Preparation method of quinolinone intermediate

Abstract

The invention belongs to the field of medicine synthesis, and relates to a preparation method of a quinolinone intermediate, in particular to a preparation method of an intermediate I compound and an intermediate II compound, and application of the intermediate I compound and the intermediate II compound in preparation of the compound shown in the formula I. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical synthesis, and relates to a preparation method of quinolinone intermediates, specifically to a preparation method of intermediate I compound and intermediate II compound, and their use for preparing compound I. Background Art

[0002] Spleen tyrosine kinase (Syk) is an intracellular tyrosine protein kinase and belongs to the members of the ZAP70 protein kinase family. Syk plays a key role in the early development of B cells, the ontogeny of lymphocytes, and the function of mature B cells. During this process, it participates in multiple signal transduction pathways and can function without phosphorylation by Src kinase. In addition to being widely expressed in hematopoietic stem cells, Syk is also expressed in non-hematopoietic cells such as epithelial cells, hepatocytes, fibroblasts, nerve cells, and mammary tissues and has multiple functions.

[0003] Dysfunction of Syk PTK exists in many human diseases, such as allergic reactions, asthma, inflammation, and autoimmune diseases. Numerous studies have shown that Syk is an important mediator in acute or chronic inflammation. Activation of Syk exists in several common B-cell malignancies. For example, antigen-independent phosphorylated Syk can be detected in follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia. Researchers have found that inhibiting Syk in follicular lymphoma and diffuse large B-cell lymphoma cells can reduce the phosphorylation level of downstream signal transduction molecules, thereby inhibiting the proliferation and survival of tumor cells. In addition, translocation of Syk has been found in myelodysplastic syndrome and peripheral T-cell lymphoma, further indicating that this kinase can act as an oncogene. Therefore, inhibition of Syk activity can be used to treat specific types of cancers including B-cell lymphoma and leukemia.

[0004] WO2018228475 discloses a Syk inhibitor as shown in the following formula I:

[0005]

[0006] Example 9 of WO2018228475 discloses a preparation method of the above-mentioned compound I, but this preparation method has a long route, a low yield, and uses palladium catalysis multiple times and silica gel column chromatography in multiple steps, which is not suitable for industrial production. Therefore, it is necessary to find a more simple, higher-yield, lower-cost, and more suitable synthetic method for the above-mentioned compound I for industrial production. Summary of the Invention

[0007] On the one hand, the present application provides a method for preparing an intermediate II compound, which is characterized by comprising: (i) reacting a SM1 compound with methyl 2-bromoacetate to obtain an intermediate I compound; (ii) reacting the intermediate I compound with a SM2 compound to obtain the intermediate II compound.

[0008]

[0009] In some embodiments of the present application, for the above method for preparing an intermediate II compound, the reaction in step (i) is carried out in the presence of a base and a catalyst.

[0010] In some embodiments of the present application, for the above method for preparing an intermediate II compound, the base in step (i) is selected from organic bases or inorganic bases; the inorganic bases are selected from sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the organic bases are selected from sodium hexamethyldisilazide, triethylamine, ethylenediamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, piperidine, N-methylpiperidine, morpholine or N-methylmorpholine. In some embodiments, the base in step (i) is selected from sodium hexamethyldisilazide, triethylamine or N,N-diisopropylethylamine; preferably sodium hexamethyldisilazide.

[0011] In some embodiments of the present application, for the above method for preparing an intermediate II compound, the catalyst in step (i) includes but is not limited to lithium iodide, sodium iodide or potassium iodide, preferably lithium iodide.

[0012] In some embodiments of the present application, for the above method for preparing an intermediate II compound, step (i) is carried out in an organic solvent; the organic solvent is selected from one or more of acetonitrile, methanol, ethanol, ethylene glycol, ethylene glycol monomethyl ether, butanol, octanol, octyl acetate, dioxane, tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, preferably one or more of dioxane, tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, more preferably a mixed solvent of N,N-dimethylformamide and tetrahydrofuran.

[0013] In some embodiments of the present application, for the above method for preparing an intermediate II compound, the molar ratio of the SM1 compound to methyl 2-bromoacetate in step (i) is 1:1 to 5, preferably 1:1 to 3, more preferably 1:1 to 2. In a specific embodiment of the present application, the molar ratio of the SM1 compound to methyl 2-bromoacetate is 1:1, 1:2 or 1:3, preferably 1:2.

[0014] In some embodiments of the present application, the preparation method of the above intermediate II compound, wherein the molar ratio of the SM1 compound to the catalyst in step (i) is 1:0.1 to 1, preferably 1:0.1 to 0.5, more preferably 1:0.2 to 0.5. In a specific embodiment of the present application, the molar ratio of the SM1 compound to the catalyst is 1:0.2, 1:0.3, 1:0.4 or 1:0.5, preferably 1:0.5.

[0015] In some embodiments of the present application, the preparation method of the above intermediate II compound, wherein the molar ratio of the SM1 compound to the base in step (i) is 1:1 to 5, preferably 1:2 to 4. In a specific embodiment of the present application, the molar ratio of the SM1 compound to the base is 1:2, 1:3 or 1:4, preferably 1:2.

[0016] In some embodiments of the present application, the preparation method of the above intermediate II compound, wherein in step (i), the SM1 compound reacts completely with methyl 2-bromoacetate at one time under the conditions of a base and a catalyst.

[0017] In some embodiments of the present application, the preparation method of the above intermediate II compound, wherein in step (i), the SM1 compound first reacts with a certain amount of methyl 2-bromoacetate and a certain amount of base in the presence of a catalyst, and then the remaining amount of methyl 2-bromoacetate and the remaining amount of base are added in batches for continuous reaction. In some embodiments, the total molar amounts of methyl 2-bromoacetate and the base in step (i) are the same. In some embodiments, the molar amounts of the certain amount of methyl 2-bromoacetate and the certain amount of base are the same. In some embodiments, the addition in batches is carried out in 1, 2, 3, 4, 5 or 6 batches. In some embodiments, the molar amounts of methyl 2-bromoacetate and the base in each batch of the addition in batches are the same. In some embodiments, the certain amount of methyl 2-bromoacetate and the certain amount of base respectively account for one half of the total molar amounts of methyl 2-bromoacetate and the base. In a more specific embodiment, in step (i), the SM1 compound first reacts with half of the amount of methyl 2-bromoacetate and half of the amount of base in the presence of a catalyst, and then the remaining half of the methyl 2-bromoacetate and the remaining half of the base are added in batches for continuous reaction, and the molar amounts of methyl 2-bromoacetate and the base in each batch are the same.

[0018] In some embodiments of the present application, the preparation method of the above intermediate II compound, wherein the reaction temperature in step (i) is 0 to -30 °C, preferably -15 to -20 °C. In a specific embodiment of the present application, the reaction temperature in step (i) is -15 °C.

[0019] In some embodiments of the present application, the preparation method of the above intermediate II compound, wherein the reaction in step (i) is carried out under nitrogen protection.

[0020] In some embodiments of the present application, for the preparation method of the above intermediate II compound, the reaction time of step (i) is 1 to 10 hours, preferably 1 to 5 hours. In a specific embodiment of the present application, the reaction time of step (i) is 1 hour, 2 hours, 3 hours, 4 hours or 5 hours.

[0021] In some embodiments of the present application, for the preparation method of the above intermediate II compound, after the reaction in step (i) is completed, the intermediate I compound is separated out and then reacted with the SM2 compound to obtain the intermediate II compound.

[0022] In some other embodiments of the present application, for the preparation method of the above intermediate II compound, in step (ii), after the reaction in step (i) is completed, the SM2 compound is directly added without separation, and the reaction is carried out to obtain the intermediate II compound.

[0023] In some embodiments of the present application, for the preparation method of the above intermediate II compound, the reaction in step (ii) is carried out under alkaline conditions.

[0024] In some embodiments of the present application, for the preparation method of the above intermediate II compound, the base in step (ii) is selected from organic bases or inorganic bases; the inorganic bases are selected from sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the organic bases are selected from sodium hexamethyldisilazide, triethylamine, ethylenediamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, piperidine, N-methylpiperidine, morpholine or N-methylmorpholine, preferably sodium hexamethyldisilazide.

[0025] In some embodiments of the present application, for the preparation method of the above intermediate II compound, the base in step (ii) is the same as or different from the base in step (i), preferably the same.

[0026] In some embodiments of the present application, for the preparation method of the above intermediate II compound, the solvent in step (ii) is the same as or different from the solvent in step (i), preferably the same.

[0027] In some embodiments of the present application, the method for preparing the above intermediate II compound, wherein step (ii) is carried out in an organic solvent; the organic solvent is selected from one or more of acetonitrile, methanol, ethanol, ethylene glycol, ethylene glycol monomethyl ether, butanol, octanol, octyl acetate, dioxane, tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, preferably one or more of dioxane, tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, more preferably a mixed solvent of N,N-dimethylformamide and tetrahydrofuran.

[0028] In some embodiments of the present application, the method for preparing the above intermediate II compound, wherein the molar ratio of the intermediate I compound to the SM2 compound in step (ii) is 1:1 to 3, preferably 1:1 to 2, more preferably 1:1 to 1.5. In a specific embodiment of the present application, the molar ratio of the SM1 compound to methyl 2-bromoacetate is 1:1.1, 1:1.2 or 1:1.3, preferably 1:1.2.

[0029] In some embodiments of the present application, the method for preparing the above intermediate II compound, wherein the molar ratio of the SM2 compound to the base in step (ii) is 1:1 to 5, preferably 1:2 to 4. In a specific embodiment of the present application, the molar ratio of the formula SM2 compound to the base is 1:2, 1:3 or 1:4, preferably 1:2.

[0030] In some embodiments of the present application, the method for preparing the above intermediate II compound, wherein the reaction temperature in step (ii) is first reacted under the condition of -15 to -20 °C, and then heated to 10 to 30 °C for reaction. In a specific embodiment of the present application, the reaction temperature in step (ii) is first reacted under the condition of -10 °C, and then heated to 15 to 25 °C for reaction.

[0031] In some embodiments of the present application, the method for preparing the above intermediate II compound, wherein the reaction time in step (ii) is 5 to 20 hours, preferably 5 to 12 hours.

[0032] In some embodiments of the present application, the method for preparing the above intermediate II compound further includes the purification of the intermediate II compound.

[0033] In some embodiments of the present application, the method for preparing the above intermediate II compound, wherein the purification step of the intermediate II compound includes: adding a first solvent to the crude intermediate II compound, heating, stirring, cooling, adding a second solvent, cooling and continuing to stir, filtering, and drying.

[0034] In some embodiments of the present application, the method for preparing the above-mentioned intermediate II compound, wherein the first solvent in the purification step of the intermediate II compound is selected from one or more of dichloromethane, ethyl acetate, diethyl ether, tetrahydrofuran or acetone, preferably dichloromethane, ethyl acetate or diethyl ether, more preferably ethyl acetate.

[0035] In some embodiments of the present application, the method for preparing the above-mentioned intermediate II compound, wherein the second solvent in the purification step of the intermediate II compound is selected from one or more of n-heptane, n-hexane, dichloromethane or diethyl ether, preferably n-heptane or n-hexane, more preferably n-heptane.

[0036] In some embodiments of the present application, the method for preparing the above-mentioned intermediate II compound, wherein the temperature is raised to 50-80 °C in the purification step of the intermediate II compound, preferably 55-65 °C.

[0037] In some embodiments of the present application, the method for preparing the above-mentioned intermediate II compound, wherein the temperature is lowered to 30-40 °C before adding the second solvent in the purification step of the intermediate II compound, preferably 35-45 °C.

[0038] In some embodiments of the present application, the method for preparing the above-mentioned intermediate II compound, wherein the temperature is lowered to 10-30 °C after adding the second solvent in the purification step of the intermediate II compound, preferably 15-25 °C.

[0039] The present application also provides a method for preparing an SM1 compound, comprising: reacting an SM1-C compound with di-tert-butyl dicarbonate to prepare an SM1 compound.

[0040]

[0041] In some embodiments of the present application, in the method for preparing the above-mentioned formula SM1 compound, the SM1-C compound reacts with di-tert-butyl dicarbonate in a solvent, and the solvent is selected from ethanol.

[0042] In some embodiments of the present application, in the method for preparing the above-mentioned formula SM1 compound, the molar ratio of the SM1-C compound to di-tert-butyl dicarbonate is 1:1-5, preferably 1:1-3. In a specific embodiment of the present application, the molar ratio of the SM1-C compound to di-tert-butyl dicarbonate is 1:2, 1:2.2, 1:2.5, 1:2.8 or 1:3, preferably 1:2.5.

[0043] In some embodiments of the present application, in the method for preparing the above-mentioned formula SM1 compound, the reaction temperature is 20-50 °C, preferably 25-35 °C.

[0044] In some embodiments of the present application, for the preparation method of the above-mentioned formula SM1 compound, the reaction time is 10 to 20 hours, preferably 12 to 15 hours.

[0045] The present application also provides a preparation method of a SM2 compound, comprising: reacting a SM2-1 compound with a brominating reagent in a solvent to obtain the SM2 compound.

[0046]

[0047] In some embodiments of the present application, for the preparation method of the above-mentioned formula SM2 compound, the brominating reagent is selected from N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin or carbon tetrabromide, preferably N-bromosuccinimide.

[0048] In some embodiments of the present application, for the preparation method of the above-mentioned formula SM2 compound, the solvent is selected from one or more of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone or dioxane, preferably acetonitrile.

[0049] In some embodiments of the present application, for the preparation method of the above-mentioned formula SM2 compound, the molar ratio of the SM2-1 compound to the brominating agent is 1:1 to 5, preferably 1:1 to 2. In a specific embodiment of the present application, the molar ratio of the SM2-1 compound to the brominating agent is 1:1.

[0050] In some embodiments of the present application, for the preparation method of the above-mentioned formula SM2 compound, the reaction temperature is -30 to -10 °C, preferably -15 to -10 °C.

[0051] In some embodiments of the present application, for the preparation method of the above-mentioned formula SM2 compound, the reaction time is 30 minutes to 5 hours, preferably 30 minutes to 1 hour.

[0052] On the other hand, the present application provides a preparation method of a formula I compound, characterized by comprising: (i) reacting a SM1 compound with methyl 2-bromoacetate to obtain an intermediate I compound; (ii) reacting the intermediate I compound with a SM2 compound to obtain an intermediate II compound; (iii) reacting the intermediate II compound with a SM3 compound to obtain an intermediate III compound; (iv) deprotecting the intermediate III compound to obtain the formula I compound.

[0053]

[0054] In some embodiments of the present application, R is selected from amino protecting groups, and the amino protecting groups are selected from formyl, acetyl, benzyl, p-methoxybenzyl, trityl, phthaloyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, tetrahydro-2H-pyran-2-yl, or (trimethylsilyl)ethoxymethyl, preferably tert-butoxycarbonyl, tetrahydro-2H-pyran-2-yl, or (trimethylsilyl)ethoxymethyl, and more preferably tetrahydro-2H-pyran-2-yl.

[0055] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the specific conditions of steps (i) and (ii) are as described in the preparation method of intermediate II compound above.

[0056] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, step (iii) is carried out under nitrogen protection.

[0057] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, step (iii) is carried out in the presence of a catalyst, a solvent, and a base.

[0058] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the catalyst used in step (iii) is a palladium catalyst.

[0059] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the catalyst used in step (iii) is selected from palladium acetate, dichlorobis(1,2-bis(diphenylphosphino)ethane)palladium(II), dichlorobis(1,3-bis(diphenylphosphino)propane)palladium(II), dichlorobis(1,4-bis(diphenylphosphino)butane)palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(benzonitrile)palladium(II), dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II), or tris(dibenzylideneacetone)dipalladium(0) or its complexes, preferably dichlorobis(triphenylphosphine)palladium(II), dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II), or its complexes, and more preferably dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) or dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane complex.

[0060] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the base in step (iii) is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine, or N-methylpiperidine, preferably sodium carbonate, potassium carbonate, or cesium carbonate, and more preferably potassium carbonate.

[0061] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the solvent in step (iii) is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water, preferably one or more mixed solvents of N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and acetonitrile. In a more specific embodiment of the present application, the solvent in step (iii) is selected from N,N-dimethylformamide.

[0062] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the molar ratio of intermediate II compound to SM3 compound in step (iii) is 1:1 to 3, preferably 1:1 to 2, more preferably 1:1 to 1.5. In a specific embodiment of the present application, the molar ratio of intermediate II compound to SM3 compound is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, preferably 1:1.5.

[0063] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the molar ratio of intermediate II compound to the catalyst in step (iii) is 1:0.01 to 0.1, preferably 1:0.01 to 0.05, more preferably 1:0.01 to 0.03. In a specific embodiment of the present application, the molar ratio of intermediate II compound to the catalyst is 1:0.01, 1:0.02 or 1:0.03, preferably 1:0.02.

[0064] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the molar ratio of intermediate II compound to the base in step (iii) is 1:1 to 6, preferably 1:2 to 4, more preferably 1:3.5. In a specific embodiment of the present application, the molar ratio of intermediate II compound to the base is 1:2, 1:2.5, 1:3, 1:3.5 or 1:4, preferably 1:3.5.

[0065] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the reaction temperature of step (iii) is 50 to 120 °C, preferably 90 to 110 °C. In a specific embodiment of the present application, the reaction temperature of step (iii) is 100 °C.

[0066] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the reaction time of step (iii) is 1 to 10 hours, preferably 2 to 5 hours. In a more specific embodiment of the present application, the reaction time of step (iii) is 2 hours.

[0067] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, step (iii) optionally further includes a palladium removal step.

[0068] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the deprotection reaction in step (iv) is carried out in the presence of a solvent and an acid.

[0069] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the solvent in step (iv) is selected from one or more of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, and water, preferably one or more of methanol, ethanol, and water. In a specific embodiment of the present application, the solvent in step (iv) is selected from a mixed solvent of ethanol and water.

[0070] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the solvent in step (iv) is selected from a mixed solvent of ethanol and water, and the volume ratio of water to ethanol is 1:1 to 5, preferably 1:2.

[0071] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the acid in step (iv) is selected from hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid, preferably trifluoroacetic acid.

[0072] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the molar ratio of intermediate III compound to acid in step (iv) is 1:1 to 8, preferably 1:2 to 6. In a specific embodiment of the present application, the molar ratio of intermediate III compound to acid is 1:5.

[0073] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the reaction temperature of the deprotection reaction in step (iv) is 10 to 50 °C, preferably 18 to 22 °C.

[0074] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the reaction time of the deprotection reaction in step (iv) is 1 to 10 hours, preferably 1 to 5 hours.

[0075] In some embodiments of the present application, the above-mentioned SM3 compound can be obtained by commercial purchase.

[0076] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the post-treatment of step (iv) includes: adding a base for post-treatment, cooling, and filtering.

[0077] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, the base used in the post-treatment of step (iv) includes triethylamine, pyridine, diisopropylamine, sodium methoxide, sodium ethoxide, tert-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium bis(trimethylsilyl)amide, potassium hexamethyldisilazide or imidazole; preferably triethylamine.

[0078] In some embodiments of the present application, for the preparation method of the above-mentioned compound of formula I, optionally, it further includes the purification of the compound of formula I.

[0079] On the other hand, the present application provides the following compounds:

[0080]

[0081] On the other hand, the present application provides the use of the following compounds in the preparation of the compound of formula I,

[0082]

[0083] On the other hand, the present application provides the use of a preparation method of an intermediate II compound in the preparation of the compound of formula I, which is characterized by including: (i) reacting a SM1 compound with methyl 2-bromoacetate to obtain an intermediate I compound; (ii) reacting the intermediate I compound with a SM2 compound to obtain an intermediate II compound,

[0084]

[0085] The reaction conditions are as described in the preparation method of the above intermediate II compound.

[0086] In the present application, all tautomeric forms are included within the scope of the present application, for example and are tautomeric forms.

[0087] In the present application, the SM1-C compound, the SM2-1 compound and methyl 2-bromoacetate can be obtained through commercial channels or can be prepared by methods in the prior art.

[0088] The preparation methods of the compound of formula I and the intermediate II compound provided by the present application have the following advantages:

[0089] (i) In the preparation of the compound of formula I in the present application, silica gel column chromatography is not used in the post-treatment of the intermediate, and the post-treatment operation is simple, economical and easily available.

[0090] (ii) The total reaction steps for the preparation of the compound of formula I in the present application are shortened, the total yield is increased, and the purities of the key intermediate and the final product are both relatively high.

[0091] (iii) The starting materials and reagents for the preparation of the compounds of Formula I in this application are all inexpensive and readily available, avoiding multi-step palladium catalysis and being very suitable for industrial production.

[0092] In this application, Pd(dppf)Cl2·CH2Cl2 represents dichloromethane complex of palladium(II) 1,1'-bis(diphenylphosphino)ferrocene dichloride; TLC represents thin-layer chromatography; HPLC represents high performance liquid chromatography. Detailed Description of the Invention

[0093] The following specific examples are intended to enable those skilled in the art to more clearly understand and implement the present invention. They should not be considered as limiting the scope of protection of the present invention, but only as exemplary illustrations and typical representatives of the present invention. Those skilled in the art should understand that there are other synthetic routes for forming the compounds of this application, and the following are non-limiting examples.

[0094] Unless otherwise specified, the temperature is in degrees Celsius. The solvents used in this application are commercially available.

[0095] Example 1 Preparation of Intermediate II Compound

[0096]

[0097] Step 1: Preparation of Intermediate I Compound

[0098] Add N,N-dimethylformamide (214 kg), SM1 (15 kg, 48.96 mol) and lithium iodide (1.35 kg, 10.09 mol) to a 500 L reaction kettle, protect with nitrogen, cool down to below -15 °C, and sequentially add 2 mol / L sodium hexamethyldisilazide tetrahydrofuran solution (22.5 kg, 49 mol) and methyl bromoacetate (7.5 kg, 49.03 mol). After stirring and reacting for 20 minutes, control the temperature below 10 °C and add 2-bromoethyl acetate (7.52 kg, 49.16 mol) and sodium hexamethyldisilazide tetrahydrofuran solution (22.4 kg, 49.2 mol) in batches and alternately. After addition, monitor by TLC until the reaction is complete, and use it directly for the next step without treatment.

[0099] Step 2: Preparation of Intermediate II Compound

[0100] Control the temperature below -10°C. Add SM2 (13.52 kg, 58.26 mol) and 2 mol / L sodium hexamethyldisilazide in tetrahydrofuran solution (54 kg, 117.5 mol) successively to the above reaction solution. After adding, react at a temperature below -10°C for 1 hour, then raise the temperature to 15 - 25°C and stir for 10 hours. Monitor the reaction by TLC until completion. Cool down to below 10°C, stir and crystallize for 0.5 hour, add purified water (450 kg), centrifuge and filter. Wash the filter cake with an appropriate amount of purified water to obtain the crude product of intermediate II.

[0101] Add the crude product to ethyl acetate (54 kg), heat to 55 - 65°C and stir for 30 minutes. Cool down to 35 - 45°C and add n-heptane (82.5 kg). Then cool down to 15 - 25°C, centrifuge and filter, and dry under reduced pressure to obtain intermediate II (18 kg).

[0102] MS m / z(ESI): 488.1075[M+H] +

[0103] 1 H-NMR(500M, DMSO-d6) δ8.11 - 8.14(m, 1H), 8.03(s, 1H), 7.85(d, J = 3Hz, 1H), 7.77(dd, J = 8Hz, 9.5Hz, 1H), 7.59(d, J = 9.5Hz, 1H), 7.40(d, J = 9Hz, 1H), 5.01(t, J = 7Hz, 2H), 4.73(t, J = 7.5Hz, 2H), 4.61 - 4.67(m, 1H), 3.03 - 3.99(m, 11H).

[0104] Preparation of the SM1 compound in Example 2

[0105]

[0106] Add absolute ethanol (253 kg) and di-tert-butyl dicarbonate (48.6 kg, 222.68 mol) to a 500 L reaction kettle. After stirring evenly, add SM1-C (21.1 kg, 90.11 mol) in batches at 25 - 35°C. After adding, react at 25 - 35°C for 12 hours. Monitor the reaction by TLC until completion. Cool down to -10°C, centrifuge and filter, wash with an appropriate amount of absolute ethanol pre-cooled to -10°C, and dry the filter cake under vacuum to obtain the SM1 compound (22.32 kg).

[0107] MS m / z(ESI): 307.1760[M+H] +

[0108] 1H-NMR(500M, DMSO-d6) δ 8.34 (dd, J = 10Hz, 3Hz, 1H), 8.04 (d, J = 2.5Hz, 1H), 7.73 (d, J = 9.5Hz, 1H), 5.00 (t, J = 6.5Hz, 2H), 4.71 (t, J = 7.5Hz, 2H), 4.60 - 4.65 (m, 1H), 4.28 (q, J = 7Hz, 2H), 3.93 - 4.01 (m, 2H), 3.42 - 3.75 (m, 4H), 3.16 - 3.27 (m, 2H), 1.30 (t, J = 7Hz, 3H).

[0109] Preparation of Compound SM2 in Example 3

[0110]

[0111] Add acetonitrile (192 kg) and SM2-1 (20.5 kg, 133.85 mol) into a 500 L reaction kettle, stir to dissolve. Under nitrogen protection, control the temperature at -15 to -10 °C and add N-bromosuccinimide (23.78 kg, 133.61 mol) in batches slowly. After addition, stir and react for 0.5 h, then slowly raise the temperature to 5 - 10 °C for reaction, and detect the reaction end point by TLC. After the reaction is completed, raise the temperature to room temperature, and slowly drip purified water (49 kg). After dripping, stir until a large amount of solid appears, and then continue to drip purified water (381 kg). After dripping, stir at 10 - 15 °C for 2 h, then centrifuge and filter, wash with an appropriate amount of purified water, and dry the filter cake by blowing air to obtain Compound SM2 (27.88 kg).

[0112] MS m / z (ESI): 231.9758 [M + H] +

[0113] 1 H-NMR(500M, DMSO-d6) δ 10.15 (s, 1H), 8.61 (d, J = 4Hz, 1H), 7.64 (t, J = 8.5Hz, 1H), 6.58 (d, J = 9Hz, 1H), 2.51 - 2.89 (m, 3H).

[0114] Preparation of Compound of Formula I in Example 4

[0115]

[0116] Step 1: Preparation of Intermediate III Compound

[0117]

[0118] Add N,N-dimethylformamide (134.4 kg), Intermediate II (17.78 kg, 36.41 mol), SM3 (15.1 kg, 54.29 mol), anhydrous potassium carbonate (17.8 kg, 128.99 mol), and Pd(dppf)Cl2·CH2Cl2 catalyst (622.3 g, 0.76 mol) into a 300 L reaction kettle. Under nitrogen protection, heat up to 100 °C and react for 2 hours. Monitor the reaction by TLC until the reaction is completely converted. Cool the reaction temperature below 30 °C, slowly add purified water (284 L), and perform centrifugal filtration to obtain the crude product of Intermediate III.

[0119] Add the crude product into dichloromethane (138 kg), control the temperature at 30 - 35 °C, stir until dissolved clearly, then add modified silica gel (5.3 kg). After stirring for 3 hours, add activated carbon (889 g), stir for 0.5 hour, and then filter. Collect the filtrate and wash it successively with L-cysteine aqueous solution (8.9 kg, 178 L) and purified water (178 kg). Collect the organic phase, add modified silica gel (5.3 kg), stir for 3 hours, then filter. Add n-heptane (122 kg) to the filtrate, stir for 0.5 hour. Control the temperature at 15 - 20 °C, perform reduced pressure concentration until no liquid flows out basically, perform centrifugal filtration, wash with an appropriate amount of n-heptane, collect the filter cake, and perform reduced pressure drying to obtain Intermediate III (16.98 kg).

[0120] MS m / z(ESI): 560.2785[M+H] +

[0121] 1 H-NMR(500M, DMSO-d6) δ 8.12 - 8.16(m, 2H), 8.07 - 8.09(m, 2H), 7.79 - 7.81(m, 1H), 7.50 - 7.59(m, 2H), 6.87(t, J = 2.5 Hz, 1H), 5.00(t, J = 7 Hz, 2H), 4.73(t, J = 7 Hz, 2H), 4.64 - 4.66(m, 2H), 3.17 - 4.04(m, 16H), 1.71 - 1.73(m, 1H), 1.37 - 1.45(m, 3H).

[0122] Step 2: Preparation of the compound of formula I

[0123]

[0124] Add purified water (96 kg), absolute ethanol (151 kg, about 190 L), and Intermediate III (12 kg, 21.44 mol) into a 500 L reaction kettle. Cool down to below 15 °C, add trifluoroacetic acid (12 kg, 105.24 mol). After adding, control the temperature of the feed liquid at 18 - 22 °C and react for 2 hours. Monitor the reaction by TLC until the reaction reaches the end point.

[0125] After the reaction was completed, the temperature of the feed liquid was controlled below 20 °C, and triethylamine (12 kg, 118.81 mol) was slowly added. After the addition was complete, the temperature was controlled at 20-25 °C and reacted for 1 hour. Then the temperature was lowered to below 10 °C, filtered, and dried under vacuum to obtain Compound I (9.9 kg).

[0126] MS m / z(ESI):476.2196[M+H] +

[0127] 1 1H-NMR(500M,DMSO-d6)δ9.04(s,1H),8.75(s,1H),8.01(d,J=3Hz,1H),7.97(m,1H),7.87(s,1H),

[0128] 7.39-7.44(m,2H),7.32(d,J=9Hz,1H),6.74(s,1H),4.57(t,J=6.5Hz,2H),4.48(t,J=6Hz,2H),3.80(s,3H),

[0129] 3.45(t,J=6.5Hz,1H),3.14(t,J=4.5Hz,4H),2.42(t,J=4.5Hz,4H).

Claims

1. A method for preparing an intermediate II compound, characterized in that: include: (i) reacting SM1 compound with methyl 2-bromoacetate to obtain intermediate I compound; (ii) the intermediate I compound reacts with the SM2 compound to obtain the intermediate II compound, 2. The method for preparing the intermediate II compound as claimed in claim 1, wherein the reaction of step (i) is carried out in the presence of a base and a catalyst; optionally, the base described in step (i) is selected from an organic base or an inorganic base; the inorganic base is selected from sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the organic base is selected from sodium hexamethyldisilazide, triethylamine, ethylenediamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, piperidine, N-methylpiperidine, morpholine or N-methylmorpholine; or, the base described in step (i) is selected from sodium hexamethyldisilazide, triethylamine or N,N-diisopropylethylamine; or, the base described in step (i) is selected from sodium hexamethyldisilazide; Optionally, the catalyst in step (i) includes but is not limited to lithium iodide, sodium iodide or potassium iodide, preferably lithium iodide.

3. The method for preparing the intermediate II compound as claimed in claim 1, wherein step (i) is carried out in an organic solvent; the organic solvent is selected from one or more mixed solvents of acetonitrile, methanol, ethanol, ethylene glycol, ethylene glycol monomethyl ether, butanol, octanol, octyl acetate, dioxane, tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, preferably one or more mixed solvents of dioxane, tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, more preferably a mixed solvent of N,N-dimethylformamide and tetrahydrofuran.

4. The method for preparing the intermediate II compound according to claim 1, wherein the molar ratio of the SM1 compound to methyl 2-bromoacetate in step (i) is 1:1-5, preferably 1:1-3, more preferably 1:1-2; The molar ratio of SM1 compound to catalyst is 1:0.1-1, preferably 1:0.1-0.5, more preferably 1:0.2-0.5; The molar ratio of the SM1 compound to the base is 1:1-5, preferably 1:2-4.

5. The method for preparing the intermediate II compound as claimed in claim 1, wherein the reaction in step (ii) is carried out under alkaline conditions; Optionally, the base in step (ii) is selected from an organic base or an inorganic base; the inorganic base is selected from sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the organic base is selected from sodium hexamethyldisilazide, triethylamine, ethylenediamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, piperidine, N-methylpiperidine, morpholine or N-methylmorpholine, preferably sodium hexamethyldisilazide; Optionally, step (ii) is carried out in an organic solvent; the organic solvent is selected from one or more mixed solvents of acetonitrile, methanol, ethanol, ethylene glycol, ethylene glycol monomethyl ether, butanol, octanol, octyl acetate, dioxane, tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, preferably one or more mixed solvents of dioxane, tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, more preferably a mixed solvent of N,N-dimethylformamide and tetrahydrofuran.

6. The method for preparing the intermediate II compound as claimed in claim 1, wherein the molar ratio of the intermediate I compound to the SM2 compound in step (ii) is 1:1-3, preferably 1:1-2, more preferably 1:1-1.5; The molar ratio of the SM2 compound to the base is 1:1-5, preferably 1:2-4.

7. A method for preparing an SM1 compound, comprising: The SM1-C compound reacts with di-tert-butyl dicarbonate to prepare the SM1 compound. in, The SM1-C compound and di-tert-butyl dicarbonate are reacted in a solvent selected from ethanol; The molar ratio of SM1-C compound to di-tert-butyl dicarbonate is 1:1 to 5, preferably 1:1 to 3; The reaction temperature is 20-50°C, preferably 25-35°C; The reaction time is 10 to 20 hours, preferably 12 to 15 hours.

8. A method for preparing an SM2 compound, comprising: The SM2-1 compound reacts with a bromination reagent in a solvent to obtain the SM2 compound, in, The bromination agent is selected from N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin or carbon tetrabromide, preferably N-bromosuccinimide; the solvent is selected from one or more mixed solvents of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone or dioxane, preferably acetonitrile; The molar ratio of SM2-1 compound to brominating agent is 1:1 to 5, preferably 1:1 to 2; The reaction temperature is -30 to -10°C, preferably -15 to -10°C; The reaction time is 30 minutes to 5 hours, preferably 30 minutes to 1 hour.

9. A method for preparing a compound of formula I, characterized in that: include: (i) reacting SM1 compound with methyl 2-bromoacetate to obtain intermediate I compound; (ii) reacting the intermediate I compound with the SM2 compound to obtain the intermediate II compound; (iii) the intermediate II compound reacts with the SM3 compound to obtain the intermediate III compound; (iv) the intermediate III compound is deprotected to obtain the compound of formula I, in, R is selected from an amino protecting group, wherein the amino protecting group is selected from formyl, acetyl, benzyl, p-methoxybenzyl, trityl, phthaloyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, tetrahydro-2H-pyran-2-yl or (trimethylsilyl)ethoxymethyl, preferably tert-butyloxycarbonyl, tetrahydro-2H-pyran-2-yl or (trimethylsilyl)ethoxymethyl, more preferably tetrahydro-2H-pyran-2-yl; Optionally, step (iii) is carried out in the presence of a catalyst, a solvent and a base; the catalyst used is a palladium catalyst; the catalyst used is selected from palladium acetate, 1,2-bis(diphenylphosphino)ethane palladium dichloride, 1,3-bis(diphenylphosphino)propane palladium dichloride, 1,4-bis(diphenylphosphino)butane palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride or tris(dibenzylideneacetone)dipalladium or a complex thereof, preferably bis(triphenylphosphine)palladium dichloride or 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride or a complex thereof, more preferably 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride or 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex; The base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine or N-methylpiperidine, preferably sodium carbonate, potassium carbonate or cesium carbonate, more preferably potassium carbonate; The solvent is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, ethylbenzene, ethylene glycol dimethyl ether, acetonitrile and water, preferably one or more mixed solvents of N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and acetonitrile; The molar ratio of the intermediate II compound to the SM3 compound is 1:1 to 3, preferably 1:1 to 2, more preferably 1:1 to 1.5; The molar ratio of the intermediate II compound to the catalyst is 1:0.01-0.1, preferably 1:0.01-0.05, more preferably 1:0.01-0.03; The molar ratio of the intermediate II compound to the base is 1:1 to 6, preferably 1:2 to 4, more preferably 1:3.5; Optionally, the deprotection reaction of step (iv) is carried out in the presence of a solvent and an acid; The solvent is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, and water, preferably one or more mixed solvents of methanol, ethanol, and water; The acid is selected from hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid, preferably trifluoroacetic acid; The molar ratio of the intermediate III compound to the acid is 1:1-8, preferably 1:2-6.

10. The following compounds:

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