Preparation method for substituted urea derivative

Abstract

Disclosed in the present invention is a preparation method for a substituted urea derivative. The preparation method provided by the present invention uses inexpensive and readily available raw materials, involves mild conditions, has a short reaction time, is safe and controllable, features a high total yield, and is particularly suitable for industrial production.

Description

Preparation method of substituted urea derivatives Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically to a method for preparing a substituted urea derivative having receptor tyrosine kinase inhibitory activity. Background Technology

[0002] Dysregulation, overactivity, or irregularity of receptor protein tyrosine kinase (RTK) activity has been observed in numerous disease conditions, including benign and malignant proliferative disorders, inflammatory disorders, and immune system disorders caused by inappropriate activation of the immune system, leading to conditions such as autoimmune diseases. To date, approximately 58 receptor tyrosine kinases have been identified, including VEGF receptors, PDGF receptors (the PDGF receptor (PDGFR) family consists of five RTKs: PDGFR-a and -b, CSFIR, c-KIT, and FLT3), and the FLK receptor family. These receptors can transduce signals to other tyrosine kinases, such as SRC, RAF, FRK, BTK, CSK, ABI, FES / FPS, FAK, JAK, and ACK.

[0003] FLT3 belongs to the type III receptor tyrosine kinase family. The FLT3 receptor plays an important role in the proliferation and mutation of hematopoietic stem cells. Activation mutations or overexpression of this receptor have been found in AML (acute myeloid leukemia) (see Heinrich Mini-Reviews, Medicinal Chemistry (2004) 4(3):255-271; Kiyoi et al., lnt J Hematol (2005) 82:85-92). Studies have shown that the FLT3 inhibitor CEP-701 can effectively reduce myelin loss in a mouse model of multiple cerebral sclerosis in autoimmune encephalomyelitis (EAE) experiments (see Whartenby et al., PNAS (2005) 102:16741-16746). High levels of FLT3 ligands were found in the serum of patients with Langerhans cell histiocytosis and systemic lupus erythematosus, which further suggests that FLT3 signals in the dysregulation of dendritic cell precursors in patients with autoimmune diseases (see Rolland et al., J Immunol. (2005) 174: 3067-3071).

[0004] Activation of the FLT3 intramural tandem repeat (ITD) is found in approximately 20% of patients with acute myeloid leukemia (AML) and is associated with several adverse prognoses. Studies have shown that FLT3-ITD inhibitors play a role in inhibiting the pathogenesis of malignant tumors and are effective therapeutic targets in AML patients (see Catherine et al., Nature (2012) 485:260-263). Mutations in FLT3 frequently occur in the coding region or point of mutations in the tyrosine kinase domain (TKD) containing the intramural tandem repeat (ITD) in AML patients. Both FLT3-ITD and FLT3-TKD mutations lead to ligand-independent diffusion due to FLT3 receptor dimerization and activity. The proportion of highly variable wild-type alleles in FLT3-ITD is associated with poor prognosis in adults and children (see AS Moore et al., Leukemia (2012) 26:1462-1470).

[0005] Bcr-ABL is a tyrosine kinase that inhibits the carcinogenesis and uncontrolled proliferation of pH-positive chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cells. The Bcr-ABL protein is a constitutively active cytoplasmic tyrosine kinase present in 90% of all CML patients and 15-30% of adult ALL patients. Numerous studies have demonstrated that activation of Bcr-ABL is necessary for the oncogenic capacity of this chimeric protein.

[0006] In recent years, abnormalities in the c-KIT gene, a member of the type III receptor tyrosine kinase family, have attracted considerable attention in AML. Mutations in the c-KIT gene lead to activation independent of receptor ligand binding, resulting in abnormal cell proliferation and potentially cancer. Mutations in the c-KIT gene in leukemia cells are closely related to the occurrence of leukemia and prognosis with treatment. The c-KIT receptor can also be constitutively activated through mutations, leading to abnormal cell proliferation and the development of diseases such as mastocytosis (D816V mutation) and various cancers (e.g., GIST (c-KITΔ27, juxtamembranous deletion)).

[0007] Patent application CN105272930A discloses a class of substituted urea derivatives with receptor tyrosine kinase inhibitory activity, specifically disclosing compounds with formula (I) and their preparation methods.

[0008] Specifically, the preparation method of the compound shown in formula (I) is disclosed below:

[0009] However, the above method still has various problems: 1) When zinc powder is used to reduce nitro in step 3, a large amount of zinc powder waste residue is generated, and the equipment stirring requirements are high, making scale-up difficult, and the post-processing separation and purification is difficult, resulting in a low yield; 2) The yield in step 4 is only 49%, and the triethylamine and p-dimethylaminopyridine used will introduce toxic impurities into API, and the post-processing is also inconvenient; 3) The total yield of the four steps is only 12.7%. Summary of the Invention

[0010] To overcome the aforementioned deficiencies in the prior art, this invention provides a novel method for preparing the compound shown in formula (I). This method uses inexpensive and readily available raw materials, operates under mild and environmentally friendly conditions, has a short reaction time, is safe and controllable, and yields a high overall yield, making it particularly suitable for industrial production.

[0011] On one hand, the present invention provides a method for preparing the compound shown in formula (I), comprising:

[0012] Step 1: The compound shown in formula (II) reacts with the compound shown in formula (III) in solvent 1 to give the compound shown in formula (I).

[0013] Solvent 1 is acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, or tert-amyl alcohol.

[0014] In some embodiments, the reaction in step 1 is carried out at a certain reaction temperature; in some embodiments, the reaction temperature is 50°C to 90°C. In some embodiments, the reaction temperature is 60°C to 90°C. In some embodiments, the reaction temperature is 70°C to 90°C. In some embodiments, the reaction temperature is 70°C to 85°C. In other embodiments, the reaction temperature is 75°C to 85°C. In other embodiments, the reaction temperature is 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, or 90°C. In still other embodiments, the reaction temperature is 75°C, 80°C, or 85°C.

[0015] In some embodiments, the volume ratio of solvent 1 to the mass of the compound represented by formula (III) is (7.5-12.5):1; in some embodiments, the volume ratio of solvent 1 to the mass of the compound represented by formula (III) is 12.5:1. In some embodiments, the volume ratio of solvent 1 to the mass of the compound represented by formula (III) is 10:1. In other embodiments, the volume ratio of solvent 1 to the mass of the compound represented by formula (III) is 7.5:1.

[0016] In some embodiments, the molar ratio of the compound shown in formula (III) to the compound shown in formula (II) is 1:(1.1-1.4); preferably, the molar ratio of the compound shown in formula (III) to the compound shown in formula (II) is 1:1.2.

[0017] In some embodiments, the method for preparing the compound of formula (I) of the present invention further includes a method for preparing the compound of formula (III) (method one), which includes:

[0018] Step 2: The compound shown in formula (V) reacts with the compound shown in formula (IV) in solvent 2 under the action of base 1 and a catalyst to give the compound shown in formula (III).

[0019] In some embodiments, the catalyst is bis(triphenylphosphine)palladium dichloride and cuprous iodide, tetra(triphenylphosphine)palladium and cuprous iodide, or tri(dibenzylacetone)palladium and cuprous iodide.

[0020] In some embodiments, the base 1 is triethylamine.

[0021] In some embodiments, the molar ratio of the compound represented by formula (V) to palladium bistriphenylphosphine dichloride is 1:(0.0015-0.02); preferably, the molar ratio of the compound represented by formula (V) to palladium bistriphenylphosphine dichloride is 1:(0.0020-0.015); more preferably, the molar ratio of the compound represented by formula (V) to palladium bistriphenylphosphine dichloride is 1:(0.0025-0.01); preferably, the molar ratio of the compound represented by formula (V) to palladium bistriphenylphosphine dichloride is 1:0.0075.

[0022] In some embodiments, the molar ratio of the compound represented by formula (V) to cuprous iodide is 1:(0.0010-0.0075); preferably, the molar ratio of the compound represented by formula (V) to cuprous iodide is 1:(0.0005-0.0080); more preferably, the molar ratio of the compound represented by formula (V) to cuprous iodide is 1:0.005.

[0023] In some embodiments, the molar ratio of the compound represented by formula (V) to triethylamine is 1:(1.0-2.0); preferably, the molar ratio of the compound represented by formula (V) to triethylamine is 1:(1.2-1.8); more preferably, the molar ratio of the compound represented by formula (V) to triethylamine is 1:1.6.

[0024] In some embodiments, the molar ratio of the compound shown in formula (V) to the compound shown in formula (IV) is 1:(1.0-1.5).

[0025] In some embodiments, the molar ratio of the compound shown in formula (V) to the compound shown in formula (IV) is 1:(1.0-1.20).

[0026] In some embodiments, the molar ratio of the compound shown in formula (V) to the compound shown in formula (IV) is 1:1.05.

[0027] In some embodiments, solvent 2 is acetonitrile or N,N-dimethylformamide.

[0028] In some embodiments, the reaction in step 2 is carried out at a certain reaction temperature; in some embodiments, the reaction temperature is 20°C to 60°C; in other embodiments, the reaction temperature is 20°C to 55°C; in still other embodiments, the reaction temperature is 25°C, 30°C, or 35°C.

[0029] In some embodiments, the method for preparing the compound of formula (I) according to the present invention further comprises the following method (method two) for preparing the compound of formula (III) from the compound of formula (VI), including:

[0030] Step A: The compound shown in formula (VI) reacts in solvent b under the action of catalyst a to give the compound shown in formula (III).

[0031] In some embodiments, catalyst a is an aqueous solution of ammonium sulfide.

[0032] In some embodiments, the reaction temperature of step A is 50°C to 100°C; preferably, the reaction temperature of step A is 50°C to 80°C; more preferably, the reaction temperature of step A is 65°C to 75°C. Optionally, the reaction in step A can be carried out at room temperature for a period of time before being heated to the aforementioned reaction temperature. Optionally, the room temperature can be 10°C to 40°C, or 15°C to 35°C, or 20°C to 35°C, or 20°C to 30°C, or around 25°C.

[0033] In some embodiments, the reaction in step A is carried out at room temperature for a period of time and then under heating conditions; preferably, the reaction in step A is carried out at 10°C to 40°C for a period of time and then heated to 50°C to 80°C to continue the reaction; more preferably, the reaction in step A is carried out at 25±10°C for a period of time and then heated to 65°C to 75°C to continue the reaction.

[0034] In some embodiments, solvent b is an alcohol. Solvent b is methanol, ethanol, isopropanol, tert-butanol, sec-butanol, or tert-amyl alcohol.

[0035] In some embodiments, the method for preparing the compound of formula (III) from the compound of formula (VI) according to the present invention further includes a method for preparing the compound of formula (VI), comprising:

[0036] Step B: The compound shown in formula (V) reacts with the compound shown in formula (VII) in solvent c, under the action of base d and catalyst e, to give the compound shown in formula (VI).

[0037] In some embodiments, the catalyst e is bis(triphenylphosphine)palladium dichloride and cuprous iodide, tetra(triphenylphosphine)palladium and cuprous iodide, or tri(dibenzylacetone)palladium and cuprous iodide.

[0038] In some embodiments, the base d is triethylamine.

[0039] In some implementations, solvent c is acetonitrile, toluene, or tetrahydrofuran.

[0040] In some embodiments, the molar ratio of the compound represented by formula (V) to bis(triphenylphosphine)palladium dichloride is 1:(0.005-0.02).

[0041] In some embodiments, the molar ratio of the compound represented by formula (V) to cuprous iodide is 1:(0.010-0.04).

[0042] In some embodiments, the molar ratio of the compound represented by formula (V) to triethylamine is 1:(1.2 -2).

[0043] In some embodiments, the molar ratio of the compound shown in formula (V) to the compound shown in formula (VII) is 1:(1.2-1.5).

[0044] In some embodiments, the reaction temperature of step B is 40°C to 60°C; preferably, the reaction temperature is 45°C to 55°C.

[0045] In some embodiments, the method for preparing the compound represented by formula (I) of the present invention further includes a method for preparing the compound represented by formula (V), comprising:

[0046] The compound shown in formula (IX) (p-iodophenol) and the compound shown in formula (VIII) (4-(3-chloropropyl)morpholine) react in solvent 3 under the action of base 2 to give the compound shown in formula (V).

[0047] In some embodiments, the solvent 3 is acetonitrile, dimethyl sulfoxide, or N,N-dimethylformamide.

[0048] In some embodiments, the base 2 is potassium carbonate, sodium carbonate, and cesium carbonate.

[0049] In some embodiments, the molar ratio of the compound represented by formula (IX) to base 2 is 1:(1.00-1.50); ​​preferably, the molar ratio of the compound represented by formula (IX) to base 2 is 1:(1.10-1.27); more preferably, the molar ratio of the compound represented by formula (IX) to base 2 is 1:1.15.

[0050] In some embodiments, the reaction of the compound represented by formula (V) is carried out at a certain reaction temperature; in some embodiments, the reaction temperature is 65°C to 90°C; in other embodiments, the reaction temperature is 70°C to 85°C; in still other embodiments, the reaction temperature is 75°C, 80°C, or 85°C.

[0051] In some embodiments, the molar ratio of the compound represented by formula (IX) to the compound represented by formula (VIII) is 1:(1.0-1.3); preferably, the molar ratio of the compound represented by formula (IX) to the compound represented by formula (VIII) is 1:(1.05-1.25); more preferably, the molar ratio of the compound represented by formula (IX) to the compound represented by formula (VIII) is 1:1.15.

[0052] This invention provides a novel method for preparing the compound shown in formula (I), which has unexpected technical advantages:

[0053] 1. In step 1 of this invention, only the solvent 1 described in this invention needs to be added to obtain compound (I) with high yield and high purity. For example, in embodiment 4-A of this invention, only tert-butanol needs to be used as solvent to achieve a yield of 86.8% and a purity of 99.9%, which is significantly higher than the 49% of the prior art. Furthermore, this invention does not require the use of DMAP catalyst and TEA base, which are prone to producing toxic impurities.

[0054] 2. This invention eliminates the need for nitro reduction, thus avoiding the generation of large amounts of zinc powder waste residue from zinc powder nitro reduction. The use of zinc powder requires high equipment stirring, making scale-up difficult, and post-processing separation and purification is challenging.

[0055] 3. In scale-up production, the total reaction yield of the present invention can be higher than 47.8%, which is significantly higher than the 12.7% of the prior art.

[0056] 4. The present invention can also use ammonium sulfide as a reducing agent to reduce nitro to prepare the compound shown in formula (III), with a yield of 71% (the prior art only has 44%). This method also has the technical advantage of not using zinc powder reduction as mentioned above.

[0057] Therefore, compared with the prior art, the new method for preparing the compound shown in formula (I) of the present invention not only has a high yield, but also has a simple preparation process, is environmentally friendly, and is more suitable for industrial production.

[0058] Detailed Description of the Invention

[0059] Definitions and general terms

[0060] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0061] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0062] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0063] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the *Handbook of Chemistry and Physics*, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito: 1999, and *March's Advanced Organic Chemistry* by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0064] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0065] In the context of this invention, all figures disclosed herein are approximate values. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, or 10%, etc. Whenever a figure with a value of N is disclosed, any figure having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" refers to addition or subtraction. Whenever a lower limit, DL, and an upper limit, DU, of a numerical range are disclosed, any value within that disclosed range is explicitly disclosed.

[0066] The "product content" or "product ratio" mentioned in this invention refers to the content of the product in the reaction system as detected by HPLC after the reaction is completed.

[0067] In this invention, "room temperature" refers to a temperature from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, etc.

[0068] The following abbreviations are used throughout this invention: MeCN,CH3CN, acetonitrile, Pd(PPh3)2Cl2, bis(triphenylphosphine)palladium dichloride, Pd(P(C6H5)3)4, tetra(triphenylphosphine)palladium, Pd2(dba)3, tris(dibenzylacetone)dipalladium, CuI, cuprous iodide, DMF, N,N-dimethylformamide, DCM, dichloromethane, DMSO, dimethyl sulfoxide, DMAP, 4-dimethylaminopyridine, DIPEA, N,N-diisopropylethylamine, TEA, triethylamine, EtOH, ethanol, Zn, zinc powder, K2CO3, potassium carbonate, NH4Cl, ammonium chloride, mL, ml, milliliters, eq, equivalent, °C, wt, weight percentage, RT, rt, room temperature, RRT, retention time. Example

[0069] Example 1: Synthesis of 4-(3-(4-iodophenoxy)propyl)morpholine

[0070] Add p-iodophenol and acetonitrile to the reaction flask, then add potassium carbonate and chloropropylmorpholine in sequence. After the addition is complete, heat to 85℃ and react. After stirring for 4 hours, start HPLC monitoring and send the sample for testing every hour. When the remaining amount of p-iodophenol is ≤1.0%, the reaction is over. Stop heating and cool down to 25±10℃. Slowly add water to the reaction solution (to crystallize). After stirring for 5 minutes, filter and wash the filter cake with water (rinsing) to obtain the product. (1) The equivalent of chloropropylmorpholine was optimized relative to p-iodophenol under the conditions of potassium carbonate: 1.27eq, acetonitrile: 5mL / g, and reaction temperature of 80℃. The experimental results are shown in the table below.

[0071] (2) The equivalent of potassium carbonate was optimized relative to p-iodophenol under the conditions of chloropropylmorpholine: 1.15 eq, acetonitrile: 5 mL / g, and reaction temperature of 80℃. The experimental results are shown in the table below.

[0072] (3) Compared with p-iodophenol, the selection of solvent was optimized under the conditions of chloropropylmorpholine: 1.15 eq, potassium carbonate: 1.15 eq, and reaction temperature of 80℃. The experimental results are shown in the table below.

[0073] (4) The reaction temperature was optimized relative to p-iodophenol under the conditions of chloropropylmorpholine: 1.15 eq, potassium carbonate: 1.15 eq, and acetonitrile: 5 mL / g. The experimental results are shown in the table below.

[0074] In summary: 1) Chloropropylmorpholine equivalents of 1.05–1.25 eq yielded good reaction results; 2) Potassium carbonate equivalents of 1.10–1.27 eq also yielded good reaction results; 3) When toluene, 2-butanone, and isopropyl acetate were used as solvents, a large amount of raw material remained after 9.5 hours of reaction; when DMSO, DMF, and acetonitrile were used as solvents, the raw material reacted completely with a high yield. Considering reaction time, post-treatment, and energy consumption, acetonitrile was the preferred solvent; 4) When the reaction temperature was 75℃–85℃, the p-iodophenol reacted almost completely. Considering reaction time and energy consumption, the reaction temperature was set at 80±5℃.

[0075] Scale-up reaction example 1-A:

[0076] Acetonitrile (114.0 kg) was added to the reactor, and stirring was started. Then, p-iodophenol (29.00 kg), potassium carbonate (20.94 kg), and chloropropylmorpholine (24.80 kg) were added sequentially. The temperature was raised to 80±5℃ and reacted for 4 hours. The temperature inside the reactor was lowered to -5±5℃ and stirred for 2 hours. After centrifugation, the filter cake was washed with water (29.0 kg) to obtain a crude wet product. Water (145.2 kg) and the crude wet product were added to the reactor, and the temperature was controlled at 25±5℃ and stirred for 1 hour. After centrifugation, the filter cake was washed with water (29.2 kg) to obtain a wet product. The wet product was dried under vacuum at 60±5℃ for 9 hours to obtain 4-(3-(4-iodophenoxy)propyl)morpholine (43.51 kg, light yellow solid, yield 95.1%, purity: 99.9%).

[0077] Example 2 Synthesis of 4-((4-(3-morpholinopropoxy)phenyl)ethynyl)aniline

[0078] The compound shown in formula (V), palladium dichloride bis(triphenylphosphine), cuprous iodide, and the compound shown in formula (IV) were added sequentially to the reaction flask. After purging with nitrogen three times with acetonitrile, the mixture was cooled to 15±5℃ under nitrogen protection with a slight opening. Triethylamine was slowly added dropwise. After the addition was complete, the temperature was raised to 30±5℃ and the timing was started. The reaction was carried out for 4 hours, and samples were taken for monitoring until the content of the compound shown in formula (V) was ≤6.5%, at which point the reaction was considered complete. The temperature was then lowered to 5±5℃, and the mixture was stirred for 30 minutes. The mixture was then filtered under reduced pressure, and the filter cake was washed with acetonitrile to obtain the crude product.

[0079] (1) Analysis of the feed equivalence of the compound shown in formula (IV)

[0080] Using bis(triphenylphosphine)palladium dichloride (0.005 eq) and cuprous iodide (0.005 eq) as catalysts, triethylamine (1.60 eq) as base, and acetonitrile: 10 mL / g, the effect of the amount of compound shown in formula (IV) on the reaction was investigated. The data are shown in the table below.

[0081] The data above show that the compound shown in formula (IV) has good reaction results when the reaction equivalent is 1.0–1.2 eq. Among them, the reaction results are better and the yield is the highest when the amount of compound shown in formula (IV) is 1.05 eq.

[0082] (2) Investigation of reaction temperature

[0083] Using bis(triphenylphosphine)palladium dichloride (0.005 eq) and cuprous iodide (0.005 eq), triethylamine (1.60 eq) as catalysts, the compound shown in formula (IV) was 1.05 eq, and acetonitrile was 10 mL / g, the effect of different temperatures on the reaction was investigated, and the data are shown in the table below.

[0084] The data comparison above shows that the target product can be obtained at temperatures ranging from 20℃ to 60℃, with better reaction results observed at temperatures ranging from 20℃ to 50℃.

[0085] (3) Screening of reaction solvents

[0086] The purpose of this experiment was to investigate the effect of solvents on the reaction under the following conditions: compound (V) : 1.0 eq, compound (IV) : 1.25 eq, bis(triphenylphosphine)palladium dichloride : 0.075 eq, cuprous iodide : 0.005 eq, triethylamine : 1.6 eq, reaction temperature: 30 °C, using acetonitrile, methyl tert-butyl ether, dichloromethane, toluene, DMF, acetone, and isopropyl acetate as solvents. The experimental data are shown below:

[0087] Experimental results show that, compared with methyl tert-butyl ether, dichloromethane, toluene, acetone and isopropyl acetate, acetonitrile or DMF as solvents all produce better reaction results.

[0088] (4) Feed Equivalent Study of Bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2)

[0089] Cuprous iodide (0.005 eq), triethylamine (1.60 eq), compound (IV) (1.05 eq), acetonitrile: 10 mL / g, reaction temperature 30 °C. The effect of different equivalents of bis(triphenylphosphine)palladium(II) dichloride on the reaction was investigated. The data are shown in the table below.

[0090] The data above show that when the feed equivalent of Pd(PPh3)2Cl2 is 0.0050-0.0075 eq, the reaction results are good.

[0091] (5) Investigation on the effect of different palladium catalysts on the reaction

[0092] The effects of bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)palladium (Pd2(dba)3), and tetra(triphenylphosphine)palladium (Pd(P(C6H5)3)4) on the conversion and yield of the product were investigated, and the data are shown in the table below.

[0093] The data above shows that, in terms of conversion rate, both bis(triphenylphosphine)palladium dichloride and tris(dibenzylideneacetone)palladium dichloride have higher conversion rates than tetra(triphenylphosphine)palladium, with Pd(PPh3)2Cl2+CuI exhibiting the best catalytic effect.

[0094] (6) Evaluation of the feed equivalence of cuprous iodide (CuI)

[0095] The reaction was carried out under the following conditions: Pd(PPh3)2Cl2 (0.075 eq), triethylamine (1.60 eq), the equivalent amount of the compound shown in formula (IV) was 1.05 eq, acetonitrile: 10 mL / g, reaction temperature 30 °C. The effect of different equivalent amounts of cuprous iodide on the reaction was investigated, and the data are shown in the table below.

[0096] The data above show that CuI feed equivalents of 0.001eq–0.0075eq all yielded good reaction results; the highest yield was achieved with a feed equivalent of 0.0050eq.

[0097] (7) Triethylamine Feed Equivalent Study

[0098] Using cuprous iodide (0.005 eq) and (PPh3)2Cl2 (0.075 eq) as metal catalysts, with a feed equivalent of 1.05 eq for the compound shown in formula (IV), acetonitrile: 10 mL / g, and a reaction temperature of 30 °C, the effect of different feed equivalents of triethylamine on the reaction was investigated. The data are shown in the table below.

[0099] The data above show that good reaction results are achieved when the triethylamine feed equivalent is between 1.2 eq and 1.8 eq.

[0100] Scale-up Production Example 2-A:

[0101] 4-(3-(4-iodophenoxy)propyl)morpholine (43.27 kg), bis(triphenylphosphine)palladium dichloride (0.658 kg), cuprous iodide (0.117 kg), and 4-ethynylaniline (16.79 kg) were added to acetonitrile (339.2 kg). After purging with nitrogen three times, the temperature inside the reactor was lowered to 20±5℃ under nitrogen protection with a slight opening. Triethylamine (20.20 kg) was slowly added dropwise, and the temperature inside the reactor was controlled not to exceed 25℃ during the dropwise addition. After the dropwise addition was completed, the temperature inside the reactor was maintained at 20±5℃ and the reaction was stirred for 30 min. The reaction was started at 30±5℃ and timed. After 4 hours, 2.19 kg of 4-ethynylaniline, 0.012 kg of cuprous iodide, and 0.064 kg of bis(triphenylphosphine)palladium dichloride were added for the second time. After three nitrogen purgings, the reaction was continued for 2 hours under slight nitrogen protection. The third addition of 2.19 kg of 4-ethynylaniline, 0.012 kg of cuprous iodide, and 0.064 kg of bis(triphenylphosphine)palladium dichloride was then performed. After three nitrogen purgings, the reaction was continued for 2 hours under slight nitrogen protection, at which point the reaction was complete. The temperature was then lowered to 5±5℃, and the mixture was stirred for 2 hours. After centrifugation, the filter cake was washed with acetonitrile (34.0 kg) to obtain the crude wet product. Acetonitrile (307.6 kg) and crude wet product were added to the reactor. The mixture was heated to 60±5℃ and stirred for 3 hours, then cooled to 0±5℃ and stirred for another 2 hours. After centrifugation, the filter cake was washed with acetonitrile (34.0 kg), and the crude wet product was obtained after centrifugation. Acetonitrile (306.0 kg) and crude wet product were added to the reactor. The mixture was heated to 60±5℃ and stirred for 3 hours, then cooled to 0±5℃ and stirred for another 2 hours. After centrifugation, the filter cake was washed with acetonitrile (34.6 kg), and the wet product was obtained after centrifugation. The wet product was dried under vacuum at 60±5℃ for 9 hours to obtain the product (36.97 kg, yellow solid, yield: 88.2%, purity: 99.8%).

[0102] Example 3 Synthesis of 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((4-(3-morpholinopropoxy)phenyl)ethynyl)phenyl)urea (compound shown in formula (I))

[0103] Solvent, compound (III), and compound (II) were added to the reaction flask. The mixture was heated to a certain temperature and stirred. After reacting for 10 hours, HPLC monitoring was started, and a sample of the system was sent for testing. The reaction was stopped, cooled to room temperature, and then filtered to obtain compound (I).

[0104] The following optimizations were made to the reaction temperature and the amount of reactants fed.

[0105] Scale-up Production Example 3-A:

[0106] 221.85 kg of tert-amyl alcohol was added to the reactor, and stirring was started. Then, 36.73 kg of 4-((4-(3-morpholinopropoxy)phenyl)ethynyl)aniline and 34.12 kg of 5-tert-butylisoxazol-3-ylcarbamate were added sequentially. The temperature inside the reactor was raised to 80±5℃, and the reaction was stirred for 16 h. The temperature was lowered to 25±10℃, and the reaction was stirred for 6 h. After centrifugation, the filter cake was washed with 44.44 kg of tert-amyl alcohol and centrifuged to dryness to obtain the wet product of the compound shown in formula (I). The wet product was dried under vacuum at 60±5℃ for 9 h to obtain the compound shown in formula (II) (47.66 kg, yellow solid, yield: 86.8%, purity: 99.9%).

[0107] Example 4 Synthesis of 4-(3-(4-((4-nitrophenyl)ethynyl)phenoxy)propyl)morpholine

[0108] Compounds of formula (V) and (VII), catalyst, base, and solvent were added to a reaction flask, heated to a certain temperature, stirred, and the mixture was sent for HPLC analysis before the reaction was stopped. The effects of different factors on the reaction were investigated, and the data are as follows.

[0109] (1) The effect of different temperatures on the reaction was investigated using bis(triphenylphosphine) palladium dichloride (0.02 eq) and cuprous iodide (0.04 eq) as catalysts. The data are shown in the table below.

[0110] (2) Using bis(triphenylphosphine) palladium dichloride (0.02 eq) and cuprous iodide (0.04 eq) as catalysts, the effect of the amount of triethylamine on the reaction was investigated at 50 °C. The data are shown in the table below.

[0111] The data above shows that 2.0 eq of triethylamine is most favorable for the reaction as a base, and reducing the amount of triethylamine will lead to a slight decrease in the reaction conversion rate.

[0112] (3) Using bis(triphenylphosphine) palladium dichloride (0.02 eq) and cuprous iodide (0.04 eq) as catalysts, and triethylamine (2.0 eq) as a base, the effect of different solvents on the reaction was investigated. The data are shown in the table below.

[0113] The data above shows that the conversion rate is slightly higher when using acetonitrile as a solvent than when using THF and toluene.

[0114] (4) Using bis(triphenylphosphine) palladium dichloride (0.02 eq) and cuprous iodide (0.04 eq) as catalysts and acetonitrile as solvent, the effect of the amount of compound shown in formula (VII) on the reaction was investigated. The data are shown in the table below.

[0115] The data above show that the compound represented by formula (VII) reacts with a higher yield at 1.5 eq.

[0116] (5) Using bis(triphenylphosphine)palladium dichloride and cuprous iodide as catalysts, the effect of the amount of catalyst on the reaction was investigated. The data are shown in the table below.

[0117] The target product has requirements regarding the content of heavy metals. When the reactants are fully reacted, the amount of catalyst used is minimized, resulting in a decrease in the content of corresponding impurities. The data above shows that the catalytic conditions in Examples 1-8 all yielded relatively high results.

[0118] Scale-up Production Example 4-A:

[0119] Acetonitrile (15.80 kg) was added to the reaction vessel, and stirring was started. Then, 4-(3-(4-iodophenoxy)propyl)morpholine (2.00 kg), bis(triphenylphosphine)palladium dichloride (0.030 kg), cuprous iodide (0.016 kg), p-nitrophenylacetylene (1.26 kg), and triethylamine (1.16 kg) were added sequentially. Nitrogen gas was purged three times, and the reaction was stopped after heating to 50±5℃ under nitrogen protection for 4 hours. The temperature was then lowered to 25±10℃, and drinking water (40.00 kg) was added to the reaction solution. The mixture was stirred without temperature control for 1 hour. After centrifugation, the filter cake was washed five times with acetonitrile (2.24 kg x 10) to obtain a crude wet product. The crude wet product was dried under vacuum at 60±5℃ for 9 hours to obtain 2.01 kg of crude product. 2.01 kg of crude product was added to dichloromethane (26.63 kg) and methanol (15.90 kg), followed by 0.2 kg of activated carbon. The mixture was heated to 45 ± 5 °C and stirred for 2 hours, then cooled to 25 ± 10 °C. The mixture was discharged into a vacuum filter tank lined with 0.56 kg of diatomaceous earth and filtered. The filter cake was washed with methanol (3.18 kg). The filtrate was transferred to a reaction vessel and concentrated under reduced pressure at 50 ± 5 °C. Acetonitrile (8.04 kg) was added to the concentrated solution from the previous step, and the mixture was heated to 85 ± 5 °C and stirred for 1 hour. The mixture was then cooled to 25 ± 10 °C and stirred for 3 hours. After centrifugation, the filter cake was washed with acetonitrile (1.61 kg), and the wet product was obtained after centrifugation. The wet product was dried under vacuum at 60±5℃ for 9 hours to obtain the compound shown in formula (IV) (1.716 kg, yellow solid, yield: 81.3%, purity: 99.19%).

[0120] Example 5 Synthesis of 4-((4-(3-morpholinopropoxy)phenyl)ethynyl)aniline

[0121] The compound shown in formula (VI), ammonium sulfide aqueous solvent (20% wt), and solvent were added to a reaction flask, heated to a certain temperature, stirred, and the reaction was stopped after HPLC analysis. The effects of different factors on the reaction were investigated, and the data are shown in the table below.

[0122] Scale-up reaction example 5-A:

[0123] 10.24 kg of sec-butanol was added to the reactor, and stirring was started. Then, the compound shown in formula (VI) (1.69 kg) and a solution of ammonium sulfide (9.63 kg) were added sequentially. The temperature in the reactor was controlled at 25 ± 10 °C and stirred for 1 h. The temperature was then increased to 70 ± 5 °C and reacted for 2 h until the reaction was complete. The temperature was lowered to 45 ± 10 °C, and drinking water (25.01 kg) was slowly added to the reaction solution. The temperature was lowered to 25 ± 10 °C, and the mixture was stirred for 2 h. After centrifugation, the filter cake was washed with drinking water (25.35 kg) to obtain a crude wet product. The crude wet product was vacuum dried at 60 ± 5 °C for 15 h until the drying was complete, yielding 1.23 kg of crude product. Toluene (8.00 kg) and crude compound (1.23 kg) of formula (III) were added to the reactor. The mixture was heated to 110±5℃ and stirred for 30 min. The temperature was then lowered to 25±5℃ and stirred for another 3 h. After centrifugation, the filter cake was washed with toluene (1.23 kg) to obtain a wet product. The wet product was dried under vacuum at 60±5℃ for 12 h. After drying, the product was cooled and discharged to obtain compound (1.106 kg, yellow solid, yield: 71.3%, purity: 97.11%) of formula (III).

[0124] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0125] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

A method for preparing the compound shown in formula (I), characterized in that... include: Step 1: The compound shown in formula (II) reacts with the compound shown in formula (III) in solvent 1 to give the compound shown in formula (I). Solvent 1 is acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, or tert-amyl alcohol. According to the method of claim 1, wherein, The reaction temperature in step 1 is 50°C to 90°C; preferably, the reaction temperature in step 1 is 75°C to 85°C. The method according to claim 1 or 2, wherein, The ratio of the volume of solvent 1 to the mass of the compound shown in formula (III) is (7.5-12.5):

1. The method according to any one of claims 1-3, wherein, The molar ratio of the compound shown in formula (III) to the compound shown in formula (II) is 1:(1.1-1.4). The method according to any one of claims 1-4, characterized in that Further methods comprising preparing the compound shown in formula (III): Step 2: The compound shown in formula (V) reacts with the compound shown in formula (IV) in solvent 2 under the action of base 1 and a catalyst to give the compound shown in formula (III). The method according to claim 5, wherein, The catalyst is bis(triphenylphosphine)palladium dichloride, tetra(triphenylphosphine)palladium or tri(dibenzylacetone)palladium, and optionally, the catalyst further includes cuprous iodide. Preferably, the catalyst is bis(triphenylphosphine)palladium dichloride and cuprous iodide, tetra(triphenylphosphine)palladium and cuprous iodide, or tri(dibenzylacetone)palladium and cuprous iodide; Optionally, the base 1 is triethylamine. The method according to claim 6, wherein, The molar ratio of the compound represented by formula (V) to palladium dichloride bis(triphenylphosphine) is 1:(0.0015-0.02); preferably, the molar ratio of the compound represented by formula (V) to palladium dichloride bis(triphenylphosphine) is 1:(0.0020-0.015); more preferably, the molar ratio of the compound represented by formula (V) to palladium dichloride bis(triphenylphosphine) is 1:(0.0025-0.01). The molar ratio of the compound shown in formula (V) to cuprous iodide is 1:(0.0005-0.0080); preferably, the molar ratio of the compound shown in formula (V) to cuprous iodide is 1:(0.0010-0.0075). The method according to any one of claims 6-7, wherein, The molar ratio of the compound shown in formula (V) to triethylamine is 1:(1.0-2.0); preferably, the molar ratio of the compound shown in formula (V) to triethylamine is 1:(1.2-1.8). Optionally, the molar ratio of the compound shown in formula (V) to the compound shown in formula (IV) is 1:(1.0-1.5). The method according to any one of claims 5-8, wherein, Solvent 2 is acetonitrile or N,N-dimethylformamide. The method according to any one of claims 5-9, wherein, The reaction temperature in step 2 is 20°C to 60°C; preferably, the reaction temperature in step 2 is 20°C to 55°C; more preferably, the reaction temperature in step 2 is 25°C to 35°C. The method according to any one of claims 1-4, characterized in that Further methods comprising preparing the compound shown in formula (III): Step A: The compound shown in formula (VI) reacts in solvent b under the action of catalyst a to give the compound shown in formula (III). The method according to claim 11, wherein, The catalyst a is an aqueous solution of ammonium sulfide. The method according to claim 11 or 12, wherein, The reaction temperature of step A is 50°C to 100°C; preferably, the reaction temperature of step A is 50°C to 80°C; more preferably, the reaction temperature of step A is 65°C to 75°C; the reaction of step A is optionally heated to the reaction temperature after reacting at room temperature for a period of time, wherein the room temperature is optionally 10°C to 40°C, or 15°C to 35°C, or 20°C to 35°C, or 20°C to 30°C, or around 25°C. The method according to any one of claims 11-13, wherein, The solvent b is an alcohol; optionally, the solvent b is methanol, ethanol, isopropanol, tert-butanol, sec-butanol or tert-amyl alcohol. The method according to any one of claims 11-14, characterized in that A further method for preparing the compound represented by formula (VI) includes: Step B: The compound shown in formula (V) reacts with the compound shown in formula (VII) in solvent c, under the action of base d and catalyst e, to give the compound shown in formula (VI). The method according to claim 15, wherein, The catalyst e is bis(triphenylphosphine)palladium dichloride and cuprous iodide, tetra(triphenylphosphine)palladium and cuprous iodide, or tri(dibenzylacetone)palladium and cuprous iodide; Optionally, the base d is triethylamine; Optionally, the solvent c is acetonitrile, toluene, or tetrahydrofuran. The method according to claim 16, wherein, The molar ratio of the compound shown in formula (V) to bis(triphenylphosphine)palladium dichloride is 1:(0.005-0.02); Optionally, the molar ratio of the compound shown in formula (V) to cuprous iodide is 1:(0.010-0.04). The method according to claim 16 or 17, wherein, The molar ratio of the compound shown in formula (V) to triethylamine is 1:(1.2-2); Optionally, the molar ratio of the compound shown in formula (V) to the compound shown in formula (VII) is 1:(1.2-1.5). The method according to any one of claims 15-18, wherein, The reaction temperature in step B is 40°C to 60°C; preferably, the reaction temperature is 45°C to 55°C. The method according to claim 5 or 15, characterized in that A further method for preparing the compound represented by formula (V) includes: Step 3: The compounds shown in formula (VI) and (VII) react in solvent 3 under the action of base 2 to give the compound shown in formula (V). The method according to claim 20, wherein, Solvent 3 is acetonitrile, dimethyl sulfoxide, or N,N-dimethylformamide. The method according to claim 20 or 21, wherein, The base 2 is potassium carbonate, sodium carbonate and cesium carbonate; optionally, the molar ratio of the compound shown in formula (VI) to base 2 is 1:(1.10-1.27). The method according to any one of claims 20-22, wherein, The reaction temperature of step 3 is 65°C to 90°C; preferably, the reaction temperature of step 4 is 70°C to 85°C; more preferably, the reaction temperature of step 4 is 75°C to 85°C; optionally, the molar ratio of the compound shown in formula (VI) to the compound shown in formula (VII) is 1:(1.05-1.25).

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