WO2021083345A1 - Preparation method for pyrazolopyrimidine compound and intermediate thereof - Google Patents

Abstract

Disclosed in the present invention is a preparation method for a pyrazolopyrimidine compound. Also disclosed in the present invention is a preparation method for a compound of formula (I) and an intermediate compound thereof.

Description

Preparation method and intermediates of pyrazolopyrimidine compounds

This application claims the following priority

CN201911045269.0, application date 2019-10-30.

Technical field

The present invention relates to a method for preparing pyrazolopyrimidine compounds. The present invention also relates to a method for preparing compounds of formula (I) and intermediate compounds thereof.

Background technique

Protein kinases are closely related to cell proliferation, differentiation, metabolism, and apoptosis. The oncogenic forms of protein kinases are abundantly expressed in many different human tumor types and are highly responsive to some specific kinase inhibitors. Among them, Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase (RTK) belonging to the insulin receptor superfamily. It is mainly expressed in the central and peripheral nervous system and is involved in the normal development of the nervous system. It plays a role in the function and has been extensively studied in a large number of preclinical and clinical studies. ALK was first discovered in a type of anaplastic large cell lymphoma (ALCL) as a continuously activated carcinogenic form due to chromosomal translocation. It is produced by the normally expressed protein nuclear phosphate NPM The fusion protein NPM-ALK is formed by fusion between the N-terminus and ALK kinase domain. At present, a variety of ALK fusion proteins have been identified and are considered to be powerful oncogenic drivers of some tumors (such as inflammatory myofibroblastoma). Therefore, ALK fusion proteins have also become important targets for cancer treatment intervention. At present, a variety of ALK inhibitors have entered clinical trials and have been approved for marketing. Among them, Crizotinib (crizotinib) was approved in 2011 for the treatment of ALK-positive non-small cell lung cancer (NSCLC) patients. In 2014, Ceritinib was approved for the treatment of ALK-positive metastatic NSCLC patients. Although ALK inhibitors have been proven effective in the initial clinical practice, relapses and ALK-acquired resistance mutations have always been observed in treated patients. Among them, the emergence of brain metastases is an obvious cause of disease recurrence in patients treated with crizotinib.

Tropomyosin-related kinase (Trk) is a type of nerve growth factor receptor (NGF), which is highly expressed in nerve cells. The Trk family is composed of highly homologous tropomyosin-related kinase A (TrkA), tropomyosin-related kinase B (TrkB), and tropomyosin-related kinase C (TrkC), which encode respectively NTRK1, NTRK2, and NTRK3, involving 4 ligands including NGF, BDNF, NT-4 and NT-3, are widely involved in cell development by regulating the main signal pathways such as PI3K-AKT, RAS-RAF-ERK, and PLCγ-PKC. Important physiological activities such as proliferation, differentiation, survival and neuron growth. The continuously activated oncogenic form of Trk was first discovered as an oncogenic fusion gene (TPM3-NTRK1) from colorectal cancer. Oncogenic Trk gene fusion does not require ligand activation to promote cancer cell proliferation and affect cancer-related downstream signaling pathways, such as ERK and AKT. Drugs targeting TRK gene fusion, such as Entrectinib (RXDX-101) and Larotrectinib (LOXO-101), have also been proven effective in the initial clinical trials. However, under sustained action, acquired resistance mutations were also produced in the treated patients. New drugs that target TRK gene fusion, such as TPX-0005 and LOXO-195, partially solve the problem of resistance mutations.

Ros1 kinase is a type of receptor tyrosine kinase, which has an important effect on normal physiological functions. The continuously activated oncogenic form of Ros1 fusion protein has also been found in a variety of human cancers, including glioblastoma, non-small cell lung cancer, and colorectal cancer. A variety of drugs targeting Ros1 fusion protein, such as crizotinib, have been clinically proven effective, but after continuous administration, acquired resistance mutations have also been found in patients.

Therefore, for the clinical treatment of some cancers, there is an urgent need for a class of compounds that can inhibit multiple oncogenic fusion kinases and their mutations.

Summary of the invention

The present invention provides a method for preparing the compound of formula (I),

It includes the following steps:

Step 1: reacting a compound of formula 1-3, a compound of formula 1B and a compound of formula 1C to obtain a compound of formula 1-4,

Step 2: Reacting the compound of formula 1-4 to obtain the compound of formula 1-5,

Step 3: Reacting the compound of formula 1-5 to obtain the compound of formula 1-6,

among them,

R _{1 is} selected from F, Cl, Br, I, OH, NH ₂ , COOH, CH ₃ and OCH ₃ ;

R _{2 is} selected from H, F, Cl, Br and I.

In some embodiments of the present invention, the method for preparing the compound of formula (I) includes the following steps: Step 1: reacting the compound of formula 1-3, the compound of formula 1B and the compound of formula 1C to obtain the compound of formula 1-4,

Step 2: Reacting the compound of formula 1-4 to obtain the compound of formula 1-5,

Step 3: Reacting the compound of formula 1-5 to obtain the compound of formula 1-6,

among them,

R _{1 is} selected from F, Cl, Br, I, OH, NH ₂ , COOH, CH ₃ and OCH ₃ ;

R _{2 is} selected from H, F, Cl, Br and I;

Reagent A is selected from benzoic acid, hydrochloric acid, acetic acid and zinc chloride;

Solvent B is selected from alkane solvents and halogenated alkane solvents;

The reducing agent C is selected from sodium borohydride, lithium tetrahydroaluminum, potassium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium cyanoborohydride;

Reagent D is selected from triphenylphosphine and tri-n-butylphosphine;

Reagent E is selected from diisopropyl azodicarboxylate, dimethyl azodicarboxylate, diethyl azodicarboxylate, di-tert-butyl azodicarboxylate and azodicarboxydipiperidine;

The solvent F is selected from ether solvents, halogenated alkane solvents and nitrile solvents.

In some aspects of the present invention, the above-mentioned preparation method, wherein:

R _{1 is} selected from F, Cl, Br, I, OH, NH ₂ , COOH, CH ₃ and OCH ₃ ;

R _{2 is} selected from H, F, Cl, Br and I;

Reagent A is selected from benzoic acid, hydrochloric acid, acetic acid and zinc chloride;

Solvent B is selected from dichloromethane and chloroform;

The reducing agent C is selected from sodium borohydride and lithium aluminum tetrahydrogen;

Reagent D is selected from triphenylphosphine;

Reagent E is selected from diisopropyl azodicarboxylate;

The solvent F is selected from tetrahydrofuran.

In some aspects of the present invention, in the above preparation method, R _{1 is} selected from OCH ₃ .

In some aspects of the present invention, in the above preparation method, R _{2 is} selected from F.

In some aspects of the present invention, the above-mentioned preparation method includes the following reaction route:

Acid G is selected from hydrochloric acid/ethyl acetate, hydrochloric acid/methanol, trifluoroacetic acid and hydrochloric acid/methyl tert-butyl ether;

Solvent H is selected from ester solvents, alcohol solvents, halogenated alkane solvents and ether solvents;

Base I is selected from N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, cesium fluoride and triethylamine;

Solvent J is selected from sulfone solvents, amide solvents and alcohol solvents;

Reagent K is selected from trimethylchlorosilane/sodium iodide, trimethylsilyl iodide and boron tribromide;

Solvent L is selected from nitrile solvents and halogenated alkane solvents;

The base M is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium trimethylsiloxide and triethylamine/lithium chloride;

Solvent N is selected from alcohol solvents, ether solvents and nitrile solvents;

Condensing agent O is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole, carbonyl diimidazole and 1-n-propyl phosphoric anhydride;

The base P is selected from N,N-diisopropylethylamine and triethylamine;

Solvent Q is selected from ether solvents, nitrile solvents, halogenated alkane solvents and amide solvents;

Condensing agent R is selected from tri-n-butylphosphine/azodicarbonate, triphenylphosphine/dimethyl azodicarboxylate and triphenylphosphine/diethyl azodicarboxylate;

The solvent S is selected from ether solvents, nitrile solvents and halogenated alkane solvents.

In some aspects of the present invention, the above-mentioned preparation method, wherein:

Acid G is selected from hydrochloric acid/ethyl acetate (4M), hydrochloric acid/methanol (4M) and hydrochloric acid/methyl tert-butyl ether (4M);

Solvent H is selected from ethyl acetate, methanol and methyl tert-butyl ether;

The base I is selected from N,N-diisopropylethylamine and triethylamine;

Solvent J is selected from dimethyl sulfoxide, N-methylpyrrolidone and n-butanol;

Reagent K is selected from trimethylchlorosilane/sodium iodide, trimethylsilyl iodide and boron tribromide;

Solvent L is selected from acetonitrile and dichloromethane;

The base M is selected from sodium hydroxide;

The solvent N is selected from methanol;

Condensing agent O is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole and 1-n-propyl phosphoric anhydride;

The base P is selected from N,N-diisopropylethylamine;

Solvent Q is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and N,N-dimethylformamide;

Condensing agent R is selected from tri-n-butylphosphine/azodicarbonate and triphenylphosphine/diethyl azodicarboxylate;

The solvent S is selected from 2-methyltetrahydrofuran, dichloromethane and tetrahydrofuran.

In some aspects of the present invention, in the above preparation method, the solvent B is selected from dichloromethane and chloroform;

Solvent F is selected from 2-methyltetrahydrofuran, dichloromethane, acetonitrile and tetrahydrofuran;

Solvent H is selected from ethyl acetate, methanol, dichloromethane, dioxane and methyl tert-butyl ether;

Solvent J is selected from dimethyl sulfoxide, N-methylpyrrolidone, isopropanol and n-butanol;

Solvent L is selected from acetonitrile and dichloromethane;

Solvent N is selected from methanol, tetrahydrofuran and acetonitrile;

Solvent Q is selected from tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane and N,N-dimethylformamide;

The solvent S is selected from 2-methyltetrahydrofuran, dichloromethane, acetonitrile and tetrahydrofuran.

In some embodiments of the present invention, in the above-mentioned preparation method, in step 1 of preparing compound 1-4, when feeding the materials into the reaction system, the temperature range of the reaction system is controlled to be 5±5°C.

In some embodiments of the present invention, in the above-mentioned preparation method, in step 1 of preparing compound 1-4, after reagents are added, the temperature range of the reaction system is controlled to be 25±5°C.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-3 to compound 1B is 1:0.2-0.5.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-3 to compound 1C is 1:1.2 to 1.5.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-3 to reagent A is 1:0.2-0.5.

In some embodiments of the present invention, in the above preparation method, in step 2 of preparing compound 1-5, the temperature range of the reaction system is controlled to be 10±5°C.

In some embodiments of the present invention, in the above-mentioned preparation method, in step 2 of preparing compound 1-5, the reaction time is 2±1 hours after reagents are added.

In some embodiments of the present invention, in the above-mentioned preparation method, in step 3 of preparing compound 1-6, when feeding materials into the reaction system, the temperature range of the reaction system is controlled to be 15±5°C.

In some embodiments of the present invention, in the above-mentioned preparation method, in step 3 of preparing compound 1-6, after reagents are added, the temperature range of the reaction system is controlled to be 25±5°C.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-5 to reagent D is 1:1.1-1.3.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-5 to reagent E is 1:1.1 to 1.5.

In some embodiments of the present invention, in the above-mentioned preparation method, in the step of preparing Compounds 1-7, when feeding materials into the reaction system, the temperature range of the reaction system is controlled to be 5±5°C.

In some embodiments of the present invention, in the above-mentioned preparation method, in the step of preparing compounds 1-7, after the reagents are added, the temperature range of the reaction system is controlled to be 25±5°C.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-6 to acid G is 1:10-15.

In some embodiments of the present invention, in the above-mentioned preparation method, in the step of preparing compounds 1-9, after the reagents are added, the temperature range of the reaction system is controlled to be 70±5°C.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-7 to compound 1-8 is 1:0.8-1.

In some embodiments of the present invention, in the above-mentioned preparation method, in the step of preparing compound 1-10, after reagents are added, the temperature of the reaction system is controlled to 20±5°C.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-9 to reagent K is 1:3.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-10 to base M is 1:4.

In some embodiments of the present invention, in the above-mentioned preparation method, in the step of preparing compound 1-13, the temperature range of the reaction system is controlled to be 20±5°C.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-11 to condensing agent O is 1:1.1-1.3.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-11 to compound 12 is 1:1.0-1.3.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-11 to base P is 1:2.5-5.0.

In some embodiments of the present invention, in the above-mentioned preparation method, in the step of preparing the compound of formula (I), the temperature range of the reaction system is controlled to be 20±10°C.

In some aspects of the present invention, in the above preparation method, the molar ratio of compound 1-13 to condensing agent R is 1:1.3 to 2.0.

The present invention also provides a compound of the following formula:

The present invention also relates to the above-mentioned compound of formula 1-4, or compound of formula 1-5, or compound of formula 1-6, or compound of formula 1-7, or compound of formula 1-9, or compound of formula 1-10, or compound of formula 1- Use of compound 11 or compound of formula 1-3 as an intermediate in preparing compound of formula (I).

The present invention also relates to the application of the compound of formula (I) obtained by the above preparation method and its intermediates in the preparation of medicines for treating diseases related to Trk, ALK and Ros1 kinase.

In some aspects of the present invention, the above application is characterized in that the drug is a drug for the treatment of solid tumors.

Definition and description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific phrase or term should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art. Well-known equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.

The chemical reaction in the specific embodiment of the present invention is completed in a suitable solvent, and the solvent must be suitable for the chemical change of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the existing embodiments.

The term "ether solvent" includes, but is not limited to, diethyl ether, methyl ethyl ether, dipropyl ether, dibutyl ether, 1,4-dioxane, furan, methyl furan, and tetrahydrofuran.

The term "amide solvent" includes but is not limited to N,N-dimethylformamide and N,N-dimethylacetamide.

The term "sulfone solvent" includes, but is not limited to, dimethyl sulfoxide, dimethyl sulfone, sulfolane, and 2,4-dimethyl sulfolane.

The term "ester solvent" includes, but is not limited to, methyl acetate, ethyl acetate, hexyl acetate, and phenyl acetate.

The term "nitrile solvent" includes but is not limited to acetonitrile.

The term "alcohol solvent" includes but is not limited to methanol, ethanol, propanol, isopropanol, butanol, pentanol, decanol, n-dodecanol, cyclopentanol, cyclohexanol, benzyl alcohol, phenethyl alcohol.

The term "alkane solvent" includes, but is not limited to, petroleum ether, n-hexane, cyclohexane, methylcyclohexane, n-heptane, and isooctane.

The term "halogenated alkane solvent", such as monochloromethane, dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane.

The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, the single crystal X-ray diffraction method (SXRD) uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultivated single crystal. The light source is CuKα radiation. The scanning method: φ/ω scanning. After the relevant data is collected, the direct method is further adopted. (Shelxs97) By analyzing the crystal structure, the absolute configuration can be confirmed. For another example, the compound of the present invention and its absolute configuration can be determined by activity. The SFC detection instrument and method of the compound of formula (I) of the present invention are consistent with those in the patent application with application number PCT/CN2020/111795, the retention time is consistent, and the absolute configuration can also be confirmed.

An important consideration in the planning of any synthetic route in the art is to select a suitable protecting group for the reactive functional group (such as the amino group in the present invention).

Hereinafter, the present invention will be specifically described through examples, and these examples are not meant to limit the present invention in any way.

All solvents used in the present invention are commercially available and can be used without further purification.

The following abbreviations are used in the present invention: aq stands for water; eq stands for equivalent or equivalent; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; Boc stands for tert-butoxycarbonyl is an amine protecting group; HOAc stands for acetic acid; rt stands for room temperature; Rt stands for retention time; O/N stands for overnight; THF stands for tetrahydrofuran ; Boc ₂ O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; iPrOH stands for 2-propanol; mp stands for melting point; PPh ₃ stands for triphenylphosphine.

Compounds are based on conventional naming principles in the field or used

The software is named, and the commercially available compounds use the supplier catalog name.

Technical effect

The process for synthesizing the compound of formula (I) and its intermediates provided by the present invention has the beneficial effects that the raw materials are cheap and easily available, and overcome the shortcomings of separation and purification difficulties and difficulty in industrialization.

specifically:

1) The raw materials of the method for preparing the compound of formula (I) of the present invention are conventional or common reagents, which are easily available in the market and low in price;

2) Using chiral natural products as raw materials to introduce the chiral center, avoiding the separation process, greatly reducing the separation cost, improving the atomic economy of the reaction, and reducing the emission of reaction waste. At the same time, the obtained compound of formula (I) has High optical purity;

3) When the compound is prepared, the reaction conditions are mild, easy to control, and simple post-treatment. The solid product is directly precipitated, and a product with higher purity can be obtained through simple recrystallization, with high yield and easy industrialization.

Therefore, the present invention has high industrial application value and economic value in preparing the compound of formula (I) and its intermediates.

Detailed ways

In order to better understand the content of the present invention, a further description will be given below in conjunction with specific embodiments, but the specific implementation manners are not a limitation on the content of the present invention.

Example 1: Preparation of the compound of formula (I)

Step 1: Synthesis of compound 1B

Dichloromethane (2000 mL) and compound 1A (200 g, 789.46 mmol, 1 eq, EE: 99.80%) were added to a clean 3000 mL reaction flask prepared in advance, and stirring was started. The temperature was lowered to 0-5°C, and then imidazole (161.23g, 2.37mol, 3eq) was added to the reaction system. Trimethylchlorosilane (214.42g, 1.97mol, 250.49mL, 2.5eq) was slowly added dropwise to the reaction system, and the temperature was controlled within the range of 0-5°C. The temperature was raised to 25-28°C for 2 hours. Add methyl tert-butyl ether (2000mL) to the reaction system, stir for minutes, and solids will appear; filter, rinse the filter cake with 500mL methyl tert-butyl ether once; combine the organic phases, and then water (1000mL*3), Wash with saturated brine (1000 mL*1); the organic phase is dried with anhydrous sodium sulfate for 15 minutes; filtered, and the filtrate is rotary evaporated under reduced pressure at 40° C. to obtain compound 1B (250 g, 0.768 mol, 97.28% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 7.58-7.53 (m, 2H), 7.49-7.36 (m, 3H), 7.34-7.28 (m, 6H), 4.14-4.11 (m, 1H), 2.89-2.79 (m, 2H), 1.69-1.65 (m, 3H), 1.47-1.41 (m, 1H), 0.00 (s, 9H); LCMS m/z=326.1 [M+H] ⁺ .

Compound 1A: SFC (column: Chiralpak AD-3, 3μm, 0.46cm id×15cm L; mobile phase: A (CO ₂ ) and B (MeOH, containing 0.05% isopropylamine); gradient: B% = 10-40% , 6min; Flow rate: 2.5mL/min; Wavelength: 220nm; Pressure: 1500psi, Rt=2.843min, chiral isomer excess 99.80%.

Compound 1B: SFC (column: Chiralpak AD-3, 3μm, 0.46cm id×15cm L; mobile phase: A (CO ₂ ) and B (MeOH, containing 0.05% isopropylamine); gradient: B% = 10-40% , 6min; Flow rate: 2.5mL/min; Wavelength: 220nm; Pressure: 1500psi, Rt=1.368min, chiral isomer excess is 99.46%.

Step 2: Synthesis of compound 1-2

In a 50L jacketed kettle, replace nitrogen for three times. Under a weak nitrogen flow, add N,N-dimethylformamide (7500mL, 5V) to the 50L kettle, and then add compound 1-1 (1.5kg, 1eq), carbonic acid Potassium (1509g, 1.5eq), tetrabutylammonium acetate (4.35kg, 2eq), 3,3-dimethoxypropene (1.125kg, 1.5eq), finally add palladium acetate (114g, 0.07eq), jacket The temperature of the outer bath of the kettle was set to 100°C. When the temperature inside the kettle was heated to 90°C, exotherm was observed. The temperature in the kettle rose rapidly (2～3 minutes) to 115°C, then the temperature began to stabilize, and then the temperature began to drop. To 93°C, react for 1.5 hours. The system was cooled down, and when the temperature dropped to 30°C, the system was filtered, and the filter cake was rinsed with N,N-dimethylformamide (3L) to obtain a filtrate containing compound 1-2, which was directly used in the next step.

Step 3: Synthesis of compound 1-3

Add water (3L) to the filtrate system containing compound 1-2 (control the temperature 25-30℃), then add hydrochloric acid (2M, 6L) and control the temperature 25-30℃, adjust the pH=2～3, React at 25°C for 4-6 hours. Then the reaction system was adjusted to pH=7 with solid sodium bicarbonate, then the system was extracted with methyl tert-butyl ether (10L*2), methyl tert-butyl ether (5L*1), and the organic phases were combined and saturated Wash with brine (7.5L*2), dry, and concentrate to obtain a crude product. Add n-heptane (2L) and methyl tert-butyl ether (200mL) to the crude product to make a slurry, stir at 25°C for 30 minutes, and collect the filter cake by filtration to obtain compound 1-3 (620g, 3.42mol, 47.01% yield) ). ¹ H NMR(400MHz, CDCl ₃ )δ9.72(d,J=7.6Hz,1H), 8.08(d,J=2.8Hz,1H), 7.62(d,J=16Hz,1H), 7.56(dd, J=3.2, 8.0 Hz, 1H), 6.82 (dd, J=7.6, 16 Hz, 1H), 4.03 (s, 3H); LCMS m/z=182.0 [M+H] ⁺ .

Step 4: Synthesis of compound 1-4

Compound 1B (179.7g, 0.55mol, 0.2eq) was added to a prepared 5L three-necked reaction flask, dichloromethane (2.5L) was added, and stirring was started; after the temperature was reduced to 0～5℃, compound 1- 3 (500g, 2.76mol, 1eq), then add benzoic acid (67.17g, 0.55mol, 842.62μL, 0.2eq), stir for 0.5 hours, add N-tert-butyl hydroxylamine (441g, 3.31mol, 1.2eq), and then stirred at 25°C for 1 hour to obtain a reaction solution containing compound 1-4. The reaction solution was used directly in the next step.

Step 5: Synthesis of compound 1-5

Add water (1.25L) to the above reaction system containing compound 1-4, and then add sodium borohydride (135.73g, 3.59mol, 1.3eq) into the reaction system in batches (with a lot of bubbles) at 10～15℃ Produced) and reacted for 2 hours. 100mL saturated ammonium chloride was added to the reaction system, the reaction was quenched and filtered, the mother liquor was separated and extracted, the organic phase was washed once with saturated sodium bicarbonate aqueous solution (2L), and the two aqueous phases were combined with dichloromethane (2L) Extract once, combine the two organic phases, wash once with saturated brine (2L), then dry with anhydrous sodium sulfate and spin dry. The crude product was mixed and purified by column chromatography, n-heptane:ethyl acetate=7:1～1:1, TLC (petroleum ether:ethyl acetate)=1:1, Rf=0.40, to obtain compound 1-5 (650g, 2.05mol, 74.45% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 7.88 (d, J = 3.2 Hz, 1H), 7.67-7.64 (dd, J = 2.8, 8.8 Hz, 1H), 5.46-5.42 (m, 1H), 3.94 ( s,3H),3.86-3.71(m,2H),2.95(s,1H),2.24-2.14(m,1H),2.08-2.00(m,1H),1.42(s,9H); LCMS m/z = 317.3 [M+H] ⁺ . SFC (column: Chiralpak IC-3, 3μm, 0.46cm id×15cm L; mobile phase: A (CO ₂ ) and B (MeOH, containing 0.05% isopropylamine); gradient: B% = 10-40%, 6min; Flow rate: 2.5mL/min; Wavelength: 220nm; Pressure: 1500psi, Rt=2.016min, chiral isomer excess 91.04%.

Step 6: Synthesis of compound 1-6

In a 3L three-neck flask, dissolve compound 1-5 (500g, 1.58mol, 1eq) in tetrahydrofuran (2.5L), then add triphenylphosphine (497.9g, 1.90mol, 1.2eq), replace with nitrogen three times, and start to cool down , Diisopropyl azodicarboxylate (478.9g, 2.37mol, 1.5eq) was added dropwise at 10-20°C, and the temperature was raised to 25°C and stirred for 1 hour. The system was directly concentrated to obtain 1450 g of crude product. Then the crude product was slurried with methyl tert-butyl ether: n-heptane=1:1 (1500 mL) at 25°C, stirred for 6 hours, then filtered to remove the filter cake (triphenylphosphine oxide), and the filtrate was concentrated to dryness . The crude compound 1-6 (780g, crude product) was obtained, which was directly used in the next step. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.88 (d, J = 3.2 Hz, 1H), 7.52-7.50 (m, 1H), 5.38-5.35 (m, 1H), 4.13-4.03 (m, 1H), 3.94(s,3H),3.89-3.82(m,1H),2.84-2.76(m,1H),2.12-2.03(m,1H),1.50(s,9H); LCMS m/z=299.3[M+ H] ⁺ .

Step 7: Synthesis of compounds 1-7

Compound 1-6 (780g, 1.58mol, 1eq) in the previous step was dissolved in ethyl acetate (500mL), and then this solution was added dropwise to the pre-prepared ethyl acetate hydrochloride (4M, 3.96L, 15.8mol, 10eq), naturally increase the temperature to 25°C and stir for 3 hours. The reaction solution was filtered, and the filter cake was rinsed twice with 500 mL of ethyl acetate (nitrogen protection, the product is easy to absorb moisture) to obtain compound 1-7 (340 g, 1.45 mol, 91.67% yield). ¹ H NMR (400MHz, CD ₃ OD) δ 8.17 (d, J = 2.8 Hz, 1H), 7.81-7.79 (m, 1H), 5.21 (t, J = 8.0 Hz, 1H), 4.60-4.54 (m , 1H), 4.40-4.32 (m, 1H), 4.04 (s, 3H), 2.96-2.80 (m, 2H); LCMS m/z = 199.3 [M+H] ⁺ .

SFC (column: Chiralpak AD-3, 3μm, 0.46cm id×15cm L; mobile phase: A (CO ₂ ) and B (MeOH, containing 0.05% isopropylamine); gradient: B% = 10-40%, 6min; Flow rate: 2.5mL/min; Wavelength: 220nm; Pressure: 1500psi, Rt=1.950min, chiral isomer excess is 89.46%.

Step 8: Synthesis of compound 1-9

Compound 1-7 (1800g, 7.67mol, 1eq) was dissolved in N-methylpyrrolidone (9000mL, 5V), and then N,N-diisopropylethylamine (2475g, 19.15mol, 2.5eq) was added, Then, compound 1-8 (1436.5 g, 6.37 mol, 0.83 eq) was added, and after replacing nitrogen for three times, the temperature was raised to 70° C. (internal temperature) and the reaction was performed for 16 hours. After the system was cooled to 25°C, it was combined with the other three batches of reaction systems (600g, 700g and 1800g). Ethyl acetate (24.5L, 5V) was added to the combined system, and then water (24.5L, 5V) was added to the combined system. ), after stirring for 30 minutes, let stand to separate the layers, separate the aqueous phase, and then extract once with (ethyl acetate 24.5L, 5V), combine the organic phases, and then wash the organic phase with saturated brine (24.5mL, 5V) twice Then, it was dried, filtered and concentrated to obtain a crude product. Then the crude product was used (ethyl acetate: n-heptane=1:3, 24.5L, 5V), and after beating and stirring at 25°C for 3 hours, filtered, the filter cake was filtered with ethyl acetate: n-heptane=1:5 (4.9 L*2) Rinse, collect the filter cake, dry, then heat the filter cake with isopropanol (24.5L, 5V) to 80°C and stir to dissolve it. After stirring for 1 hour (not completely dissolved), start to cool to 50°C. Filter while hot, collect the filtrate, and concentrate and dry the filtrate to obtain compound 1-9 (3.90 kg, 10.07 mol, 48.22% yield). ¹ H NMR(400MHz,CDCl ₃ )δ8.48(d,J=7.6Hz,1H),8.39(s,1H),7.92(d,J=3.2Hz,1H),7.58-7.55(m,1H) ,7.03(d,J=7.6Hz,1H),6.06(dd,J=5.2,8.8Hz,1H),4.33-4.24(m,2H),4.22-4.18(m,1H),4.01(s,3H) ),3.93-3.87(m,1H),2.94-2.90(m,1H),2.36-2.30(m,1H),1.27(t,J=6.8Hz,3H); LCMS m/z=388.3[M+ H] ⁺ .

SFC (column: Chiralpak AD-3, 3μm, 0.46cm id×15cm L; mobile phase: A (CO ₂ ) and B (EtOH, containing 0.05% isopropylamine); gradient: B% = 10-40%, 6min; Flow rate: 2.5mL/min; Wavelength: 220nm; Pressure: 1500psi, Rt=2.624min, chiral isomer excess 97.94%.

Step 9: Synthesis of compound 1-10

Compound 1-9 (1.925kg, 4.969mol, 1eq) was dissolved in acetonitrile (9625mL), then sodium iodide (2.23kg, 14.9mol, 3eq) was added, followed by nitrogen replacement 3 times, and the addition of trimethylchlorosilane ( 1.62kg, 14.9mol, 3eq), reacted at 25°C for 16 hours. Then it was combined with another batch of reaction system (1.925kg), and the combined system was slowly poured into the pre-configured aqueous solution (58.5L, sodium bicarbonate (1.69kg, 2eq) and sodium thiosulfate (845g)). 15V), the suspension was stirred for 1 hour and then filtered, the filter cake was rinsed with water (2L), then the filter cake was slurried with ethyl acetate (15.6L, 4V), stirred at 25°C for 3 hours, then filtered, the filter cake It was rinsed with ethyl acetate (3.9L, 1V), and then the filter cake was collected and dried under reduced pressure with an oil pump to obtain compound 1-10 (3.25kg, 8.71mol, 87.60% yield). ¹ H NMR(400MHz,CD ₃ OD)δ8.69(d,J=7.6Hz,1H),8.30(s,1H),7.63-7.60(m,1H),7.38(t,J=3.2Hz,1H ), 7.10(d,J=5.6,1H),5.79-5.75(m,1H),4.26-4.19(m,3H),2.98–2.90(m,1H),2.35-2.29(m,1H),1.25 (t, J=7.2 Hz, 3H); LCMS m/z=374.3 [M+H] ⁺ .

SFC (column: Chiralpak AD-3, 3μm, 0.46cm id×10cm L; mobile phase: A (CO ₂ ) and B (iPrOH, containing 0.05% isopropylamine); gradient: B% = 10-40%, 5min; Flow rate: 4.0mL/min; Wavelength: 220nm; Pressure: 100bar, Rt=2.30min, chiral isomer excess 98.66%.

Step 10: Synthesis of compound 1-11

Compound 1-10 (1.6kg, 4.29mol, 1eq) was dissolved in methanol (8L, 5V), then sodium hydroxide (5.7L, 3M, 17.14mol, 4eq) was added and reacted at 60°C for 1 hour. After cooling the system to 25°C, combine it with another batch of reaction system (1.6kg), add hydrochloric acid (14L, 3M) to the combined system, stir for 1 hour, filter, and rinse the filter cake with water (2L). Then the filter cake was slurried with acetonitrile (16L, 5V), stirred at 18°C for 1 hour, then filtered, the filter cake was rinsed with acetonitrile, the filter cake was collected, and dried in an oven at 45°C to obtain compound 1-11 (2.9kg, 8.40mol, 98.01% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.84 (s, 1H), 8.95 (d, J = 7.6 Hz, 1H), 8.33 (s, 1H), 7.58-7.56 (m, 1H), 7.48 ( t,J=3.2Hz,1H),7.03(d,J=5.6,1H), 5.70-5.67(m,1H), 4.20-4.17(m,1H),3.93-3.89(m,1H), 2.76- 2.74 (m, 1H), 2.26-2.23 (m, 1H); LCMS m/z=346.2 [M+H] ⁺ .

SFC (column: Chiralpak AD-3, 3μm, 0.46cm id×10cm L; mobile phase: A (CO ₂ ) and B (MeOH, containing 0.05% isopropylamine); gradient: B% = 10-40%, 5min; Flow rate: 4.0mL/min; Wavelength: 220nm; Pressure: 100bar, Rt=3.51min, chiral isomer excess 98.08%.

Step 11: Synthesis of compound 1-13

In a 5L three-necked flask, compound 1-11 (430.00g, 1.245mol, 1eq), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluoro Phosphate (520.88g, 1.37mol, 1.1eq) and compound 1-12 (169.29g, 1.37mol, 1.1eq) were added to N,N-dimethylformamide (2.15L, 5V) and stirred uniformly. After the formed white suspension was replaced with nitrogen three times, N,N-diisopropylethylamine (563.29g, 4.36mol, 3.5eq) was added dropwise to the above solution (control the dropping temperature at 15～25℃ ), and continue to react for 12 hours, the white suspension slowly turns into a light yellow clear solution. Saturated ammonium chloride solution (43.5mL) was added to the above reaction solution to quench the reaction, and then combined with the other two batches of reaction (430.00g and 430.00g), the combined reaction solution was concentrated to dryness under reduced pressure, and the temperature was controlled to 55. ～60℃. After dissolving and diluting the residue with dichloromethane (2510 mL), add 100-200 mesh silica gel (5277.48 g), mix the sample and spin dry. The sample was separated by column chromatography (methanol/dichloromethane=0-50%) to obtain 2150.23 g of the crude product. The crude product after column chromatography was added to acetonitrile (3890 mL) and stirred vigorously at 15-20°C for 2 hours. Filter with a pad of filter cloth, and rinse the filter cake twice with acetonitrile, 500 mL each time. The filter cake was vacuum dried at 45-55°C to obtain compound 1-13 (1040.00 g, 2.51 mol, 67.18% yield). ¹ H NMR (400MHz, CD ₃ OD) δ8.49 (d, J = 8.0Hz, 1H), 8.42 (s, 1H), 7.80 (s, 1H), 7.63-7.60 (m, 1H), 7.35 (s ,1H),6.95(d,J=8.0Hz,1H),5.78-5.74(m,1H),4.36-4.31(m,1H),4.02-3.96(m,1H),3.69-3.66(m,1H) ),3.59-3.56(m,1H),3.13-3.06(m,1H),2.37-2.28(m,1H),0.95-0.80(m,3H),0.67-0.62(m,1H); LCMS m/ z=415.3 [M+H] ⁺ .

Step 12: Synthesis of the compound of formula (I)

In a 5L three-necked flask, compound 1-13 (345.00g, 0.83mol, 1eq) was added to tetrahydrofuran (3.45L, 10V) and stirred uniformly. After the formed white suspension was replaced with nitrogen three times, tri-n-butylphosphine (252.66 g, 1.25 mol, 1.5 eq) was added dropwise to the above solution. Under the protection of nitrogen, add azodicarboxydipiperidine (315.08g, 1.25mol, 1.5eq) to the reaction solution (control the dropping temperature at 10～30℃), and continue the reaction at 10～25℃ 3 hours. After the completion of the reaction, it was combined with the other two batches of reaction (345.00 g and 345.00 g), the combined reaction solution was filtered, and the filter cake was rinsed with tetrahydrofuran (500 mL). The filtrate was concentrated under reduced pressure to about 4L. The concentrated solution was added to the separator, and 4.15 L of ethyl acetate was added. After stirring for 5 minutes, 4.14 L of deionized water was added. After vigorous stirring for 10 minutes, let stand to separate layers. The organic phase was separated and washed twice with dilute hydrochloric acid solution (4.16L, 1M) and once with saturated brine (4.16L). The organic phase was dried with anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was then added to ethanol (2560 mL) and stirred vigorously at 15-20°C for 16 hours. Filter with a pad of filter cloth, and rinse the filter cake twice with ethanol, 500 mL each time. The filter cake was vacuum dried at 45-55° C. to obtain the compound of formula (I) (815.05 g, 2.06 mol, 81.93% yield). ¹ H NMR(400MHz, CDCl ₃ )δ9.27(s,1H), 8.42(d,J=7.6Hz,1H), 8.30(s,1H), 7.97(d,J=2.8Hz,1H), 7.59 -7.57 (m, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.11 (t, J = 8.4 Hz, 1H), 4.88 (d, J = 10.8 Hz, 1H), 4.53 (t, J = 8.0Hz,1H),.33.97-3.90(m,1H),3.84(d,J=10.8Hz,1H),3.08-3.01(m,1H),2.60-2.46(m,1H),2.39-2.33( m, 1H), 1.48-1.42 (m, 1H), 0.95-0.90 (m, 1H), 0.87-0.81 (m, 1H); LCMS m/z=397.3 [M+H] ⁺ .

SFC (column: Chiralcel OD-3, 3μm, 0.46cm id×10cm L; mobile phase: A (CO ₂ ) and B (MeOH, containing 0.05% isopropylamine); gradient: B% = 5-40%, 5min; Flow rate: 4.0mL/min; Wavelength: 220nm; Pressure: 100bar, Rt = 2.14min, the chiral isomer excess is 98.98%.

Claims (33)

1. The preparation method of the compound of formula (I),

   

   It includes the following steps:

   Step 1: reacting a compound of formula 1-3, a compound of formula 1B and a compound of formula 1C to obtain a compound of formula 1-4,

   

   Step 2: Reacting the compound of formula 1-4 to obtain the compound of formula 1-5,

   

   Step 3: Reacting the compound of formula 1-5 to obtain the compound of formula 1-6,

   

   among them,

   R _{1 is} selected from F, Cl, Br, I, OH, NH ₂ , COOH, CH ₃ and OCH ₃ ;

   R _{2 is} selected from H, F, Cl, Br and I.
2. The preparation method according to claim 1, which comprises the following steps:

   Step 1: reacting a compound of formula 1-3, a compound of formula 1B and a compound of formula 1C to obtain a compound of formula 1-4,

   

   Step 2: Reacting the compound of formula 1-4 to obtain the compound of formula 1-5,

   

   Step 3: Reacting the compound of formula 1-5 to obtain the compound of formula 1-6,

   

   among them,

   R _{1 is} selected from F, Cl, Br, I, OH, NH ₂ , COOH, CH ₃ and OCH ₃ ;

   R _{2 is} selected from H, F, Cl, Br and I;

   Reagent A is selected from benzoic acid, hydrochloric acid, acetic acid and zinc chloride;

   Solvent B is selected from alkane solvents and halogenated alkane solvents;

   The reducing agent C is selected from sodium borohydride, lithium tetrahydroaluminum, potassium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium cyanoborohydride;

   Reagent D is selected from triphenylphosphine and tri-n-butylphosphine;

   Reagent E is selected from diisopropyl azodicarboxylate, dimethyl azodicarboxylate, diethyl azodicarboxylate, di-tert-butyl azodicarboxylate and azodicarboxydipiperidine;

   The solvent F is selected from ether solvents, halogenated alkane solvents and nitrile solvents.
3. The preparation method according to claim 2, which comprises the following reaction route:

   

   Acid G is selected from hydrochloric acid/ethyl acetate, hydrochloric acid/methanol, trifluoroacetic acid and hydrochloric acid/methyl tert-butyl ether;

   Solvent H is selected from ester solvents, alcohol solvents, halogenated alkane solvents and ether solvents;

   Base I is selected from N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, cesium fluoride and triethylamine;

   Solvent J is selected from sulfone solvents, amide solvents and alcohol solvents;

   Reagent K is selected from trimethylchlorosilane/sodium iodide, trimethylsilyl iodide and boron tribromide;

   Solvent L is selected from nitrile solvents and halogenated alkane solvents;

   The base M is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium trimethylsiloxide and triethylamine/lithium chloride;

   Solvent N is selected from alcohol solvents, ether solvents and nitrile solvents;

   Condensing agent O is selected from 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole, carbonyl diimidazole and 1-n-propyl phosphoric anhydride;

   The base P is selected from N,N-diisopropylethylamine and triethylamine;

   Solvent Q is selected from ether solvents, nitrile solvents, halogenated alkane solvents and amide solvents;

   Condensing agent R is selected from tri-n-butylphosphine/azodicarbonate, triphenylphosphine/dimethyl azodicarboxylate and triphenylphosphine/diethyl azodicarboxylate;

   The solvent S is selected from ether solvents, nitrile solvents and halogenated alkane solvents.
4. The preparation method according to claim 2 or 3, wherein:

   Solvent B is selected from dichloromethane and chloroform;

   Solvent F is selected from 2-methyltetrahydrofuran, dichloromethane, acetonitrile and tetrahydrofuran;

   Solvent H is selected from ethyl acetate, methanol, dichloromethane, dioxane and methyl tert-butyl ether;

   Solvent J is selected from dimethyl sulfoxide, N-methylpyrrolidone, isopropanol and n-butanol;

   Solvent L is selected from acetonitrile and dichloromethane;

   Solvent N is selected from methanol, tetrahydrofuran and acetonitrile;

   Solvent Q is selected from tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane and N,N-dimethylformamide;

   The solvent S is selected from 2-methyltetrahydrofuran, dichloromethane, acetonitrile and tetrahydrofuran.
5. The preparation method according to claim 2 or 3, wherein, in step 1 of preparing compound 1-4, when feeding into the reaction system, the temperature range of the reaction system is controlled to be 5±5°C.
6. The preparation method according to claim 2 or 3, wherein in step 1 of preparing compound 1-4, after the reagents are added, the temperature range of the reaction system is controlled to be 25±5°C.
7. The preparation method according to claim 2 or 3, wherein the molar ratio of compound 1-3 to compound 1B is 1:0.2-0.5.
8. The preparation method according to claim 2 or 3, wherein the molar ratio of compound 1-3 to compound 1C is 1:1.2 to 1.5.
9. The preparation method according to claim 2 or 3, wherein the molar ratio of compound 1-3 to reagent A is 1:0.2-0.5.
10. The preparation method according to claim 2 or 3, wherein in step 2 of preparing compound 1-5, the temperature range of the reaction system is controlled to be 10±5°C.
11. The preparation method according to claim 2 or 3, wherein in step 2 of preparing compound 1-5, the reaction time is 2±1 hours after reagents are added.
12. The preparation method according to claim 2 or 3, wherein in step 3 of preparing compound 1-6, the temperature range of the reaction system is controlled to be 15±5°C when feeding materials into the reaction system.
13. The preparation method according to claim 2 or 3, wherein in step 3 of preparing compound 1-6, after reagents are added, the temperature range of the reaction system is controlled to be 25±5°C.
14. The preparation method according to claim 2 or 3, wherein the molar ratio of compound 1-5 to reagent D is 1:1.1-1.3.
15. The preparation method according to claim 2 or 3, wherein the molar ratio of compound 1-5 to reagent E is 1:1.1 to 1.5.
16. The preparation method according to claim 3, wherein in the step of preparing compounds 1-7, the temperature range of the reaction system is controlled to be 5±5°C when feeding materials into the reaction system.
17. The preparation method according to claim 3, wherein, in the step of preparing compounds 1-7, after the reagents are added, the temperature of the reaction system is controlled within a range of 25±5°C.
18. The preparation method according to claim 3, wherein the molar ratio of compound 1-6 to acid G is 1:10-15.
19. The preparation method according to claim 3, wherein in the step of preparing compounds 1-9, after the reagents are added, the temperature of the reaction system is controlled to be 70±5°C.
20. The preparation method according to claim 3, wherein the molar ratio of compound 1-7 to compound 1-8 is 1:0.8-1.
21. The preparation method according to claim 3, wherein in the step of preparing compound 1-10, after the reagents are added, the temperature of the reaction system is controlled to 20±5°C.
22. The preparation method according to claim 3, wherein the molar ratio of compound 1-9 to reagent K is 1:1-3.
23. The preparation method according to claim 3, wherein the molar ratio of compound 1-10 to base M is 1:4.
24. The preparation method according to claim 3, wherein in the step of preparing compound 1-13, the temperature range of the reaction system is controlled to be 20±5°C.
25. The preparation method according to claim 3, wherein the molar ratio of compound 1-11 to condensing agent O is 1:1.1-1.3.
26. The preparation method according to claim 3, wherein the molar ratio of compound 1-11 to compound 12 is 1:1.0-1.3.
27. The preparation method according to claim 3, wherein the molar ratio of compound 1-11 to base P is 1:2.5-5.0.
28. The preparation method according to claim 3, wherein in the step of preparing the compound of formula (I), the temperature range of the reaction system is controlled to be 20±10°C.
29. The preparation method according to claim 3, wherein the molar ratio of compound 1-13 to condensing agent R is 1:1.3 to 2.0.
30. Compounds of the following formula:

    
31. The use of the compound according to claim 30 as an intermediate in the preparation of the compound of formula (I).
32. The compound of formula (I) and its intermediates obtained by the preparation method according to any one of claims 1-29, or the compound according to claim 30 in the preparation of drugs for the treatment of diseases related to Trk, ALK and Ros1 kinase Applications.
33. The use according to claim 32, wherein the medicine is a medicine for treating solid tumors.