Intermediates of a fibroblast growth factor receptor inhibitor and methods of making and using the same

Abstract

The present application relates to a kind of intermediate of fibroblast growth factor receptor inhibitor and its preparation method and purposes.The intermediate is named 3-(3,5-dimethoxyphenyl) propionic acid isopropyl ester, and the fibroblast growth factor receptor inhibitor is AZD4547.The present application discloses that the key intermediate 3-(3,5-dimethoxyphenyl) 1H-pyrazole-5-amine of AZD4547 is prepared by two-step reaction using the intermediate as raw material, and the above-mentioned intermediate and its preparation method and purposes in the industrialization production of AZD4547 bulk drug.The present application is mature and stable, and the production operation is simple, with high yield, low cost, safety and environmental protection, and the bulk drug prepared can meet the needs of AZD4547 clinical research and drug marketing, and solves the problem of drug accessibility.

Description

TECHNICAL FIELD

[0001] The present application is in the field of pharmaceutical synthesis and relates to an intermediate for a fibroblast growth factor receptor inhibitor and its preparation and use. BACKGROUND

[0002] Protein kinases are a class of proteins (enzymes) that regulate a variety of cellular functions. This is accomplished by phosphorylation of specific amino acids on protein substrates, which results in a change in the conformation of the substrate protein. The change in conformation modulates the activity of the substrate or its ability to interact with other binding partners. Enzymatic activity of a protein kinase refers to the rate at which the kinase adds phosphate groups to a substrate. This can be measured, for example, by determining the amount of substrate converted to product as a function of time. Phosphorylation of the substrate occurs at the active site of the protein kinase.

[0003] Tyrosine kinases are a subset of protein kinases that catalyze the transfer of the terminal phosphate from adenosine triphosphate (ATP) to a tyrosine residue on a protein substrate. These kinases play an important role in the propagation of growth factor signaling that leads to cell proliferation, differentiation, and migration.

[0004] Fibroblast growth factors (FGFs) are believed to be important mediators of many physiological processes, such as morphogenesis during development and angiogenic processes. There are currently over 25 known members of the FGF family. The fibroblast growth factor receptor (FGFR) family includes four members, each composed of an extracellular ligand-binding region, a single transmembrane region, and an intracellular cytoplasmic protein tyrosine kinase region. Upon FGF stimulation, FGFRs dimerize and transphosphorylate, which leads to receptor activation. Activation of the receptor is sufficient to recruit and activate specific downstream signaling partners that are involved in the regulation of a variety of processes, such as cell growth, cell metabolism, and cell survival (reviewed in Eswarakumar, V.P., et al., Cytokine & Growth Factor Reviews 2005, 16, pp. 139-149). As a result, FGFs and FGFRs have the potential to cause and / or promote tumor formation.

[0005] There is now considerable evidence that FGF signaling is directly implicated in human cancer. Increased expression of various FGFs has been reported in a range of tumor types such as bladder, renal cell and prostate (among others). FGFs have also been described as potent angiogenic factors. FGFRs have also been reported to be expressed in endothelial cells. Activating mutations in various FGFRs have been associated with bladder cancer and multiple myeloma (among others), while there is literature to suggest expression of the receptors in prostate and bladder cancer and others (reviewed in Grose, R. et al., Cytokine & Growth Factor Reviews 2005, 16, pages 179-186 and Kwabi-Addo, B. et al., Endocrine-Related Cancer 2004, 11, pages 709-724). For these reasons, and in particular since therapies targeting FGFR and / or FGF signaling can directly affect tumor cells and tumor angiogenesis, the FGF signaling system is an attractive therapeutic target.

[0006] In 2008, AstraZeneca AB disclosed compounds targeting FGFR and / or FGF signaling in a patent application WO2008075068A2, in which the most representative compound is the compound of Example 154 (AZD4547), the chemical structure of which is as follows:

[0007]

[0008] At present, the preparation of AZD4547 mainly includes the following methods:

[0009] (1) The patent application WO2008075068A1 discloses a preparation method, which comprises the following steps:

[0010]

[0011] In this preparation method, AZD4547 is prepared from 3-(3,5-dimethoxyphenyl)propionic acid ethyl ester through three-step reactions, wherein the first step reaction needs to be purified by column chromatography, and the yield is only 42%; the second step reaction needs to be refluxed for 24 hours, and hydrazine hydrate is prone to explosion in high-temperature reaction, and hydrazine hydrate is a highly toxic and genotoxic reagent, and direct high-temperature reaction is not friendly to people and environment; the third step reaction also needs to be purified by column chromatography, and the total yield of the three-step reactions for preparing AZD4547 is only 21.08%; therefore, the preparation method has column chromatography operation in multiple-step reactions, poor safety, low yield, and is not suitable for industrialization, and cannot solve the problem of drug accessibility.

[0012] (2) The patent application CN111072638A discloses another preparation method, which comprises the following steps:

[0013]

[0014] In the preparation method, 3-(3, 5-dimethoxyphenyl) propionic acid is used as a starting material, and AZD4547 is prepared through five reaction steps, and the total yield is 42.5%. In the preparation method, toxic reagent ethyl cyanoacetate and expensive reagents such as palladium carbon, stannous chloride and Raney nickel are needed, and the preparation method is not suitable for industrial production.

[0015] (3) In addition, patent application WO2016137506A1 discloses a preparation method of AZD4547 key intermediate 3-(3, 5-dimethoxyphenyl) ethyl)-1H-pyrazole-5-amine, which is as follows:

[0016]

[0017] In the preparation method, the first step reaction adopts ethanol reflux reaction, the solvent consumption of the second step reaction is large, and the reaction needs to be carried out at-78℃ ultra-low temperature, and after the reaction is completed, column chromatography purification is needed, which is not suitable for industrial application.

[0018] In summary, the preparation methods of AZD4547 disclosed in the prior art are not suitable for industrial application, and the drug accessibility problem cannot be solved. Therefore, it is particularly necessary to develop an industrialized preparation method to meet the needs of AZD4547 clinical research and drug marketing. SUMMARY

[0019] The purpose of the present application is to provide a fibroblast growth factor receptor inhibitor intermediate and a preparation method and use thereof, to solve the drug accessibility problem and meet the needs of AZD4547 clinical research and drug marketing.

[0020] The first aspect of the present application provides a compound of formula (A), i.e. 3-(3, 5-dimethoxyphenyl) propionic acid isopropyl ester:

[0021]

[0022] The second aspect of the present application provides a preparation method of the compound of formula (A), which comprises the following steps:

[0023]

[0024] The compound of formula (SM) is prepared into the compound of formula (A) through esterification reaction.

[0025] As a preferred scheme, in the preparation method, the compound of formula (SM) is reacted with isopropyl alcohol to generate the compound of formula (A), and the mass-volume ratio of the compound of formula (SM) and isopropyl alcohol is 1: (1-50).

[0026] As a further preferred scheme, in the preparation method, the compound of formula (SM) is reacted with isopropanol to form the compound of formula (A), and the mass / volume ratio of the compound of formula (SM) and isopropanol is 1:(5-20).

[0027] As a further preferred scheme, in the preparation method, the compound of formula (SM) is reacted with isopropanol to form the compound of formula (A), and the mass / volume ratio of the compound of formula (SM) and isopropanol is 1:(5-20).

[0028] As a preferred scheme, in the preparation method, SOCl2 is added to the reaction system of the compound of formula (SM) and isopropanol, and the molar ratio of the compound of formula (SM) and SOCl2 is 1:(0.1-10).

[0029] As a further preferred scheme, in the preparation method, SOCl2 is added to the reaction system of the compound of formula (SM) and isopropanol, and the molar ratio of the compound of formula (SM) and SOCl2 is 1:(0.5-2).

[0030] As a preferred scheme, in the preparation method, the reaction is carried out at 40-80°C.

[0031] As a preferred scheme, in the preparation method, the reaction is carried out at 55-65°C.

[0032] The third aspect of the present application provides a use of a compound of formula (A) in the preparation of a compound of formula (C) or an acid salt thereof, and the preparation comprises the following steps:

[0033]

[0034] 1) the compound of formula (A) is prepared into a compound of formula (B) through reaction;

[0035] 2) the compound of formula (B) is prepared into a compound of formula (C) or an acid salt thereof through reaction.

[0036] As a preferred scheme, in the use, the acid salt is an inorganic acid salt or an organic acid salt, the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide or phosphate; and the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, methanesulfonate, ethanesulfonate, benzoate, citrate, malate, tartrate, formate, fumarate, galactarate, malonate, glycolate, oxalate, propionate, 4-acetylamino-benzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate or 1-hydroxy-2-naphthoate.

[0037] As a preferred solution, in the step 1) of the use, the compound of formula (A) is reacted with acetonitrile to form the compound of formula (B), and the molar ratio of the compound of formula (A) to acetonitrile is 1:(1-50).

[0038] As a further preferred solution, in the step 1) of the use, the compound of formula (A) is reacted with acetonitrile to form the compound of formula (B), and the molar ratio of the compound of formula (A) to acetonitrile is 1:(1-25).

[0039] As a further preferred solution, in the step 1) of the use, the compound of formula (A) is reacted with acetonitrile to form the compound of formula (B), and the molar ratio of the compound of formula (A) to acetonitrile is 1:(1-25).

[0040] As a preferred solution, in the step 1) of the use, a basic reagent is added to the reaction system of the compound of formula (A) and acetonitrile, and the basic reagent is selected from one or more of lithium diisopropylamide, n-butyllithium, sodium hexamethyldisilylamide, potassium hexamethyldisilylamide or lithium hexamethyldisilylamide.

[0041] As a further preferred solution, in the step 1) of the use, the molar ratio of the compound of formula (A) to the basic reagent is 1:(1-20).

[0042] As a further preferred solution, in the step 1) of the use, the molar ratio of the compound of formula (A) to the basic reagent is 1:(2-8).

[0043] As a preferred solution, in the step 1) of the use, the basic reagent added to the reaction system of the compound of formula (A) and acetonitrile is lithium diisopropylamide, and the temperature of the reaction system is controlled to be -78°C to 0°C when the lithium diisopropylamide is added.

[0044] As a preferred solution, in the step 1) of the use, the basic reagent added to the reaction system of the compound of formula (A) and acetonitrile is lithium diisopropylamide, and the temperature of the reaction system is controlled to be -30°C to -10°C when the lithium diisopropylamide is added.

[0045] As a preferred solution, in the step 2) of the use, the compound of formula (B) is reacted with hydrazine hydrate to prepare the compound of formula (C) or its acid salt, and the molar ratio of the compound of formula (B) to hydrazine hydrate is 1:(0.5-20).

[0046] As a further preferred solution, in the step 2) of the use, the compound of formula (B) is reacted with hydrazine hydrate to prepare the compound of formula (C) or its acid salt, and the molar ratio of the compound of formula (B) to hydrazine hydrate is 1:(0.5-5).

[0047] As a preferred solution, in the step 2) of the use, the reaction is carried out under acidic conditions, the acid is an inorganic acid or an organic acid, the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, benzene sulfonic acid, p-toluene sulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, malonic acid, oxalic acid or salicylic acid.

[0048] As a further preferred solution, in the step 2) of the use, the reaction is carried out under acetic acid conditions, the molar ratio of the compound of formula (B) to acetic acid is 1:(0.5-20).

[0049] As a further preferred solution, in the step 2) of the use, the reaction is carried out under acetic acid conditions, the molar ratio of the compound of formula (B) to acetic acid is 1:(0.5-20).

[0050] As a further preferred solution, in the step 2) of the use, the hydrazine hydrate and acetic acid are mixed first, and then the compound of formula (B) or its C 1-4 alcohol solution or C 1-4 aqueous alcohol solution.

[0051] As a further preferred solution, in the step 2) of the use, the reaction is carried out at 40-80°C.

[0052] As a further preferred solution, in the step 2) of the use, the reaction is carried out at 60-70°C.

[0053] The fourth aspect of the present application provides a use of a compound of formula (A) in the preparation of a compound of formula (B), comprising the following steps:

[0054]

[0055] The compound of formula (A) is prepared by reaction to obtain the compound of formula (B).

[0056] As a preferred solution, in the use, the compound of formula (A) is reacted with acetonitrile to form the compound of formula (B), and the molar ratio of the compound of formula (A) to acetonitrile is 1:(2-20).

[0057] As a further preferred solution, in the use, a basic reagent is added to the reaction system of the compound of formula (A) and acetonitrile, and the basic reagent is selected from one or more of lithium diisopropylamide, n-butyllithium, sodium hexamethyldisilylamide, potassium hexamethyldisilylamide or lithium hexamethyldisilylamide.

[0058] As a further preferred solution, in the use, the molar ratio of the compound of formula (A) to the basic reagent is 1:(2-8).

[0059] As a further preferred solution, in the use, the basic reagent added in the reaction system of the compound of formula (A) and acetonitrile is lithium diisopropylamide, and the temperature of the reaction system is controlled to be -30℃ to -10℃ when the lithium diisopropylamide is added.

[0060] The fifth aspect of the present application provides a compound of formula (B'):

[0061]

[0062] The sixth aspect of the present application provides a use of a compound of formula (A) in the preparation of AZD4547 or an acid salt thereof, which comprises preparing a compound of formula (C) or an acid salt thereof from the compound of formula (A) by the aforementioned preparation method, and further comprising the following steps:

[0063]

[0064] reacting the compound of formula (C) or an acid salt thereof with a compound of formula (D) to obtain AZD4547 or an acid salt thereof,

[0065] wherein R is C 1-8 alkyl, preferably methyl, ethyl or isopropyl; the acid salt is an inorganic acid salt or an organic acid salt; the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, methanesulfonate, ethanesulfonate, benzoate, citrate, malate, tartrate, embonate, fumarate, galacterate, malonate, glycolate, oxalate, propionate, 4-acetylamino-benzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate or 1-hydroxy-2-naphthoate.

[0066] As a preferred solution, in the use, the compound of formula (C) or an acid salt thereof is condensed with the compound of formula (D) in the presence of a basic reagent to obtain AZD4547 or an acid salt thereof, and the basic reagent is selected from one or more of potassium tert-pentoxide, potassium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisopropylamide.

[0067] The seventh aspect of the present application provides a preparation method of a compound of formula (B), which comprises the following steps:

[0068]

[0069] The compound of formula (A) is reacted with acetonitrile in the presence of sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisopropylamide to obtain the compound of formula (B).

[0070] As a preferred solution, in the preparation method, the molar ratio of the compound of formula (A) to acetonitrile is 1:(2-20).

[0071] As a further preferred solution, in the preparation method, the molar ratio of the compound of formula (A) to lithium diisopropylamide is 1:(2-8).

[0072] As a further preferred solution, in the preparation method, lithium diisopropylamide is added to the reaction system of the compound of formula (A) and acetonitrile, and the temperature of the reaction system is controlled to be -30°C to -10°C when lithium diisopropylamide is added.

[0073] The eighth aspect of the present application provides a preparation method of a compound of formula (C) or an acid salt thereof, comprising the following steps:

[0074]

[0075] 1) The compound of formula (A) is reacted with acetonitrile under alkaline conditions to prepare the compound of formula (B);

[0076] 2) The compound of formula (B) is condensed with hydrazine hydrate under acidic conditions to generate the compound of formula (C) or an acid salt thereof;

[0077] The acid salt is an inorganic acid salt or an organic acid salt; the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, methanesulfonate, ethanesulfonate, benzoate, citrate, malate, tartrate, formate, fumarate, galactarate, malonate, glycolate, oxalate, propionate, 4-acetylamino benzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate or 1-hydroxy-2-naphthoate.

[0078] As a preferred solution, in the preparation method step 1), the molar ratio of the compound of formula (A) to acetonitrile is 1:(2-20).

[0079] As a further preferred solution, in the preparation method step 1), a basic reagent is added to the reaction system of the compound of formula (A) and acetonitrile, and the basic reagent is selected from one or more of lithium diisopropylamide, n-butyllithium, sodium hexamethyldisilylamide, potassium hexamethyldisilylamide or lithium hexamethyldisilylamide.

[0080] As a further preferred solution, in the preparation method step 1), the molar ratio of the compound of formula (A) to the basic reagent is 1:(2-8).

[0081] As a further preferred solution, in the step 1) of the preparation method, the basic reagent added in the reaction system of the compound of formula (A) and acetonitrile is lithium diisopropylamide, and the temperature of the reaction system is controlled to be -30℃ to -10℃ when the lithium diisopropylamide is added.

[0082] As a further preferred solution, in the step 2) of the preparation method, the molar ratio of the compound of formula (B) to hydrazine hydrate is 1:(0.5-5).

[0083] As a further preferred solution, the step 2) of the preparation method is carried out under acidic conditions, and the acid is an inorganic acid or an organic acid, the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, malonic acid, oxalic acid or salicylic acid.

[0084] As a further preferred solution, in the step 2) of the preparation method, the reaction is carried out under acetic acid conditions, and the molar ratio of the compound of formula (B) to acetic acid is 1:(2-6).

[0085] As a further preferred solution, in the step 2) of the preparation method, hydrazine hydrate and acetic acid are first mixed, and then the compound of formula (B) or a C 1-4 alcohol solution or a C 1-4 alcohol aqueous solution.

[0086] As a further preferred solution, in the step 2) of the preparation method, the reaction is carried out at 60℃ to 70℃.

[0087] The ninth aspect of the present application provides a preparation method of AZD4547 or an acid salt thereof, comprising the following steps:

[0088]

[0089] Step 1: the compound of formula (SM) is reacted with isopropyl alcohol in the presence of SOCl2 to prepare the compound of formula (A);

[0090] Step 2: the compound of formula (A) is reacted with acetonitrile under basic conditions to prepare the compound of formula (B);

[0091] Step 3: the compound of formula (B) is condensed with hydrazine hydrate under acidic conditions to generate the compound of formula (C) or an acid salt thereof;

[0092] Step 4: the compound of formula (C) or an acid salt thereof is reacted with the compound of formula (D) to obtain AZD4547 or an acid salt thereof;

[0093] wherein R is C 1-8alkyl, preferably methyl, ethyl or isopropyl; the acid salt in step (3) or (4) is an inorganic acid salt or an organic acid salt; the inorganic acid salt is selected from the group consisting of a hydrochloride, a sulfate, a hydrobromide, a hydrofluoride, a hydroiodide or a phosphate; the organic acid salt is selected from the group consisting of an acetate, a trifluoroacetate, a benzenesulfonate, a p-toluenesulfonate, a 4-chlorobenzenesulfonate, a methanesulfonate, an ethanesulfonate, a benzoate, a citrate, a malate, a tartrate, a formate, a fumarate, a galactarate, a malonate, a glycolate, an oxalate, a propionate, a 4-acetamidobenzoate, a 4-aminobenzoate, a salicylate, a 4-aminosalicylate, a 2,5-dihydroxybenzoate or a 1-hydroxy-2-naphthoate.

[0094] As a preferred solution, in step 1 of the preparation method, the mass-volume ratio of the compound of formula (SM) and isopropanol is 1:(5-10).

[0095] As a preferred solution, in step 1 of the preparation method, SOCl2 is added to the reaction system of the compound of formula (SM) and isopropanol, and the molar ratio of the compound of formula (SM) to SOCl2 is 1:(0.5-2).

[0096] As a further preferred solution, in step 1 of the preparation method, the reaction is carried out at 55-65°C.

[0097] As a preferred solution, in step 2 of the preparation method, the molar ratio of the compound of formula (A) to acetonitrile is 1:(2-20).

[0098] As a further preferred solution, in step 2 of the preparation method, a basic reagent is added to the reaction system of the compound of formula (A) and acetonitrile, and the basic reagent is selected from one or more of lithium diisopropylamide, n-butyllithium, sodium hexamethyldisilylamide, potassium hexamethyldisilylamide or lithium hexamethyldisilylamide.

[0099] As a further preferred solution, in step 2 of the preparation method, the molar ratio of the compound of formula (A) to the basic reagent is 1:(2-8).

[0100] As a further preferred solution, in step 2 of the preparation method, the basic reagent added to the reaction system of the compound of formula (A) and acetonitrile is lithium diisopropylamide, and the temperature of the reaction system is controlled to be -30 to -10°C when lithium diisopropylamide is added.

[0101] As a further preferred solution, in step 3 of the preparation method, the molar ratio of the compound of formula (B) to hydrazine hydrate is 1:(0.5-5).

[0102] As a further preferred solution, the preparation method step 3 is reacted under acetic acid condition, and the molar ratio of the compound of formula (B) to acetic acid is 1:(2-6).

[0103] As a further preferred solution, the preparation method step 3 is reacted under acetic acid condition, and the molar ratio of the compound of formula (B) to acetic acid is 1:(2-6). 1-4 alcohol solution or C 1-4 alcohol solution or C

[0104] As a further preferred solution, the preparation method step 3 is reacted under acetic acid condition, and the molar ratio of the compound of formula (B) to acetic acid is 1:(2-6).

[0105] As a further preferred solution, the preparation method step 3 is reacted under acetic acid condition, and the molar ratio of the compound of formula (B) to acetic acid is 1:(2-6).

[0106] As a further preferred solution, the preparation method step 4 is that the compound of formula (C) or its acid salt is condensed with the compound of formula (D) under the condition of a basic reagent selected from one or more of potassium tert-pentoxide, potassium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisopropylamide to obtain AZD4547 or its acid salt.

[0107] The tenth aspect of the present application provides a preparation method of AZD4547 or its acid salt, comprising the following steps:

[0108]

[0109] The compound of formula (C) or its acid salt is condensed with the compound of formula (D) in the presence of potassium tert-pentoxide, potassium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisopropylamide to obtain AZD4547 or its acid salt.

[0110] Compared with the prior art, the present application has the following advantages:

[0111] (1) The present application designs to use isopropyl ester structure, and provides a new compound of formula (A), i.e. isopropyl 3-(3,5-dimethoxyphenyl)propionate. The ester compound is stable in structure, and can make the reaction solution homogeneous and clear in the industrial production process, so that the problem that the reaction process cannot be effectively stirred due to the occurrence of sticky glue phenomenon in the reaction process when using methyl ester compound of formula (A') or ethyl ester compound of formula (A") as the reaction raw material can be effectively avoided, and the problem that the preparation method cannot be industrialized is solved.

[0112] (2) The present application adopts ethanol to quench the reaction in Example 3 or 4, which can avoid the self-polymerization of the compound of formula (B) in the reaction liquid to the greatest extent, and affect the difficulty of post-treatment and the purity of the product.

[0113] (3) The present application adopts acid, especially acetic acid, to carry out the reaction in Example 5 step 2, which can neutralize the hydrazine hydrate in the reaction, so that the reaction process is safer, or the residual basic reagent in the reaction liquid in the previous step is neutralized.

[0114] (4) The preparation method of the present application has mild reaction conditions, avoids ultra-low temperature reaction, and avoids the use of column chromatography purification, has less solvent consumption, high yield, strong operability, and can realize industrial application. BRIEF DESCRIPTION OF DRAWINGS

[0115] Figure 1 is the HPLC chromatogram of the reaction control in Experiment 2 in Comparative Experiment 2.

[0116] Figure 2 is the HPLC chromatogram of the organic phase in Example 2.

[0117] Figure 3 is the HPLC chromatogram of the impurity-containing mother liquor in Example 2, and the impurity compound has a peak time of 14.084 min.

[0118] Figure 4 is the LCMS chromatogram of the impurity in Example 2, and the impurity compound has a peak time of 2.284 min, corresponding to the peak at 14.084 min in the HPLC chromatogram.

[0119] Figure 5 is the HPLC chromatogram of the impurity in Example 2 1 HNMR spectrum. DETAILED DESCRIPTION

[0120] The inventors of the present application have designed and provided a new AZD4547 intermediate, namely isopropyl 3-(3,5-dimethoxyphenyl)propionate, through extensive and in-depth research, and further disclosed a two-step reaction for preparing a key intermediate 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine of AZD4547 from the intermediate, and disclosed the above two intermediates, the preparation method thereof and the use thereof in preparing AZD4547 active pharmaceutical ingredient (API). The process of the present application is mature and stable, simple to operate, high in yield, low in cost, safe and environmentally friendly, and the prepared API can meet the needs of AZD4547 clinical research and drug marketing, and solves the problem of drug accessibility.

[0121] The following terms used in the specification and claims have the following meanings.

[0122] LDA refers to lithium diisopropylamide, n-BuLi refers to n-butyllithium, LiHMDS refers to lithium hexamethyldisilylamide, NaHMDS refers to sodium hexamethyldisilylamide, LiOH refers to lithium hydroxide, AcOH refers to acetic acid, HCl refers to hydrochloric acid, THF refers to tetrahydrofuran, KO-tam refers to potassium tert-amylate, TFA refers to trifluoroacetic acid. eq refers to equivalent of reaction.

[0123] The present application will be further described in detail in connection with the following examples, which by no means limit the present application, and the present application is not limited to the contents of the examples.

[0124] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR). NMR chemical shifts (δ) are given in parts per million (ppm).

[0125] The NMR determination is performed by using a Bruker AVANCE-400 / 500 nuclear magnetic instrument, and the determination solvents are deuterium dimethyl sulfoxide (DMSO-d6), deuterium methanol (CD3OD) and deuterium chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0126] The determination of liquid chromatography-mass spectrometry (LC-MS) is performed by using an Agilent Technologies InifinityLab LC / MSD mass spectrometer.

[0127] The HPLC determination is performed by using an equipment of Agilent Technologies 1260Infinity II, a chromatographic column of Poroshell 120 EC-C18 4μm 4.6×150mm, a mobile phase of A phase: water+0.05% trifluoroacetic acid, B phase: acetonitrile+0.05% trifluoroacetonitrile, and a flow rate of 1.0ml / min.

[0128] The starting materials in the examples of the present application are known and can be bought in the market, or can be synthesized by using or according to the methods known in the art. For example, the acid salts of the present application can be prepared by reacting free substances with corresponding acids according to the methods known in the art.

[0129] Unless otherwise specified, all the reactions of the present application are performed under dry nitrogen or argon atmosphere, the solvent is dry solvent, and the reaction temperature unit is Celsius (℃).

[0130] Example 1

[0131] Into a 1 L three-necked flask, add isopropyl alcohol (300 mL), 3-(3,5-dimethoxyphenyl)propionic acid (60.0 g, 0.285 mol), and warm to 40±5°C, and stir for 5-10 minutes to dissolve the contents. At 40±5°C, add SOCl2(37.3 g, 0.314 mol) dropwise, and the dropwise addition takes ≥0.5 hours (the exothermic heat is obvious during the dropwise addition). After the dropwise addition is complete, the temperature rises to 60±5°C, and the reaction is stirred for 1 hour. HPLC detection shows that the starting material is completely reacted. The reaction solution is cooled to 35±5°C, and is concentrated under reduced pressure to dryness at a temperature controlled below 50°C. Add methyl tert-butyl ether (300 mL) to dissolve the contents, and add 5% aqueous K2CO3solution to adjust the pH of the reaction solution to 8-9 in an ice bath. Stir for 0.5 hours at a temperature controlled at 25±5°C, and separate the layers. Wash the organic phase with saturated brine, and concentrate under reduced pressure at a temperature controlled at 45°C to dryness to obtain 3-(3,5-dimethoxyphenyl)propionic acid isopropyl ester as a light yellow oil (72.1 g), with a purity of 94% and a yield of 94.3%.

[0132] 1 HNMR (DMSO-d6, 400 MHz) δ 6.384-6.378 (d, 2H), 6.318-6.306 (t, 1H), 4.925-4.831 (m, 1H), 3.706 (s, 6H), 2.787-2.749 (t, 2H), 2.571-2.533 (t, 2H), 1.164-1.148 (d, 6H).

[0133] Example 2

[0134] Into a 500 mL three-necked flask, add 3-(3,5-dimethoxyphenyl)propionic acid isopropyl ester (20.0 g, 0.079 mol), anhydrous acetonitrile (80 mL), and anhydrous tetrahydrofuran (100 mL). Cool the reaction solution to an internal temperature of about -20°C, and slowly add lithium diisopropylamide (83 mL, 0.166 mol, 2M THF solution) dropwise. The dropwise addition takes about 25 minutes, and stirring is continued for 5-10 minutes. HPLC detection shows that the starting material is completely reacted. Add acetic acid solution (15 mL) to quench the reaction, and concentrate under reduced pressure. Add water (100 mL), and adjust the pH to neutral with 25% aqueous Na2CO3solution. Add ethyl acetate (200 mL) to extract (HPLC chart is shown in Figure 2 ), and concentrate the organic layer under reduced pressure to dryness. Add ethanol (200 mL) to stir and slurry, filter, and dry the filter cake under vacuum at 45°C to obtain 5-(3,5-dimethoxyphenyl)-3-oxovaleramide (14.8 g) with a purity of 98% and a yield of 76%.

[0135] 1HNMR (DMSO-d6, 400 MHz) δ 6.370-6.364 (s, 2H), 6.320-6.309 (s, 1H), 4.038 (s, 2H), 3.709 (s, 6H), 2.851-2.815 (t, 2H), 2.739-2.702 (t, 2H).

[0136] After preliminary separation, the impurity-containing mother liquor HPLC, impurity LCMS and 1 HNMR spectrum is shown in Figures 3-5 After analysis, the main impurity is generated by self-polymerization of 5-(3,5-dimethoxyphenyl)-3-oxovaleride, and the structure of the impurity compound [compound of formula (B')] is as follows:

[0137]

[0138] Example 3

[0139] Under nitrogen protection, 3-(3,5-dimethoxyphenyl) propyl isopropyl ester (11.29 g, 0.045 mol), anhydrous acetonitrile (40 ml) and anhydrous tetrahydrofuran (50 ml) were added into a 500 ml three-necked reaction flask, the reaction solution was cooled to -20°C, and lithium diisopropylamide tetrahydrofuran solution (47 ml, 0.094 mol) was slowly added dropwise, about 25 minutes for dropwise addition, and the stirring reaction was continued for 5-10 minutes. HPLC detection showed that the raw material was completely reacted. Anhydrous ethanol (20 ml) was added to quench the reaction, and 2-methyltetrahydrofuran (50 g) was added for extraction. The water layer was adjusted to neutral pH with hydrochloric acid, filtered, and the filter cake was dried at 45°C under vacuum to obtain 5-(3,5-dimethoxyphenyl)-3-oxovaleride 9.28 g, purity: 99.5%, yield: 88.0%.

[0140] Example 4

[0141] Under nitrogen protection, 3-(3,5-dimethoxyphenyl) propyl isopropyl ester (11.29 g, 0.045 mol), anhydrous acetonitrile (40 ml) and anhydrous tetrahydrofuran (50 ml) were added into a 500 ml three-necked reaction flask, the reaction solution was cooled to -20°C, and lithium diisopropylamide tetrahydrofuran solution (47 ml, 0.094 mol) was slowly added dropwise, about 25 minutes for dropwise addition, and the stirring reaction was continued for 5-10 minutes. HPLC detection showed that the raw material was completely reacted. Anhydrous ethanol (20 ml) was added to quench the reaction, and 2-methyltetrahydrofuran (50 g) was added for extraction. The water layer was adjusted to neutral pH with hydrochloric acid, filtered, and the filter cake was dried at 45°C under vacuum to obtain 5-(3,5-dimethoxyphenyl)-3-oxovaleride 9.28 g, purity: 99.5%, yield: 88.0%.

[0142] In addition, the inventors investigated the effects of the reaction raw material, anhydrous acetonitrile, a basic reagent, and a reaction temperature on the reaction, the HPLC detection of the controlled purity, and the reaction phenomenon, as follows:

[0143]

[0144]

[0145] From the above experimental factors and experimental phenomena, the effects of different reaction raw material ester groups, acetonitrile amounts, and basic reagents on the reaction are known.

[0146] (1) Effects of reaction raw material ester groups on the reaction

[0147] When the reaction raw material is a compound of formula (A') having a methyl ester group, sticky glue groups are formed in the reaction, affecting stirring, and the controlled purity in the reaction is not high. Specifically, sticky glue groups appear in the reaction liquid at the beginning of the reaction, affecting stirring, and as the reaction proceeds, the reaction liquid gradually becomes sticky, and even sticky wall phenomenon occurs, which cannot be stirred.

[0148] When the reaction raw material is a compound of formula (A") having an ethyl ester group, the controlled purity in the reaction is increased to 87%, but sticky glue groups are still formed in the reaction, affecting stirring, and the specific situation is similar to that when the reaction raw material is a compound of formula (A') having a methyl ester group.

[0149] The appearance of sticky glue groups during process amplification can easily lead to incomplete reaction, and even dangerous situations such as winding stirring paddles and burning motors, so the above two preparation processes are not suitable for industrial amplification production.

[0150] When the ester group structure of the reaction raw material is changed to an isopropyl ester, the reaction liquid is homogeneous and clear, no sticky glue groups are present, the controlled purity in the reaction is increased to more than 97%, and it is suitable for industrial amplification production. The inventors analyzed that the above experimental phenomenon may be due to the higher stability of the isopropyl ester structure, which reduces the formation of side reactions.

[0151] (2) Effects of acetonitrile amount on the reaction

[0152] In experiments 6 and 3 in the experiments of the present application, when the molar ratio of acetonitrile to the reaction raw material was increased from 10 eq to 20 eq, the controlled purity in the reaction was increased from 90.4% to 97.2%.

[0153] In comparison experiment 1, experiments 2 and 3, when the molar ratio of acetonitrile to the reaction raw material was increased from 1.2 eq to 25 eq, the controlled purity in the reaction was increased from 60.8% to 92.8%.

[0154] (3) Effects of the selection and amount of a basic reagent on the reaction

[0155] From the above experimental results, it can be seen that the reaction control purity of NaHMDS, LDA and n-BuLi is relatively high.

[0156] The optimal molar ratio of the basic reagent to the reaction raw material is 2.1 eq, and less than 2 eq can lead to incomplete reaction.

[0157] Example 5

[0158] Step 1: Synthesis of 5-(3,5-dimethoxyphenyl)-3-oxopentanenitrile (compound of formula (B))

[0159] Under nitrogen protection, 3-(3,5-dimethoxyphenyl)propyl isopropyl ester (20.0 g, 0.079 mol), anhydrous acetonitrile (80 ml), anhydrous tetrahydrofuran (100 ml) were added into a 500 ml three-necked reaction flask, the reaction liquid was cooled to -20°C, and diisopropyl lithium (83 ml, 0.166 mol, 2M THF solution) was slowly added dropwise. It took about 25 min to complete the addition, and the reaction was stirred for 5-10 min. HPLC detection showed that the raw material was completely reacted. Anhydrous ethanol (40 ml) was added, and the concentrated solution was reduced to a viscous state under reduced pressure. Anhydrous ethanol (60 ml) was added to prepare an ethanol solution, which was directly used in the next step reaction.

[0160] Step 2: Preparation of 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (compound of formula (C))

[0161] Into a 500 ml three-necked reaction flask, acetic acid (26.0 g, 0.436 mol), ethanol (100 ml), 80% hydrazine hydrate (15.0 g, 0.238 mol) were added, and heated to an internal temperature of about 68°C. The ethanol solution (18.5 g, 0.079 mol) of the product obtained in step 1 was slowly added to the mixed solution of acetic acid and hydrazine hydrate at this temperature. It took about 40 min to complete the addition, and the reaction was stirred at an internal temperature of about 68°C for 1 h. HPLC detection showed that 5-(3,5-dimethoxyphenyl)-3-oxopentanenitrile was completely converted. The reaction liquid was concentrated under reduced pressure, water (100 ml) and ethyl acetate (200 ml) were added, and about 25% Na2CO3 (40 ml) was added to adjust the pH of the water layer to 7-8. The water layer was separated, washed with saturated brine (20 ml), and the organic layer was concentrated under reduced pressure until no distillate was obtained. Isopropyl acetate (100 ml) was added to reduce the pressure to a viscous state, isopropyl acetate (120 ml) was added to dissolve the solution, and the solution was cooled to crystallize. Filtration was performed at about 10°C, and the product was dried under vacuum at 50°C to obtain 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine 16.3 g, with a purity of 99.6%, and a total yield of two steps of 83%.

[0162] 1HNMR (DMSO-d6, 400 MHz) δ 6.370-6.364 (s, 2H), 6.320-6.309 (s, 1H), 4.038 (s, 2H), 3.709 (s, 6H), 2.851-2.815 (t, 2H), 2.739-2.702 (t, 2H).

[0163] In addition, the inventors investigated the effect of the amount of acetic acid on the reaction in this step, and the control purity detected by HPLC was as follows:

[0164]

[0165] In addition, the inventors also investigated the reaction of the solid compound of formula (B) obtained after purification of the product of step 1 with hydrazine hydrate in the presence of acetic acid, and the compound of formula (B) was also completely converted to obtain a high-purity compound of formula (C).

[0166] Example 6

[0167] Into a reaction kettle was added 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (100.0 g, 0.4044 mol), ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (132.5 g, 0.5050 mol), 2-methyltetrahydrofuran (1300 ml), heated to 50-55°C and stirred for 1 hour, filtered through diatomite, the filtrate was added to a clean reaction kettle, heated to distill water at normal pressure, the temperature in the reaction was controlled at 78-88°C, 25% KO-tAm toluene solution (490.0 g) was slowly added dropwise, the dropwise addition time was about 2 hours, after the dropwise addition was completed, the temperature in the reaction was adjusted to 83-88°C and stirred for 3-6 hours, the sample was detected to determine that the reaction of the raw material was completed, the reaction system was cooled to 30-60°C, water (8 ml) was slowly added to quench the reaction, and stirred at 30-60°C for 0.5 hours, then cooled to about 25°C, water (400 ml) was added, stirred and separated into layers, the organic phase was separated, water (200 ml) was added, heated to about 50°C and stirred for 0.5 hours, the water layer was separated, and this was repeated 2-3 times until the pH of the water layer was 7.0-9.5; the organic layer was concentrated under reduced pressure to remove part of the solvent, the residue was heated to 80-90°C and stirred for 1 hour, slowly cooled to 20-30°C, and continued to stir for 2-5 hours, filtered, rinsed twice with ethyl acetate, and dried at 45°C under vacuum to obtain the product (AZD4547) 155.6 g in the form of white amorphous solid, purity: 98.5%, yield: 83%.

[0168] 1HNMR (DMSO-d6, 400 MHz) δ 12.067 (s, 1H), 10.275 (s, 1H), 7.888-7.867 (d, 2H), 6.943-6.922 (d, 2H), 6.437-6.409 (m, 3H), 6.317 (s, 1H), 3.712-3.692 (m, 8H), 2.861-2.803 (m, 6H), 2.230-2.174 (m, 3H), 1.036-1.020 (d, 6H).

[0169] Example 7

[0170] Into a reaction flask was added 3-(3,5-dimethoxyphenethyl)-lH-pyrazol-5-amine (10.0 g, 0.040 mol), ethyl 4-((3R,5S)-3,5-dimethylpiperazin-l-yl)benzoate (12.1 g, 0.047 mol), anhydrous tetrahydrofuran (170 ml), heated normal pressure distillation until about 100 ml remained, cooled to -30°C to -20°C, slowly added NaHMDS (0.125 mol, 63 ml, 2M THF solution), controlled the reaction system temperature to about -25°C, stirred for 20 minutes, HPLC detected that the starting material was substantially completely reacted, slowly added water (30 ml) under temperature control to quench, then added glacial acetic acid (about 10 ml) to neutralize, warmed to about 0°C and stirred, added 20% Na2CO3(10 ml), reduced pressure concentrated until no distillate remained, added ethyl acetate (120 ml) to the residue, heated to about 45°C and stirred to separate the layers, added saturated brine (30 ml) to wash once, reduced pressure concentrated the organic layer until about 30 ml remained, then added ethyl acetate (30 ml), again reduced pressure concentrated, repeated this twice, a large amount of solid precipitated, added ethyl acetate to bring the volume of the material to about 50 ml, stirred at 0-10°C for 1 hour, filtered, and vacuum dried at 45°C to obtain the product (AZD4547) as a white amorphous solid, 16.87 g, purity 99.8%, yield: 91%.

[0171] All documents referred to in this disclosure are incorporated by reference herein as if each document were individually incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and equivalents thereof which fall within the scope of the appended claims.

Claims

1. Compound of formula (A):

2. A method for preparing a compound of formula (A), characterized in that, Compound of formula (SM) was prepared by esterification to obtain compound of formula (A), and the reaction route is as follows: The compound of formula (SM) reacts with isopropanol to generate compound of formula (A), wherein the mass-to-volume ratio of the compound of formula (SM) to isopropanol is 1:(1-50). SOCl2 is added to the reaction system of compound (SM) and isopropanol, wherein the molar ratio of compound (SM) to SOCl2 is 1:(0.1-10).

3. The preparation method according to claim 2, characterized in that, The mass-to-volume ratio of the compound of formula (SM) to isopropanol is 1:(5-20).

4. The preparation method according to claim 2, characterized in that, The mass-to-volume ratio of the compound of formula (SM) to isopropanol is 1:(5-10).

5. The preparation method according to claim 2, characterized in that, SOCl2 is added to the reaction system of compound (SM) and isopropanol, wherein the molar ratio of compound (SM) to SOCl2 is 1:(0.5-2).

6. The preparation method according to claim 2, characterized in that, The reaction was carried out at 40℃-80℃.

7. The preparation method according to claim 2, characterized in that, The reaction was carried out at 55℃-65℃.

8. The use of a compound of formula (A) in the preparation of a compound of formula (C) or its acid salt, characterized in that, The synthesis steps include the following: 1) In step 1), compound (A) reacts with acetonitrile to produce compound (B), wherein the molar ratio of compound (A) to acetonitrile is 1:(1-50); 2)(B) compound is reacted with hydrazine hydrate to prepare compound (C) or its acid salt, wherein the molar ratio of compound (B) to hydrazine hydrate is 1:(0.5-20); the reaction route is as follows:

9. The application according to claim 8, characterized in that, The acid salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoric acid, hydroiodide, or phosphate. The organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, methanesulfonate, ethanesulfonate, benzoate, citrate, malate, tartrate, formate, fumarate, galactonate, malonate, glycolate, oxalate, propionate, 4-acetaminobenzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate, or 1-hydroxy-2-naphthoate.

10. The application according to claim 8, characterized in that, The molar ratio of the compound of formula (A) to acetonitrile is 1:(1-25).

11. The application according to claim 8, characterized in that, In step 1), compound (A) reacts with acetonitrile to generate compound (B), and the molar ratio of compound (A) to acetonitrile is 1:(2-20).

12. The application according to claim 8, characterized in that, In step 1), an alkaline reagent is added to the reaction system of compound (A) with acetonitrile. The alkaline reagent is selected from one or more of diisopropylaminolithium, n-butyllithium, sodium hexamethyldisilamino, potassium hexamethyldisilamino, or lithium hexamethyldisilamino.

13. The application according to claim 8, characterized in that, In step 1), the molar ratio of compound (A) to alkaline reagent is 1:(1-20).

14. The application according to claim 8, characterized in that, The molar ratio of the compound of formula (A) to the basic reagent is 1:(2-8).

15. The application according to claim 8, characterized in that, In step 1), the alkaline reagent added to the reaction system of compound (A) and acetonitrile is lithium diisopropylamino, and the temperature of the reaction system is controlled to be -78℃ to 0℃ when lithium diisopropylamino is added.

16. The application according to claim 8, characterized in that, The temperature of the reaction system is controlled at -30℃ to 10℃.

17. The application according to claim 8, characterized in that, The molar ratio of compound (B) and hydrazine hydrate in step 2) is 1:(0.5-5).

18. The application according to claim 8, characterized in that, Step 2) is carried out under acidic conditions, wherein the acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid; and the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, malonic acid, oxalic acid or salicylic acid.

19. The application according to claim 8, characterized in that, Step 2) involves a reaction under acetic acid conditions, wherein the molar ratio of compound (B) to acetic acid is 1:(0.5-20).

20. The application according to claim 19, characterized in that, Step 2) involves a reaction under acetic acid conditions, wherein the molar ratio of compound (B) to acetic acid is 1:(2-6).

21. The application according to claim 19, characterized in that, In step 2), hydrazine hydrate and acetic acid are first mixed, and then compound of formula (B) or its lower alcohol solution or lower alcohol aqueous solution is added to the above mixture.

22. The application according to claim 8, characterized in that, The reaction in step 2) is carried out at 40℃-80℃.

23. The application according to claim 22, characterized in that, The reaction in step 2) is carried out at 60℃-70℃.

24. The use of a compound of formula (A) in the preparation of a compound of formula (B), characterized in that, The synthesis includes the following steps: Compound (A) is reacted to prepare compound (B), and the reaction route is as follows:

25. The use of a compound of formula (A) in the preparation of AZD4547 or its acid salt, characterized in that, The application according to any one of claims 8-23 yields a compound of formula (C) or its acid salt, further comprising reacting the compound of formula (C) or its acid salt with a compound of formula (D) to obtain AZD4547 or its acid salt, the synthetic route being as follows: Wherein R is methyl, ethyl, or isopropyl; the acid salt is an inorganic acid salt or an organic acid salt; the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoric acid, hydroiodide, or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, methanesulfonate, ethanesulfonate, benzoate, citrate, malate, tartrate, formate, fumarate, galacturonate, malonate, glycolate, oxalate, propionate, 4-acetaminobenzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate, or 1-hydroxy-2-naphthoate.

26. The application according to claim 25, characterized in that, Compound (C) or its acid salt is condensed with compound (D) under alkaline conditions to give AZD4547 or its acid salt, wherein the alkaline reagent is selected from one or more of potassium tert-amyloxide, potassium tert-butoxide, lithium hexamethyldisilamide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, or lithium diisopropylamide.

27. A method for preparing a compound of formula (B), characterized in that, The synthesis includes the following steps: Compound (A) is reacted with acetonitrile in the presence of sodium hexamethyldisilamide, potassium hexamethyldisilamide, lithium hexamethyldisilamide, or lithium diisopropylamino to prepare compound (B), and the reaction route is as follows:

28. A method for preparing a compound of formula (C) or its acid salt, characterized in that, The synthesis steps include the following: 1) Compound (A) is reacted with acetonitrile under alkaline conditions to prepare compound (B); 2) Compound (B) reacts with hydrazine hydrate under acidic conditions to produce compound (C) or its acid salt; The reaction route is as follows: The acid salt is an inorganic acid salt or an organic acid salt; the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoric acid, hydroiodide, or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, methanesulfonate, ethanesulfonate, benzoate, citrate, malate, tartrate, formate, fumarate, galactonate, malonate, glycolate, oxalate, propionate, 4-acetaminobenzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate, or 1-hydroxy-2-naphthoate.

29. A method for preparing AZD4547 or its acid salt, characterized in that, The synthesis steps include the following: (1) Compound (SM) was reacted with isopropanol in the presence of SOCl2 to prepare compound (A); (2) Compound (A) was reacted with acetonitrile under alkaline conditions to prepare compound (B); (3) Compound (B) reacts with hydrazine hydrate under acidic conditions to produce compound (C) or its acid salt; (4) The compound of formula (C) or its acid salt reacts with the compound of formula (D) to give AZD4547 or its acid salt; The reaction route is as follows: R is methyl, ethyl, or isopropyl; the acid salt is an inorganic acid salt or an organic acid salt; the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoric acid, hydroiodide, or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, methanesulfonate, ethanesulfonate, benzoate, citrate, malate, tartrate, formate, fumarate, galactobionate, malonate, glycolate, oxalate, propionate, 4-acetaminobenzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate, or 1-hydroxy-2-naphthoate.

Images