TW202340151A - Synthesis method of intermediates for preparing imidazolo[1,2-b]pyridazines - Google Patents

Abstract

The invention relates to a synthetic method of intermediates for preparing imidazolo[1,2-b]pyridazines. The invention pertains to the field of pharmaceutical chemistry. More specifically, the invention relates to a new synthesis method of intermediates that can be used to synthesize imidazolo[1,2-b]pyridazines as well as some new intermediates.

Description

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

The invention belongs to the field of medicinal chemistry. More specifically, the present invention relates to new synthetic methods for intermediates useful in the synthesis of imidazo[1,2-b]pyridazines, and also to some new intermediate compounds.

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

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 multiple synthetic routes depicted in Scheme I and Scheme II of patent application WO2016/045591A1.

Synthetic route I of WO2016/045591A1 is shown in Figure 1. In this synthetic route, the preparation of the final product imidazo[1,2-b]pyridazine compounds includes more than a dozen steps, wherein formula (i-8) The preparation of intermediates involves up to 7 steps:

Step 1: React the compound of formula i-1 with N,O -dimethylhydroxylamine to obtain the amide compound of formula i-2.

Step 2: React the compound of formula i-2 with M-H to obtain the compound of formula i-3.

Step 3: The compound of formula i-3 and the compound of formula ArB(OH) ₂ are catalyzed by an appropriate palladium reagent, and the compound of formula i-4 is obtained by Suzuki coupling reaction. 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, etc., in a suitable base such as TEA, DIPEA, Cs ₂ CO ₃ , KOAc, etc., Catalysts such as Pd(OAc) ₂ , Pd(dppf)Cl ₂ , Pd(PPh ₃ ) ₄ or Pd ₂ (dba) ₃ are used.

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

Alternatively, steps 4 to 6 are performed as follows: the compound of formula i-4 is reduced in the presence of an appropriate reducing agent to obtain compound i-5'. Compound i-5' is condensed with ( R )-2-methylpropane-2-sulfinamide, and then reacts with Grignard reagent (alkyl magnesium halide) under appropriate conditions to generate the compound of formula i-7.

Step 7: Remove the protecting group from the compound of formula i-7 to obtain the compound of formula i-8.

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

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

In addition, the synthesis route disclosed in WO2016/045591A1 all uses 3,6-dichloropyridazine-4-carboxylic acid as the starting raw material. This raw material is not easy to obtain and is expensive. The commercial price per kilogram is as high as about 17,000 yuan. RMB. This results in high production costs for new imidazo[1,2-b]pyridazine compounds.

Therefore, new synthesis methods are needed to improve the above-mentioned shortcomings of the existing technology.

In a first aspect, the invention relates to a method for preparing compounds of formula ( 1-i ) and formula ( 1-ii ),

in,

R ₁ is selected from hydrogen or C _1-6 alkyl; preferably, R ₁ is C _1-6 alkyl; more preferably, R ₁ is methyl;

R ₂ is selected from C _1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl, Phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tertiary butyl;

Ar is an aryl or heteroaryl group, optionally substituted with one or more substituents independently selected from: 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, -NH ₂ , -NH(C _1-6 alkyl) group) or -N(C _1-6 alkyl)(C _1-6 alkyl); preferably, Ar is an aryl group; more preferably, Ar is a phenyl group,

As shown in Figure 2A and Figure 2B, this method includes 4 steps:

(i) Let the compound of formula ( 2 )

_Among them, _{X 1 and} Different, each is independently selected from halogen; more preferably, X ₁ and X ₂ are both chlorine;

A nucleophilic substitution reaction occurs with the compound of formula ( 3-i ) or formula ( 3-ii ) respectively, and a chiral amine is introduced.

Wherein, R ₁ is selected from hydrogen or C _1-6 alkyl; preferably, R ₁ is C _1-6 alkyl; more preferably, R ₁ is methyl, and R ₂ is selected from C _1-6 alkyl , phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl, phenyl, p-methylphenyl, benzyl group or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tert-butyl,

Obtain the compound of formula ( 4-i ) or formula ( 4-ii ),

Among them, X ₁ , X ₂ , R ₁ and R ₂ are as defined above;

(ii) subjecting the compound of formula ( 4-i ) or formula ( 4-ii ) to Buchwald reaction with amine R ₃ NH ₂ respectively to obtain the compound of formula ( 5-i ) or formula ( 5-ii ),

Among them, X ₁ , R ₁ and R ₂ are as defined above; and R ₃ is an amino protecting group; preferably, R ₃ is an amino protecting group selected from the following: C _1-6 alkyl group, triphenyl group Methyl, benzyl, benzyl, succinyl, phthalyl, -NHC(O)OC _1-6 alkyl, Pmb (p-methoxybenzyl), Boc (No. Tributyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl); more preferably, R ₃ is a C _1-6 alkyl group; further preferably, R ₃ is a special pentyl;

(iii) The compound of formula ( 5-i ) or formula ( 5-ii ) is subjected to a Suzuki coupling reaction with ArB(OH) ₂ , and an Ar group is introduced into the pyridazine ring to obtain formula ( 6-i ) or Compounds of formula ( 6-ii ),

wherein R ₁ , R ₂ and R ₃ are as defined above, and Ar is an aryl or heteroaryl group, optionally substituted with one or more substituents independently selected from: halogen, -CN, hydroxyl , mercapto group, 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 base) OH, -NH ₂ , -NH (C _1-6 alkyl) or -N (C _1-6 alkyl) (C _1-6 alkyl); preferably, Ar is an aryl group; more preferably , Ar is phenyl;

(iv) Deprotect the compound of formula ( 6-i ) or formula ( 6-ii ) to remove the amino protecting group R ₃ to obtain the compounds of formula ( 1-i ) and formula ( 1-ii ) respectively,

Wherein, R ₁ , R ₂ and Ar are as defined above.

Compared with the method for preparing intermediate (i-8) in WO2016/045591A1, the method of the present invention has various advantages. First, the method of the present invention includes fewer steps, the operation is significantly simplified, the synthesis steps are reduced, and the overall yield is also greatly improved. Secondly, the method of the present invention has a specific synthesis sequence and is a chiral synthesis method that can directly obtain the required stereoisomer without the need for separation and purification by column chromatography. It is very suitable for large-scale industrial production. . Third, the compound of formula ( 2 ) in which X ₁ and X ₂ are halogens used as starting materials in the method of the present invention is very cheap, with a commercial price of only a few hundred yuan per kilogram. 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.

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,

R ₁ is C _1-6 alkyl;

R ₂ is C _3-6 alkyl;

R ₃ is C _1-6 alkyl group;

Ar is an aryl group, optionally substituted with one or more substituents independently selected from: 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, -NH ₂ , -NH(C _1-6 alkyl) or - N(C _1-6 alkyl)(C _1-6 alkyl);

X ₁ and X ₂ may be the same or different and are each independently selected from halogen.

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,

R ₁ is methyl;

R ₂ is tertiary butyl;

R ₃ is pivalyl group;

Ar is phenyl;

X ₁ and X ₂ are both chlorine.

In an embodiment of the first aspect, the compound of formula ( 2 ) described in step (i) is 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 prepared by mixing acetaldehyde with a commercially available compound of formula ( 7-i ) or formula ( 7-ii ) in an acidic catalyst and a dehydrating agent. Obtained by carrying out nucleophilic substitution reaction in solvent in the presence of

Wherein, R ₂ is selected from C _1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl base, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tert-butyl base,

The acidic catalyst is selected from the group consisting 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 One or more of them; 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, monohydrated p-toluenesulfonic acid, and methane sulfonic acid;

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, alumina, and montmorillonite desiccants; preferably, the dehydrating agent One or more selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous copper sulfate, molecular sieve, calcium sulfate, silica gel, and anhydrous calcium chloride; more preferably, the dehydrating agent is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous sulfuric acid One or more of copper, molecular sieve, calcium sulfate, and silica gel;

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

In an embodiment of the first aspect, the nucleophilic substitution reaction of the compound of formula ( 2 ) and the compound of formula ( 3-i ) or formula ( 3-ii ) described in step (i) can be known in the art carried out under normal conditions. For example, the reaction can be carried out in the presence of a base. The base is selected from n-butyllithium, tert-butyllithium, sec-butyllithium, sodium hexamethyldisilamide, lithium hexamethyldisilamide, and potassium hexamethyldisilamide , one or more of lithium diisopropylamide. The reaction is carried out in a solvent, which 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 -120℃~-70℃, -120℃~-80℃, -120℃~-90℃, -120℃~-100℃, -120℃~-110℃, -110℃~-70℃ , -110℃~-80℃, -110℃~-90℃, -110℃~-100℃, -100℃~-70℃, -100℃~-80℃ or -100℃~-90℃ For example, it can be carried out at -120℃~-110℃, -110℃~-100℃, -100℃~-90℃ or -90℃~-80℃. For example, it can be carried out at -120℃ ~-115℃, -115℃~-110℃, -110℃~-105℃, -105℃~-100℃, -100℃~-95℃, -95℃~-90℃-, 90℃~- Conducted at temperatures of 85°C, -85°C~-80°C, and -60°C~-70°C.

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 ) can be mixed with the compound of formula ( 3-i ) or formula ( 3-ii ) first in the reaction solvent and reduce it to the temperature required for the reaction, and then add the base to carry out nucleophilic substitution reaction. Alternatively, the base can be lowered to the temperature required for the reaction in the reaction solvent first, and then the compound of formula ( 2 ) and the compound of formula ( 3-i ) or formula ( 3-ii ) can be added to perform a nucleophilic substitution reaction. Alternatively, the reaction solvent can 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 formula ( 3-ii ) can be added in sequence to perform a nucleophilic substitution reaction. Alternatively, the reaction solvent can be lowered to the temperature required for the reaction, and then the compound of formula ( 2 ), the compound of formula ( 3-i ) or formula ( 3-ii ), and the base can be added in sequence to perform a nucleophilic substitution reaction .

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

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

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 90℃-120℃, 100℃-120℃, 110℃-120℃, 80℃-110℃, 90℃-110℃, 90-105℃, 100℃-110℃, 80℃-100℃, It can be carried out at a temperature of 90°C-100°C or 80°C-90°C, or at a temperature of 80°C-90°C, 90°C-100°C, 100°C-110°C or 110°C-120°C.

If the Buchwald reaction of step (ii) is carried out in the presence of a catalyst, optional catalyst ligands and a base, the compound of formula ( 4-i ) or formula ( 4-ii ), the amine R ₃ NH ₂ and the base can first be Mix in the reaction solvent, then add the catalyst and optional catalyst ligands under the protection of an inert gas, and raise the temperature to the temperature required for the reaction to perform the Buchwald reaction. Alternatively, the catalyst and optional catalyst ligands can be added to the reaction solvent under the protection of inert gas, and then the compound of formula ( 4-i ) or formula ( 4-ii ) and amine R ₃ NH ₂ can be added and a base, and raise the temperature to the temperature required for the reaction to perform the Buchwald reaction.

The product of step (ii) may not be separated, and the reaction system may be directly used in step (iii).

In an embodiment of the first aspect, the Suzuki coupling reaction described in step (iii) may be performed under conventional conditions known in the art. For example, the Suzuki coupling reaction can be performed in the presence of a catalyst selected from the group consisting of Pd ₂ (dba) ₃ , palladium acetate, Pd(PPh ₃ ) ₄ and Pd(dppf)Cl, optional catalyst ligands and a base. One or more of ₂ , the catalyst ligand can be selected from one or more of dppf, BINAP and XPhos, the base can be selected from the group consisting of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate , one or more of potassium fluoride, cesium fluoride, sodium hydroxide, and disodium hydrogen phosphate.

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.

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 80℃-120℃, 90℃-120℃, 100℃-120℃, 110℃-120℃, 80℃-110℃, 90℃-110℃, 100℃-110℃, 80-105℃, 80℃-100℃, 90℃-100℃, 80℃-90℃, 70℃-90℃ or 70℃-80℃, or at 70℃-80℃, 80℃-90℃, 90℃ ℃-100℃, 100℃-110℃ or 110℃-120℃.

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

In an embodiment of the first aspect, the deprotection described in step (iv) may be performed under conventional conditions known in the art for the removal of amine protecting groups. For example, the deprotection can be performed by hydrolysis in the presence of a base. The base may be selected from 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, phosphoric acid One or more types of disodium hydroxide are preferably selected from one or more types of sodium hydroxide, lithium hydroxide, potassium hydroxide, and cesium hydroxide. More preferably, the base is sodium hydroxide. The solvent used for this hydrolysis can be selected from one or more of water, C _1-6 alkyl alcohol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetonitrile, and is preferably selected from water. , one or more of methanol, ethanol, tetrahydrofuran, isopropyl alcohol, butanol, 1,4-dioxane, ethyl acetate, isopropyl acetate, butanol, and acetonitrile.

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

In a second aspect, the invention relates to compounds of formula ( 4-i ) or formula ( 4-ii ),

in,

_{X 1 and _} Independently selected from halogen; more preferably, X ₁ and X ₂ are both chlorine;

R ₁ is selected from hydrogen or C _1-6 alkyl; preferably, R ₁ is C _1-6 alkyl; more preferably, R ₁ is methyl;

R ₂ is selected from C _1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl, Phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tertiary butyl.

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

X ₁ and X ₂ may be the same or different, and are each independently selected from halogen;

R ₁ is C _1-6 alkyl;

R ₂ is C _3-6 alkyl.

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

X ₁ and X ₂ are both chlorine;

R ₁ is methyl;

R ₂ is tertiary butyl.

In a third aspect, the invention relates to compounds of formula ( 5-i ) or formula ( 5-ii ),

in,

X ₁ is selected from halogen, trihalomethoxy, trihaloethoxy, and p-toluenesulfonyl; preferably, X ₁ is selected from halogen; more preferably, X ₁ is chlorine;

R ₁ is selected from hydrogen or C _1-6 alkyl; preferably, R ₁ is C _1-6 alkyl; more preferably, R ₁ is methyl;

R ₂ is selected from C _1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl, Phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tertiary butyl;

R ₃ is an amino protecting group; preferably, R ₃ is an amino protecting group selected from the following: C _1-6 alkyl group, triphenylmethyl, benzyl, benzyl, succinyl group , Phthalyl, -NHC(O)OC _1-6 alkyl, Pmb (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethoxy (carbonyl) or Cbz (benzyloxycarbonyl); more preferably, R ₃ is a C _1-6 alkyl group; further preferably, R ₃ is a pivalyl group.

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

X ₁ is selected from halogen;

R ₁ is C _1-6 alkyl;

R ₂ is C _3-6 alkyl;

R ₃ is C _1-6 alkyl group.

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

X ₁ is chlorine;

R ₁ is methyl;

R ₂ is tertiary butyl;

R ₃ is pivalyl group.

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

In the fifth aspect, the present invention relates to 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 ) use.

Implementation plan

Embodiment 1. Methods for preparing compounds of formula ( 1-i ) and formula ( 1-ii ),

in,

R ₁ is selected from hydrogen or C _1-6 alkyl; preferably, R ₁ is C _1-6 alkyl; more preferably, R ₁ is methyl;

R ₂ is selected from C _1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl, Phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tertiary butyl;

Ar is an aryl or heteroaryl group, optionally substituted with one or more substituents independently selected from: 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, -NH ₂ , -NH(C _1-6 alkyl) group) or -N(C _1-6 alkyl)(C _1-6 alkyl); preferably, Ar is an aryl group; more preferably, Ar is a phenyl group,

The method includes the following steps:

(iv) Deprotect the compound of formula ( 6-i ) or formula ( 6-ii ) to remove the amino protecting group R ₃ ,

Among them, R ₁ , R ₂ and Ar are as defined above, and R ₃ is an amino protecting group; preferably, R ₃ is an amino protecting group selected from the following: C _1-6 alkyl, triphenylmethyl base, benzyl, benzyl, succinyl, phthalyl, -NHC(O)OC _1-6 alkyl, Pmb (p-methoxybenzyl), Boc (tertiary butyl) (oxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl); more preferably, R ₃ is C _1-6 alkyl group; further preferably, R ₃ is pivalenyl base,

Compounds of formula ( 1-i ) and formula ( 1-ii ) were obtained respectively;

Optionally, the above method further includes step (iii) before step (iv):

(iii) The compound of formula ( 5-i ) or formula ( 5-ii ) is subjected to a Suzuki coupling reaction with ArB(OH) ₂ , and an Ar group is introduced into the pyridazine ring,

Among them, R ₁ , R ₂ , R ₃ and Ar are as defined above, and X ₁ is selected from halogen, trifluoromethoxy, trifluoroacetyl, p-toluenesulfonyloxy; preferably, X ₁ is selected from Halogen; more preferably, X ₁ is chlorine,

Obtain the compound of formula ( 6-i ) or formula ( 6-ii ) in step (iv);

Optionally, the above method further includes step (ii) before step (iii):

(ii) causing the compound of formula ( 4-i ) or formula ( 4-ii ) to undergo a Buchwald reaction with the amine R ₃ NH ₂ respectively,

Among them, R ₁ , R ₂ and R ₃ are as defined above, and X ₁ and X ₂ can be the same or different, each independently selected from halogen, trifluoromethoxy, trifluoroacetyl, p-toluenesulfonyloxy base; preferably, X ₁ and X ₂ can be the same or different, and are each independently selected from halogen; more preferably, X ₁ and X ₂ are both chlorine,

Obtain the compound of formula ( 5-i ) or formula ( 5-ii ) in step (iii);

Optionally, the above method further includes step (i) before step (ii):

(i) Let the compound of formula ( 2 )

_Among them, _{X 1 and} Different, each is independently selected from halogen; more preferably, X ₁ and X ₂ are both chlorine;

A nucleophilic substitution reaction occurs with the compound of formula ( 3-i ) or formula ( 3-ii ) respectively, and a chiral amine is introduced.

where R ₁ and R ₂ are as defined above,

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

Embodiment 2. The method of Embodiment 1, wherein R ₂ is C _3-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl.

Embodiment 3. The method of Embodiment 2, wherein R ₂ is C _3-6 alkyl.

Embodiment 4. The method of Embodiment 3, wherein _R2 is tert-butyl.

Embodiment 5. The method of any one of embodiments 1 to 4, wherein R ₁ is C _1-6 alkyl.

Embodiment 6. The method of embodiment 5, wherein _R1 is methyl.

Embodiment 7. The method of any one of embodiments 1 to 6, wherein R ₃ is C _1-6 alkylyl.

Embodiment 8. The method of embodiment 7, wherein _R3 is pivalyl.

Embodiment 9. The method of any one of embodiments 1 to 8, wherein Ar is an aryl group, optionally substituted with one or more substituents independently selected from: halogen, -CN, Hydroxy, hydrocarbon group, 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, -NH ₂ , -NH(C _1-6 alkyl) or -N(C _1-6 alkyl)(C _1-6 alkyl).

Embodiment 10. The method of embodiment 9, wherein Ar is phenyl.

Embodiment 11. The method according to any one of embodiments 1 to 10, wherein X ₁ and X ₂ may be the same or different and are each independently selected from halogen.

Embodiment 12. The method of embodiment 11, wherein X ₁ and X ₂ are both chlorine.

Embodiment 13. The method of embodiment 1, wherein,

R ₁ is C _1-6 alkyl;

R ₂ is C _3-6 alkyl;

R ₃ is C _1-6 alkyl group;

Ar is an aryl group, optionally substituted with one or more substituents independently selected from: 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, -NH ₂ , -NH(C _1-6 alkyl) or - N(C _1-6 alkyl)(C _1-6 alkyl);

X ₁ and X ₂ may be the same or different and are each independently selected from halogen.

Embodiment 14. The method of embodiment 13, wherein,

R ₁ is methyl;

R ₂ is tertiary butyl;

R ₃ is pivalyl group;

Ar is phenyl;

X ₁ and X ₂ are both chlorine.

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

Wherein, R ₂ is as defined in any one of embodiments 1 to 14, respectively,

The acidic catalyst is selected from the group consisting 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 one or more of,

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, alumina, and montmorillonite desiccants,

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

Embodiment 16. The method according to any one of embodiments 1 to 15, wherein the deprotection described in step (iv) is achieved by hydrolysis in a solvent in the presence of a base selected from carbonic acid One of cesium, 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 Or more, the solvent is selected from one or more of water, C _1-6 alkyl alcohol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, and acetonitrile.

Embodiment 17. The method according to any one of embodiments 1 to 16, wherein the Suzuki coupling reaction described in step (iii) is in the presence of a catalyst, optional catalyst ligands and a base, in a solvent It is carried out at a temperature of 40°C to 140°C. The catalyst is selected from one or more of Pd ₂ (dba) ₃ , palladium acetate, Pd(PPh ₃ ) ₄ and Pd(dppf)Cl ₂ . The catalyst ligand is selected from One or more of dppf, BINAP and One or more of sodium, the solvent is selected from one or more of 1,4-dioxane, toluene, water, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile.

Embodiment 18. The method according to any one of embodiments 1 to 17, wherein the Buchwald reaction in step (ii) is carried out in the presence of a catalyst, optional catalyst ligands and a base in a solvent at 40 It is carried out at a temperature of -140°C. The catalyst is selected from one or more of palladium acetate, Pd ₂ (dba) ₃ , PdCl ₂ (PPh ₃ ) ₂ and Pd(dppf)Cl _2. The catalyst ligand is selected from Xantphos , dppf, BINAP and XPhos, one or more, the base is selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide and hydrogen phosphate One or more of disodium, the solvent is selected from one or more of 1,4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile.

Embodiment 19. The 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 -140°C to -40°C. temperature, and the base is selected from n-butyllithium, tert-butyllithium, sec-butyllithium, sodium hexamethyldisilazide, lithium hexamethyldisilamide, and hexamethyldisilica One or more of potassium amide and lithium diisopropylamide, and the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, n-hexane, and n-heptane.

Embodiment 20. The method according to any one of embodiments 1 to 19, wherein the reactants of step (ii) are used directly in step (iii) without isolating the product of step (ii).

Embodiment 21. Compounds of formula ( 4-i ) or formula ( 4-ii ),

in,

_{X 1 and _} Independently selected from halogen; more preferably, X ₁ and X ₂ are both chlorine;

R ₁ is selected from hydrogen or C _1-6 alkyl; preferably, R ₁ is C _1-6 alkyl; more preferably, R ₁ is methyl;

R ₂ is selected from C _1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl, Phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tertiary butyl.

Embodiment 22. The compound of formula ( 4-i ) or formula ( 4-ii ) according to embodiment 21, wherein X ₁ and X ₂ may be the same or different, and each is independently selected from halogen.

Embodiment 23. The compound of formula ( 4-i ) or formula ( 4-ii ) according to embodiment 22, wherein X ₁ and X ₂ are both chlorine.

Embodiment 24. The compound of formula ( 4-i ) or formula ( 4-ii ) according to any one of embodiments 21 to 23, wherein R ₁ is C _1-6 alkyl.

Embodiment 25. The compound of formula ( 4-i ) or formula ( 4-ii ) according to embodiment 24, wherein R ₁ is methyl.

Embodiment 26. The compound of formula ( 4-i ) or formula ( 4-ii ) according to any one of embodiments 21 to 25, wherein R ₂ is selected from C _3-6 alkyl, phenyl, p- Methylphenyl, benzyl or 2,4,6-trimethylphenyl.

Embodiment 27. The compound of formula ( 4-i ) or formula ( 4-ii ) according to embodiment 26, wherein R ₂ is C _3-6 alkyl.

Embodiment 28. The compound of formula ( 4-i ) or formula ( 4-ii ) according to embodiment 27, wherein R ₂ is tertiary butyl.

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

X ₁ and X ₂ may be the same or different, and are each independently selected from halogen;

R ₁ is C _1-6 alkyl;

R ₂ is C _3-6 alkyl.

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

X ₁ and X ₂ are both chlorine;

R ₁ is methyl;

R ₂ is tertiary butyl.

Embodiment 31. Compounds of formula ( 5-i ) or formula ( 5-ii ),

in,

X ₁ is selected from halogen, trihalomethoxy, trihaloethoxy, and p-toluenesulfonyl; preferably, X ₁ is selected from halogen; more preferably, X ₁ is chlorine;

R ₁ is selected from hydrogen or C _1-6 alkyl; preferably, R ₁ is C _1-6 alkyl; more preferably, R ₁ is methyl;

R ₂ is selected from C _1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tertiary butyl,

R ₃ is an amino protecting group; preferably, R ₃ is an amino protecting group selected from the following: C _1-6 alkyl group, triphenylmethyl, benzyl, benzyl, succinyl group , Phthalyl group, -NHC(O)OC _1-6 alkyl group; more preferably, R ₃ is C _1-6 alkyl group; further preferably, R ₃ is pivalyl group.

Embodiment 32. The compound of formula ( 5-i ) or formula ( 5-ii ) according to embodiment 31, wherein X ₁ is selected from halogen.

Embodiment 33. The compound of formula ( 5-i ) or formula ( 5-ii ) according to Embodiment 32, wherein X ₁ is chlorine.

Embodiment 34. The compound of formula ( 5-i ) or formula ( 5-ii ) according to any one of embodiments 31 to 33, wherein R ₁ is C _1-6 alkyl.

Embodiment 35. The compound of formula ( 5-i ) or formula ( 5-ii ) according to embodiment 34, wherein R ₁ is methyl.

Embodiment 36. The compound of formula ( 5-i ) or formula ( 5-ii ) according to any one of embodiments 31 to 35, wherein R ₂ is selected from C _3-6 alkyl, phenyl, p- Methylphenyl, benzyl or 2,4,6-trimethylphenyl.

Embodiment 37. The compound of formula ( 5-i ) or formula ( 5-ii ) according to embodiment 36, wherein R ₂ is C _3-6 alkyl.

Embodiment 38. The compound of formula ( 5-i ) or formula ( 5-ii ) according to embodiment 37, wherein R ₂ is tertiary butyl.

Embodiment 39. The compound of formula ( 5-i ) or formula ( 5-ii ) according to any one of embodiments 31 to 38, wherein R ₃ is an amino protecting group C _1-6 selected from the following Alkyl, triphenylmethyl, benzyl, benzyl, succinyl, phthalyl, -NHC(O)OC _1-6 alkyl.

Embodiment 40. The compound of formula ( 5-i ) or formula ( 5-ii ) according to embodiment 39, wherein R ₃ is a C _1-6 alkyl group.

Embodiment 41. The compound of formula ( 5-i ) or formula ( 5-ii ) according to embodiment 40, wherein R ₃ is pivaloyl group.

Embodiment 42. The compound of formula ( 5-i ) or formula ( 5-ii ) according to embodiment 31, wherein,

X ₁ is selected from halogen;

R ₁ is C _1-6 alkyl;

R ₂ is C _3-6 alkyl;

R ₃ is C _1-6 alkyl group.

Embodiment 43. The compound of formula ( 5-i ) or formula ( 5-ii ) according to embodiment 42, wherein,

X ₁ is chlorine;

R ₁ is methyl;

R ₂ is tertiary butyl;

R ₃ is pivalyl group.

Embodiment 44. The compound of formula ( 4-i ) as defined in any one of embodiments 21 to 30 or the compound of formula ( 5-i ) as defined in any one of embodiments 31 to 43 is used to prepare the embodiment Use of compounds of formula ( 1-i ) as defined in any one of 1 to 20.

Embodiment 45. The compound of formula ( 4-ii ) as defined in any one of Embodiments 21 to 30 or the compound of Formula ( 5-ii ) as defined in any one of Embodiments 31 to 43 is used in the preparation of Embodiments 1 to 43 Use of the compound of formula ( 1-ii ) described in any one of 20.

definition

The term "C _1-6 alkyl" as used herein refers to a linear or branched saturated monovalent hydrocarbon group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, 6 carbon atoms. . The C _1-6 alkyl group is preferably a C _1-4 alkyl group or a C _3-6 alkyl group, that is, a straight-chain or branched saturated alkyl group having 1 to 4 carbon atoms or having 3 to 6 carbon atoms. Monovalent hydrocarbon group. Examples of C _1-6 alkyl include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, including -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₂ CH ₃ , -CH ₂ CH ₂ CH(CH ₃ ) ₂ , -CH(C ₂ H ₅ )CH ₂ CH ₃ , -CH ₂ CH(C ₂ H ₅ )CH ₃ , -C(CH ₃ ) ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , -CH ₂ C(CH ₃ ) ₃ , -CH ₂ C(CH ₃ ) ₂ CH ₂ CH ₃ , etc.

The term "C _2-6 alkenyl" as used herein refers to a carbon-carbon double bond (C=C) containing one or more, such as 1, 2 or 3, especially 1 or 2, containing 2-6 A linear or branched unsaturated monovalent hydrocarbon group of carbon atoms. The C _2-6 alkenyl group is preferably a C _2-4 alkenyl group, that is, a straight chain of 2 to 4 carbon atoms containing 1 or 2, preferably 1 carbon-carbon double bond (C=C). Or branched unsaturated monovalent hydrocarbon group. Examples of C _2-6 alkenyl groups include, but are not limited to, vinyl, 2-propenyl and 2-butenyl.

The term "C _2-6 alkynyl" as used herein refers to a straight-chain or branched chain containing 2-6 carbon atoms containing one or more, such as 1, 2 or 3 carbon-carbon triple bonds (C≡C). A chain of unsaturated monovalent hydrocarbon groups. The C _2-6 alkynyl group is preferably a C _2-4 alkynyl group, that is, a straight chain of 2 to 4 carbon atoms containing 1 or 2, preferably 1 carbon-carbon triple bond (C≡C) Or branched unsaturated monovalent hydrocarbon group. Examples of C _2-6 alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

The term "C _1-6 haloalkyl" as used herein refers to a group as described herein in which one or more, for example 1, 2, 3, 4 or 5, especially 1, 2 or 3, hydrogen atoms are substituted by halogen. C _1-6 alkyl. The C _1-6 haloalkyl group is preferably a C _1-4 haloalkyl group, that is, one or more, such as 1, 2, 3, 4 or 5, especially 1, 2 or 3 hydrogen atoms are replaced by Halogen substituted C _1-4 alkyl groups described herein. When more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same as or different from each other. Examples of C _1-6 haloalkyl groups include, but are not limited to, -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -CH(CF ₃ ) ₂ and the like.

The term "halogen" or "halogen" as used herein refers to fluorine, chlorine, bromine and iodine, preferably chlorine and bromine, more preferably chlorine.

As used herein, the term "C _1-6 alkyl" refers to the group RC(=O)-, where R is H or C _1-5 alkyl. The C _1-6 alkyl group is preferably a C _1-4 alkyl group, that is, the group RC(=O)-, where R is H or C _1-3 alkyl. Examples of C _1-6 alkyl groups include, but are not limited to, formyl, acetyl, n-propyl, isopropyl, n-butyl, isobutyl, 2nd butyl, 3rd butyl, and the like.

The term "aryl" as used herein refers to a carbocyclic hydrocarbon group consisting of one ring or multiple fused rings, such as a monocyclic or bicyclic ring, containing 6 to 14 ring carbon atoms, at least one of which is an aromatic ring. . Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, with phenyl and naphthyl being preferred.

The term "aryl acyl" as used herein refers to the group R'-C(=O)-, where R' is an aryl group as defined herein. Examples of arylyl groups include, but are not limited to, benzyl, naphthoyl, and the like.

As used herein, the term "heteroaryl" means:

A monocyclic aromatic hydrocarbon group with 5, 6 or 7 ring atoms, preferably 6 ring atoms, which contains one or more, such as 1, 2 or 3, preferably 1 or 2 independently, in the ring ring heteroatoms selected from N, O and S (preferably N), the remaining ring atoms being carbon atoms; and

A bicyclic aromatic hydrocarbon group with 8-12 ring atoms, preferably 9 or 10 ring atoms, which contains one or more, such as 1, 2, 3 or 4, preferably 2, 3 or 4 ring heteroatoms independently selected from N, O and S (preferably N), the remaining ring atoms are carbon atoms, at least one of which is an aromatic ring. For example, bicyclic heteroaryl 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.

Examples of heteroaryl include, but are not limited to: pyridyl, N-oxypyridyl, such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl or N-oxide thereof; pyrazinyl, such as pyridinyl Azin-2-yl, pyrazin-3-yl; pyrimidinyl, such as pyrimidin-2-yl, pyrimidin-4-yl; pyrazolyl, such as pyrazol-1-yl, pyrazol-3-yl, pyrazole -4-yl, pyrazol-5-yl; imidazolyl, such as imidazol-2-yl, imidazol-4-yl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; tetrazoline Azolyl, such as tetrazol-5-yl; triazolyl; thienyl; furyl; pyranyl; pyrrolyl; pyridazinyl; benzodioxolyl, such as benzo[d][ 1,3]dioxolyl; benzoxazolyl, such as benzo[d]oxazolyl; imidazopyridyl, such as imidazo[1,2-a]pyridyl; triazolo Pyridyl, such as [1,2,4]triazolo[4,3-a]pyridyl and [1,2,4]triazolo[1,5-a]pyridyl; indazolyl; pyrrolo Pyrimidinyl, such as pyrro[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; pyrazolopyrimidinyl, such as pyrazolo[1,5-a]pyrimidinyl; Tetrazolopyridyl, such as tetrazolo[1,5-a]pyridyl; benzothienyl; benzofuryl; benzimidazolinyl; indolyl; indolinyl; purinyl, such as 9H -Purinyl and 7H-purinyl; quinolyl; isoquinolyl; 1,2,3,4-tetrahydroquinolyl and 5,6,7,8-tetrahydroisoquinolyl.

The term "hydroxy" as used herein refers to the group -OH.

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

The term "amine protecting group" as used herein, also known as nitrogen protecting group, refers to a group that can reversibly block or protect the amine and/or amide functional groups to allow reactions to proceed on other functional groups of the compound. Suitable amine groups are described, for example, in the relevant chapters of JFWMcOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene and PGMWuts, "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 or-ga-ni-schen Chemie" (Organic Chemical Methods), Houben-Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974. Examples of the amino group protection include, but are not limited to, C _1-6 alkyl, triphenylmethyl, benzyl, benzyl, succinyl, phthalyl, -NHC(O)OC _1-6 alkyl, Pmb (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) and Cbz (benzyloxycarbonyl), etc., are preferred C _1-6 alkyl group (such as formyl, acetyl, tert-butyl, pivalyl, etc.) and benzyl; more preferably pivalyl.

Removal of the amino protecting group can be conveniently carried out according to methods well known in the art, for example, it can be carried out 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.

The term "optional" means that the substance defined by the term may be present or absent or the event defined by the term may or may not occur.

Terms not defined herein have their conventional meaning in the art.

In any structural formula herein, if there is a spare valence on any atom, the spare valency is actually a hydrogen atom which is not specifically depicted for simplicity.

In this article, if both the name and the structural formula of a compound are given, in the event of inconsistency, the structure of the compound shall prevail, unless the context indicates that the structure of the compound is incorrect but the name is correct.

Figure 1 is the synthetic route I of WO2016/045591A1.

Figure 2A is a synthetic route diagram of the compound of formula ( 1-i ) of the present invention.

Figure 2B is a synthetic route diagram of the compound of formula ( 1-ii ) of the present invention.

Figure 3 is an ellipsoid diagram of the three-dimensional structure of the product of Example 4.

Figure 4A 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. .

Figure 4B 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. .

The following examples are illustrative of the present invention and should not be construed as limiting the scope of the present invention in any way. The disclosed data (eg, quantities, temperatures, etc.) are intended to be accurate, but some experimental errors and offsets may exist. Unless otherwise stated, parts in the present invention are parts by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. All hydrogen spectrum data were measured by Varian 400-MR. All yields are calculated based on the actual content of the pure substance in the product obtained. Unless otherwise stated, all reagents used in the examples were obtained from commercial sources.

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

Example 1

Synthesis of ( R )- N -(( S )-1-(3,6-dichloropyridazin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

Under nitrogen protection, add lithium diisopropylamine (2.0 M solution in tetrahydrofuran, n-heptane and ethylbenzene, 390 mL) to toluene (900 mL) at -60~-70°C. After the addition is completed, the internal temperature is controlled not to be higher than -60°C, and the compound 3,6-dichloropyridazine (45g, 0.3mol) and ( R ) -N -ethylene-2-methylpropane-2-ylidene are added. A solution of sulfonamide (66.8 g, 0.45 mmol) in toluene (450 mL) was added dropwise to the previously prepared toluene solution of lithium diisopropylamide. After the reaction is completed, add the above reaction solution to a saturated aqueous ammonium chloride solution (1L) at 0°C to 10°C to quench it, let it stand, separate the layers, wash the organic phase with a saturated aqueous ammonium chloride solution (300mL), and combine the aqueous phases. , extracted twice with 2-methyltetrahydrofuran (100mL×2), combined the organic phases, concentrated under reduced pressure, stirred and cooled to 0℃~5℃, continued stirring for 1~2 hours, filtered, filtered with methyl tertiary butyl Rinse with ether and dry to obtain 40g of off-white solid, yield 45%.

MS(m/z)=296[M+H] ⁺

¹ H NMR(400MHz, DMSO- d ₆ )δ 8.06(s,1H),5.81(d,J=7.2Hz,1H),4.63(t,J=6.9Hz,1H),1.52(d,J=6.8 Hz,3H),1.12(s,9H).

Example 2

N -(5-(( S )-1-(( R )-tert-butylsulfinyl)amino)ethyl)-6-chloropyridazin-3-yl)trimethylacetyl Synthesis of amines

method 1

To a solution of the product of Example 1 (500g, 1.688mol) and pivalidamide (172g, 1.700mol) in 1,4-dioxane (4000mL) at 20°C to 30°C, potassium carbonate was added (350g, 2.532mol), and nitrogen gas was introduced into the reaction system. Add Pd ₂ (dba) ₃ (46g, 0.050mol) and Xantphos (97g, 0.168mol), replace the air in the reaction kettle with nitrogen, and then raise the temperature to 100°C~110°C. After the reaction is completed, filter while hot, and concentrate the filtrate under reduced pressure. At room temperature, add ethyl acetate (2.5L), concentrate under reduced pressure, then add ethyl acetate (6.5L), and add activated carbon (50g) for decolorization. Filter. The filtrate was concentrated, 2-methyltetrahydrofuran (4L) was added, dissolved into a clear solution at 30°C, and washed twice with water (1L × 2). The organic phase was concentrated to dryness, and methyl tert-butyl ether (4L) was added to beat. The solid obtained after filtration was dried under reduced pressure at 45°C to 50°C to obtain the target product as a brown product, 473g, yield: 60%.

LC-MS: 361[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.70 (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).

Method 2

The product of Example 1 (40g, 135.04mmol) and pivalidamide (14.34g, 141.77mmol) were dissolved in 1,4-dioxane (400mL), and potassium carbonate (28.0g, 202.60mmol) was added to the solution. ), replace the air in the reaction kettle with nitrogen three times, and then add Xantphos (7.81g, 13.50mmol) and Pd ₂ (dba) ₃ (3.71g, 4.05mmol). The nitrogen was replaced three more 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 in the next reaction. By NMR analysis, the product obtained was consistent with the product obtained by method 1. The filtrate was analyzed by quantitative HPLC external standard method, and the reaction yield was calculated to be 74.51%.

Example 3

N -(5-(( S )-1-((( R )-tert-butylsulfinyl)amino)ethyl)-6-phenylpyridazin-3-yl)trimethylethyl Synthesis of amide

The product of Method 1 of Example 2 (438.5g, 930mmol), phenylboronic acid (136g, 1.12mol), 1,4-dioxane (3.4L), and water (33.5g, 1.86mol) were added in sequence to the reaction flask. and potassium carbonate (257g, 1.86mol). After replacing the air in the flask with nitrogen three times, add Pd(dppf)Cl ₂ (68g, 93mmol), replace the nitrogen three times again, heat the reaction system to about 100°C, stop heating after 16 hours of reaction, cool down and filter. The filter cake was washed three times with tetrahydrofuran (0.5L×3), the filtrate was concentrated, and the residue was slurried with a mixture of methyl tert-butyl ether (500 mL) and ethyl acetate (200 mL). Wash three times with tributyl ether (500 mL×3), collect the filter cake, and dry under reduced pressure at 50-60°C to obtain a total of about 314 g of product with a yield of 71.4%.

LC-MS: 403[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ 10.43(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).

Example 4

Synthesis of ( R )- N -(( S )-1-(6-amino-3phenylpyridazin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

Add ethanol (246kg), water (42kg), the product of Example 3 (33.5kg) and 7.3% w/w sodium hydroxide aqueous solution (44.7kg) to the reaction kettle in sequence, and heat the reaction system to 45-55°C. After the reaction is complete, water is added and concentrated to remove most of the ethanol. Then water was added for pulping, and the slurry was filtered to obtain a solid, which was dried at a temperature lower than 50°C to obtain 23.6kg of the target product with a yield of 89.8%.

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

Single crystal X-ray diffractometer: Bruker SMART APEX-II

Test conditions: Measured according to the first method of Part Four General Chapter 0451 of the 2020 edition of the "Chinese Pharmacopoeia", CuKα radiation, φ/ω scanning.

Structural analysis:

The direct method (Shelxs97) was used to analyze the crystal structure. It belongs to the monoclinic crystal system, the space group is P2 ₁ , and the unit cell parameters: a=6.5397(1)Å, b=11.1887(3)Å, c=12.4029(3)Å; α=γ=90.00°, β=95.903(1)°; unit cell volume V=902.72(4)Å ³ , and the number of asymmetric units in the unit cell Z=2. The least squares method was used to correct the structural parameters and identify atomic types, and the geometric calculation method was used to obtain the positions of all hydrogen atoms. The final reliability factor R ₁ =0.0355, wR ₂ =0.0982, S=1.051. The stoichiometric formula of the asymmetric unit was finally determined to be C ₁₆ H ₂₂ N ₄ OS, the calculated molecular weight was 318.44, and the calculated crystal density was 1.172g/cm ³ .

The results show that the molecular arrangement in the crystalline state belongs to the first type of space group, and the sample has optical activity. The Flack coefficient is 0.081 (16), which can determine the absolute configuration of the compound in the crystal. As shown in this example, the ellipsoid diagram of its three-dimensional structure is shown in Figure 3.

Example 5

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

The product of Example 4 (60.72g, 0.191mol), ethanol (576mL), water (24mL), sodium bicarbonate (35.24g, 0.419mol) and 40% w/w chloroacetaldehyde (67.35g) were added to the reaction flask. ,0.343mol), raise the temperature of the reaction system to 65℃-70℃, after 9 hours of reaction, cool down to 15℃-20℃, filter, after the filtrate is concentrated, add water dropwise to precipitate the product, filter, put the filter cake at 45℃- Dry under reduced pressure at 60°C, and crystallize the obtained solid with a mixture of dichloromethane and isopropyl ether (25:1 w/w) to obtain 67.5 g of the target product.

LC-MS: 343[M+H] ⁺

Example 6

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

To the solution of the product of Example 5 (1055g, 3.08mol) in ethanol (4747mL), a 4M ethanol solution of hydrogen chloride (3085mL) was added dropwise at 20°C to 25°C, and the reaction was carried out for 16 hours at 20°C to 35°C. , after concentrating to remove most of the solvent, add ethyl acetate, concentrate, reflux and beat, filter after cooling, and vacuum dry the filter cake at 55°C-65°C to obtain 900g of the target product.

LC-MS: 239[M+H] ⁺ .

Example 7

Synthesis of ( S )-N-(( R )-1-(3,6-dichloropyridazin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

Using 3,6-dichloropyridazine and ( S )-N-ethylene-2-methylpropan-2-sulfinamide as starting materials, the title compound was prepared according to the method of Example 1 as a solid ,42g.

MS(m/z)=296[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.04 (s, 1H), 5.78 (d, 1H), 4.61 (m, 1H), 1.51 (d, 3H), 1.10 (s, 9H).

Example 8

N -(5-(( R )-1-((( S )-tert-butylsulfenyl)amino)ethyl)-6-chloropyridazin-3-yl)trimethylacetyl Synthesis of amines

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

¹ H NMR(400MHz, DMSO-d ₆ )δ 10.68(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).

Example 9

N -(5-((R)-1-((( S )-tert-butylsulfinyl)amino)ethyl)-6-phenylpyridazin-3-yl)trimethylethyl Synthesis of amide

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

¹ H NMR (400MHz, DMSO-d ₆ )δ 10.57 (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).

Example 10

Synthesis of ( S )- N -(( R )-1-(6-amino-3phenylpyridazin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

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

¹ H NMR(400MHz, DMSO-d ₆ )δ 7.47-7.40(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).

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

The product of Example 4, the product of Example 10 and the four isomers of Isomer 1 and Isomer 2 are passed through a chiral chromatography column, where the retention time of the product prepared in Example 4 is 13.03min, the retention time of the product prepared in Example 10 is 11.52min, the retention time of isomer 1 is 6.26min, and the retention time of isomer 2 is 8.31min; the four isomers can be separated by chiral tube The column is completely separated. The conditions for chiral chromatography columns are as follows:

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

Chromatography column: Brand: CHIRALPAK OJ; Model: 4.6mm*25mm, 5μm;

Elution gradient: 0~30min, 10% (A%);

Flow rate: 1mL/min;

UV: 244nm.

In addition, the above four isomers were detected by an achiral HPLC column. The results showed that the retention times of the products prepared in Example 4 and Example 10 were basically the same. The retention time of the product prepared in Example 4 was 9.95 min, the retention time of the product prepared in Example 10 is 9.99 min; the retention time of isomer 1 and isomer 2 are both 11.34 min. 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 for achiral HPLC are as follows:

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

Chromatography column: Brand: Welch Xtimate; Model: 4.6mm*250mm, 5μm;

Flush gradient:

Flow rate: 1mL/min;

UV: 248nm.

Since the configuration of the chiral carbon and chiral sulfur of the product prepared in Example 4 has been proved by single crystal diffraction, and it is the enantiomer of the product prepared in Example 10, the two intermediates are further combined The hydrogen spectrum data of the solid body proves the configuration of the chiral carbon and chiral sulfur of the product prepared in Example 10.

Example 11

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

Using the product in Example 10 as a starting material, the title compound was prepared according to the method of Example 5 as a brown solid, 205 g, yield 73.4%

¹ H NMR (400MHz, DMSO-d ₆ )δ 8.26-8.25(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).

Example 12

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

Add the product of Example 11 (200g, 0.584mol) and ethanol (700mL) to the reaction vessel in sequence, stir and cool to 0°C, then dropwise add 4M hydrogen chloride ethanol solution (584mL), and then heat to 20-25°C to react. After completion, add ethyl acetate to crystallize, filter, collect the filter cake and dry it under reduced pressure at 60°C. Dissolve the obtained filter cake in water, add sodium bicarbonate to adjust the pH to 8-9, filter, wash the filter cake with water, and dry under reduced pressure at 52°C. The target product was obtained as a brown solid, 162 g, with a yield of 89.5%.

LC-MS: 239.1[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ 8.34(s,1H),8.23(dd, J =1.2,0.8Hz,1H),7.77(t, J =1.2Hz,1H),7.65-7.38(m ,5H),4.06-3.96(m,1H),2.03(s,2H),1.09(d, J =6.5Hz,3H).

Example 13

Synthesis of ( R ) -N -ethylene-2-methylpropane-2-sulfinamide

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

MS(m/z)=148.20[M+H] ⁺

Claims (10)

A method for preparing compounds of formula ( 1-i ) and formula ( 1-ii ),

in, R ₁ is selected from hydrogen or C _1-6 alkyl; preferably, R ₁ is C _1-6 alkyl; more preferably, R ₁ is methyl; R ₂ is selected from C _1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl, Phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tertiary butyl; Ar is an aryl or heteroaryl group, optionally substituted with one or more substituents independently selected from: 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, -NH ₂ , -NH(C _1-6 alkyl) group) or -N(C _1-6 alkyl)(C _1-6 alkyl); preferably, Ar is an aryl group; more preferably, Ar is a phenyl group, The method includes the following steps: (iv) Deprotect the compound of formula ( 6-i ) or formula ( 6-ii ) to remove the amino protecting group R ₃ ,

Among them, R ₁ , R ₂ and Ar are as defined above, and R ₃ is an amino protecting group; preferably, R ₃ is an amino protecting group selected from the following: C _1-6 alkyl, triphenylmethyl base, benzyl, benzyl, succinyl, phthalyl, -NHC(O)OC _1-6 alkyl, Pmb (p-methoxybenzyl), Boc (tertiary butyl) (oxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl); more preferably, R ₃ is C _1-6 alkyl group; further preferably, R ₃ is pivalenyl base, Compounds of formula ( 1-i ) and formula ( 1-ii ) were obtained respectively; Optionally, the above method further includes step (iii) before step (iv): (iii) The compound of formula ( 5-i ) or formula ( 5-ii ) is subjected to a Suzuki coupling reaction with ArB(OH) ₂ , and an Ar group is introduced into the pyridazine ring,

Among them, R ₁ , R ₂ , R ₃ and Ar are as defined above, and X ₁ is selected from halogen, trifluoromethoxy, trifluoroacetyl, p-toluenesulfonyloxy; preferably, X ₁ is selected from Halogen; more preferably, X ₁ is chlorine, Obtain the compound of formula ( 6-i ) or formula ( 6-ii ) in step (iv); Optionally, the above method further includes step (ii) before step (iii): (ii) causing the compound of formula ( 4-i ) or formula ( 4-ii ) to undergo a Buchwald reaction with the amine R ₃ NH ₂ respectively,

Among them, R ₁ , R ₂ and R ₃ are as defined above, and X ₁ and X ₂ can be the same or different, each independently selected from halogen, trifluoromethoxy, trifluoroacetyl, p-toluenesulfonyloxy base; preferably, X ₁ and X ₂ can be the same or different, and are each independently selected from halogen; more preferably, X ₁ and X ₂ are both chlorine, Obtain the compound of formula ( 5-i ) or formula ( 5-ii ) in step (iii); Optionally, the above method further includes step (i) before step (ii): (i) Let the compound of formula ( 2 )

_Among them, _{X 1 and} Different, each is independently selected from halogen; more preferably, X ₁ and X ₂ are both chlorine; A nucleophilic substitution reaction occurs with the compound of formula ( 3-i ) or formula ( 3-ii ) respectively, and a chiral amine is introduced.

where R ₁ and R ₂ are as defined above, The compound of formula ( 4-i ) or formula ( 4-ii ) in step (ii) is obtained. The method as described in claim 1, wherein the compound of formula ( 3-i ) or formula ( 3-ii ) described in step (i) is prepared by mixing acetaldehyde with formula ( 7-i ) or formula ( 7 The compound of -ii ) is obtained by performing a nucleophilic substitution reaction in a solvent in the presence of an acidic catalyst and a dehydrating agent,

where R ₂ is as defined in claim 1, The acidic catalyst is selected from the group consisting 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, one or more phosphoric acids, 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, alumina, and montmorillonite desiccants, The solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethylbenzene, toluene, n-hexane, n-heptane, cyclohexane, cyclopentane, and methylcyclohexane. The method of claim 1 or 2, wherein the deprotection described in step (iv) is achieved by hydrolysis in a solvent in the presence of a base, the base being selected from the group consisting of cesium carbonate, potassium carbonate, sodium carbonate, One or more of 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 , one or more of C _1-6 alkyl alcohol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, and acetonitrile. The method according to any one of claims 1 to 3, wherein the Suzuki coupling reaction described in step (iii) is carried out in the presence of a catalyst, optional catalyst ligands and a base in a solvent at 40°C- It is carried out at a temperature of 14-0°C. The catalyst is selected from one or more of Pd ₂ (dba) ₃ , palladium acetate, Pd(PPh ₃ ) ₄ and Pd(dppf)Cl _2. The catalyst ligand is selected from dppf, One or more of BINAP and XPhos, the base is selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, and disodium hydrogen phosphate One or more solvents, the solvent is selected from one or more types of 1,4-dioxane, toluene, water, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile. The method according to any one of claims 1 to 4, wherein the Buchwald reaction in step (ii) is carried out in the presence of a catalyst, optional catalyst ligands and a base in a solvent at 40°C to 140°C. _{at a temperature of _ _} and one or more of XPhos, the base is selected from the group consisting of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium fluoride, cesium fluoride, sodium hydroxide and disodium hydrogen phosphate. One or more solvents, the solvent is selected from one or more types of 1,4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile. The method according to any one of claims 1 to 5, 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, The base is selected from n-butyllithium, tert-butyllithium, sec-butyllithium, sodium hexamethyldisilamide, lithium hexamethyldisilamide, and potassium hexamethyldisilamide , one or more of lithium diisopropylamide, and the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, n-hexane, and n-heptane. 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). A compound of formula ( 4-i ) or formula ( 4-ii ),

in, _{X 1 and _} Independently selected from halogen; more preferably, X ₁ and X ₂ are both chlorine; R ₁ is selected from hydrogen or C _1-6 alkyl; preferably, R ₁ is C _1-6 alkyl; more preferably, R ₁ is methyl; R ₂ is selected from C _1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl, Phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tertiary butyl. A compound of formula ( 5-i ) or formula ( 5-ii ),

in, X ₁ is selected from halogen, trihalomethoxy, trihaloethoxy, and p-toluenesulfonyl; preferably, X ₁ is selected from halogen; more preferably, X ₁ is chlorine; R ₁ is selected from hydrogen or C _1-6 alkyl; preferably, R ₁ is C _1-6 alkyl; more preferably, R ₁ is methyl; R ₂ is selected from C _1-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; preferably, R ₂ is selected from C _3-6 alkyl, phenyl, p-methylphenyl, benzyl or 2,4,6-trimethylphenyl; more preferably, R ₂ is C _3-6 alkyl; further preferably, R ₂ is tertiary butyl, R ₃ is an amino protecting group; preferably, R ₃ is an amino protecting group selected from the following: C _1-6 alkyl group, triphenylmethyl, benzyl, benzyl, succinyl group , Phthalyl group, -NHC(O)OC _1-6 alkyl group; more preferably, R ₃ is C _1-6 alkyl group; further preferably, R ₃ is pivalyl group. A compound of formula ( 4-i ) or formula ( 4-ii ) as defined in claim 8 or a compound of formula ( 5-i ) or formula ( 5-ii ) as defined in claim 9 for The use of preparing compounds of formula ( 1-i ) or formula ( 1-ii ) as defined in any one of claims 1 to 7.

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