl are optionally substituted by one or more substituent groups Q 1 ;

[0010] R 3 and R 4 each independently is selected from a hydrogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, mercapto, amino optionally protected by an amino protecting group, 3- to 10-membered cycloalkyl, 3- to 10-membered heteroalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl are optionally substituted by one or more substituents Q 1 , or R 3 and R 4and together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or heterocycloalkyl group by one or more substituents Q 1 substituted;

[0011] R 5 selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein the alkyl, alkenyl and alkynyl are optionally substituted by one or more substituent groups Q 1 substituted;

[0012] Substituent group Q 1 each independently selected from C 1 -C 6 alkyl, halogen, hydroxy, mercapto, amino optionally protected by an amino protecting group, oxo, thioxo, -C(O)R k 、-C(O)OR k 、-S(O)R k 、-S(O)OR k 、-S(O)(O)R k 、-S(O)(O)OR k 、-C(S)R k 、nitro, cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl;

[0013] R k independently selected from a hydrogen atom, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, amino optionally protected by an amino protecting group, wherein the alkyl, alkoxy, haloalkyl are optionally substituted by a group selected from C 1 -C 6 alkyl, halogen, hydroxy, mercapto, amino optionally protected by an amino protecting group, oxo, thioxo, carboxyl, nitro, cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered hetero cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, each optionally substituted with one or more substituents;

[0014] m = 0, 1, 2, 3, 4, or 5;

[0015] n = 0, 1, 2, 3, 4, 5, or 6.

[0016] In some embodiments, R 1 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more substituent groups Q 1 as defined herein.

[0017] In some embodiments, R 1 is C 1 -C 1 alkyl optionally substituted with one or more substituent groups Q 6 as defined herein.

[0018] In some embodiments, each R 2 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, mercapto, amino optionally protected with an amino protecting group, carboxy, oxo, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with one or more substituent groups Q 1 as defined herein.

[0019] In some embodiments, each R 2 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, amino optionally protected with an amino protecting group, and carboxy, wherein the alkyl and alkoxy are each optionally substituted with one or more substituents selected from halogen, hydroxy, and amino.

[0020] In some embodiments, R 3 and R 4 are each independently selected from hydrogen, C 1-C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, mercapto, amino optionally protected by an amino protecting group, carboxy, oxo, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted by one or more substituents Q 1 substituted.

[0021] In some embodiments, R 3 and R 4 are each independently selected from hydrogen, C 1 -C 6 alkyl, halogen, hydroxy, amino optionally protected by an amino protecting group, and carboxy.

[0022] In some embodiments, R 5 is C 1 -C 1 -C 6 alkyl optionally substituted by one or more substituent groups Q

[0023] In some embodiments, examples of ring A include, but are not limited to

[0024]

[0025] In some embodiments, R k is independently selected from a hydrogen atom, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl, C 1 to C 6 alkoxy, hydroxy, amino optionally protected by an amino protecting group.

[0026] In some embodiments, the substituent groups Q 1 are each independently selected from C 1 -C 6 alkyl, halogen, hydroxy, mercapto, amino optionally protected by an amino protecting group, oxo, thioxo, -C(O)R k ,-C(O)OR k ,-S(O)R k ,-S(O)OR k ,-S(O)(O)R k ,-S(O)(O)OR k ,-C(S)R k nitro, cyano, C 1 -C 6 alkoxy, C 1 -C6 alkylthio group, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl.

[0027] In some embodiments, the substituent Q 1 are each independently selected from C 1 -C 6 alkyl, halogen, hydroxy, amino optionally protected by an amino protecting group, oxo, -C(O)R k 、-C(O)OR k 、cyano, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl.

[0028] In some embodiments, the compound represented by formula (I-A) is wherein R 6 is amino optionally protected by an amino protecting group.

[0029] In some embodiments, the compound represented by formula (II-A) is wherein x is 0, 1, 2, 3, 4 or 5.

[0030] In some embodiments, the compound represented by formula (III-A) is the compound represented by formula (III-B), wherein R 6 is amino optionally protected by an amino protecting group, x is 0, 1, 2, 3, 4 or 5,

[0031]

[0032] In some embodiments, the amino protecting groups described in the present disclosure are selected from p-methoxybenzyl (PMB), acetyl, methoxyacetyl, trifluoroacetyl, trichloroacetyl, pivaloyl, formyl, benzoyl, phthaloyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl and benzyloxycarbonyl, such as p-methoxybenzyl, tert-butoxycarbonyl and benzyloxycarbonyl.

[0033] In some embodiments, the salt of iridium metal is selected from (1,5-cyclooctadiene)iridium(III) dichloride dimer, chloro(cyclooctene)iridium(III) dimer, 1,5-cyclooctadiene bis(methylbiphenylphosphine)iridium(III) hexafluorophosphate, methoxy(cyclooctadiene)iridium(III) dimer, bis(1,5-cyclooctadiene)iridium(III) hexafluoroantimonate, bis(1,5-cyclooctadiene)iridium(III) tetrafluoroborate or bis(1,5-cyclooctadiene)iridium(III) tetrakis(3,5-bis(trifluoromethyl)phenyl)borate, such as (1,5-cyclooctadiene)iridium(III) dichloride dimer.

[0034] In some embodiments, the ligand Walphos is a class of chiral ferrocenylphosphine ligands as shown below, where R and R' are each independently selected from C 1 -C 6 alkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C10 aryl, and C5-C10 heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, hydroxy, and amino.

[0035]

[0036] In some embodiments, the ligand Walphos is

[0037]

[0038] In some embodiments, the reaction is carried out in the presence of an additive, and the additive is a combination of a Bronsted acid, a titanate, and an iodine-containing compound.

[0039] In some embodiments, the Bronsted acid is selected from one or more of formic acid, acetic acid, propionic acid, benzoic acid, p-toluic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, methanesulfonic acid, sulfuric acid, and phosphoric acid.

[0040] In some embodiments, the titanate is selected from one or more of tetra(isopropyl) titanate, tetra(methyl) titanate, tetra(hexyl) titanate, and tetra(propyl) titanate, such as tetra(isopropyl) titanate.

[0041] In some embodiments, the iodine-containing compound is selected from one or more of molecular iodine, ammonium iodide, tetrabutylammonium iodide, bismuth iodide, zinc iodide, N-iodosuccinimide, potassium iodide, and sodium iodide, such as potassium iodide.

[0042] In some embodiments, the reaction solvent is independently selected from one or more of ethyl acetate, isopropyl acetate, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, xylene, dimethyl sulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, isopropyl alcohol, propanol, ethanol, methanol, for example, one or more of isopropyl alcohol, propanol, ethanol, methanol.

[0043] In some embodiments, the reaction temperatures are -20 - 150 °C respectively, for example 0 - 100 °C.

[0044] In some embodiments, the preparation method of the present disclosure optionally further comprises a purification step, and the purification step comprises one or more of column chromatography, solvent pulping, and recrystallization.

[0045] The salts of the compounds described in the present disclosure can be inorganic acid salts and organic acid salts. The inorganic acid salts can be hydrochloride, sulfate, phosphate, hydrobromide, trifluoroacetate, etc., and the organic acids can be formate, acetate, sulfonate, arbitrarily substituted alkyl sulfonate, succinate, maleate, tartrate, citrate, lactate, oxalate, gluconate, fumarate, malonate, malate, etc.

[0046] The present disclosure provides a one-pot reductive amination method catalyzed by a transition metal, which efficiently realizes the preparation of N-alkyl α-chiral amines from ketones. This method has certain functional group compatibility and substrate structure generality, and has high catalytic activity and process stability, with less catalyst consumption and lower hydrogenation pressure, which is beneficial to industrial production.

[0047] The method described in the present disclosure can be used for the synthesis of various drugs, such as pan KRAS inhibitors or their intermediates. The KRAS protein encoded by the KARS gene is a small GTPase and belongs to the RAS superprotein family. Due to the lack of traditional small molecule binding sites on the surface of the KRAS protein and its extremely high affinity for guanosine nucleotides, it is difficult to be competitively inhibited by small molecules, and has long been considered an undruggable drug target. However, due to the importance and universality of KRAS abnormal activation in cancer progression, KRAS has always been and still is a very concerned target for drug development. Currently, the publicly disclosed patent applications related to pan KRAS inhibitors include WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, WO2022132200A1, WO2022188729A1, WO2022194245A1, WO2022199587A1, WO2022216762A1, and WO2021000885A1, etc.

[0048] On the other hand, the present disclosure provides a method for preparing a pan - KRAS inhibitor, the method comprising the step of preparing the compound of formula (III - A) or its salt as described in the present disclosure.

[0049] In some embodiments, the pan - KRAS inhibitor is selected from

[0050]

[0051]

[0052] The pan - KRAS inhibitor can be prepared by referring to the methods disclosed in WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, WO2022132200A1, WO2022188729A1, WO2022194245A1, WO2022199587A1, WO2022216762A1, WO2021000885A1, and CN202310991959.5, etc.

[0053] On the other hand, the present disclosure provides a method for preparing a compound of formula (VI - B) or its salt, the method comprising the step of preparing the compound of formula (III - B) or its salt as described in the present disclosure,

[0054]

[0055] wherein x is 1, R 6 is an amino group optionally protected by an amino - protecting group, R 7 each independently selected from C 1 -C 6 alkyl, halogen, hydroxyl, an amino group optionally protected by an amino - protecting group, carboxyl, cyano, and C 1 -C 6 alkoxy, n1 is 0, 1 or 2, R 8 is selected from hydrogen, C 1 -C 6 alkyl, halogen, hydroxyl, an amino group optionally protected by an amino - protecting group, carboxyl, cyano, and C 1 -C 6 alkoxy.

[0056] In some embodiments, the method further comprises the step of reacting the compound of formula (III - B) or its salt with the compound of formula (IV - B) or its salt to obtain the compound of formula (V - B) or its salt, wherein X is halogen, R 6 、R 7 、R 8, the definition of n1 is as described above.

[0057]

[0058] In some embodiments, the method further comprises a step of cyclizing the compound represented by formula (V-B) or a salt thereof to obtain the compound represented by formula (VI-B) or a salt thereof.

[0059] In the preparation method described in the present disclosure, the reactions connected by "→" all refer to one-step reactions to obtain the desired products.

[0060] "Carboxyl protecting group" is a suitable group known in the art for protecting carboxyl groups. See the carboxyl protecting groups in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. T. W. Greene & P. G. M. Wuts). As an example, preferably, the carboxyl protecting group may be a substituted or unsubstituted C 1-10 linear or branched alkyl group, a substituted or unsubstituted C 2-10 linear or branched alkenyl or alkynyl group, a substituted or unsubstituted C 3-8 cyclic alkyl group, a substituted or unsubstituted C 5-10 aryl or heteroaryl group, or a (C 1-8 alkyl or aryl) 3 silyl group; preferably a C 1-6 linear or branched alkyl group, more preferably a C 1-4 linear or branched alkyl group. For example, methyl, ethyl, allyl, isopentenyl, trimethylsilylethyl, etc.

[0061] "Hydroxy protecting group" is a group known in the art and capable of protecting a hydroxyl group. See the hydroxy protecting groups in the literature ("Protective Groups in Organic Synthesis", 5Th Ed. T.W. Greene & P.G.M. Wuts). By way of example, and without limitation, preferably, the hydroxy protecting group may be a (C1-10 alkyl or aryl)3 silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; it may be a C1-10 alkyl or substituted alkyl group, such as: methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; it may be a (C1-10 alkyl or aromatic group) acyl group, such as: formyl, acetyl, benzoyl, etc.; it may be a (C1-6 alkyl or C6-10 aryloxy) sulfonyl group; or it may be a (C1-6 alkoxy or C6-10 aryloxy) carbonyl group, which may be acetyl (Ac), 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methylthiomethyl ether (MTM).

[0062] "Amino protecting group" is a group known in the art and capable of protecting an amino group. See the amino protecting groups in the literature ("Protective Groups in Organic Synthesis", 5Th Ed. T.W. Greene & P.G.M. Wuts). By way of example, and without limitation, it includes but is not limited to carbamate protecting groups, such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl)-ethoxy-carbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups, such as formyl, acetyl, trichloroacetyl, benzoyl, and nitrophenylacetyl; sulfonamide - protecting groups, such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups, such as phthalimido and dithiosuccinyl.

[0063] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0064] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms may be isolated in optically pure form or in racemic form. The optically pure form may be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0065] The optically active (R)- and (S)-isomers and D- and L-isomers may be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography employing a chiral stationary phase and optionally in combination with chemical derivatization (such as formation of a carbamate from an amine).

[0066] In the chemical structure of the compounds of the present disclosure, the bond represents an unspecified configuration, that is, if chiral isomers exist in the chemical structure, the bond may be or may contain both configurations. In the chemical structure of the compounds of the present disclosure, the bond does not specify the configuration, that is, the configuration of the bond may be E or Z, or may contain both E and Z configurations.

[0067] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerizations. Exemplary isomerization instances containing lactam-lactim structures are, for example, between A and B as shown below.

[0068]

[0069] All compounds in the present disclosure can be drawn in the form of A or B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

[0070] "Optionally" or "optional" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "optionally substituted by halogen or cyano C 1 -C 6 alkyl" means that halogen or cyano can but does not have to be present, and this description includes the cases where the alkyl is substituted by halogen or cyano and the cases where the alkyl is not substituted by halogen and cyano.

[0071] The terms "about" or "approximately" mean that a numerical value is within an acceptable error range of a specific value determined by a person of ordinary skill in the art, and the numerical value depends in part on how it is measured or determined (i.e., the limitations of the measurement system). For example, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially includes" can mean a range of up to 20%, for example, varying between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, between 0.5% and 1%. In the present disclosure, each case where a numerical value or numerical range is preceded by the term "about" also includes the embodiment of the given number. Unless otherwise stated, when a specific value appears in the present disclosure, the meaning of "about" or "substantially includes" should be within the acceptable error range of the specific value.

[0072] The numerical values in the disclosure are instrument measurement values or calculated values after instrument measurement, and there is a certain degree of error. Generally speaking, plus or minus 10% is within a reasonable error range. Of course, the context in which the numerical value is used needs to be considered. For example, for the content of total impurities, the error of this numerical value after measurement does not exceed plus or minus 10%, and can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5%.

[0073] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and thus exert biological activity.

[0074] "Excipient" includes, but is not limited to, any adjuvant, carrier, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent that has been approved by the US Food and Drug Administration (FDA) for acceptable use in humans or domestic animals.

[0075] "Effective amount" or "effective therapeutic amount" as described in the present disclosure includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical disorder. The effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the disorder to be treated, the overall health of the patient, the method of administration, the route and dose, and the severity of side effects. The effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0076] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups having 1 to 20 carbon atoms. Alkyl groups having 1 to 6 carbon atoms. 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, and various branched isomers thereof, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0077] "Alkenyl" refers to an unsaturated aliphatic straight-chain or branched-chain hydrocarbon group and contains one or more carbon-carbon double bonds. Exemplary alkenyl groups include C 2 -C 8 、C 2 -C 7 、C 2 -C 6 、C 2 -C 4 、C 3 -C 12 and C3 -C 6 Alkenyl. Include but not limited to, vinyl (i.e., ethenyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), etc. The alkenyl used in any context herein is optionally substituted in the same manner as alkyl.

[0078] "Alkynyl" includes branched and straight-chain alkynyl groups having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if a specific number of carbon atoms is specified, it means that specific number. For example, ethynyl, propynyl (such as 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl.

[0079] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl includes spiro, fused, and bridged cycloalkyl. Cycloalkyl can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, and the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0080] The term "heterocycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, which contain 3 to 20 ring atoms, and one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but does not include the ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, where 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl" include:

[0081]

[0082] and so on.

[0083] The heterocycloalkyl ring can be fused to an aryl or heteroaryl ring, and the ring connected to the parent structure is heterocycloalkyl. Non-limiting examples include:

[0084] etc.

[0085] The heterocycloalkyl group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, hydroxy, oxo, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, and the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0086] The term "alkoxy" means -O-(alkyl), where the alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. The alkoxy can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl, and the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0087] Similarly, the definitions of "cycloalkoxy", "heterocycloalkoxy" and "alkylthio" in "cycloalkylthio" and "heterocycloalkylthio" are the same as those of the above-mentioned "alkoxy".

[0088] The term "alkylene" represents the remaining part after removing 2 hydrogen atoms from an alkane molecule, including straight-chain and branched alkylene groups with 1 to 20 carbon atoms. Non-limiting examples of alkylene with 1 to 6 carbon atoms include methylene (-CH 2 -), ethylene (such as -CH 2 CH 2 - or -CH(CH 3 ). Unless otherwise specified, the alkylene can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available connection point, preferably one or more of the following groups, independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0089] Similarly, the definitions of "alkyleneoxy", "alkenylene", "alkenyloxy", "cycloalkylene" and "heterocycloalkylene" are the same as those of "alkylene".

[0090] The term "aryl" refers to a 6- to 14-membered fully carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring attached to the parent structure is the aryl ring, and non-limiting examples thereof include:

[0091]

[0092] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered heterocycloalkoxy, 3- to 8-membered cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0093] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 6- to 12-membered, more preferably 5- or 6-membered. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, etc.

[0094] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring, and non-limiting examples thereof include:

[0095]

[0096] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0097] The term "spiro" refers to a compound in which two rings share a single atom. Non-limiting examples of spiroalkyl groups include:

[0098]

[0099] The term "fused ring" refers to a compound formed by the fusion of two or more rings through the sharing of two adjacent atoms. Non-limiting examples of fused cycloalkyl groups include:

[0100]

[0101] The term "bridged ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0102]

[0103] The term "heterocycle" means that the atoms constituting the ring include other atoms in addition to carbon atoms, and it includes heterocycloalkyl and heteroaryl rings.

[0104] The term "hydroxy" refers to the -OH group.

[0105] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0106] The term "cyano" refers to -CN.

[0107] The term "amino" refers to -NH 2 .

[0108] The term "nitro" refers to -NO 2 .

[0109] The term "oxo" refers to the =O substituent.

[0110] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1-3 hydrogen atoms, are independently replaced by the corresponding number of substituents. When the substituent is a ketone or oxo (i.e., =O), then two (2) hydrogens on the atom are replaced. Detailed Description of the Invention

[0111] The present disclosure will be explained in detail below in conjunction with specific examples, so that those skilled in the art can more comprehensively understand the present disclosure. The specific examples are only used to illustrate the technical solutions of the present disclosure and do not limit the present disclosure in any way.

[0112] Among them, the structure of Walphos is

[0113]

[0114] [Ir(COD)Cl] 2 has the structure of

[0115]

[0116] Example 1

[0117]

[0118] Dissolve 4.5 kg of 3-acetyl-2-chloropyridine (28.9 mol, 1.0 eq) in 22.5 L of DMF, add 7.44 kg of bis-(4-methoxybenzyl)-amine (31.8 mol, 1.1 eq), 7.48 kg of diisopropylethylamine (57.9 mol, 2.0 eq), raise the external temperature to 120 - 125 °C, and keep stirring until the reaction is completed. Cool the reaction solution to an internal temperature of 15 °C, add 90 L of water, extract twice with ethyl acetate, combine the organic phases and wash three times with water. Adjust the pH value of the organic phase to about 6 with 1N dilute hydrochloric acid solution. Stir at room temperature for 30 min, filter, wash the organic phase successively with saturated sodium bicarbonate solution and saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 10 kg of crude product.

[0119] Add 5 L of anhydrous ethanol to 10 kg of the crude product, stir at room temperature for 30 min, cool to about 10 °C and stir, filter by suction, and dry the filter cake under vacuum to obtain 6.5 kg of Compound 2.

[0120] 1 H NMR(CD 3 Cl-d3) δ ppm 8.33 - 8.34 (m, 1H), 7.77 - 7.79 (m, 1H), 7.01 - 7.03 (m, 4H), 6.80 - 6.84 (m, 5H), 4.43 (s, 4H), 3.79 (s, 6H), 2.50 (s, 3H),

[0121] Example 2

[0122] [Ir(Cod)Cl] 2 +2Walphos → 2Ir(Walphos)I 2 K + KCl

[0123] In a reaction flask filled with nitrogen, dissolve 133 mg of [Ir(COD)Cl] 2 about (0.2 mmol, 1 eq) and 294 mg of walphos (0.44 mmol, 2.2 eq) in 3 mL of THF, stir for 10 min, then add 4 g of KI and 12 mL of TBME, and continue stirring for 20 min for later use.

[0124] Example 3

[0125]

[0126] In a high-pressure reactor, 73.2 g of Compound 2 (0.2 mol, 1 eq) was added. Subsequently, 210 mL of anhydrous THF, 14.64 g of ethanolamine (0.24 mol, 1.2 eq), and 68.16 g of titanium tetraisopropoxide (0.24 mol, 1.2 eq) were successively added to the reactor. The high-pressure reactor was sealed, and the heating temperature of the reactor was maintained at 80 - 85 °C, and the reaction was stirred until it ended.

[0127] At room temperature, approximately 880 mL of anhydrous TBME was added to the reaction solution. 30.5 g of glacial acetic acid (0.5 mol, 2.5 eq) was slowly added dropwise under stirring, and then 6.64 g of KI (0.04 mmol, 0.2 eq) powder was added. After the high-pressure reactor was cooled to room temperature, the iridium catalyst in Example 2 (Ir ratio 0.1 mol%) was quickly added. The reaction kettle was sealed, the hydrogen pressure in the kettle was maintained at 20 bar, the jacket was heated to 50 °C, and the reaction was stirred until it ended.

[0128] The reaction solution was transferred to a 10 L reactor, approximately 1.5 L of TBME was added, and then approximately 1.2 L of acetic acid solution (containing 30.5 g of glacial acetic acid) was slowly poured in and stirred. Then approximately 1.2 L of saturated sodium carbonate solution was slowly poured in. Stirring was continued for 30 min. Filtration was carried out to separate the organic phase. Then the aqueous phase was extracted three times with TBME (0.5 L * 3), the combined organic phases were washed three times with pure water (1 L * 3), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 85 g of Compound 3 was obtained, with a yield of 95% and an ee value of 92%.

[0129] 1 H NMR (DMSO-d 6 ) δ ppm 8.18 - 8.15 (m, 1H), 7.83 - 7.80 (m, 1H), 7.17 (d, J = 8.8 Hz, 4H), 7.07 - 7.04 (m, 1H), 6.83 (d, J = 8.8 Hz, 4H), 4.44 (br, 1H), 4.31 (q, J = 6.4 Hz, 1H), 4.09 (m, 4H), 3.70 (s, 6H), 3.47 - 3.28 (m, 3H), 2.38 - 2.31 (m, 1H), 2.17 - 2.10 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H)

[0130] Example 4

[0131]

[0132] According to the method disclosed in CN202310991959.5, 190 g of Compound 3 was put in, and 135 g of Compound 5 was obtained. The total yield of the two steps was 48%.

[0133] Example 5

[0134]

[0135] In a high-pressure reactor, 31.1 g of Compound 4 (0.2 mol, 1 eq) was added. Subsequently, 210 mL of anhydrous THF, 14.64 g of ethanolamine (0.24 mol, 1.2 eq) were added to the reactor in sequence, and 68.16 g of titanium tetraisopropoxide (0.24 mol, 1.2 eq) was slowly added. The high-pressure reactor was sealed, and the heating temperature of the reactor was maintained at 80 - 85 °C, and the reaction was stirred until completion.

[0136] At room temperature, approximately 880 mL of anhydrous TBME was added to the reaction solution. 30.5 g of glacial acetic acid (0.5 mol, 2.5 eq) was slowly added dropwise under stirring, and then 6.64 g of KI (0.04 mmol, 0.2 eq) powder was added. After the high-pressure reactor was cooled to room temperature, the iridium catalyst in Example 2 (Ir ratio 0.1 mol%) was quickly added. The reaction kettle was sealed, the hydrogen pressure in the kettle was maintained at 20 bar, and it was heated to 50 °C by jacket heating and stirred until the reaction ended.

[0137] The reaction solution was transferred to a 10 L reactor, approximately 1.5 L of TBME was added, and then approximately 1.2 L of acetic acid solution (containing 30.5 g of glacial acetic acid) was slowly poured in and stirred. Then approximately 1.2 L of saturated sodium carbonate solution was slowly poured in. Stirring was continued for 30 min. Filtration was carried out to separate the organic phase. Then the aqueous phase was extracted three times with TBME (0.5 L * 3), the combined organic phases were washed three times with pure water (1 L * 3), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 36.8 g of Compound 5 was obtained, with a yield of 92% and an ee value of 95%.

[0138] 1 H NMR (DMSO-d6) δ ppm 8.29 - 8.05 (m, 1H), 8.04 - 8.02 (m, 1H), 7.47 - 7.44 (m, 1H), 7.07 - 7.04 (m, 1H), 4.52 (br, 1H), 4.08 (q, J = 6.4 Hz, 1H), 3.45 - 3.40 (m, 2H), 2.50 - 2.32 (m, 2H), 1.26 (d, J = 6.4 Hz, 3H)

[0139] Since the present disclosure has been described in terms of its particular embodiments, certain modifications and equivalent variations will be apparent to those skilled in the art and are included within the scope of the present disclosure.

Claims

1. A method for preparing a compound represented by formula (III-A) or a salt thereof, comprising the steps of hydrogenating a compound represented by formula (IA) with a compound represented by formula (II-A) in the presence of a metal iridium catalyst Ir-L or a salt thereof, in, Ir is a salt of metal iridium, and L is a ligand Walphos; Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R1 is selected from C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents Q1; R2 is independently selected from C1-C6 alkyl, halogen, hydroxyl, thiol, amino optionally protected by an amino protecting group, oxo, thioxo, -C(O)R k 、-C(O)OR k 、-S(O)R k 、-S(O)OR k 、-S(O)(O)R k 、-S(O)(O)OR k 、-C(S)R k , nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents Q1; R3 and R4 are each independently selected from a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen, a hydroxyl group, a thiol group, an amino group optionally protected by an amino protecting group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocycloalkyl group, the aryl group, the heteroaryl group are optionally substituted with one or more substituents Q1, or R3 and R4 together with the carbon atom to which they are attached form a cycloalkyl group or a heterocycloalkyl group optionally substituted with one or more substituents Q1; R5 is selected from C1-C6 alkyl, 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents Q1; The substituent groups Q1 are each independently selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, amino optionally protected by an amino protecting group, oxo, thio, -C(O)R k 、-C(O)OR k 、-S(O)R k 、-S(O)OR k 、-S(O)(O)R k 、-S(O)(O)OR k 、-C(S)R k , nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R k independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, amino optionally protected by an amino protecting group, wherein the alkyl, alkoxy, haloalkyl is optionally substituted by one or more substituents selected from C1-C6 alkyl, halogen, hydroxy, sulfhydryl, amino optionally protected by an amino protecting group, oxo, thioxo, carboxyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; m = 0, 1, 2, 3, 4 or 5; n=0, 1, 2, 3, 4, 5 or 6.

2. The preparation method according to claim 1, wherein R1 is selected from C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, wherein the alkyl, alkenyl and alkynyl are optionally substituted by one or more substituent groups Q1, preferably R1 is a C1-C6 alkyl optionally substituted by one or more substituent groups Q1.

3. according to the preparation method described in claim 1 or 2, wherein R2 is each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, sulfhydryl, amino optionally protected by amino protecting group, carboxyl, oxo, 3 to 10 yuan cycloalkyl, 3 to 10 yuan heterocyclic radical, 6 to 10 yuan aryl and 5 to 10 yuan heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally replaced by one or more substituents Q1, preferably R2 is each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, amino optionally protected by amino protecting group and carboxyl, wherein said alkyl, alkoxy are optionally replaced by one or more substituents selected from halogen, hydroxyl and amino.

4. according to the preparation method described in any one of claims 1-3, wherein R3 and R4 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, sulfhydryl, amino optionally protected by an amino protecting group, carboxyl, oxo, 3 to 10 yuan of cycloalkyl, 3 to 10 yuan of heterocyclic radical, 6 to 10 yuan of aryl and 5 to 10 yuan of heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally replaced by one or more substituents Q1, preferably R3 and R4 are each independently selected from hydrogen, C1-C6 alkyl, halogen, hydroxyl, amino optionally protected by an amino protecting group and carboxyl.

5. The preparation method according to any one of claims 1 to 4, wherein R5 is a C1-C6 alkyl group optionally substituted by one or more substituent groups Q1.

6. The preparation method according to any one of claims 1 to 5, wherein ring A is selected from 7. The preparation method according to any one of claims 1 to 6, wherein R k independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl, amino optionally protected by an amino protecting group; the substituent groups Q1 are independently selected from C1-C6 alkyl, halogen, hydroxyl, thiol, amino optionally protected by an amino protecting group, oxo, thio, -C(O)R k 、-C(O)OR k 、-S(O)R k 、-S(O)OR k 、-S(O)(O)R k 、-S(O)(O)OR k 、-C(S)R k , nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl or C2-C6 alkynyl, preferably the substituent groups Q1 are each independently selected from C1-C6 alkyl, halogen, hydroxyl, amino optionally protected by an amino protecting group, oxo, -C(O)R k 、-C(O)OR k , cyano, C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

8. The preparation method according to any one of claims 1 to 7, wherein the compound represented by formula (III-A) is a compound represented by formula (III-B), wherein R6 is an amino group optionally protected by an amino protecting group, x is 0, 1, 2, 3, 4 or 5, 9. The preparation method according to any one of claims 1 to 8, wherein the salt of the metallic iridium is selected from (1,5-cyclooctadiene) iridium dichloride dimer, chlorobis(cyclooctene) iridium dimer, 1,5-cyclooctadiene bis(methylbiphenylphosphine) iridium hexafluoride phosphine salt, methoxy(cyclooctadiene) iridium dimer, bis(1,5-cyclooctadiene) iridium antimony hexafluoride salt, bis(1,5-cyclooctadiene) iridium tetrafluoroborate, bis(1,5-cyclooctadiene) iridium tetra(3,5-bis(trifluoromethyl)phenyl)borate or iridium trichloride and its hydrate, preferably (1,5-cyclooctadiene) iridium dichloride dimer.

10. The preparation method according to any one of claims 1 to 9, wherein the ligand Walphos is a chiral ferrocenylphosphine ligand as shown below, wherein R and R' are each independently selected from C1-C6 alkyl, 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclic group, 6 to 10-membered aryl and 5 to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, hydroxyl and amino, Best 11. The preparation method according to any one of claims 1 to 10, wherein the reaction is carried out in the presence of an additive, the additive being a combination of a Bronsted acid, a titanate, and an iodine-containing compound, the Bronsted acid being preferably selected from one or more of formic acid, acetic acid, propionic acid, benzoic acid, p-toluic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, methanesulfonic acid, sulfuric acid, and phosphoric acid, the titanate being preferably selected from one or more of tetraisopropyl titanate, tetramethyl titanate, tetrahexyl titanate, and tetrapropyl titanate, and the iodine-containing compound being preferably selected from one or more of molecular iodine, ammonium iodide, tetrabutylammonium iodide, bismuth iodide, zinc iodide, N-iodosuccinimide, potassium iodide, and sodium iodide.

12. A method for preparing a pan KRAS inhibitor, the method comprising the step of preparing the compound represented by formula (III-A) or a salt thereof according to any one of claims 1 to 11.

13. The preparation method according to claim 12, wherein the pan KRAS inhibitor is selected from 14. A method for preparing a compound represented by formula (VI-B) or a salt thereof, the method comprising the steps of preparing a compound represented by formula (III-B) or a salt thereof according to any one of claims 8 to 11, in, x is 1, R6 is an amino group optionally protected by an amino protecting group, R7 are each independently selected from C1-C6 alkyl, halogen, hydroxyl, an amino group optionally protected by an amino protecting group, carboxyl, cyano and C1-C6 alkoxy, n1 is 0, 1 or 2, and R8 is selected from hydrogen, C1-C6 alkyl, halogen, hydroxyl, an amino group optionally protected by an amino protecting group, carboxyl, cyano and C1-C6 alkoxy.

15. The preparation method according to claim 14, wherein the method further comprises the step of reacting the compound represented by formula (III-B) or its salt with the compound represented by formula (IV-B) or its salt to obtain the compound represented by formula (VB) or its salt, wherein X is a halogen, and the definitions of R6, R7, R8, and n1 are as described in claim 14, and preferably further comprises the step of ring-closing the compound represented by formula (VB) or its salt to obtain the compound represented by formula (VI-B) or its salt,

Images