Synthesis method of intermediates of imidazo[1,2-b]pyridazine compounds

Abstract

The present invention relates to a method for synthesizing an intermediate of an imidazo[1,2-b]pyridazine compound. The present invention belongs to the field of medicinal chemistry. More specifically, the present invention relates to a novel method for synthesizing an intermediate of an imidazo[1,2-b]pyridazine compound, and also to some novel intermediate compounds.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. More specifically, the present invention relates to a novel synthesis method of intermediates that can be used to synthesize imidazo[1,2-b]pyridazine compounds, and also to some novel intermediate compounds. Background Art

[0002] The compounds of formula (1-i) and formula (1-ii) are an important class of pharmaceutical intermediates and can be used to prepare a variety of pharmaceutical substances. For example, they can be used to prepare the imidazo[1,2-b]pyridazine compounds disclosed in WO2016 / 045591A1 for treating inflammatory diseases, autoimmune diseases or cancer.

[0003]

[0004] The synthesis of compounds of formula (1-i) and formula (1-ii) has been reported. For example, such pharmaceutical intermediates can be synthesized according to the multiple synthesis routes described in the synthesis route I (Scheme I) and the synthesis route II (Scheme II) of the patent application WO2016 / 045591A1.

[0005] Synthesis route I of WO2016 / 045591A1 is as follows Figure 1 As shown, in this synthetic route, the preparation of the final product imidazo[1,2-b]pyridazine compound includes more than a dozen steps, among which the preparation of the intermediate of formula (i-8) includes as many as 7 steps:

[0006] Step 1: The compound of formula i-1 reacts with N,O-dimethylhydroxylamine to obtain an amide compound of formula i-2.

[0007] Step 2: The compound of formula i-2 is reacted with MH to obtain a compound of formula i-3.

[0008] Step 3: The compound of formula i-3 and the compound of formula ArB(OH)2 are reacted by Suzuki coupling reaction under the catalysis of an appropriate palladium reagent to obtain a compound of formula i-4. The palladium-catalyzed carbon-carbon coupling reaction is carried out under appropriate conditions: in a suitable polar solvent such as DMF, ACN, THF or DMSO, in a suitable base such as TEA, DIPEA, Cs2CO3, KOAc, etc., using a catalyst such as Pd(OAc)2, Pd(dppf)Cl2, Pd(PPh3)4 or Pd2(dba)3, etc.

[0009] Step 4-Step 6: The compound of formula i-4 reacts with a Grignard reagent (alkyl magnesium halide) under appropriate conditions to generate a compound of formula i-5. The compound of formula i-5 is condensed with (R)-2-methylpropane-2-sulfenamide and then reduced in the presence of an appropriate reducing agent to obtain a compound of formula i-7.

[0010] Alternatively, step 4 to step 6 are carried out as follows: the compound of formula i-4 is reduced in the presence of a suitable reducing agent to obtain compound i-5'. Compound i-5' is condensed with (R)-2-methylpropane-2-sulfenamide and then reacted with a Grignard reagent (alkyl magnesium halide) under appropriate conditions to generate a compound of formula i-7.

[0011] Step 7: Removing the protecting group from the compound of formula i-7 to obtain a compound of formula i-8.

[0012] Example 1 of WO2016 / 045591A1 discloses a more specific synthesis operation.

[0013] It can be seen that the synthesis route disclosed in WO2016 / 045591A1 includes many reaction steps, low total yield, harsh reaction conditions, and multiple steps involve chromatographic column separation operations. Due to its lengthy and cumbersome process, this synthesis route is not conducive to industrial large-scale production.

[0014] In addition, the synthetic routes disclosed in WO2016 / 045591A1 all use 3,6-dichloropyridazine-4-carboxylic acid as a starting material, which is difficult to obtain and expensive, with a market price of up to about RMB 17,000 per kilogram, which results in high production costs for new imidazo[1,2-b]pyridazine compounds.

[0015] Therefore, new synthesis methods are needed to improve the above-mentioned defects of the prior art. Summary of the invention

[0016] In a first aspect, the present invention relates to a process for preparing compounds of formula (1-i) and formula (1-ii),

[0017]

[0018] in,

[0019] R1 is selected from hydrogen or C 1-6 Alkyl; preferably, R1 is C 1-6 Alkyl; More preferably, R1 is methyl;

[0020] R2 is selected from C 1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R2 is selected from C 3-6More preferably, R2 is C 3-6 Alkyl; further preferably, R2 is tert-butyl;

[0021] Ar is aryl or heteroaryl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, hydroxyl, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), -(C 1-6 Alkyl)OH, -NH2, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl); preferably, Ar is aryl; more preferably, Ar is phenyl,

[0022] like Figure 2A and Figure 2B As shown, the method includes 4 steps:

[0023] (i) making a compound of formula (2)

[0024]

[0025] Wherein, X1 and X2 may be the same or different, and are independently selected from halogen, trifluoromethoxy, trifluoroacetyl, p-toluenesulfonyloxy; preferably, X1 and X2 may be the same or different, and are independently selected from halogen; more preferably, X1 and X2 are both chlorine;

[0026] Respectively react with the compound of formula (3-i) or formula (3-ii) to introduce a chiral amine,

[0027]

[0028] Wherein R1 is selected from hydrogen or C 1-6 Preferably, R1 is C 1-6 More preferably, R1 is methyl, and R2 is selected from C 1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R2 is selected from C 3-6 More preferably, R2 is C 3-6 Alkyl; further preferably, R2 is tert-butyl,

[0029] Obtaining a compound of formula (4-i) or formula (4-ii),

[0030]

[0031] wherein X1, X2, R1 and R2 are as defined above;

[0032] (ii) subjecting the compound of formula (4-i) or formula (4-ii) to a Buchwald reaction with an amine R3NH2 to obtain a compound of formula (5-i) or formula (5-ii),

[0033]

[0034] wherein X1, R1 and R2 are as defined above; and R3 is an amino protecting group; preferably, R3 is an amino protecting group selected from the following: C 1-6 Alkanoyl, triphenylmethyl, benzyl, benzoyl, succinyl, phthaloyl, -NHC(O)OC 1-6 alkyl, Pmb (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl); more preferably, R3 is C 1-6 Alkanoyl; further preferably, R3 is pivaloyl;

[0035] (iii) subjecting the compound of formula (5-i) or formula (5-ii) to Suzuki coupling reaction with ArB(OH)2 to introduce an Ar group on the pyridazine ring to obtain a compound of formula (6-i) or formula (6-ii),

[0036]

[0037] wherein R1, R2 and R3 are as defined above, and Ar is aryl or heteroaryl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, hydroxyl, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), -(C 1-6 Alkyl)OH, -NH2, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl); preferably, Ar is aryl; more preferably, Ar is phenyl;

[0038] (iv) deprotecting the compound of formula (6-i) or formula (6-ii) to remove the amino protecting group R3 to obtain compounds of formula (1-i) and formula (1-ii), respectively;

[0039]

[0040] wherein R1, R2 and Ar are as defined above.

[0041] Compared with the method for preparing intermediate (i-8) in WO2016 / 045591A1, the method of the present invention has multiple advantages. First, the method of the present invention includes fewer steps, the operation is significantly simplified, the synthesis steps are reduced, and the total yield is also greatly improved. Second, the method of the present invention has a specific synthesis sequence, is a chiral synthesis method, can directly produce the desired stereoisomer, does not need to be separated and purified by column chromatography, and is very suitable for large-scale industrial production. Third, the compound of formula (2) in which X1 and X2 are halogens used as starting materials in the method of the present invention is very cheap, and the commercial price per kilogram is only a few hundred yuan. Compared with the starting material 3,6-dichloropyridazine-4-carboxylic acid used in WO2016 / 045591A1, the cost is reduced by about twenty to thirty times.

[0042] In a preferred embodiment of the first aspect, the present invention relates to the above-mentioned method for preparing compounds of formula (1-i) and formula (1-ii), wherein:

[0043] R1 is C 1-6 alkyl;

[0044] R2 is C 3-6 alkyl;

[0045] R3 is C 1-6 Alkanoyl;

[0046] Ar is aryl, which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, hydroxyl, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), -(C 1-6 Alkyl)OH, -NH2, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl);

[0047] X1 and X2 may be the same or different and are each independently selected from halogen.

[0048] In a more preferred embodiment of the first aspect, the present invention relates to the above-mentioned method for preparing compounds of formula (1-i) and formula (1-ii), wherein:

[0049] R1 is methyl;

[0050] R2 is tert-butyl;

[0051] R3 is pivaloyl;

[0052] Ar is phenyl;

[0053] X1 and X2 are both chlorine.

[0054] In an embodiment of the first aspect, the compound of formula (2) described in step (i) can be commercially available. The compound of formula (3-i) or formula (3-ii) described in step (i) can be prepared according to the method disclosed in the present invention. For example, the compound of formula (3-i) or formula (3-ii) can be obtained by subjecting acetaldehyde to a nucleophilic substitution reaction with a commercially available compound of formula (7-i) or formula (7-ii) in the presence of an acidic catalyst and a dehydrating agent in a solvent.

[0055]

[0056] Wherein, R2 is selected from C 1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R2 is selected from C 3-6 More preferably, R2 is C 3-6 Alkyl; further preferably, R2 is tert-butyl,

[0057] The acidic catalyst is selected from one or more of pyridinium p-toluenesulfonate, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, trichloroacetic acid, hydrogen chloride, sulfuric acid, and phosphoric acid; preferably, the acidic catalyst is selected from one or more of p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid, trifluoroacetic acid, and acetic acid; more preferably, the acidic catalyst is selected from one or more of p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, and methanesulfonic acid;

[0058] The dehydrating agent is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous copper sulfate, molecular sieves, calcium sulfate, silica gel, anhydrous calcium chloride, aluminum oxide, and montmorillonite desiccant; preferably, the dehydrating agent is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous copper sulfate, molecular sieves, calcium sulfate, silica gel, and anhydrous calcium chloride; more preferably, the dehydrating agent is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous copper sulfate, molecular sieves, calcium sulfate, and silica gel;

[0059] The solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethylbenzene, toluene, n-hexane, n-heptane, cyclohexane, cyclopentane, and methylcyclohexane.

[0060] In the embodiment of the first aspect, the nucleophilic substitution reaction of the compound of formula (2) described in step (i) with the compound of formula (3-i) or formula (3-ii) can be carried out under conventional conditions known in the art. For example, the reaction can be carried out in the presence of a base. The base is selected from one or more of n-butyl lithium, tert-butyl lithium, sec-butyl lithium, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, and lithium diisopropylamide. The reaction is carried out in a solvent, and the solvent can be selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethylbenzene, toluene, n-hexane, n-heptane, cyclohexane, cyclopentane, and methylcyclohexane. The reaction can be carried out at a temperature of -140°C to -40°C, preferably at a temperature of -120°C to -60°C. For example, at a temperature of -120°C to -70°C, -120°C to -80°C, -120°C to -90°C, -120°C to -100°C, -120°C to -110°C, -110°C to -70°C, -110°C to -80°C, -110°C to -90°C, -110°C to -100°C, -100°C to -70°C, -100°C to -80°C or -100°C to -90°C, for example, at -120°C The process can be carried out at a temperature of -120°C to -115°C, -115°C to -110°C, -110°C to -105°C, -105°C to -100°C, -100°C to -95°C, -95°C to -90°C, 90°C to -85°C, -85°C to -80°C, or -60°C to -70°C.

[0061] In step (i), if the nucleophilic substitution reaction of step (i) is carried out in the presence of a base, the compound of formula (2) and the compound of formula (3-i) or (3-ii) may be mixed in a reaction solvent and lowered to the temperature required for the reaction, and then the base may be added to carry out the nucleophilic substitution reaction. Alternatively, the base may be lowered to the temperature required for the reaction in the reaction solvent, and then the compound of formula (2) and the compound of formula (3-i) or (3-ii) may be added to carry out the nucleophilic substitution reaction. Alternatively, the reaction solvent may be lowered to the temperature required for the reaction, and then the base, the compound of formula (2), and the compound of formula (3-i) or (3-ii) may be added in sequence to carry out the nucleophilic substitution reaction. Alternatively, the reaction solvent may be lowered to the temperature required for the reaction, and then the compound of formula (2), the compound of formula (3-i) or (3-ii), and the base may be added in sequence to carry out the nucleophilic substitution reaction.

[0062] In an embodiment of the first aspect, the Buchwald reaction described in step (ii) can be carried out under conventional conditions known in the art. For example, the reaction can be carried out in the presence of a catalyst, an optional catalyst ligand, and a base. The catalyst can be selected from one or more of palladium acetate, Pd2(dba)3, PdCl2(PPh3)2, and Pd(dppf)Cl2; the catalyst ligand can be selected from one or more of Xantphos, dppf, BINAP, and XPhos; the base can be selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, and disodium hydrogen phosphate.

[0063] The Buchwald reaction can be carried out in a suitable solvent, which can be selected from one or more of 1,4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile.

[0064] The Buchwald reaction can be carried out at a temperature of 40°C-140°C, preferably at a temperature of 80°C-120°C. For example, at a temperature of 90°C-120°C, 100°C-120°C, 110°C-120°C, 80°C-110°C, 90°C-110°C, 90-105°C, 100°C-110°C, 80°C-100°C, 90°C-100°C or 80°C-90°C, such as at a temperature of 80°C-90°C, 90°C-100°C, 100°C-110°C or 110°C-120°C.

[0065] If the Buchwald reaction of step (ii) is carried out in the presence of a catalyst, an optional catalyst ligand and a base, the compound of formula (4-i) or (4-ii), amine R3NH2 and a base may be first mixed in the reaction solvent, and then under the protection of an inert gas, the catalyst and the optional catalyst ligand are added, and the temperature is raised to the required reaction temperature to carry out the Buchwald reaction. Alternatively, the catalyst and the optional catalyst ligand may be added to the reaction solvent under the protection of an inert gas, and then the compound of formula (4-i) or (4-ii), amine R3NH2 and a base are added, and the temperature is raised to the required reaction temperature to carry out the Buchwald reaction.

[0066] The product of step (ii) may not be isolated, but the reaction system may be directly used in step (iii).

[0067] In the embodiment of the first aspect, the Suzuki coupling reaction described in step (iii) can be carried out under conventional conditions known in the art. For example, the Suzuki coupling reaction can be carried out in the presence of a catalyst, an optional catalyst ligand and a base, the catalyst can be selected from one or more of Pd2(dba)3, palladium acetate, Pd(PPh3)4 and Pd(dppf)Cl2, the catalyst ligand can be selected from one or more of dppf, BINAP and XPhos, and the base can be selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, and disodium hydrogen phosphate.

[0068] The solvent that can be used for the Suzuki coupling reaction can be selected from one or more of 1,4-dioxane, water, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile.

[0069] The Suzuki coupling reaction can be carried out at a temperature of 40°C-140°C, preferably at a temperature of 70°C-120°C. For example, at a temperature of 80°C-120°C, 90°C-120°C, 100°C-120°C, 110°C-120°C, 80°C-110°C, 90°C-110°C, 100°C-110°C, 80-105°C, 80°C-100°C, 90°C-100°C, 80°C-90°C, 70°C-90°C or 70°C-80°C, for example, at a temperature of 70°C-80°C, 80°C-90°C, 90°C-100°C, 100°C-110°C or 110°C-120°C.

[0070] In step (iii), if the Suzuki coupling reaction is carried out in the presence of a catalyst, an optional catalyst ligand and a base, the compound of formula (5-i) or (5-ii), ArB(OH)2 and a base may be first mixed in the reaction solvent, and then under the protection of an inert gas, the catalyst and the optional catalyst ligand are added, and the temperature is raised to the required reaction temperature to carry out the Suzuki coupling reaction. Alternatively, the catalyst and the optional catalyst ligand may be added to the reaction solvent under the protection of an inert gas, and then the compound of formula (5-i) or (5-ii), ArB(OH)2 and a base are added, and the temperature is raised to the required reaction temperature to carry out the Suzuki coupling reaction.

[0071] In an embodiment of the first aspect, the deprotection described in step (iv) can be carried out under conventional conditions known in the art for removing amino protecting groups. For example, the deprotection can be carried out by hydrolysis in the presence of a base. The base can be selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, and disodium hydrogen phosphate, preferably selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide, and cesium hydroxide, and more preferably the base is sodium hydroxide. The solvent used for the hydrolysis can be selected from water, C 1-6 One or more of alkyl alcohol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetonitrile, preferably one or more of water, methanol, ethanol, tetrahydrofuran, isopropanol, butanol, 1,4-dioxane, ethyl acetate, isopropyl acetate, butanol, acetonitrile.

[0072] The hydrolysis reaction can be carried out at a temperature of 30°C-110°C, preferably at a temperature of 30°C-60°C. For example, at 30°C-110°C, 40°C-110°C, 50°C-110°C, 60°C-110°C, 70°C-110°C, 80°C-110°C, 90°C-110°C, 100°C-110°C, 30°C-100°C, 40°C-100°C, 50°C-100°C, 60°C-100°C, 70°C-100°C, 80°C-100°C, 90°C-100°C, 30°C-90°C, 40°C-90°C, 50°C-100°C, -90°C, 60°C-90°C, 70°C-90°C, 80°C-90°C, 30°C-80°C, 40°C-80°C, 50°C-80°C, 60°C-80°C or 70°C-80°C; for example, at a temperature of 30°C-40°C, 40°C-50°C, 45°C-55°C, 50°C-60°C, 60°C-70°C, 70°C-80°C, 80°C-90°C, 90°C-100°C or 100°C-110°C.

[0073] In a second aspect, the present invention relates to a compound of formula (4-i) or formula (4-ii),

[0074]

[0075] in,

[0076] X1 and X2 may be the same or different, and are independently selected from halogen, trihalomethoxy, trihaloethoxy, p-toluenesulfonyl; preferably, X1 and X2 may be the same or different, and are independently selected from halogen; more preferably, X1 and X2 are both chlorine;

[0077] R1 is selected from hydrogen or C 1-6 Alkyl; preferably, R1 is C1-6 Alkyl; More preferably, R1 is methyl;

[0078] R2 is selected from C 1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R2 is selected from C 3-6 More preferably, R2 is C 3-6 Alkyl; further preferably, R2 is tert-butyl.

[0079] In a preferred embodiment of the second aspect, the present invention relates to a compound of the above formula (4-i) or formula (4-ii), wherein

[0080] X1 and X2 may be the same or different and are independently selected from halogen;

[0081] R1 is C 1-6 alkyl;

[0082] R2 is C 3-6 alkyl.

[0083] In a more preferred embodiment of the second aspect, the present invention relates to a compound of the above formula (4-i) or formula (4-ii), wherein:

[0084] X1 and X2 are both chlorine;

[0085] R1 is methyl;

[0086] R2 is tert-butyl.

[0087] In a third aspect, the present invention relates to a compound of formula (5-i) or formula (5-ii),

[0088]

[0089] in,

[0090] X1 is selected from halogen, trihalomethoxy, trihaloethoxy, p-toluenesulfonyl; preferably, X1 is selected from halogen; more preferably, X1 is chlorine;

[0091] R1 is selected from hydrogen or C 1-6 Alkyl; preferably, R1 is C 1-6 Alkyl; More preferably, R1 is methyl;

[0092] R2 is selected from C 1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R2 is selected from C 3-6 More preferably, R2 is C 3-6Alkyl; further preferably, R2 is tert-butyl;

[0093] R3 is an amino protecting group; preferably, R3 is an amino protecting group selected from the following: C 1-6 Alkanoyl, triphenylmethyl, benzyl, benzoyl, succinyl, phthaloyl, -NHC(O)OC 1-6 alkyl, Pmb (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl); more preferably, R3 is C 1-6 Alkanoyl; further preferably, R3 is pivaloyl.

[0094] In a preferred embodiment of the third aspect, the present invention relates to a compound of the above formula (5-i) or formula (5-ii), wherein:

[0095] X1 is selected from halogen;

[0096] R1 is C 1-6 alkyl;

[0097] R2 is C 3-6 alkyl;

[0098] R3 is C 1-6 Alkanoyl.

[0099] In a more preferred embodiment of the third aspect, the present invention relates to a compound of the above formula (5-i) or formula (5-ii), wherein:

[0100] X1 is chlorine;

[0101] R1 is methyl;

[0102] R2 is tert-butyl;

[0103] R3 is pivaloyl.

[0104] In a fourth aspect, the present invention relates to use of a compound of formula (4-i) as described in the second aspect or formula (5-i) as described in the third aspect for preparing a compound of formula (1-i).

[0105] In the fifth aspect, the present invention relates to the use of the compound of formula (4-ii) described in the second aspect or the compound of formula (5-ii) described in the third aspect for preparing the compound of formula (1-ii). Specific implementation plan

[0106] Embodiment 1. The method for preparing the compound of formula (1-i) and formula (1-ii),

[0107]

[0108] in,

[0109] R1 is selected from hydrogen or C 1-6 Alkyl; preferably, R1 is C 1-6 Alkyl; More preferably, R1 is methyl;

[0110] R2 is selected from C 1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R2 is selected from C 3-6 More preferably, R2 is C 3-6 Alkyl; further preferably, R2 is tert-butyl;

[0111] Ar is aryl or heteroaryl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, hydroxyl, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), -(C 1-6 Alkyl)OH, -NH2, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl); preferably, Ar is aryl; more preferably, Ar is phenyl,

[0112] The method comprises the following steps:

[0113] (iv) deprotecting the compound of formula (6-i) or (6-ii) to remove the amino protecting group R3,

[0114]

[0115] wherein R1, R2 and Ar are as defined above, and R3 is an amino protecting group; preferably, R3 is an amino protecting group selected from the following: C 1-6 Alkanoyl, triphenylmethyl, benzyl, benzoyl, succinyl, phthaloyl, -NHC(O)OC 1-6 alkyl, Pmb (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl); more preferably, R3 is C 1-6 Alkanoyl; further preferably, R3 is pivaloyl,

[0116] Respectively obtain compounds of formula (1-i) and formula (1-ii);

[0117] Optionally, the above method further comprises step (iii) before step (iv):

[0118] (iii) subjecting the compound of formula (5-i) or formula (5-ii) to Suzuki coupling reaction with ArB(OH)2 to introduce an Ar group on the pyridazine ring,

[0119]

[0120] wherein R1, R2, R3 and Ar are as defined above, X1 is selected from halogen, trifluoromethoxy, trifluoroacetyl, p-toluenesulfonyloxy; preferably, X1 is selected from halogen; more preferably, X1 is chlorine,

[0121] Obtaining the compound of formula (6-i) or formula (6-ii) in step (iv);

[0122] Optionally, the above method further comprises step (ii) before step (iii):

[0123] (ii) subjecting the compound of formula (4-i) or formula (4-ii) to a Buchwald reaction with an amine R3NH2,

[0124]

[0125] wherein R1, R2 and R3 are as defined above, and X1 and X2 may be the same or different, and are independently selected from halogen, trifluoromethoxy, trifluoroacetyl, p-toluenesulfonyloxy; preferably, X1 and X2 may be the same or different, and are independently selected from halogen; more preferably, X1 and X2 are both chlorine,

[0126] Obtaining the compound of formula (5-i) or formula (5-ii) in step (iii);

[0127] Optionally, the above method further comprises step (i) before step (ii):

[0128] (i) making a compound of formula (2)

[0129]

[0130] Wherein, X1 and X2 may be the same or different, and are independently selected from halogen, trifluoromethoxy, trifluoroacetyl, p-toluenesulfonyloxy; preferably, X1 and X2 may be the same or different, and are independently selected from halogen; more preferably, X1 and X2 are both chlorine;

[0131] Respectively react with the compound of formula (3-i) or formula (3-ii) to introduce a chiral amine,

[0132]

[0133] Wherein, R1 and R2 are as defined above,

[0134] The compound of formula (4-i) or formula (4-ii) in step (ii) is obtained.

[0135] Embodiment 2. The method according to embodiment 1, wherein R2 is C 3-6 Alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl.

[0136] Embodiment 3. The method according to embodiment 2, wherein R2 is C 3-6 alkyl.

[0137] Embodiment 4. The method according to Embodiment 3, wherein R2 is tert-butyl.

[0138] Embodiment 5. The method according to any one of embodiments 1 to 4, wherein R1 is C 1-6 alkyl.

[0139] Embodiment 6. The method according to embodiment 5, wherein R1 is methyl.

[0140] Embodiment 7. The method according to any one of embodiments 1 to 6, wherein R3 is C 1-6 Alkanoyl.

[0141] Embodiment 8. The method of Embodiment 7, wherein R3 is pivaloyl.

[0142] Embodiment 9. The method according to any one of embodiments 1 to 8, wherein Ar is aryl, which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, hydroxyl, thiol, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), -(C 1-6 Alkyl)OH, -NH2, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl).

[0143] Embodiment 10. The method of Embodiment 9, wherein Ar is phenyl.

[0144] Embodiment 11. The method according to any one of Embodiments 1 to 10, wherein X1 and X2 may be the same or different and are each independently selected from halogen.

[0145] Embodiment 12. The method according to Embodiment 11, wherein X1 and X2 are both chlorine.

[0146] Embodiment 13. The method according to embodiment 1, wherein

[0147] R1 is C 1-6 alkyl;

[0148] R2 is C 3-6 alkyl;

[0149] R3 is C 1-6 Alkanoyl;

[0150] Ar is aryl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, hydroxyl, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), -(C 1-6 Alkyl)OH, -NH2, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl);

[0151] X1 and X2 may be the same or different and are each independently selected from halogen.

[0152] Embodiment 14. The method according to embodiment 13, wherein

[0153] R1 is methyl;

[0154] R2 is tert-butyl;

[0155] R3 is pivaloyl;

[0156] Ar is phenyl;

[0157] X1 and X2 are both chlorine.

[0158] Embodiment 15. The method according to any one of Embodiments 1 to 14, wherein the compound of formula (3-i) or (3-ii) described in step (i) is obtained by subjecting acetaldehyde to a nucleophilic substitution reaction with a compound of formula (7-i) or (7-ii) in the presence of an acidic catalyst and a dehydrating agent in a solvent,

[0159]

[0160] wherein R2 is as defined in any one of Embodiments 1 to 14,

[0161] The acidic catalyst is selected from one or more of pyridinium p-toluenesulfonate, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, trichloroacetic acid, hydrogen chloride, sulfuric acid, and phosphoric acid.

[0162] The dehydrating agent is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous copper sulfate, molecular sieve, calcium sulfate, silica gel, anhydrous calcium chloride, aluminum oxide, and montmorillonite desiccant.

[0163] The solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethylbenzene, toluene, n-hexane, n-heptane, cyclohexane, cyclopentane, and methylcyclohexane.

[0164] Embodiment 16. The method according to any one of embodiments 1 to 15, wherein the deprotection in step (iv) is achieved by hydrolysis in the presence of a base in a solvent, wherein the base is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, and disodium hydrogen phosphate, and the solvent is selected from water, C 1-6 One or more of alkyl alcohol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, and acetonitrile.

[0165] Embodiment 17. A method according to any one of Embodiments 1 to 16, wherein the Suzuki coupling reaction described in step (iii) is carried out in the presence of a catalyst, an optional catalyst ligand and a base in a solvent at a temperature of 40°C-140°C, the catalyst is selected from one or more of Pd2(dba)3, palladium acetate, Pd(PPh3)4 and Pd(dppf)Cl2, the catalyst ligand is selected from one or more of dppf, BINAP and XPhos, the base is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, disodium hydrogen phosphate, and the solvent is selected from one or more of 1,4-dioxane, toluene, water, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile.

[0166] Embodiment 18. A method according to any one of Embodiments 1 to 17, wherein the Buchwald reaction described in step (ii) is carried out in the presence of a catalyst, an optional catalyst ligand and a base in a solvent at a temperature of 40°C-140°C, the catalyst is selected from one or more of palladium acetate, Pd2(dba)3, PdCl2(PPh3)2 and Pd(dppf)Cl2, the catalyst ligand is selected from one or more of Xantphos, dppf, BINAP and XPhos, the base is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide and disodium hydrogen phosphate, and the solvent is selected from one or more of 1,4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile.

[0167] Embodiment 19. A method according to any one of Embodiments 1 to 18, wherein the nucleophilic substitution reaction described in step (i) is carried out in the presence of a base in a solvent at a temperature of -140°C to -40°C, and the base is selected from one or more of n-butyl lithium, tert-butyl lithium, sec-butyl lithium, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, and lithium diisopropylamide, and the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, n-hexane, and n-heptane.

[0168] Embodiment 20. The method according to any one of Embodiments 1 to 19, wherein the product of step (ii) is not isolated and the reactant of step (ii) is directly used in step (iii).

[0169] Embodiment 21. The compound of formula (4-i) or formula (4-ii),

[0170]

[0171] in,

[0172] X1 and X2 may be the same or different, and are independently selected from halogen, trihalomethoxy, trihaloethoxy, p-toluenesulfonyl; preferably, X1 and X2 may be the same or different, and are independently selected from halogen; more preferably, X1 and X2 are both chlorine;

[0173] R1 is selected from hydrogen or C 1-6 Alkyl; preferably, R1 is C 1-6 Alkyl; More preferably, R1 is methyl;

[0174] R2 is selected from C 1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R2 is selected from C 3-6More preferably, R2 is C 3-6 Alkyl; further preferably, R2 is tert-butyl.

[0175] Embodiment 22. The compound of formula (4-i) or formula (4-ii) according to Embodiment 21, wherein X1 and X2 may be the same or different and are each independently selected from halogen.

[0176] Embodiment 23. A compound of formula (4-i) or formula (4-ii) according to Embodiment 22, wherein X1 and X2 are both chlorine.

[0177] Embodiment 24. A compound of formula (4-i) or formula (4-ii) according to any one of Embodiments 21 to 23, wherein R1 is C 1-6 alkyl.

[0178] Embodiment 25. A compound of formula (4-i) or (4-ii) according to Embodiment 24, wherein R1 is methyl.

[0179] Embodiment 26. A compound of formula (4-i) or formula (4-ii) according to any one of embodiments 21 to 25, wherein R2 is selected from C 3-6 Alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl.

[0180] Embodiment 27. A compound of formula (4-i) or formula (4-ii) according to Embodiment 26, wherein R2 is C 3-6 alkyl.

[0181] Embodiment 28. A compound of formula (4-i) or (4-ii) according to Embodiment 27, wherein R2 is tert-butyl.

[0182] Embodiment 29. The compound of formula (4-i) or formula (4-ii) according to Embodiment 21, wherein

[0183] X1 and X2 may be the same or different and are independently selected from halogen;

[0184] R1 is C 1-6 alkyl;

[0185] R2 is C 3-6 alkyl.

[0186] Embodiment 30. The compound of formula (4-i) or formula (4-ii) according to Embodiment 29, wherein

[0187] X1 and X2 are both chlorine;

[0188] R1 is methyl;

[0189] R2 is tert-butyl.

[0190] Embodiment 31. The compound of formula (5-i) or formula (5-ii),

[0191]

[0192] in,

[0193] X1 is selected from halogen, trihalomethoxy, trihaloethoxy, p-toluenesulfonyl; preferably, X1 is selected from halogen; more preferably, X1 is chlorine;

[0194] R1 is selected from hydrogen or C 1-6 Preferably, R1 is C 1-6 Alkyl; More preferably, R1 is methyl;

[0195] R2 is selected from C 1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R2 is selected from C 3-6 More preferably, R2 is C 3-6 Alkyl; further preferably, R2 is tert-butyl,

[0196] R3 is an amino protecting group; preferably, R3 is an amino protecting group selected from the following: C 1-6 Alkanoyl, triphenylmethyl, benzyl, benzoyl, succinyl, phthaloyl, -NHC(O)OC 1-6 More preferably, R3 is C 1-6 Alkanoyl; further preferably, R3 is pivaloyl.

[0197] Embodiment 32. A compound of formula (5-i) or formula (5-ii) according to Embodiment 31, wherein X1 is selected from halogen.

[0198] Embodiment 33. A compound of formula (5-i) or formula (5-ii) according to Embodiment 32, wherein X1 is chloro.

[0199] Embodiment 34. A compound of formula (5-i) or formula (5-ii) according to any one of embodiments 31 to 33, wherein R1 is C 1-6 alkyl.

[0200] Embodiment 35. A compound of formula (5-i) or (5-ii) according to Embodiment 34, wherein R1 is methyl.

[0201] Embodiment 36. A compound of formula (5-i) or formula (5-ii) according to any one of embodiments 31 to 35, wherein R2 is selected from C 3-6 Alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl.

[0202] Embodiment 37. A compound of formula (5-i) or formula (5-ii) according to Embodiment 36, wherein R2 is C 3-6 alkyl.

[0203] Embodiment 38. A compound of formula (5-i) or (5-ii) according to Embodiment 37, wherein R2 is tert-butyl.

[0204] Embodiment 39. A compound of formula (5-i) or formula (5-ii) according to any one of embodiments 31 to 38, wherein R3 is an amino protecting group selected from the following C 1-6 Alkanoyl, triphenylmethyl, benzyl, benzoyl, succinyl, phthaloyl, -NHC(O)OC 1-6 alkyl.

[0205] Embodiment 40. A compound of formula (5-i) or formula (5-ii) according to Embodiment 39, wherein R3 is C 1-6 Alkanoyl.

[0206] Embodiment 41. A compound of formula (5-i) or (5-ii) according to Embodiment 40, wherein R3 is pivaloyl.

[0207] Embodiment 42. A compound of formula (5-i) or formula (5-ii) according to Embodiment 31, wherein

[0208] X1 is selected from halogen;

[0209] R1 is C 1-6 alkyl;

[0210] R2 is C 3-6 alkyl;

[0211] R3 is C 1-6 Alkanoyl.

[0212] Embodiment 43. A compound of formula (5-i) or formula (5-ii) according to Embodiment 42, wherein

[0213] X1 is chlorine;

[0214] R1 is methyl;

[0215] R2 is tert-butyl;

[0216] R3 is pivaloyl.

[0217] Embodiment 44. Use of a compound of formula (4-i) as defined in any one of Embodiments 21 to 30 or a compound of formula (5-i) as defined in any one of Embodiments 31 to 43 for the preparation of a compound of formula (1-i) as defined in any one of Embodiments 1 to 20.

[0218] Embodiment 45. Use of a compound of formula (4-ii) as defined in any one of Embodiments 21 to 30 or formula (5-ii) as defined in any one of Embodiments 31 to 43 for the preparation of a compound of formula (1-ii) as defined in any one of Embodiments 1 to 20.

[0219] definition

[0220] The term "C 1-6 "Alkyl" refers to a linear or branched saturated monovalent hydrocarbon group having 1 to 6 carbon atoms, for example, 1, 2, 3, 4, 5, or 6 carbon atoms. 1-6 The alkyl group is preferably C 1-4 Alkyl or C 3-6 Alkyl, that is, a linear or branched saturated monovalent hydrocarbon group having 1 to 4 carbon atoms or having 3 to 6 carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, including -CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)CH2CH3, -CH2CH2CH(CH3)2, -CH(C2H5)CH2CH3, -CH2CH(C2H5)CH3, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, -CH2C(CH3)3, -CH2C(CH3)2CH2CH3, and the like.

[0221] The term "C 2-6 "Alkenyl" refers to a linear or branched unsaturated monovalent hydrocarbon group containing 2 to 6 carbon atoms, containing one or more, for example 1, 2 or 3, especially 1 or 2, carbon-carbon double bonds (C=C). The C 2-6 Alkenyl is preferably C 2-4 Alkenyl is a linear or branched unsaturated monovalent hydrocarbon group having 2 to 4 carbon atoms and containing 1 or 2, preferably 1, carbon-carbon double bond (C=C). 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, and 2-butenyl.

[0222] The term "C 2-6"Alkynyl" refers to a linear or branched unsaturated monovalent hydrocarbon group containing 2 to 6 carbon atoms and containing one or more, for example 1, 2 or 3, carbon-carbon triple bonds (C≡C). 2-6 Alkynyl is preferably C 2-4 Alkynyl is a linear or branched unsaturated monovalent hydrocarbon group having 2 to 4 carbon atoms and containing 1 or 2, preferably 1, carbon-carbon triple bond (C≡C). 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

[0223] The term "C 1-6 "Haloalkyl" refers to a C group as described herein in which one or more, for example 1, 2, 3, 4 or 5, in particular 1, 2 or 3, hydrogen atoms are replaced by halogen. 1-6 Alkyl. 1-6 The haloalkyl group is preferably C 1-4 Haloalkyl, i.e., a C alkyl radical as described herein, wherein one or more, for example 1, 2, 3, 4 or 5, in particular 1, 2 or 3, hydrogen atoms are replaced by halogen. 1-4 When more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be identical to or different from each other. 1-6 Examples of haloalkyl include, but are not limited to, -CF3, -CHF2, -CH2CF3, -CH(CF3)2, and the like.

[0224] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine, preferably chlorine and bromine, more preferably chlorine.

[0225] The term "C 1-6 "Alkanoyl" refers to the group RC(=O)-, where R is H or C 1-5 Alkyl. 1-6 Alkanoyl is preferably C 1-4 Alkanoyl, i.e., the group RC(=O)-, where R is H or C 1-3 Alkyl. C 1-6 Examples of alkanoyl groups include, but are not limited to, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl, tert-butyryl, and the like.

[0226] The term "aryl" as used herein refers to a carbocyclic hydrocarbon group consisting of one ring or multiple condensed rings, such as a monocyclic or bicyclic ring, containing 6-14 ring carbon atoms, wherein at least one ring is an aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, indole, preferably phenyl and naphthyl.

[0227] The term "arylayl" as used herein refers to the group R'-C(=O)-, wherein R' is aryl as defined herein. Examples of arylayl include, but are not limited to, benzoyl, naphthoyl, and the like.

[0228] As used herein, the term "heteroaryl" refers to:

[0229] a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, preferably having 6 ring atoms, which contains one or more, for example 1, 2 or 3, more preferably 1 or 2, ring heteroatoms independently selected from N, O and S (preferably N) in the ring, the remaining ring atoms being carbon atoms; and

[0230] A bicyclic aromatic hydrocarbon group having 8-12 ring atoms, preferably 9 or 10 ring atoms, which contains one or more, for example 1, 2, 3 or 4, preferably 2, 3 or 4, ring heteroatoms independently selected from N, O and S (preferably N) in the ring, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring. For example, a bicyclic heteroaryl group includes a 5-6 membered heteroaryl ring fused to a 5-6 membered cycloalkenyl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other.

[0231] Examples of heteroaryl groups include, but are not limited to, pyridinyl, N-oxypyridinyl, such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, or N-oxides thereof; pyrazinyl, such as pyrazin-2-yl, pyrazin-3-yl; pyrimidinyl, such as pyrimidin-2-yl, pyrimidin-4-yl; pyrazolyl, such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl; imidazolyl, such as imidazol-2-yl, imidazol-4-yl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; tetrazolyl, such as tetrazol-5-yl; triazolyl; thienyl; furanyl; pyranyl; pyrrolyl; pyridazinyl; benzodioxolyl, such as benzo[d][1,3]dioxolyl; benzoxazolyl, such as benzo[d] oxazolyl; imidazopyridinyl, for example imidazo[1,2-a]pyridinyl; triazolopyridinyl, for example [1,2,4]triazolo[4,3-a]pyridinyl and [1,2,4]triazolo[1,5-a]pyridinyl; indazolyl; pyrrolopyrimidinyl, for example pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; pyrazolopyrimidinyl pyrazolo[1,5-a]pyrimidinyl; tetrazolopyridinyl, for example tetrazolopyridinyl; benzothienyl; benzofuranyl; benzimidazolinyl; indolyl; indolyl; purinyl, for example 9H-purinyl and 7H-purinyl; quinolyl; isoquinolyl; 1,2,3,4-tetrahydroquinolyl and 5,6,7,8-tetrahydroisoquinolyl.

[0232] As used herein, the term "hydroxy" refers to the group -OH.

[0233] As used herein, the term "mercapto" refers to the group -SH.

[0234] The term "amino protecting group" as used herein, also known as a nitrogen protecting group, refers to a group that can reversibly block or protect an amino and / or amide functional group so that the reaction is carried out on other functional groups of the compound. Suitable amino groups are described, for example, in the relevant chapters of the following works: JFWMcOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TWGreene and PGM Wuts, "Greene's Protective Groups in Organic Synthesis", 4th edition, Wiley, New York 2007; "The Peptides"; Volume 3 (Editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 and "Methoden der organischen Chemie" (Organic Chemistry Methods), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974. Examples of amino protection include, but are not limited to, C 1-6 Alkanoyl, triphenylmethyl, benzyl, benzoyl, succinyl, phthaloyl, -NHC(O)OC 1-6 alkyl, Pmb (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) and Cbz (benzyloxycarbonyl), etc., preferably C 1-6 Alkanoyl (eg, formyl, acetyl, tert-butyryl, pivaloyl, etc.) and benzoyl; more preferably pivaloyl.

[0235] The removal of the amino protecting group can be conveniently carried out according to methods well known in the art, for example, by hydrolysis, for example, by hydrolysis in the presence of a base. The base includes, but is not limited to, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide or disodium hydrogen phosphate, preferably sodium hydroxide.

[0236] The term "optional" means that the material defined by the term may or may not be present or the event defined by the term may or may not occur.

[0237] Terms not defined herein have the ordinary meanings in the art.

[0238] In any formula herein, if vacant valences are present on any atom, the vacant valences are actually hydrogen atoms which are not specifically depicted for the sake of simplicity.

[0239] In this document, if both the name and structural formula of a compound are given, in the event of a discrepancy between the two, the structure of the compound shall prevail unless the context indicates that the structure of the compound is incorrect and the name is correct. DETAILED DESCRIPTION

[0241] The following examples are illustrative of the present invention and should not be construed as limiting the scope of protection of the present invention in any way. The disclosed data (e.g., amount, temperature, etc.) strive to ensure its accuracy, but there may be some experimental errors and offsets. Unless otherwise stated, the parts in the present invention are parts by weight, the temperature is Celsius, and the pressure is atmospheric pressure or near atmospheric pressure. All hydrogen spectrum data are measured by Varian 400-MR. All yields are calculated after measuring the actual content of pure substances of the obtained products. Unless otherwise stated, all reagents used in the examples are obtained from commercial channels.

[0242] The following is a list of abbreviations used herein and in the Examples:

[0243] DCM Methyl Chloroform

[0244] Et3N Triethylamine

[0245] EtOH

[0246] HOAc Acetic acid

[0247] MeOH Methanol

[0248] ph phenyl

[0249] THF Tetrahydrofuran

[0250] LC-MS liquid chromatography-mass spectrometry

[0251] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0252] dppf 1,1′-bis(diphenylphosphino)ferrocene

[0253] BINAP (±)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl

[0254] Xphos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0255] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium

[0256] PdCl2(PPh3)2 Bistriphenylphosphine Palladium dichloride

[0257] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride

[0258] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium

[0259] Piv Pivaloyl

[0260] LDA Lithium Diisopropylamide

[0261] g

[0262] L Liter

[0263] mL milliliters

[0264] mol mole

[0265] h hour

[0266] w / w weight ratio

[0267] DMSO-d6 Deuterated dimethyl sulfoxide

[0268] Example 1

[0269] Synthesis of (R)-N-((S)-1-(3,6-dichloropyridazin-4-yl)ethyl)-2-methylpropane-2-sulfenamide

[0270]

[0271] Under nitrogen protection, lithium diisopropylamide (2.0M solution in tetrahydrofuran, n-heptane and ethylbenzene, 390 mL) was added to toluene (900 mL) at -60 to -70°C. After the addition was completed, the internal temperature was controlled not to be higher than -60°C, and a solution of compound 3,6-dichloropyridazine (45 g, 0.3 mol) and (R)-N-ethylidene-2-methylpropane-2-sulfenamide (66.8 g, 0.45 mmol) in toluene (450 mL) was added dropwise to the toluene solution of lithium diisopropylamide prepared previously. After the reaction is completed, the reaction solution is added to a saturated aqueous ammonium chloride solution (1 L) at 0°C to 10°C to quench, allowed to stand, separated, the organic phase is washed with a saturated aqueous ammonium chloride solution (300 mL), the aqueous phases are combined, extracted twice with 2-methyltetrahydrofuran (100 mL×2), the organic phases are combined, concentrated under reduced pressure, cooled to 0°C to 5°C with stirring, continued to stir for 1 to 2 hours, filtered, the filter cake is rinsed with methyl tert-butyl ether, and dried to obtain 40 g of an off-white solid with a yield of 45%.

[0272] MS (m / z) = 296 [M + H] +

[0273] 1 H NMR (400MHz, DMSO-d6) δ 8.06 (s, 1H), 5.81 (d, J = 7.2Hz, 1H), 4.63 (t, J = 6.9Hz, 1H), 1.52 (d, J = 6.8Hz, 3H), 1.12 (s, 9H).

[0274] Example 2

[0275] Synthesis of N-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-6-chloropyridazin-3-yl)trimethylacetamide

[0276]

[0277] Method 1

[0278] At 20°C to 30°C, potassium carbonate (350g, 2.532mol) was added to a solution of the product of Example 1 (500g, 1.688mol) and pivalamide (172g, 1.700mol) in 1,4-dioxane (4000mL), and nitrogen was introduced into the reaction system. Pd2(dba)3 (46g, 0.050mol) and Xantphos (97g, 0.168mol) were added, and the air in the reactor was replaced with nitrogen, and the temperature was raised to 100°C to 110°C. After the reaction was completed, the mixture was filtered while hot, and the filtrate was concentrated under reduced pressure. At room temperature, ethyl acetate (2.5L) was added, and ethyl acetate (6.5L) was added after concentration under reduced pressure, and activated carbon (50g) was added for decolorization. Filter. The filtrate was concentrated, 2-methyltetrahydrofuran (4L) was added, and after dissolving into a clear solution at 30°C, it was washed twice with water (1L×2). The organic phase was concentrated to dryness, and methyl tert-butyl ether (4 L) was added for slurrying. The solid obtained after filtration was dried under reduced pressure at 45°C to 50°C to obtain the target product, which was a brown product, 473 g, with a yield of 60%.

[0279] LC-MS: 361[M+H] + .

[0280] 1 H NMR (400MHz, DMSO-d6) δ10.70 (s, 1H), 8.54 (d, J=0.5Hz, 1H), 5.86-5.61 (m, 1H), 4 .62 (t, J=6.6Hz, 1H), 1.50 (d, J=6.8Hz, 3H), 1.26 (s, J=11.2Hz, 9H), 1.13 (s, 9H).

[0281] Method 2

[0282] The product of Example 1 (40g, 135-04mmol), pivalamide (14.34g, 141.77mmol) were dissolved in 1,4-dioxane (400mL), potassium carbonate (28.0g, 202.60mmol) was added to the solution, and the air in the reactor was replaced with nitrogen three times, and Xantphos (7.81g, 13.50mmol) and Pd2(dba)3 (3.71g, 4.05mmol) were added. Nitrogen was replaced three times, and the reaction system was heated to 100°C under nitrogen protection. After reacting for 24 hours, the temperature was lowered to 20°C, filtered, and the filter cake was washed with 1,4-dioxane. The obtained filtrate was directly used for the next step of the reaction. By nuclear magnetic analysis, the obtained product was consistent with the product obtained in method 1. The obtained filtrate was analyzed by quantitative HPLC external standard method, and the calculated yield of the reaction was 74.51%.

[0283] Example 3

[0284] Synthesis of N-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-6-phenylpyridazin-3-yl)trimethylacetamide

[0285]

[0286] The product of method 1 of Example 2 (438.5 g, 930 mmol), phenylboronic acid (136 g, 1.12 mol), 1,4-dioxane (3.4 L), water (33.5 g, 1.86 mol) and potassium carbonate (257 g, 1.86 mol) were added sequentially into the reaction flask. After replacing the air in the flask with nitrogen three times, Pd(dppf)Cl2 (68 g, 93 mmol) was added, and after replacing the nitrogen three times again, the reaction system was heated to about 100°C. After reacting for 16 hours, heating was stopped, and the temperature was lowered and filtered. The filter cake was washed three times with tetrahydrofuran (0.5 L×3), and the filtrate was concentrated. The residue was slurried with a mixture of methyl tert-butyl ether (500 mL) and ethyl acetate (200 mL), the slurry was filtered, and the filter cake was washed three times with methyl tert-butyl ether (500 mL×3). The filter cake was collected and dried under reduced pressure at 50-60°C to obtain a total of about 314 g of product with a yield of 71.4%.

[0287] LC-MS: 403 [M+H] + .

[0288] 1H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.52 (d, J=1.4Hz, 1H), 7.66-7.40 (m, 5H), 5.54 (d , J=5.0Hz, 1H), 4.50 (p, J=6.6Hz, 1H), 1.36 (d, J=6.7Hz, 3H), 1.29 (s, 9H), 1.08 (s, 9H).

[0289] Example 4

[0290] Synthesis of (R)-N-((S)-1-(6-amino-3-phenylpyridazin-4-yl)ethyl)-2-methylpropane-2-sulfenamide

[0291]

[0292] Ethanol (246 kg), water (42 kg), the product of Example 3 (33.5 kg) and 7.3% w / w sodium hydroxide aqueous solution (44.7 kg) were added to the reactor in sequence, and the reaction system was heated to 45-55° C. After the reaction was completed, water was added and concentrated to remove most of the ethanol. Water was then added to slurry, and the slurry was filtered to obtain a solid, which was dried at a temperature below 50° C. to obtain 23.6 kg of the target product with a yield of 89.8%.

[0293] It was purified by crystallization with a mixture of dichloromethane and n-heptane (3:3.5 v / v), and 100 mg of the purified product was crystallized with ethyl acetate (2 mL). X-ray single crystal diffraction experiments showed that the structure was consistent with the target structure. The single crystal structure is as follows Figure 3 The conditions for single crystal diffraction are as follows:

[0294] Single crystal X-ray diffractometer: Bruker SMART APEX-II

[0295] Test conditions: Determined according to the first method of 0451 of the fourth general rules of the 2020 edition of the Chinese Pharmacopoeia, CuKα radiation, scanning.

[0296] Structural analysis:

[0297] The crystal structure was analyzed by direct method (Shelxs97), which belongs to monoclinic system, space group is P21, unit cell parameters are: α=γ=90.00°,β=95.903(1)°;unit cell volume The number of asymmetric units in the unit cell is Z = 2. The least squares method is used to correct the structural parameters and determine the atomic types, and the geometric calculation method is used to obtain the positions of all hydrogen atoms. The final reliability factor is R1 = 0.0355, wR2 = 0.0982, and S = 1.051. The chemical formula of the asymmetric unit is finally determined to be C16 H 22 N4OS, calculated molecular weight is 318.44, calculated crystal density is 1.172 g / cm 3 .

[0298] The results show that the molecular arrangement in the crystalline state belongs to the first type of space group, the sample is optically active, and the Flack coefficient is 0.081 (16). The absolute configuration of the compound in the crystal can be determined as shown in this example, and its stereoscopic structure ellipsoid diagram is shown in Figure 3 .

[0299] Example 5

[0300] Synthesis of (R)-2-methyl-N-((S)-1-(6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)propane-2-sulfenamide

[0301]

[0302] The product of Example 4 (60.72 g, 0.191 mol), ethanol (576 mL), water (24 mL), sodium bicarbonate (35.24 g, 0.419 mol) and 40% w / w chloroacetaldehyde (67.35 g, 0.343 mol) were added to a reaction flask, and the reaction system was heated to 65°C-70°C. After reacting for 9 hours, the temperature was lowered to 15°C-20°C and filtered. After the filtrate was concentrated, water was added dropwise to precipitate the product, which was filtered. The filter cake was dried under reduced pressure at 45°C-60°C, and the obtained solid was crystallized with a mixture of dichloromethane and isopropyl ether (25:1 w / w) to obtain 67.5 g of the target product.

[0303] LC-MS: 343 [M+H] + .

[0304] Example 6

[0305] Synthesis of (S)-1-(6-phenylimidazo[1,2-b]pyridazin-7-yl)ethylamine hydrochloride

[0306]

[0307] To a solution of the product of Example 5 (1055 g, 3.08 mol) in ethanol (4747 mL) was added dropwise 4 M ethanol solution of hydrogen chloride (3085 mL) at 20°C-25°C, and the mixture was reacted at 20°C-35°C for 16 hours. After concentrating to remove most of the solvent, ethyl acetate was added, the mixture was concentrated and refluxed for pulping, the temperature was lowered and the filter cake was dried in vacuo at 55°C-65°C to obtain 900 g of the target product.

[0308] LC-MS: 239 [M+H] + .

[0309] Example 7

[0310] Synthesis of (S)-N-((R)-1-(3,6-dichloropyridazin-4-yl)ethyl)-2-methylpropane-2-sulfenamide

[0311]

[0312] The title compound was prepared as a solid (42 g) using 3,6-dichloropyridazine and (S)-N-ethylidene-2-methylpropane-2-sulfenamide as starting materials according to the method of Example 1.

[0313] MS (m / z) = 296 [M + H] + .

[0314] 1 H NMR (400MHz, DMSO-d6) δ8.04 (s, 1H), 5.78 (d, 1H), 4.61 (m, 1H), 1.51 (d, 3H), 1.10 (s, 9H).

[0315] Example 8

[0316] Synthesis of N-(5-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-6-chloropyridazin-3-yl)trimethylacetamide

[0317]

[0318] The product in Example 7 was used as a starting material and the title compound was prepared according to the method of Example 2 as a brown solid, 222 g, with a yield of 40.5%.

[0319] 1 H NMR (400MHz, DMSO-d6) δ10.68 (s, 1H), 8.52 (s, 1H), 5.73 (d, 1H), 4.60 (m, 1H), 1.49 (m, 3H), 1.23 (s, 9H), 1.09 (s, 9H).

[0320] Example 9

[0321] Synthesis of N-(5-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-6-phenylpyridazin-3-yl)trimethylacetamide

[0322]

[0323] The product in Example 8 was used as a starting material and the title compound was prepared according to Method 1 of Example 3 as a brown solid, 560 g, with a yield of 77.1%.

[0324] 1 H NMR (400MHz, DMSO-d6) δ10.57 (S, 1H), 8.50 (s, 1H), 7.60-7.42 (m, 5H), 5.61 (d, J=5.0Hz, 1H ), 4.46 (dd, J=6.6, 5.1Hz, 1H), 1.32 (d, J=6.7Hz, 3H), 1.26 (S, 9H), 1.03 (d, J=12.3Hz, 9H).

[0325] Example 10

[0326] Synthesis of (S)-N-((R)-1-(6-amino-3-phenylpyridazin-4-yl)ethyl)-2-methylpropane-2-sulfenamide

[0327]

[0328] The product in Example 9 was used as a starting material and the title compound was prepared according to the method of Example 4 as a brown solid, 300 g, with a yield of 68.9%.

[0329] 1 H NMR (400MHz, DMSO-d6) δ7.47-7.40 (m, 5H), 6.90 (S, 1H), 6.43 (s, 2H), 5.45 (d, J=4.9Hz, 1H), 4.40-4.37 (m, 1H), 1.26 (d, J=6.7Hz, 3H), 1.07 (S, 9H).

[0330] The product prepared in Example 10 has two chiral centers and is an enantiomer with the product prepared in Example 4. In addition, two other isomers were synthesized by other methods (the structural formula is as follows, and the specific synthesis steps are not given).

[0331]

[0332] The product of Example 4, the product of Example 10, and the four isomers of isomer 1 and isomer 2 were passed through a chiral chromatographic column, wherein the retention time of the product prepared in Example 4 was 13.03 min, the retention time of the product prepared in Example 10 was 11.52 min, the retention time of isomer 1 was 6.26 min, and the retention time of isomer 2 was 8.31 min; the four isomers can be completely separated by the chiral column. The conditions of the chiral chromatographic column are as follows:

[0333] Mobile phase: Mobile phase A: ethanol containing 0.1% triethylamine, mobile phase B: n-hexane;

[0334] Chromatographic column: Brand: CHIRALPAK OJ; Model: 4.6mm*25mm, 5μm;

[0335] Elution gradient: 0-30 min, 10% (A%);

[0336] Flow rate: 1 mL / min;

[0337] UV: 244nm.

[0338] In addition, the above four isomers were detected by non-chiral HPLC column, and the results showed that the retention time of the products prepared in Example 4 and Example 10 was basically the same, wherein the retention time of the product prepared in Example 4 was 9.95min, and the retention time of the product prepared in Example 10 was 9.99min; the retention time of isomer 1 and isomer 2 was consistent, both being 11.34min. This proves that the products prepared in Example 4 and Example 10 are a pair of enantiomers, and isomer 1 and isomer 2 are a pair of enantiomers. The conditions of non-chiral HPLC are as follows:

[0339] Mobile phase: Mobile phase A: acetonitrile containing 0.01% trifluoroacetic acid, mobile phase B: water containing 0.02% trifluoroacetic acid;

[0340] Chromatographic column: Brand: Welch Xtimate; Model: 4.6mm*250mm, 5μm;

[0341] Elution gradient:

[0342]

[0343] Flow rate: 1 mL / min;

[0344] UV: 248nm.

[0345] Since the configurations of the chiral carbon and chiral sulfur of the product prepared in Example 4 have been confirmed by single crystal diffraction, and it is the enantiomer of the product prepared in Example 10, the configurations of the chiral carbon and chiral sulfur of the product prepared in Example 10 are confirmed by further combining the hydrogen spectrum data of the two intermediates.

[0346] Embodiment 11

[0347] Synthesis of (S)-2-methyl-N-((R)-1-(6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)propane-2-sulfenamide

[0348]

[0349] The product in Example 10 was used as a starting material and the title compound was prepared according to the method of Example 5. The product was a brown solid, 205 g, with a yield of 73.4%.

[0350] 1 H NMR (400MHz, DMSO-d6) δ8.26-8.25(m, 2H), 7.82(s, 1H), 7.57-7.52(m, 5H), 5. 56 (d, J=6.4Hz, 1H), 4.44 (p, J=6.6Hz, 1H), 1.38 (d, J=6.7Hz, 3H), 1.12 (s, 9H).

[0351] Example 12

[0352] Synthesis of (R)-1-(6-phenylimidazo[1,2-b]pyridazin-7-yl)ethylamine

[0353]

[0354] The product of Example 11 (200 g, 0.584 mol) and ethanol (700 mL) were added to the reaction vessel in sequence, stirred and cooled to 0°C, then 4M hydrogen chloride ethanol solution (584 mL) was added dropwise, and then the temperature was raised to 20-25°C. After the reaction was complete, ethyl acetate was added to crystallize, filtered, the filter cake was collected and dried under reduced pressure at 60°C. The obtained filter cake was dissolved in water, sodium bicarbonate was added to adjust the pH to 8-9, filtered, the filter cake was washed with water, and dried under reduced pressure at 52°C. The target product was obtained as a brown solid, 162 g, with a yield of 89.5%.

[0355] LC-MS: 239.1[M+H] + .

[0356] 1 H NMR (400MHz, DMSO-d6) δ8.34 (s, 1H), 8.23 ​​(dd, J=1.2, 0.8Hz, 1H), 7.77 (t, J=1.2H z, 1H), 7.65-7.38 (m, 5H), 4.06-3.96 (m, 1H), 2.03 (S, 2H), 1.09 (d, J=6.5Hz, 3H).

[0357] Example 13

[0358] Synthesis of (R)-N-ethylidene-2-methylpropane-2-sulfenamide

[0359] R-tert-butylsulfenamide (150g, 1.24mol), toluene (1250mL), molecular sieve (225g) and pyridinium p-toluenesulfonate (15.5g, 0.06mol) were added to a reaction flask, cooled to 0-10°C, anhydrous magnesium sulfate (150g) was added, and a toluene (250mL) solution of acetaldehyde (104mL, 1.86mol) was added to the above reaction system. Anhydrous magnesium sulfate (150g) and acetaldehyde (50mL, 0.89mol) were added to the above reaction system. After the reaction was completed, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a toluene solution of the target product of 161.8g, which can be directly used in the next step.

[0360] MS (m / z) = 148.20 [M+H] + . BRIEF DESCRIPTION OF THE DRAWINGS

[0361] Figure 1 It is the synthetic route I of WO2016 / 045591A1.

[0362] Figure 2A The following is a synthetic route of the compound of formula (1-i) of the present invention.

[0363] Figure 2B This is a synthetic route for the compound of formula (1-ii) of the present invention.

[0364] Figure 3 This is the three-dimensional structural ellipsoid diagram of the product of Example 4.

[0365] Figure 4A This is a flow chart for preparing the imidazo[1,2-b]pyridazine compounds disclosed in WO2016045591A1 using the compound of formula (1-i) of the present invention. For specific examples, see Examples 5-6 in the Examples.

[0366] Figure 4B This is a flow chart for preparing the imidazo[1,2-b]pyridazine compounds disclosed in WO2016045591A1 using the compound of formula (1-ii) of the present invention. For specific examples, see Examples 11-12 in the Examples.

Claims

1. A method for preparing compounds of formula (1-i) and formula (1-ii), in, R1 is selected from hydrogen or C 1-6 alkyl; R2 is selected from C 1-6 Alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; Ar is aryl or heteroaryl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, hydroxyl, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), -(C 1-6 Alkyl)OH, -NH2, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl), the aryl group refers to a monocyclic or bicyclic carbocyclic hydrocarbon group containing 6 to 14 ring carbon atoms, wherein at least one ring is an aromatic ring, the heteroaryl group refers to a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, which contains 1, 2 or 3 ring heteroatoms independently selected from N, O and S in the ring, and the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group having 8 to 12 ring atoms, which contains 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S in the ring, and the remaining ring atoms are carbon atoms, and wherein at least one ring is an aromatic ring, The method comprises the following steps: (i) making a compound of formula (2) Wherein, X1 and X2 may be the same or different and are independently selected from halogen; Respectively react with the compound of formula (3-i) or formula (3-ii) to introduce a chiral amine, Wherein, R1 and R2 are as defined above, Obtaining a compound of formula (4-i) or formula (4-ii), Wherein, R1, R2, X1 and X2 are as defined above, (ii) subjecting the compound of formula (4-i) or formula (4-ii) to a Buchwald reaction with an amine R3NH2 to obtain a compound of formula (5-i) or formula (5-ii), Wherein, R1, R2, and X1 are as defined above, R3 is an amino protecting group, (iii) subjecting the compound of formula (5-i) or formula (5-ii) to Suzuki coupling reaction with ArB(OH)2 to introduce an Ar group on the pyridazine ring to obtain a compound of formula (6-i) or formula (6-ii), wherein R1, R2, R3 and Ar are as defined above, (iv) Deprotecting the compound of formula (6-i) or formula (6-ii) to remove the amino protecting group R3 to obtain compounds of formula (1-i) and formula (1-ii), respectively.

2. The method according to claim 1, wherein: R1 is C 1-6 alkyl.

3. The method according to claim 1, wherein: R1 is methyl.

4. The method according to claim 1, wherein: R2 is selected from C 3-6 Alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl.

5. The method according to claim 1, wherein: R2 is C 3-6 alkyl.

6. The method according to claim 1, wherein: R2 is tert-butyl.

7. The method according to any one of claims 1 to 6, wherein: Ar is aryl, which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, hydroxyl, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), -(C 1-6 Alkyl)OH, -NH2, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 The aryl group refers to a monocyclic or bicyclic carbocyclic hydrocarbon group containing 6 to 14 ring carbon atoms, wherein at least one ring is an aromatic ring.

8. The method according to any one of claims 1 to 6, wherein: Ar is phenyl, which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, hydroxy, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), -(C 1-6 Alkyl)OH, -NH2, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl).

9. The method according to any one of claims 1 to 6, wherein: R3 is an amino protecting group selected from the group consisting of: 1-6 Alkanoyl, triphenylmethyl, benzyl, benzoyl, succinyl, phthaloyl, -NHC(O)OC 1-6 alkyl, Pmb (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl).

10. The method according to any one of claims 1 to 6, wherein: R3 is an amino protecting group, which is C 1-6 Alkanoyl.

11. The method according to any one of claims 1 to 6, wherein: R3 is an amino protecting group, which is pivaloyl.

12. The method according to any one of claims 1 to 6, wherein: X1 is chlorine.

13. The method according to any one of claims 1 to 6, wherein: X1 and X2 are both chlorine.

14. The method according to any one of claims 1 to 6, wherein: The compound of formula (3-i) or formula (3-ii) wherein R1 is methyl in step (i) It is obtained by subjecting acetaldehyde to a nucleophilic substitution reaction with a compound of formula (7-i) or formula (7-ii) in the presence of an acidic catalyst and a dehydrating agent in a solvent, wherein R2 is as defined in any one of claims 1 to 6, and the acidic catalyst is selected from one or more of pyridinium p-toluenesulfonate, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, trichloroacetic acid, hydrogen chloride, sulfuric acid, and phosphoric acid, The dehydrating agent is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous copper sulfate, molecular sieve, calcium sulfate, silica gel, anhydrous calcium chloride, aluminum oxide, and montmorillonite. The solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethylbenzene, toluene, n-hexane, n-heptane, cyclohexane, cyclopentane, and methylcyclohexane.

15. The method according to any one of claims 1 to 6, wherein: The deprotection in step (iv) is achieved by hydrolysis in the presence of a base in a solvent, wherein the base is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, and disodium hydrogen phosphate, and the solvent is selected from water, C 1-6 One or more of alkyl alcohol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, and acetonitrile.

16. The method according to any one of claims 1 to 6, wherein: The Suzuki coupling reaction described in step (iii) is carried out in the presence of a catalyst, an optional catalyst ligand and a base in a solvent at a temperature of 40°C-140°C, wherein the catalyst is selected from one or more of Pd2(dba)3, palladium acetate, Pd(PPh3)4 and Pd(dppf)Cl2, the catalyst ligand is selected from one or more of dppf, BINAP and XPhos, the base is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, disodium hydrogen phosphate, and the solvent is selected from one or more of 1,4-dioxane, toluene, water, tetrahydrofuran, 2-methyltetrahydrofuran and acetonitrile.

17. The method according to any one of claims 1 to 6, wherein: The Buchwald reaction described in step (ii) is carried out in the presence of a catalyst, an optional catalyst ligand and a base in a solvent at a temperature of 40°C-140°C, wherein the catalyst is selected from one or more of palladium acetate, Pd2(dba)3, PdCl2(PPh3)2 and Pd(dppf)Cl2, the catalyst ligand is selected from one or more of Xantphos, dppf, BINAP and XPhos, the base is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide and disodium hydrogen phosphate, and the solvent is selected from one or more of 1,4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran and acetonitrile.

18. The method according to any one of claims 1 to 6, wherein: The nucleophilic substitution reaction described in step (i) is carried out in the presence of a base in a solvent at a temperature of -140°C to -40°C, wherein the base is selected from one or more of n-butyl lithium, tert-butyl lithium, sec-butyl lithium, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, and lithium diisopropylamide, and the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, n-hexane, and n-heptane.

19. The method according to any one of claims 1 to 6, wherein: The product of step (ii) is not isolated, and the reactant of step (ii) is directly used in step (iii).

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